Conference Coverage

PARIS — Pregnancy is a period of asthma instability; it entails an increased risk for exacerbations. While therapeutic de-escalation, if not the outright cessation of maintenance treatment, is common, experts used the 19th Francophone Congress of Allergology to emphasize the importance of well-controlled asthma for the mother, the fetus, and the pregnancy.

About 12% of women of childbearing age have asthma. It is the most common chronic condition in pregnant women. Pregnancy affects asthma, and vice versa. Due to mechanical, hormonal, and immunological changes, allergic conditions, including asthma, can worsen.

First, pregnancy exerts mechanical pressure on respiratory function because of the progressive increase in uterine volume, diaphragm elevation, and various anatomical changes leading to chest expansion. The latter changes include increased subcostal angle, anteroposterior and transverse diameters, and thoracic circumference. 

Respiratory function is affected, with a decrease in functional residual capacity and expiratory reserve volume but an increase in inspiratory capacity, maximal ventilation, and tidal volume. The resulting hyperventilation manifests clinically as dyspnea, which affects up to 70% of pregnant women and can be mistaken for exacerbation symptoms.

Besides mechanical impact, hormonal changes occur during pregnancy, including elevated estrogen and progesterone levels. Placental hormones increase during the third trimester. These steroid hormones weaken the respiratory mucosa through structural changes in the bronchial wall and the activity of inflammatory cells involved in asthma, while influencing bronchial muscle tone. Estrogens have a dual effect. They are immunostimulatory at low doses and immunosuppressive at high doses (as in late pregnancy). This phenomenon suggests a role in immune tolerance toward the fetus.
 

The Rule of Thirds

Asthma progression during pregnancy is unpredictable. According to older studies, about one third of cases remain stable, one third worsen, and one third improve. In 60% of cases, the course remains similar from one pregnancy to another. Pregnancy is considered a period of asthma instability, with a doubled risk for exacerbation compared with nonpregnant women. Several pregnancy-specific factors contribute, including gastroesophageal reflux, excessive weight gain, active or passive smoking, and usual risk factors like infections. However, the main risk factor for exacerbation and loss of asthma control is insufficient maintenance treatment.

“The control of asthma during pregnancy is influenced by pregnancy itself, but especially by the severity of the disease before pregnancy and the underuse of inhaled corticosteroids,” said Mohammed Tawfik el Fassy Fihry, MD, pulmonologist at Ibn Sina Souissi Hospital in Rabat, Morocco. “This treatment insufficiency is the main cause of poor asthma control and sometimes of severe exacerbations.”
 

Inhaled Corticosteroid Often Insufficient

A 2017 study conducted in France found that one third of women had their asthma treatment reduced in the first trimester of pregnancy. Another observation was the frequent replacement of fixed combinations (such as long- and short-acting bronchodilators and inhaled corticosteroids) with simple inhaled corticosteroid therapy.

“A significant proportion of pregnant women on maintenance therapy decide to stop it as soon as they discover their pregnancy,” said Chantal Raherison-Semjen, PhD, coordinator of the Women and Lung group of the French Society of Pulmonology (SPLF) and of the pulmonology department at the University Hospital of Pointe-à-Pitre in Guadeloupe, France. “Treating physicians also often opt for therapeutic de-escalation, which involves stopping long-acting bronchodilators in favor of only inhaled corticosteroid therapy, which is usually insufficient for optimal asthma control.”

In severe exacerbations, especially during the first trimester of pregnancy, poorly controlled asthma can lead to complications in fetal development, such as low birth weight, intrauterine growth retardation, prematurity, and congenital malformations.

It can also affect maternal health by increasing the risk for gestational diabetes and affecting the course of pregnancy itself, favoring the occurrence of preeclampsia, placenta previa, placental abruption, premature rupture of membranes, spontaneous miscarriage, cesarean section, and hemorrhagic complications before and after delivery.

“When a pregnant woman presents to the emergency room due to an asthma exacerbation, physicians are often reluctant to administer optimal treatment for fear of the effects of bronchodilators and systemic corticosteroids,” said Dr. Raherison-Semjen. “As a result, these women generally receive less effective treatment in such situations, compared with nonpregnant women. This is despite the risk that severe asthma exacerbations pose to the mother and her child.”
 

‘Pregnant Woman’ Pictogram

In France, manufacturers of teratogenic or fetotoxic drugs are required to display a pictogram on the label indicating the danger for pregnant women or the fetus. The guidelines for this labeling are left to the discretion of the laboratories, however, which sometimes leads to unjustified warnings on the packaging of inhaled corticosteroids or emergency treatments. French medical societies were not consulted on this matter, which complicates prescriptions for pregnant asthmatic women, said Dr. Raherison-Semjen. The SPLF condemns the harmful effects of this decision.

Corticosteroids and Omalizumab

“Given the low, if any, risks associated with the main asthma treatments for the mother and fetus, continuing treatments started before conception is highly recommended,” said Dr. Raherison-Semjen. Inhaled corticosteroids, the cornerstone of asthma treatment, are the primary therapy, and the dosage can be adjusted as strictly necessary. “When properly managed, treatment generally allows for asthma control and reduces the risk for complications during pregnancy to the same level observed in the general population.”

Depending on asthma control levels, long-acting beta-2 agonists (eg, formoterol, salmeterol, and indacaterol) can be added, and possibly leukotriene antagonists. Before pregnancy, prescribed medications should be continued, including biologics prescribed for severe asthma. The exception is omalizumab, which can be started during pregnancy without risk.

For its part, allergen immunotherapy should also be maintained but without dose increases. Oral corticosteroids are reserved for severe exacerbations.

As specified by the GINA report of 2023, the benefits of active asthma treatment during pregnancy far outweigh the risks of usual asthma medications (Level A). This view is supported by reassuring data from the Reference Center for Teratogenic Agents. “There is no scientific-medical evidence justifying that pregnant women with asthma should not be treated the same way as when they are not pregnant,” said Dr. Raherison-Semjen.
 

Useful Links

The Asthma Control Test is a quick questionnaire that allows practitioners to ensure their patient›s asthma control. A score below 20 of 25 indicates poor asthma control. It has been specifically validated for pregnancy.

Dr. Tawfik el Fassy Fihry reported having no relevant financial relationships. Dr. Raherison-Semjen reported receiving compensation from AstraZeneca, B. Ingelheim, ALK, Novartis, Banook, GSK, and Mundi Pharma.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

PARIS — Pregnancy is a period of asthma instability; it entails an increased risk for exacerbations. While therapeutic de-escalation, if not the outright cessation of maintenance treatment, is common, experts used the 19th Francophone Congress of Allergology to emphasize the importance of well-controlled asthma for the mother, the fetus, and the pregnancy.

About 12% of women of childbearing age have asthma. It is the most common chronic condition in pregnant women. Pregnancy affects asthma, and vice versa. Due to mechanical, hormonal, and immunological changes, allergic conditions, including asthma, can worsen.

First, pregnancy exerts mechanical pressure on respiratory function because of the progressive increase in uterine volume, diaphragm elevation, and various anatomical changes leading to chest expansion. The latter changes include increased subcostal angle, anteroposterior and transverse diameters, and thoracic circumference. 

Respiratory function is affected, with a decrease in functional residual capacity and expiratory reserve volume but an increase in inspiratory capacity, maximal ventilation, and tidal volume. The resulting hyperventilation manifests clinically as dyspnea, which affects up to 70% of pregnant women and can be mistaken for exacerbation symptoms.

Besides mechanical impact, hormonal changes occur during pregnancy, including elevated estrogen and progesterone levels. Placental hormones increase during the third trimester. These steroid hormones weaken the respiratory mucosa through structural changes in the bronchial wall and the activity of inflammatory cells involved in asthma, while influencing bronchial muscle tone. Estrogens have a dual effect. They are immunostimulatory at low doses and immunosuppressive at high doses (as in late pregnancy). This phenomenon suggests a role in immune tolerance toward the fetus.
 

The Rule of Thirds

Asthma progression during pregnancy is unpredictable. According to older studies, about one third of cases remain stable, one third worsen, and one third improve. In 60% of cases, the course remains similar from one pregnancy to another. Pregnancy is considered a period of asthma instability, with a doubled risk for exacerbation compared with nonpregnant women. Several pregnancy-specific factors contribute, including gastroesophageal reflux, excessive weight gain, active or passive smoking, and usual risk factors like infections. However, the main risk factor for exacerbation and loss of asthma control is insufficient maintenance treatment.

“The control of asthma during pregnancy is influenced by pregnancy itself, but especially by the severity of the disease before pregnancy and the underuse of inhaled corticosteroids,” said Mohammed Tawfik el Fassy Fihry, MD, pulmonologist at Ibn Sina Souissi Hospital in Rabat, Morocco. “This treatment insufficiency is the main cause of poor asthma control and sometimes of severe exacerbations.”
 

Inhaled Corticosteroid Often Insufficient

A 2017 study conducted in France found that one third of women had their asthma treatment reduced in the first trimester of pregnancy. Another observation was the frequent replacement of fixed combinations (such as long- and short-acting bronchodilators and inhaled corticosteroids) with simple inhaled corticosteroid therapy.

“A significant proportion of pregnant women on maintenance therapy decide to stop it as soon as they discover their pregnancy,” said Chantal Raherison-Semjen, PhD, coordinator of the Women and Lung group of the French Society of Pulmonology (SPLF) and of the pulmonology department at the University Hospital of Pointe-à-Pitre in Guadeloupe, France. “Treating physicians also often opt for therapeutic de-escalation, which involves stopping long-acting bronchodilators in favor of only inhaled corticosteroid therapy, which is usually insufficient for optimal asthma control.”

In severe exacerbations, especially during the first trimester of pregnancy, poorly controlled asthma can lead to complications in fetal development, such as low birth weight, intrauterine growth retardation, prematurity, and congenital malformations.

It can also affect maternal health by increasing the risk for gestational diabetes and affecting the course of pregnancy itself, favoring the occurrence of preeclampsia, placenta previa, placental abruption, premature rupture of membranes, spontaneous miscarriage, cesarean section, and hemorrhagic complications before and after delivery.

“When a pregnant woman presents to the emergency room due to an asthma exacerbation, physicians are often reluctant to administer optimal treatment for fear of the effects of bronchodilators and systemic corticosteroids,” said Dr. Raherison-Semjen. “As a result, these women generally receive less effective treatment in such situations, compared with nonpregnant women. This is despite the risk that severe asthma exacerbations pose to the mother and her child.”
 

‘Pregnant Woman’ Pictogram

In France, manufacturers of teratogenic or fetotoxic drugs are required to display a pictogram on the label indicating the danger for pregnant women or the fetus. The guidelines for this labeling are left to the discretion of the laboratories, however, which sometimes leads to unjustified warnings on the packaging of inhaled corticosteroids or emergency treatments. French medical societies were not consulted on this matter, which complicates prescriptions for pregnant asthmatic women, said Dr. Raherison-Semjen. The SPLF condemns the harmful effects of this decision.

Corticosteroids and Omalizumab

“Given the low, if any, risks associated with the main asthma treatments for the mother and fetus, continuing treatments started before conception is highly recommended,” said Dr. Raherison-Semjen. Inhaled corticosteroids, the cornerstone of asthma treatment, are the primary therapy, and the dosage can be adjusted as strictly necessary. “When properly managed, treatment generally allows for asthma control and reduces the risk for complications during pregnancy to the same level observed in the general population.”

Depending on asthma control levels, long-acting beta-2 agonists (eg, formoterol, salmeterol, and indacaterol) can be added, and possibly leukotriene antagonists. Before pregnancy, prescribed medications should be continued, including biologics prescribed for severe asthma. The exception is omalizumab, which can be started during pregnancy without risk.

For its part, allergen immunotherapy should also be maintained but without dose increases. Oral corticosteroids are reserved for severe exacerbations.

As specified by the GINA report of 2023, the benefits of active asthma treatment during pregnancy far outweigh the risks of usual asthma medications (Level A). This view is supported by reassuring data from the Reference Center for Teratogenic Agents. “There is no scientific-medical evidence justifying that pregnant women with asthma should not be treated the same way as when they are not pregnant,” said Dr. Raherison-Semjen.
 

Useful Links

The Asthma Control Test is a quick questionnaire that allows practitioners to ensure their patient›s asthma control. A score below 20 of 25 indicates poor asthma control. It has been specifically validated for pregnancy.

Dr. Tawfik el Fassy Fihry reported having no relevant financial relationships. Dr. Raherison-Semjen reported receiving compensation from AstraZeneca, B. Ingelheim, ALK, Novartis, Banook, GSK, and Mundi Pharma.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

PARIS — Pregnancy is a period of asthma instability; it entails an increased risk for exacerbations. While therapeutic de-escalation, if not the outright cessation of maintenance treatment, is common, experts used the 19th Francophone Congress of Allergology to emphasize the importance of well-controlled asthma for the mother, the fetus, and the pregnancy.

About 12% of women of childbearing age have asthma. It is the most common chronic condition in pregnant women. Pregnancy affects asthma, and vice versa. Due to mechanical, hormonal, and immunological changes, allergic conditions, including asthma, can worsen.

First, pregnancy exerts mechanical pressure on respiratory function because of the progressive increase in uterine volume, diaphragm elevation, and various anatomical changes leading to chest expansion. The latter changes include increased subcostal angle, anteroposterior and transverse diameters, and thoracic circumference. 

Respiratory function is affected, with a decrease in functional residual capacity and expiratory reserve volume but an increase in inspiratory capacity, maximal ventilation, and tidal volume. The resulting hyperventilation manifests clinically as dyspnea, which affects up to 70% of pregnant women and can be mistaken for exacerbation symptoms.

Besides mechanical impact, hormonal changes occur during pregnancy, including elevated estrogen and progesterone levels. Placental hormones increase during the third trimester. These steroid hormones weaken the respiratory mucosa through structural changes in the bronchial wall and the activity of inflammatory cells involved in asthma, while influencing bronchial muscle tone. Estrogens have a dual effect. They are immunostimulatory at low doses and immunosuppressive at high doses (as in late pregnancy). This phenomenon suggests a role in immune tolerance toward the fetus.
 

The Rule of Thirds

Asthma progression during pregnancy is unpredictable. According to older studies, about one third of cases remain stable, one third worsen, and one third improve. In 60% of cases, the course remains similar from one pregnancy to another. Pregnancy is considered a period of asthma instability, with a doubled risk for exacerbation compared with nonpregnant women. Several pregnancy-specific factors contribute, including gastroesophageal reflux, excessive weight gain, active or passive smoking, and usual risk factors like infections. However, the main risk factor for exacerbation and loss of asthma control is insufficient maintenance treatment.

“The control of asthma during pregnancy is influenced by pregnancy itself, but especially by the severity of the disease before pregnancy and the underuse of inhaled corticosteroids,” said Mohammed Tawfik el Fassy Fihry, MD, pulmonologist at Ibn Sina Souissi Hospital in Rabat, Morocco. “This treatment insufficiency is the main cause of poor asthma control and sometimes of severe exacerbations.”
 

Inhaled Corticosteroid Often Insufficient

A 2017 study conducted in France found that one third of women had their asthma treatment reduced in the first trimester of pregnancy. Another observation was the frequent replacement of fixed combinations (such as long- and short-acting bronchodilators and inhaled corticosteroids) with simple inhaled corticosteroid therapy.

“A significant proportion of pregnant women on maintenance therapy decide to stop it as soon as they discover their pregnancy,” said Chantal Raherison-Semjen, PhD, coordinator of the Women and Lung group of the French Society of Pulmonology (SPLF) and of the pulmonology department at the University Hospital of Pointe-à-Pitre in Guadeloupe, France. “Treating physicians also often opt for therapeutic de-escalation, which involves stopping long-acting bronchodilators in favor of only inhaled corticosteroid therapy, which is usually insufficient for optimal asthma control.”

In severe exacerbations, especially during the first trimester of pregnancy, poorly controlled asthma can lead to complications in fetal development, such as low birth weight, intrauterine growth retardation, prematurity, and congenital malformations.

It can also affect maternal health by increasing the risk for gestational diabetes and affecting the course of pregnancy itself, favoring the occurrence of preeclampsia, placenta previa, placental abruption, premature rupture of membranes, spontaneous miscarriage, cesarean section, and hemorrhagic complications before and after delivery.

“When a pregnant woman presents to the emergency room due to an asthma exacerbation, physicians are often reluctant to administer optimal treatment for fear of the effects of bronchodilators and systemic corticosteroids,” said Dr. Raherison-Semjen. “As a result, these women generally receive less effective treatment in such situations, compared with nonpregnant women. This is despite the risk that severe asthma exacerbations pose to the mother and her child.”
 

‘Pregnant Woman’ Pictogram

In France, manufacturers of teratogenic or fetotoxic drugs are required to display a pictogram on the label indicating the danger for pregnant women or the fetus. The guidelines for this labeling are left to the discretion of the laboratories, however, which sometimes leads to unjustified warnings on the packaging of inhaled corticosteroids or emergency treatments. French medical societies were not consulted on this matter, which complicates prescriptions for pregnant asthmatic women, said Dr. Raherison-Semjen. The SPLF condemns the harmful effects of this decision.

Corticosteroids and Omalizumab

“Given the low, if any, risks associated with the main asthma treatments for the mother and fetus, continuing treatments started before conception is highly recommended,” said Dr. Raherison-Semjen. Inhaled corticosteroids, the cornerstone of asthma treatment, are the primary therapy, and the dosage can be adjusted as strictly necessary. “When properly managed, treatment generally allows for asthma control and reduces the risk for complications during pregnancy to the same level observed in the general population.”

Depending on asthma control levels, long-acting beta-2 agonists (eg, formoterol, salmeterol, and indacaterol) can be added, and possibly leukotriene antagonists. Before pregnancy, prescribed medications should be continued, including biologics prescribed for severe asthma. The exception is omalizumab, which can be started during pregnancy without risk.

For its part, allergen immunotherapy should also be maintained but without dose increases. Oral corticosteroids are reserved for severe exacerbations.

As specified by the GINA report of 2023, the benefits of active asthma treatment during pregnancy far outweigh the risks of usual asthma medications (Level A). This view is supported by reassuring data from the Reference Center for Teratogenic Agents. “There is no scientific-medical evidence justifying that pregnant women with asthma should not be treated the same way as when they are not pregnant,” said Dr. Raherison-Semjen.
 

Useful Links

The Asthma Control Test is a quick questionnaire that allows practitioners to ensure their patient›s asthma control. A score below 20 of 25 indicates poor asthma control. It has been specifically validated for pregnancy.

Dr. Tawfik el Fassy Fihry reported having no relevant financial relationships. Dr. Raherison-Semjen reported receiving compensation from AstraZeneca, B. Ingelheim, ALK, Novartis, Banook, GSK, and Mundi Pharma.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

A meta-analysis showed that the use of oral tranexamic acid along with the standard triple combination cream (TCC) reduces melasma severity and recurrence in patients with melasma, without increasing toxicity.

METHODOLOGY:

• Current treatments for melasma focus on inducing remission and preventing relapse. Tranexamic acid, an antifibrinolytic drug, has shown promise in recent studies, but its optimal use, either alone or as an adjunct to TCC, remains unclear.
• Researchers conducted a meta-analysis of four randomized controlled trials patients that compared oral tranexamic acid plus TCC (hydroquinone, retinoic acid, and hydrocortisone) and TCC alone in 480 patients with melasma, divided almost evenly into the two treatment groups.
• The main outcome was the change in the Melasma Severity Area Index (MASI) score and recurrence rate from baseline.

TAKEAWAY:

• Patients treated with oral tranexamic acid plus TCC showed a greater reduction in MASI scores compared with those who received TCC alone (mean difference, −3.10; P = .03).
• The recurrence rate of melasma was significantly lower in the tranexamic acid plus TCC group (risk ratio [RR], 0.28; P < .001).
• There was no significant difference in the incidences of erythema (RR, 0.63; P = .147) and burning (RR, 0.59; P = .131).

IN PRACTICE:

“Evidence indicates that oral tranexamic acid confers clinical benefits, contributing to the enhancement of treatment outcomes in melasma when used in conjunction with TCC therapy,” and results are promising with regards to minimizing recurrence, the authors concluded.

SOURCE:

The study was led by Ocílio Ribeiro Gonçalves, MS, of the Federal University of Piauí, Teresina, Brazil, and was published online on June 8, 2024, in Clinical and Experimental Dermatology.

LIMITATIONS:

There was heterogeneity across studies, including different methods of administration, treatment protocols (including dosage), and timing of treatment.

DISCLOSURES:

The study reported receiving no funding. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

A meta-analysis showed that the use of oral tranexamic acid along with the standard triple combination cream (TCC) reduces melasma severity and recurrence in patients with melasma, without increasing toxicity.

METHODOLOGY:

• Current treatments for melasma focus on inducing remission and preventing relapse. Tranexamic acid, an antifibrinolytic drug, has shown promise in recent studies, but its optimal use, either alone or as an adjunct to TCC, remains unclear.
• Researchers conducted a meta-analysis of four randomized controlled trials patients that compared oral tranexamic acid plus TCC (hydroquinone, retinoic acid, and hydrocortisone) and TCC alone in 480 patients with melasma, divided almost evenly into the two treatment groups.
• The main outcome was the change in the Melasma Severity Area Index (MASI) score and recurrence rate from baseline.

TAKEAWAY:

• Patients treated with oral tranexamic acid plus TCC showed a greater reduction in MASI scores compared with those who received TCC alone (mean difference, −3.10; P = .03).
• The recurrence rate of melasma was significantly lower in the tranexamic acid plus TCC group (risk ratio [RR], 0.28; P < .001).
• There was no significant difference in the incidences of erythema (RR, 0.63; P = .147) and burning (RR, 0.59; P = .131).

IN PRACTICE:

“Evidence indicates that oral tranexamic acid confers clinical benefits, contributing to the enhancement of treatment outcomes in melasma when used in conjunction with TCC therapy,” and results are promising with regards to minimizing recurrence, the authors concluded.

SOURCE:

The study was led by Ocílio Ribeiro Gonçalves, MS, of the Federal University of Piauí, Teresina, Brazil, and was published online on June 8, 2024, in Clinical and Experimental Dermatology.

LIMITATIONS:

There was heterogeneity across studies, including different methods of administration, treatment protocols (including dosage), and timing of treatment.

DISCLOSURES:

The study reported receiving no funding. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

A meta-analysis showed that the use of oral tranexamic acid along with the standard triple combination cream (TCC) reduces melasma severity and recurrence in patients with melasma, without increasing toxicity.

METHODOLOGY:

• Current treatments for melasma focus on inducing remission and preventing relapse. Tranexamic acid, an antifibrinolytic drug, has shown promise in recent studies, but its optimal use, either alone or as an adjunct to TCC, remains unclear.
• Researchers conducted a meta-analysis of four randomized controlled trials patients that compared oral tranexamic acid plus TCC (hydroquinone, retinoic acid, and hydrocortisone) and TCC alone in 480 patients with melasma, divided almost evenly into the two treatment groups.
• The main outcome was the change in the Melasma Severity Area Index (MASI) score and recurrence rate from baseline.

TAKEAWAY:

• Patients treated with oral tranexamic acid plus TCC showed a greater reduction in MASI scores compared with those who received TCC alone (mean difference, −3.10; P = .03).
• The recurrence rate of melasma was significantly lower in the tranexamic acid plus TCC group (risk ratio [RR], 0.28; P < .001).
• There was no significant difference in the incidences of erythema (RR, 0.63; P = .147) and burning (RR, 0.59; P = .131).

IN PRACTICE:

“Evidence indicates that oral tranexamic acid confers clinical benefits, contributing to the enhancement of treatment outcomes in melasma when used in conjunction with TCC therapy,” and results are promising with regards to minimizing recurrence, the authors concluded.

SOURCE:

The study was led by Ocílio Ribeiro Gonçalves, MS, of the Federal University of Piauí, Teresina, Brazil, and was published online on June 8, 2024, in Clinical and Experimental Dermatology.

LIMITATIONS:

There was heterogeneity across studies, including different methods of administration, treatment protocols (including dosage), and timing of treatment.

DISCLOSURES:

The study reported receiving no funding. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

CHICAGO —The use of kratom, an opioid-like supplement widely available over the counter at convenience stores, smoke shops, and online, is resulting in emerging cases of hyperpigmentation, most often on the face and hands.

“This is something we will see more and more,” Heather Woolery-Lloyd, MD, director of the Skin of Color Division at the University of Miami Department of Dermatology, said at the Pigmentary Disorders Exchange Symposium. The key marker of this hyperpigmentation, she said, is that “it’s strongly photoaccentuated,” affecting areas exposed to the sun — but it also tends to spare the knuckles on patients’ hands.
 

Used Like an Opioid, But It’s Not Regulated

Kratom is a plant common in southeast Asia and is used as an analgesic. It’s marketed as a “legal opioid” or “legal high” and is sold in 2- or 3-ounce containers of extract or sold as a powder, Dr. Woolery-Lloyd said. The leaves may be boiled into a tea, smoked, chewed, or put into capsules, according to a case report published in February in the Journal of Integrative Dermatology. It is used worldwide and is not regulated in the United States.

“Many of our patients think kratom is a safe, herbal supplement” but often don’t know it can have several side effects and can be addictive, Dr. Woolery-Lloyd said. Its popularity is increasing as reflected by the number of posts related to kratom on social media platforms.

In the February case report, Shaina Patel, BA, and Nathaniel Phelan, MD, from Kansas City University, Kansas City, Missouri, wrote that side effects of kratom include drowsiness, tachycardia, vomiting, respiratory depression, and cardiac arrest, in addition to confusion and hallucinations.

Kratom also has many different effects on the psyche, Dr. Woolery-Lloyd said at the meeting. At low doses, it blocks the reuptake of norepinephrine, serotonin, and dopamine, producing a motivational effect, and at high doses, it creates an analgesic, calming effect. And people who chronically consume high doses of kratom may be susceptible to hyperpigmentation.

Kratom-associated hyperpigmentation should be considered as a diagnosis when evaluating patients for other drug-associated pigmentary disorders, “especially if pigment is photodistributed,” she said. “If you see new-onset hyperpigmentation or onset over several months and it’s very photoaccentuated, definitely ask about use of kratom.”
 

Case Reports Show Patterns of Presentation

A 2022 report from Landon R. Powell, BS, with the department of biology, Whitworth University in Spokane, Washington, and coauthors, published in JAAD Case Reports, noted that kratom use in the United States has increased dramatically. “As measured by call reports to the United States National Poison Data System, in 2011, there were 11 reported kratom exposures, and in the first 7 months of 2018, there were 357 reported exposures,” they wrote.

An estimated 1.7 million Americans aged ≥ 12 years said they had used kratom in the previous year, according to the Substance Abuse and Mental Health Services Administration 2021 National Survey on Drug Use and Health.

In the case report, Mr. Powell and coauthors described a 54-year-old White male patient who had been using kratom for the previous four to five years to reduce opioid use. During this period, he consumed kratom powder mixed with orange juice three to four times a day. He presented with “diffuse hyperpigmented patches on his arms and face in a photodistributed manner, with notable sparing of the knuckles on both hands.”
 

Dark Gray-Blue Skin

In the more recent case report, Ms. Patel and Dr. Phelan described a 30-year-old White male patient who presented with dark gray-blue skin coloring on his cheeks, back of his neck, and the backs of his hands and forearms. He had no other medical conditions and did not take any medications or supplements that cause hyperpigmentation while using kratom.

The patient had been taking kratom for years in the wake of an opioid addiction following medications for a high school injury. He developed an opioid use disorder and tried to replace his pain medications with kratom.

“The patient stopped using kratom in May 2022, but the discoloration remains. It has not regressed in the following 16 months after discontinuing kratom use,” the authors wrote, noting that “whether or not the hyperpigmentation is able to regress is unknown.”

Dr. Woolery-Lloyd is a consultant for AbbVie, Incyte, Johnson & Johnson Consumer, LivDerm, and L’Oreal; a speaker for Eli Lilly, Incyte, L’Oreal, and Ortho Dermatologics; and a researcher/investigator for AbbVie, Allergan, Eirion Therapeutics, Galderma, Pfizer, Sanofi, and Vyne Therapeutics.
 

According to an information page on kratom on the Food and Drug Administration website, health care professionals and consumers can report adverse reactions associated with kratom to the FDA’s MedWatch program.

A version of this article appeared on Medscape.com.

CHICAGO —The use of kratom, an opioid-like supplement widely available over the counter at convenience stores, smoke shops, and online, is resulting in emerging cases of hyperpigmentation, most often on the face and hands.

“This is something we will see more and more,” Heather Woolery-Lloyd, MD, director of the Skin of Color Division at the University of Miami Department of Dermatology, said at the Pigmentary Disorders Exchange Symposium. The key marker of this hyperpigmentation, she said, is that “it’s strongly photoaccentuated,” affecting areas exposed to the sun — but it also tends to spare the knuckles on patients’ hands.
 

Used Like an Opioid, But It’s Not Regulated

Kratom is a plant common in southeast Asia and is used as an analgesic. It’s marketed as a “legal opioid” or “legal high” and is sold in 2- or 3-ounce containers of extract or sold as a powder, Dr. Woolery-Lloyd said. The leaves may be boiled into a tea, smoked, chewed, or put into capsules, according to a case report published in February in the Journal of Integrative Dermatology. It is used worldwide and is not regulated in the United States.

“Many of our patients think kratom is a safe, herbal supplement” but often don’t know it can have several side effects and can be addictive, Dr. Woolery-Lloyd said. Its popularity is increasing as reflected by the number of posts related to kratom on social media platforms.

In the February case report, Shaina Patel, BA, and Nathaniel Phelan, MD, from Kansas City University, Kansas City, Missouri, wrote that side effects of kratom include drowsiness, tachycardia, vomiting, respiratory depression, and cardiac arrest, in addition to confusion and hallucinations.

Kratom also has many different effects on the psyche, Dr. Woolery-Lloyd said at the meeting. At low doses, it blocks the reuptake of norepinephrine, serotonin, and dopamine, producing a motivational effect, and at high doses, it creates an analgesic, calming effect. And people who chronically consume high doses of kratom may be susceptible to hyperpigmentation.

Kratom-associated hyperpigmentation should be considered as a diagnosis when evaluating patients for other drug-associated pigmentary disorders, “especially if pigment is photodistributed,” she said. “If you see new-onset hyperpigmentation or onset over several months and it’s very photoaccentuated, definitely ask about use of kratom.”
 

Case Reports Show Patterns of Presentation

A 2022 report from Landon R. Powell, BS, with the department of biology, Whitworth University in Spokane, Washington, and coauthors, published in JAAD Case Reports, noted that kratom use in the United States has increased dramatically. “As measured by call reports to the United States National Poison Data System, in 2011, there were 11 reported kratom exposures, and in the first 7 months of 2018, there were 357 reported exposures,” they wrote.

An estimated 1.7 million Americans aged ≥ 12 years said they had used kratom in the previous year, according to the Substance Abuse and Mental Health Services Administration 2021 National Survey on Drug Use and Health.

In the case report, Mr. Powell and coauthors described a 54-year-old White male patient who had been using kratom for the previous four to five years to reduce opioid use. During this period, he consumed kratom powder mixed with orange juice three to four times a day. He presented with “diffuse hyperpigmented patches on his arms and face in a photodistributed manner, with notable sparing of the knuckles on both hands.”
 

Dark Gray-Blue Skin

In the more recent case report, Ms. Patel and Dr. Phelan described a 30-year-old White male patient who presented with dark gray-blue skin coloring on his cheeks, back of his neck, and the backs of his hands and forearms. He had no other medical conditions and did not take any medications or supplements that cause hyperpigmentation while using kratom.

The patient had been taking kratom for years in the wake of an opioid addiction following medications for a high school injury. He developed an opioid use disorder and tried to replace his pain medications with kratom.

“The patient stopped using kratom in May 2022, but the discoloration remains. It has not regressed in the following 16 months after discontinuing kratom use,” the authors wrote, noting that “whether or not the hyperpigmentation is able to regress is unknown.”

Dr. Woolery-Lloyd is a consultant for AbbVie, Incyte, Johnson & Johnson Consumer, LivDerm, and L’Oreal; a speaker for Eli Lilly, Incyte, L’Oreal, and Ortho Dermatologics; and a researcher/investigator for AbbVie, Allergan, Eirion Therapeutics, Galderma, Pfizer, Sanofi, and Vyne Therapeutics.
 

According to an information page on kratom on the Food and Drug Administration website, health care professionals and consumers can report adverse reactions associated with kratom to the FDA’s MedWatch program.

A version of this article appeared on Medscape.com.

CHICAGO —The use of kratom, an opioid-like supplement widely available over the counter at convenience stores, smoke shops, and online, is resulting in emerging cases of hyperpigmentation, most often on the face and hands.

“This is something we will see more and more,” Heather Woolery-Lloyd, MD, director of the Skin of Color Division at the University of Miami Department of Dermatology, said at the Pigmentary Disorders Exchange Symposium. The key marker of this hyperpigmentation, she said, is that “it’s strongly photoaccentuated,” affecting areas exposed to the sun — but it also tends to spare the knuckles on patients’ hands.
 

Used Like an Opioid, But It’s Not Regulated

Kratom is a plant common in southeast Asia and is used as an analgesic. It’s marketed as a “legal opioid” or “legal high” and is sold in 2- or 3-ounce containers of extract or sold as a powder, Dr. Woolery-Lloyd said. The leaves may be boiled into a tea, smoked, chewed, or put into capsules, according to a case report published in February in the Journal of Integrative Dermatology. It is used worldwide and is not regulated in the United States.

“Many of our patients think kratom is a safe, herbal supplement” but often don’t know it can have several side effects and can be addictive, Dr. Woolery-Lloyd said. Its popularity is increasing as reflected by the number of posts related to kratom on social media platforms.

In the February case report, Shaina Patel, BA, and Nathaniel Phelan, MD, from Kansas City University, Kansas City, Missouri, wrote that side effects of kratom include drowsiness, tachycardia, vomiting, respiratory depression, and cardiac arrest, in addition to confusion and hallucinations.

Kratom also has many different effects on the psyche, Dr. Woolery-Lloyd said at the meeting. At low doses, it blocks the reuptake of norepinephrine, serotonin, and dopamine, producing a motivational effect, and at high doses, it creates an analgesic, calming effect. And people who chronically consume high doses of kratom may be susceptible to hyperpigmentation.

Kratom-associated hyperpigmentation should be considered as a diagnosis when evaluating patients for other drug-associated pigmentary disorders, “especially if pigment is photodistributed,” she said. “If you see new-onset hyperpigmentation or onset over several months and it’s very photoaccentuated, definitely ask about use of kratom.”
 

Case Reports Show Patterns of Presentation

A 2022 report from Landon R. Powell, BS, with the department of biology, Whitworth University in Spokane, Washington, and coauthors, published in JAAD Case Reports, noted that kratom use in the United States has increased dramatically. “As measured by call reports to the United States National Poison Data System, in 2011, there were 11 reported kratom exposures, and in the first 7 months of 2018, there were 357 reported exposures,” they wrote.

An estimated 1.7 million Americans aged ≥ 12 years said they had used kratom in the previous year, according to the Substance Abuse and Mental Health Services Administration 2021 National Survey on Drug Use and Health.

In the case report, Mr. Powell and coauthors described a 54-year-old White male patient who had been using kratom for the previous four to five years to reduce opioid use. During this period, he consumed kratom powder mixed with orange juice three to four times a day. He presented with “diffuse hyperpigmented patches on his arms and face in a photodistributed manner, with notable sparing of the knuckles on both hands.”
 

Dark Gray-Blue Skin

In the more recent case report, Ms. Patel and Dr. Phelan described a 30-year-old White male patient who presented with dark gray-blue skin coloring on his cheeks, back of his neck, and the backs of his hands and forearms. He had no other medical conditions and did not take any medications or supplements that cause hyperpigmentation while using kratom.

The patient had been taking kratom for years in the wake of an opioid addiction following medications for a high school injury. He developed an opioid use disorder and tried to replace his pain medications with kratom.

“The patient stopped using kratom in May 2022, but the discoloration remains. It has not regressed in the following 16 months after discontinuing kratom use,” the authors wrote, noting that “whether or not the hyperpigmentation is able to regress is unknown.”

Dr. Woolery-Lloyd is a consultant for AbbVie, Incyte, Johnson & Johnson Consumer, LivDerm, and L’Oreal; a speaker for Eli Lilly, Incyte, L’Oreal, and Ortho Dermatologics; and a researcher/investigator for AbbVie, Allergan, Eirion Therapeutics, Galderma, Pfizer, Sanofi, and Vyne Therapeutics.
 

According to an information page on kratom on the Food and Drug Administration website, health care professionals and consumers can report adverse reactions associated with kratom to the FDA’s MedWatch program.

A version of this article appeared on Medscape.com.

SAN DIEGO — A new analysis of patients with new daily persistent headache (NDPH) lends insight into the condition and provides some hints as to some of the more effective treatments, including some calcitonin gene-related peptide (CGRP) inhibitors.

“There’s just not a lot [of information] about these patients,” Mark Burish, MD, PhD, associate professor of neurology at UT Houston, said in an interview. He presented the results of the survey at the annual meeting of the American Headache Society.

There have been some retrospective analyses of patient data, but that has a lot of potential for bias. “It’s only the patients who can afford to be there, and who needed those treatments, and so we want to do more of a general survey,” said Dr. Burish.

The results weren’t particularly surprising, and tended to reaffirm what was known anecdotally, including symptoms similar to those of migraine, but it gave some insight into treatments. “Some of the CGRP inhibitors and the onabotulinum toxin seem to be some of the more effective treatments, according to our survey, so those are probably worth looking into for these patients if you can get them approved by insurance, and if you can get patients to accept the idea they might have to give themselves an injection of some sort,” said Dr. Burish.

Despite having some promise, there was variation among CGRP inhibitors. Eptinezumab, rimegepant, and atogepant were commonly reported as effective, but others, such as erenumab and galcanezumab, were less often reported. “None of them were incredibly effective. These were just the best things we have at this time,” said Dr. Burish.
 

Additional Information on a Rare, Hard-to-Treat Condition

Jason Sico, MD, who moderated the session, was asked for comment. “I’m so appreciative that the team has looked at a new daily persistent headache. It’s a rare type of headache disorder. It’s also one that is notoriously difficult to treat and something that we that we really need to know more about. It is difficult to really get good, robust in-depth information on these patients, and the team did a really nice job with that,” said Dr. Sico, associate professor of neurology and internal medicine at Yale School of Medicine and national director of the Headache Centers of Excellence Program within the Veterans Health Administration.

He noted that the researchers found that opioids were the most commonly used acute treatment. That’s not surprising, but “it would be interesting to see what was tried before someone had gotten to opioids,” he said.

The findings also gave some unexpected insight into the condition. “I really found it striking that an overwhelming majority of patients reported brain fog. Given the context that it is daily persistent headache, one could surmise that they have brain fog a lot of the time,” said Dr. Sico.
 

‘A Good Data Set’

The researchers analyzed data from 337 international patients who responded to a survey. They also randomly selected 34 patients for an interview, and 32 of those were deemed likely to have NDPH. “So we really spent some effort making sure this was a good data set,” said Dr. Burish. The participant population was 72% female, 83.7% White, and 70.7% were based in the United States, though other countries included Canada, the United Kingdom, Australia, Ireland, Germany, Sweden, and Switzerland. The mean age was 41.2 years. The peak ages of onset were between 11 and 40 years, though there were a few cases in the 0-5 age range and over 70. Possible triggers that occurred in the 3 months before onset included psychological stressors (34%), infection or inflammation (32%, COVID infection (5%), injury or surgery (8%), or a change in medications (4%). No clear trigger was identified by 22% of respondents.

The survey included information on associated features, and frequently reported issues included brain fog (approximate 75%), sound sensitivity (about 62%), light sensitivity (57%), nausea (39%), smell sensitivity (32%), visual disturbances (28%), vomiting (13%), and chills (9%).
 

Insights Into Treatment Efficacy

Dr. Burish showed a slide of responses to questions about acute treatments that respondents had tried at least once and viewed as ‘completely effective,’ ‘mostly effective,’ or ‘somewhat effective.’

“No medicine was completely effective, which I think a lot of people know from NDPH. It is notoriously difficult to treat. The things on the top of the list are mostly opioids. There’s one (non-opioid), the DHE (dihydroergotamine) injection. All the way on the other side, you have diphenhydramine. The NSAIDs and triptans are mostly in the middle. We did ask about some of the wearable devices, and we had extra questions about, are you using it appropriately? Those are kind of in the middle or towards the bottom [in frequency],” said Dr. Burish.

There was a similar question regarding effective preventive medications that had been tried for at least 2 months or 3 months in the cause of onabotulinum toxin or CGRP medications. “This one had a little bit more of a pattern to it: A lot of the CGRP medications are up toward the top. It’s not perfect. Erenumab and galcanezumab are closer to the bottom, but it was interesting that a lot of the CGRP medicines were toward the top. Onabotulinum toxin was also somewhat toward the top. We looked at a few different anti-inflammatories. Methylprednisolone is kind of toward the upper half at least, whereas prednisone and montelukast are at the absolute bottom. And the prednisone is a pretty good dose, 50 milligrams or higher. There are some people thinking that this is an inflammation or infectious etiology, (but) it wasn’t that all of the anti-inflammatories were necessarily toward the top of the list,” said Dr. Burish.

Dr. Burish has received funding from Lundbeck. Dr. Sico has no relevant financial disclosures.

SAN DIEGO — A new analysis of patients with new daily persistent headache (NDPH) lends insight into the condition and provides some hints as to some of the more effective treatments, including some calcitonin gene-related peptide (CGRP) inhibitors.

“There’s just not a lot [of information] about these patients,” Mark Burish, MD, PhD, associate professor of neurology at UT Houston, said in an interview. He presented the results of the survey at the annual meeting of the American Headache Society.

There have been some retrospective analyses of patient data, but that has a lot of potential for bias. “It’s only the patients who can afford to be there, and who needed those treatments, and so we want to do more of a general survey,” said Dr. Burish.

The results weren’t particularly surprising, and tended to reaffirm what was known anecdotally, including symptoms similar to those of migraine, but it gave some insight into treatments. “Some of the CGRP inhibitors and the onabotulinum toxin seem to be some of the more effective treatments, according to our survey, so those are probably worth looking into for these patients if you can get them approved by insurance, and if you can get patients to accept the idea they might have to give themselves an injection of some sort,” said Dr. Burish.

Despite having some promise, there was variation among CGRP inhibitors. Eptinezumab, rimegepant, and atogepant were commonly reported as effective, but others, such as erenumab and galcanezumab, were less often reported. “None of them were incredibly effective. These were just the best things we have at this time,” said Dr. Burish.
 

Additional Information on a Rare, Hard-to-Treat Condition

Jason Sico, MD, who moderated the session, was asked for comment. “I’m so appreciative that the team has looked at a new daily persistent headache. It’s a rare type of headache disorder. It’s also one that is notoriously difficult to treat and something that we that we really need to know more about. It is difficult to really get good, robust in-depth information on these patients, and the team did a really nice job with that,” said Dr. Sico, associate professor of neurology and internal medicine at Yale School of Medicine and national director of the Headache Centers of Excellence Program within the Veterans Health Administration.

He noted that the researchers found that opioids were the most commonly used acute treatment. That’s not surprising, but “it would be interesting to see what was tried before someone had gotten to opioids,” he said.

The findings also gave some unexpected insight into the condition. “I really found it striking that an overwhelming majority of patients reported brain fog. Given the context that it is daily persistent headache, one could surmise that they have brain fog a lot of the time,” said Dr. Sico.
 

‘A Good Data Set’

The researchers analyzed data from 337 international patients who responded to a survey. They also randomly selected 34 patients for an interview, and 32 of those were deemed likely to have NDPH. “So we really spent some effort making sure this was a good data set,” said Dr. Burish. The participant population was 72% female, 83.7% White, and 70.7% were based in the United States, though other countries included Canada, the United Kingdom, Australia, Ireland, Germany, Sweden, and Switzerland. The mean age was 41.2 years. The peak ages of onset were between 11 and 40 years, though there were a few cases in the 0-5 age range and over 70. Possible triggers that occurred in the 3 months before onset included psychological stressors (34%), infection or inflammation (32%, COVID infection (5%), injury or surgery (8%), or a change in medications (4%). No clear trigger was identified by 22% of respondents.

The survey included information on associated features, and frequently reported issues included brain fog (approximate 75%), sound sensitivity (about 62%), light sensitivity (57%), nausea (39%), smell sensitivity (32%), visual disturbances (28%), vomiting (13%), and chills (9%).
 

Insights Into Treatment Efficacy

Dr. Burish showed a slide of responses to questions about acute treatments that respondents had tried at least once and viewed as ‘completely effective,’ ‘mostly effective,’ or ‘somewhat effective.’

“No medicine was completely effective, which I think a lot of people know from NDPH. It is notoriously difficult to treat. The things on the top of the list are mostly opioids. There’s one (non-opioid), the DHE (dihydroergotamine) injection. All the way on the other side, you have diphenhydramine. The NSAIDs and triptans are mostly in the middle. We did ask about some of the wearable devices, and we had extra questions about, are you using it appropriately? Those are kind of in the middle or towards the bottom [in frequency],” said Dr. Burish.

There was a similar question regarding effective preventive medications that had been tried for at least 2 months or 3 months in the cause of onabotulinum toxin or CGRP medications. “This one had a little bit more of a pattern to it: A lot of the CGRP medications are up toward the top. It’s not perfect. Erenumab and galcanezumab are closer to the bottom, but it was interesting that a lot of the CGRP medicines were toward the top. Onabotulinum toxin was also somewhat toward the top. We looked at a few different anti-inflammatories. Methylprednisolone is kind of toward the upper half at least, whereas prednisone and montelukast are at the absolute bottom. And the prednisone is a pretty good dose, 50 milligrams or higher. There are some people thinking that this is an inflammation or infectious etiology, (but) it wasn’t that all of the anti-inflammatories were necessarily toward the top of the list,” said Dr. Burish.

Dr. Burish has received funding from Lundbeck. Dr. Sico has no relevant financial disclosures.

SAN DIEGO — A new analysis of patients with new daily persistent headache (NDPH) lends insight into the condition and provides some hints as to some of the more effective treatments, including some calcitonin gene-related peptide (CGRP) inhibitors.

“There’s just not a lot [of information] about these patients,” Mark Burish, MD, PhD, associate professor of neurology at UT Houston, said in an interview. He presented the results of the survey at the annual meeting of the American Headache Society.

There have been some retrospective analyses of patient data, but that has a lot of potential for bias. “It’s only the patients who can afford to be there, and who needed those treatments, and so we want to do more of a general survey,” said Dr. Burish.

The results weren’t particularly surprising, and tended to reaffirm what was known anecdotally, including symptoms similar to those of migraine, but it gave some insight into treatments. “Some of the CGRP inhibitors and the onabotulinum toxin seem to be some of the more effective treatments, according to our survey, so those are probably worth looking into for these patients if you can get them approved by insurance, and if you can get patients to accept the idea they might have to give themselves an injection of some sort,” said Dr. Burish.

Despite having some promise, there was variation among CGRP inhibitors. Eptinezumab, rimegepant, and atogepant were commonly reported as effective, but others, such as erenumab and galcanezumab, were less often reported. “None of them were incredibly effective. These were just the best things we have at this time,” said Dr. Burish.
 

Additional Information on a Rare, Hard-to-Treat Condition

Jason Sico, MD, who moderated the session, was asked for comment. “I’m so appreciative that the team has looked at a new daily persistent headache. It’s a rare type of headache disorder. It’s also one that is notoriously difficult to treat and something that we that we really need to know more about. It is difficult to really get good, robust in-depth information on these patients, and the team did a really nice job with that,” said Dr. Sico, associate professor of neurology and internal medicine at Yale School of Medicine and national director of the Headache Centers of Excellence Program within the Veterans Health Administration.

He noted that the researchers found that opioids were the most commonly used acute treatment. That’s not surprising, but “it would be interesting to see what was tried before someone had gotten to opioids,” he said.

The findings also gave some unexpected insight into the condition. “I really found it striking that an overwhelming majority of patients reported brain fog. Given the context that it is daily persistent headache, one could surmise that they have brain fog a lot of the time,” said Dr. Sico.
 

‘A Good Data Set’

The researchers analyzed data from 337 international patients who responded to a survey. They also randomly selected 34 patients for an interview, and 32 of those were deemed likely to have NDPH. “So we really spent some effort making sure this was a good data set,” said Dr. Burish. The participant population was 72% female, 83.7% White, and 70.7% were based in the United States, though other countries included Canada, the United Kingdom, Australia, Ireland, Germany, Sweden, and Switzerland. The mean age was 41.2 years. The peak ages of onset were between 11 and 40 years, though there were a few cases in the 0-5 age range and over 70. Possible triggers that occurred in the 3 months before onset included psychological stressors (34%), infection or inflammation (32%, COVID infection (5%), injury or surgery (8%), or a change in medications (4%). No clear trigger was identified by 22% of respondents.

The survey included information on associated features, and frequently reported issues included brain fog (approximate 75%), sound sensitivity (about 62%), light sensitivity (57%), nausea (39%), smell sensitivity (32%), visual disturbances (28%), vomiting (13%), and chills (9%).
 

Insights Into Treatment Efficacy

Dr. Burish showed a slide of responses to questions about acute treatments that respondents had tried at least once and viewed as ‘completely effective,’ ‘mostly effective,’ or ‘somewhat effective.’

“No medicine was completely effective, which I think a lot of people know from NDPH. It is notoriously difficult to treat. The things on the top of the list are mostly opioids. There’s one (non-opioid), the DHE (dihydroergotamine) injection. All the way on the other side, you have diphenhydramine. The NSAIDs and triptans are mostly in the middle. We did ask about some of the wearable devices, and we had extra questions about, are you using it appropriately? Those are kind of in the middle or towards the bottom [in frequency],” said Dr. Burish.

There was a similar question regarding effective preventive medications that had been tried for at least 2 months or 3 months in the cause of onabotulinum toxin or CGRP medications. “This one had a little bit more of a pattern to it: A lot of the CGRP medications are up toward the top. It’s not perfect. Erenumab and galcanezumab are closer to the bottom, but it was interesting that a lot of the CGRP medicines were toward the top. Onabotulinum toxin was also somewhat toward the top. We looked at a few different anti-inflammatories. Methylprednisolone is kind of toward the upper half at least, whereas prednisone and montelukast are at the absolute bottom. And the prednisone is a pretty good dose, 50 milligrams or higher. There are some people thinking that this is an inflammation or infectious etiology, (but) it wasn’t that all of the anti-inflammatories were necessarily toward the top of the list,” said Dr. Burish.

Dr. Burish has received funding from Lundbeck. Dr. Sico has no relevant financial disclosures.

Glofitamab, a fixed-duration CD20xCD3 bispecific antibody, combined with a chemotherapy regimen of gemcitabine and oxaliplatin (GemOx), shows significant survival benefits in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), compared with the standard-of-care regimen.

“Glofitamab is the first CD20xCD3 bispecific antibody to demonstrate an overall survival benefit in DLBCL in a randomized phase 3 trial,” said first author Jeremy Abramson, MD, of the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, in a press briefing at the annual meeting of the European Hematology Association (EHA) in Madrid.

“These results support the use of glofitamab GemOx as new, off-the-shelf treatment for relapsed/refractory DLBCL in patients who are transplant ineligible in the second-line or later setting,” he said.

The findings are from the phase 3 STARGLO study involving 274 patients with R/R DLBCL who had previously been treated either with at least two prior lines of therapy, or—if only one prior line of therapy—were determined to be ineligible for autologous stem cell transplant (ASCT).

At a median follow-up of 21 months, those treated with glofitamab combined with GemOx had a significantly higher median overall survival of 25.5 months, compared with those treated with the standard of care of rituximab and GemOx (12.9 months; hazard ratio [HR], 0.62; P = .006).

“The results show a 38% lower risk of death with the glofitamab plus GemOx, compared with [the rituximab regimen],” Dr. Abramson said.

Secondary endpoints showed consistent benefits with the glofitamab regimen, with significant improvements in progression-free survival and complete remission.
 

Unmet Need for Accessible Therapies

Relapsed/refractory DLBCL, the most common form of non-Hodgkin lymphoma (NHL) in the United States, is an aggressive blood cancer. The standard second-line therapy is high-dose chemotherapy followed by ASCT. However, factors including older age or coexisting medical conditions can compromise response, and those who relapse or are refractory to subsequent therapies have poor outcomes.

“Relapsed DLBCL in the second-line setting or later continues to represent an area of medical need,” Dr. Abramson said.

While several CD20xCD3 bispecific antibody drugs are under development to address the need, glofitamab was the first off-the-shelf, fixed-duration bispecific antibody to receive accelerated approval from the US Food and Drug Administration (FDA) for the treatment of R/R DLBCL, specifically as monotherapy after two or more lines of systemic therapy.

That approval was based on results from a pivotal phase 1/2 study, which showed high rates of deep and durable complete remission with the monotherapy.

To further evaluate glofitamab in combination with GemOx, the authors conducted the multicenter, open-label STARGLO trial, which extended enrollment to patients with just one prior therapy if they were determined to be stem cell transplant ineligible. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

Patients were randomized 2:1 either to treatment with glofitamab combined with GemOx, involving 8 cycles, in addition to 4 cycles of glofitamab monotherapy (n = 183), or to the rituximab plus GemOx regimen in 8 cycles (n = 91).

Overall, 153 (55.8%) of patients had primary refractory disease and 166 (60.6%) were refractory to their last therapy. The median age was 68, and 37% had two or more lines of therapy, including some who had received chimeric antigen receptor T-cell (CAR T) therapy (8.8% in the glofitamab group and 7.1% in the rituximab group).

In addition to the significant overall survival benefit, the glofitamab regimen also showed significantly improved progression-free survival at a median follow-up of 16.1 months, as observed by IRC-assessed PFS, with a median progression-free survival rate of 13.8 months vs 3.6 months (HR, 0.40; P < .0001).

The complete remission rate was doubled with glofitamab-GemOx, with a rate of 58.5% vs 25.3%, respectively; P < .0001.

Similar results were observed in subgroups, including relapsed vs refractory patients and those treated as a second or third line of care.

The median number of cycles received was higher among those receiving glofitamab (11 vs four cycles).

Adverse event (AE) rates were higher with glofitamab vs rituximab, including grade 3-4 AEs (69.4 vs 36.4%), grade 5 AEs (8.3 vs 4.5%; primarily driven by an imbalance of COVID-19 AEs), and serious AEs (54.4 vs 17.0%; primarily cytokine release syndrome [CRS]).

CRS was the most frequently reported AE in the glofitamab group (grade 1: 31.4%; grade 2: 10.5%; and grade 3: 2.3%), and events consistent with immune effector cell–associated neurotoxicity syndrome were reported in four patients (2.3%), all of which were concurrent with CRS.

Other AEs were consistent with the known risks associated with the therapy regimens.

“We found that with glofitamab GemOx, the toxicities were manageable, and the most common toxicity of CRS was predominantly low-grade and occurred with step-up dosing in cycle one and was completely reversible,” Dr. Abramson said.

He noted that the higher rate of grade 5 AEs with glofitamab GemOx “was far outweighed by the survival benefit for disease control.”

Overall, “these findings represent the best outcomes observed in a phase 3 trial for relapsed/refractory diffuse large B-cell lymphoma patients who are considered transplant ineligible,” Dr. Abramson said in an interview.
 

Improved Accessibility Vs CAR-T Therapy

Among key developments in the treatment of R/R DLBCL has been the advent and approval of potentially highly effective CAR T-cell therapy, with the anti-CD19 CAR T cell isiocabtagene maraleucel also FDA approved in the non–transplant eligible DLBCL second-line setting.

Asked in the press briefing about the role of glofitamab GemOx in relation to CAR T cell’s significant benefits, Dr. Abramson underscored the important limitations in CAR T-cell accessibility.

“What I would say is a rising tide lifts all boats,” he responded. “It’s great to have multiple effective immunotherapy strategies.”

However, “CAR T cells of course are not available to most people in the US or worldwide,” he explained.

“They are more difficult to access, they require lymphodepleting chemotherapy, and so ultimately, the majority of patients who could potentially benefit from a CAR T cell probably don’t have access to them in the first place.”

He noted that “the appeal of a regimen like [glofitamab] is that it is an off-the-shelf, targeted immunotherapy combined with a well-tolerated chemotherapy backbone and should be more broadly accessible outside of just tertiary care centers in major cities.”
 

Long-Term Durability?

Looking ahead, Dr. Abramson noted that a key issue of focus is how long the encouraging results actually last.

“The major ongoing question with this trial is the long-term durability of remissions,” he said.

“Thus far, with a median of 21 months of follow-up for overall survival, the results are encouraging but longer follow-up is needed,” he added.

“Further trials are needed in a broader large B-cell lymphoma population as this trial was limited to DLBCL not otherwise specified, so did not include patients with transformed lymphoma, primary mediastinal B-cell lymphoma, high grade B-cell lymphoma, etc.” 
 

Is Chemo Necessary?

Commenting on the findings, Jonathan W. Friedberg, MD, director of the Wilmot Cancer Institute, University of Rochester School of Medicine, in Rochester, New York, underscored that, “given the overall survival benefit, these findings are clearly clinically significant.”

Noting that “these results add to evidence of high activity of bispecific antibodies in this disease,” Dr. Friedberg speculated on the role of chemotherapy with the therapy.

“Indeed, an important question in this study is whether the addition of chemotherapy to glofitamab is necessary, as high response rates with durable responses in patients who achieve complete remission have been demonstrated with single agent bispecific antibody therapy,” he said. 

With the durability of CAR T therapy shown in long-term follow-up of trials to exceed 5 years, Dr. Friedberg added that “it is not known how bispecific antibody therapy, with or without chemotherapy, compares to CAR T-cell therapy and how to sequence CAR T and bispecific antibody therapy.”

Dr. Friedberg agreed that longer-term results are needed get a clearer, fuller picture of the therapy’s effects.

“I have no doubt that the overall survival benefit will endure, but in DLBCL our goal should be cure, and whether glofitamab cures as many patients as CAR T-cell therapy is not currently known and will require further follow-up of this and other trials.”

The study was sponsored by F. Hoffman-La Roche Ltd. Dr. Abramson reported ties with AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, BMS, Cellectar, Caribou Biosciences, Celgene, Genentech, Gilead, Incyte, Interius, Janssen, Lilly, Novartis, F. Hoffmann-La Roche Ltd, Seagen, and Takeda. Dr. Friedberg had no disclosures.

Glofitamab, a fixed-duration CD20xCD3 bispecific antibody, combined with a chemotherapy regimen of gemcitabine and oxaliplatin (GemOx), shows significant survival benefits in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), compared with the standard-of-care regimen.

“Glofitamab is the first CD20xCD3 bispecific antibody to demonstrate an overall survival benefit in DLBCL in a randomized phase 3 trial,” said first author Jeremy Abramson, MD, of the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, in a press briefing at the annual meeting of the European Hematology Association (EHA) in Madrid.

“These results support the use of glofitamab GemOx as new, off-the-shelf treatment for relapsed/refractory DLBCL in patients who are transplant ineligible in the second-line or later setting,” he said.

The findings are from the phase 3 STARGLO study involving 274 patients with R/R DLBCL who had previously been treated either with at least two prior lines of therapy, or—if only one prior line of therapy—were determined to be ineligible for autologous stem cell transplant (ASCT).

At a median follow-up of 21 months, those treated with glofitamab combined with GemOx had a significantly higher median overall survival of 25.5 months, compared with those treated with the standard of care of rituximab and GemOx (12.9 months; hazard ratio [HR], 0.62; P = .006).

“The results show a 38% lower risk of death with the glofitamab plus GemOx, compared with [the rituximab regimen],” Dr. Abramson said.

Secondary endpoints showed consistent benefits with the glofitamab regimen, with significant improvements in progression-free survival and complete remission.
 

Unmet Need for Accessible Therapies

Relapsed/refractory DLBCL, the most common form of non-Hodgkin lymphoma (NHL) in the United States, is an aggressive blood cancer. The standard second-line therapy is high-dose chemotherapy followed by ASCT. However, factors including older age or coexisting medical conditions can compromise response, and those who relapse or are refractory to subsequent therapies have poor outcomes.

“Relapsed DLBCL in the second-line setting or later continues to represent an area of medical need,” Dr. Abramson said.

While several CD20xCD3 bispecific antibody drugs are under development to address the need, glofitamab was the first off-the-shelf, fixed-duration bispecific antibody to receive accelerated approval from the US Food and Drug Administration (FDA) for the treatment of R/R DLBCL, specifically as monotherapy after two or more lines of systemic therapy.

That approval was based on results from a pivotal phase 1/2 study, which showed high rates of deep and durable complete remission with the monotherapy.

To further evaluate glofitamab in combination with GemOx, the authors conducted the multicenter, open-label STARGLO trial, which extended enrollment to patients with just one prior therapy if they were determined to be stem cell transplant ineligible. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

Patients were randomized 2:1 either to treatment with glofitamab combined with GemOx, involving 8 cycles, in addition to 4 cycles of glofitamab monotherapy (n = 183), or to the rituximab plus GemOx regimen in 8 cycles (n = 91).

Overall, 153 (55.8%) of patients had primary refractory disease and 166 (60.6%) were refractory to their last therapy. The median age was 68, and 37% had two or more lines of therapy, including some who had received chimeric antigen receptor T-cell (CAR T) therapy (8.8% in the glofitamab group and 7.1% in the rituximab group).

In addition to the significant overall survival benefit, the glofitamab regimen also showed significantly improved progression-free survival at a median follow-up of 16.1 months, as observed by IRC-assessed PFS, with a median progression-free survival rate of 13.8 months vs 3.6 months (HR, 0.40; P < .0001).

The complete remission rate was doubled with glofitamab-GemOx, with a rate of 58.5% vs 25.3%, respectively; P < .0001.

Similar results were observed in subgroups, including relapsed vs refractory patients and those treated as a second or third line of care.

The median number of cycles received was higher among those receiving glofitamab (11 vs four cycles).

Adverse event (AE) rates were higher with glofitamab vs rituximab, including grade 3-4 AEs (69.4 vs 36.4%), grade 5 AEs (8.3 vs 4.5%; primarily driven by an imbalance of COVID-19 AEs), and serious AEs (54.4 vs 17.0%; primarily cytokine release syndrome [CRS]).

CRS was the most frequently reported AE in the glofitamab group (grade 1: 31.4%; grade 2: 10.5%; and grade 3: 2.3%), and events consistent with immune effector cell–associated neurotoxicity syndrome were reported in four patients (2.3%), all of which were concurrent with CRS.

Other AEs were consistent with the known risks associated with the therapy regimens.

“We found that with glofitamab GemOx, the toxicities were manageable, and the most common toxicity of CRS was predominantly low-grade and occurred with step-up dosing in cycle one and was completely reversible,” Dr. Abramson said.

He noted that the higher rate of grade 5 AEs with glofitamab GemOx “was far outweighed by the survival benefit for disease control.”

Overall, “these findings represent the best outcomes observed in a phase 3 trial for relapsed/refractory diffuse large B-cell lymphoma patients who are considered transplant ineligible,” Dr. Abramson said in an interview.
 

Improved Accessibility Vs CAR-T Therapy

Among key developments in the treatment of R/R DLBCL has been the advent and approval of potentially highly effective CAR T-cell therapy, with the anti-CD19 CAR T cell isiocabtagene maraleucel also FDA approved in the non–transplant eligible DLBCL second-line setting.

Asked in the press briefing about the role of glofitamab GemOx in relation to CAR T cell’s significant benefits, Dr. Abramson underscored the important limitations in CAR T-cell accessibility.

“What I would say is a rising tide lifts all boats,” he responded. “It’s great to have multiple effective immunotherapy strategies.”

However, “CAR T cells of course are not available to most people in the US or worldwide,” he explained.

“They are more difficult to access, they require lymphodepleting chemotherapy, and so ultimately, the majority of patients who could potentially benefit from a CAR T cell probably don’t have access to them in the first place.”

He noted that “the appeal of a regimen like [glofitamab] is that it is an off-the-shelf, targeted immunotherapy combined with a well-tolerated chemotherapy backbone and should be more broadly accessible outside of just tertiary care centers in major cities.”
 

Long-Term Durability?

Looking ahead, Dr. Abramson noted that a key issue of focus is how long the encouraging results actually last.

“The major ongoing question with this trial is the long-term durability of remissions,” he said.

“Thus far, with a median of 21 months of follow-up for overall survival, the results are encouraging but longer follow-up is needed,” he added.

“Further trials are needed in a broader large B-cell lymphoma population as this trial was limited to DLBCL not otherwise specified, so did not include patients with transformed lymphoma, primary mediastinal B-cell lymphoma, high grade B-cell lymphoma, etc.” 
 

Is Chemo Necessary?

Commenting on the findings, Jonathan W. Friedberg, MD, director of the Wilmot Cancer Institute, University of Rochester School of Medicine, in Rochester, New York, underscored that, “given the overall survival benefit, these findings are clearly clinically significant.”

Noting that “these results add to evidence of high activity of bispecific antibodies in this disease,” Dr. Friedberg speculated on the role of chemotherapy with the therapy.

“Indeed, an important question in this study is whether the addition of chemotherapy to glofitamab is necessary, as high response rates with durable responses in patients who achieve complete remission have been demonstrated with single agent bispecific antibody therapy,” he said. 

With the durability of CAR T therapy shown in long-term follow-up of trials to exceed 5 years, Dr. Friedberg added that “it is not known how bispecific antibody therapy, with or without chemotherapy, compares to CAR T-cell therapy and how to sequence CAR T and bispecific antibody therapy.”

Dr. Friedberg agreed that longer-term results are needed get a clearer, fuller picture of the therapy’s effects.

“I have no doubt that the overall survival benefit will endure, but in DLBCL our goal should be cure, and whether glofitamab cures as many patients as CAR T-cell therapy is not currently known and will require further follow-up of this and other trials.”

The study was sponsored by F. Hoffman-La Roche Ltd. Dr. Abramson reported ties with AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, BMS, Cellectar, Caribou Biosciences, Celgene, Genentech, Gilead, Incyte, Interius, Janssen, Lilly, Novartis, F. Hoffmann-La Roche Ltd, Seagen, and Takeda. Dr. Friedberg had no disclosures.

Glofitamab, a fixed-duration CD20xCD3 bispecific antibody, combined with a chemotherapy regimen of gemcitabine and oxaliplatin (GemOx), shows significant survival benefits in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), compared with the standard-of-care regimen.

“Glofitamab is the first CD20xCD3 bispecific antibody to demonstrate an overall survival benefit in DLBCL in a randomized phase 3 trial,” said first author Jeremy Abramson, MD, of the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, in a press briefing at the annual meeting of the European Hematology Association (EHA) in Madrid.

“These results support the use of glofitamab GemOx as new, off-the-shelf treatment for relapsed/refractory DLBCL in patients who are transplant ineligible in the second-line or later setting,” he said.

The findings are from the phase 3 STARGLO study involving 274 patients with R/R DLBCL who had previously been treated either with at least two prior lines of therapy, or—if only one prior line of therapy—were determined to be ineligible for autologous stem cell transplant (ASCT).

At a median follow-up of 21 months, those treated with glofitamab combined with GemOx had a significantly higher median overall survival of 25.5 months, compared with those treated with the standard of care of rituximab and GemOx (12.9 months; hazard ratio [HR], 0.62; P = .006).

“The results show a 38% lower risk of death with the glofitamab plus GemOx, compared with [the rituximab regimen],” Dr. Abramson said.

Secondary endpoints showed consistent benefits with the glofitamab regimen, with significant improvements in progression-free survival and complete remission.
 

Unmet Need for Accessible Therapies

Relapsed/refractory DLBCL, the most common form of non-Hodgkin lymphoma (NHL) in the United States, is an aggressive blood cancer. The standard second-line therapy is high-dose chemotherapy followed by ASCT. However, factors including older age or coexisting medical conditions can compromise response, and those who relapse or are refractory to subsequent therapies have poor outcomes.

“Relapsed DLBCL in the second-line setting or later continues to represent an area of medical need,” Dr. Abramson said.

While several CD20xCD3 bispecific antibody drugs are under development to address the need, glofitamab was the first off-the-shelf, fixed-duration bispecific antibody to receive accelerated approval from the US Food and Drug Administration (FDA) for the treatment of R/R DLBCL, specifically as monotherapy after two or more lines of systemic therapy.

That approval was based on results from a pivotal phase 1/2 study, which showed high rates of deep and durable complete remission with the monotherapy.

To further evaluate glofitamab in combination with GemOx, the authors conducted the multicenter, open-label STARGLO trial, which extended enrollment to patients with just one prior therapy if they were determined to be stem cell transplant ineligible. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

Patients were randomized 2:1 either to treatment with glofitamab combined with GemOx, involving 8 cycles, in addition to 4 cycles of glofitamab monotherapy (n = 183), or to the rituximab plus GemOx regimen in 8 cycles (n = 91).

Overall, 153 (55.8%) of patients had primary refractory disease and 166 (60.6%) were refractory to their last therapy. The median age was 68, and 37% had two or more lines of therapy, including some who had received chimeric antigen receptor T-cell (CAR T) therapy (8.8% in the glofitamab group and 7.1% in the rituximab group).

In addition to the significant overall survival benefit, the glofitamab regimen also showed significantly improved progression-free survival at a median follow-up of 16.1 months, as observed by IRC-assessed PFS, with a median progression-free survival rate of 13.8 months vs 3.6 months (HR, 0.40; P < .0001).

The complete remission rate was doubled with glofitamab-GemOx, with a rate of 58.5% vs 25.3%, respectively; P < .0001.

Similar results were observed in subgroups, including relapsed vs refractory patients and those treated as a second or third line of care.

The median number of cycles received was higher among those receiving glofitamab (11 vs four cycles).

Adverse event (AE) rates were higher with glofitamab vs rituximab, including grade 3-4 AEs (69.4 vs 36.4%), grade 5 AEs (8.3 vs 4.5%; primarily driven by an imbalance of COVID-19 AEs), and serious AEs (54.4 vs 17.0%; primarily cytokine release syndrome [CRS]).

CRS was the most frequently reported AE in the glofitamab group (grade 1: 31.4%; grade 2: 10.5%; and grade 3: 2.3%), and events consistent with immune effector cell–associated neurotoxicity syndrome were reported in four patients (2.3%), all of which were concurrent with CRS.

Other AEs were consistent with the known risks associated with the therapy regimens.

“We found that with glofitamab GemOx, the toxicities were manageable, and the most common toxicity of CRS was predominantly low-grade and occurred with step-up dosing in cycle one and was completely reversible,” Dr. Abramson said.

He noted that the higher rate of grade 5 AEs with glofitamab GemOx “was far outweighed by the survival benefit for disease control.”

Overall, “these findings represent the best outcomes observed in a phase 3 trial for relapsed/refractory diffuse large B-cell lymphoma patients who are considered transplant ineligible,” Dr. Abramson said in an interview.
 

Improved Accessibility Vs CAR-T Therapy

Among key developments in the treatment of R/R DLBCL has been the advent and approval of potentially highly effective CAR T-cell therapy, with the anti-CD19 CAR T cell isiocabtagene maraleucel also FDA approved in the non–transplant eligible DLBCL second-line setting.

Asked in the press briefing about the role of glofitamab GemOx in relation to CAR T cell’s significant benefits, Dr. Abramson underscored the important limitations in CAR T-cell accessibility.

“What I would say is a rising tide lifts all boats,” he responded. “It’s great to have multiple effective immunotherapy strategies.”

However, “CAR T cells of course are not available to most people in the US or worldwide,” he explained.

“They are more difficult to access, they require lymphodepleting chemotherapy, and so ultimately, the majority of patients who could potentially benefit from a CAR T cell probably don’t have access to them in the first place.”

He noted that “the appeal of a regimen like [glofitamab] is that it is an off-the-shelf, targeted immunotherapy combined with a well-tolerated chemotherapy backbone and should be more broadly accessible outside of just tertiary care centers in major cities.”
 

Long-Term Durability?

Looking ahead, Dr. Abramson noted that a key issue of focus is how long the encouraging results actually last.

“The major ongoing question with this trial is the long-term durability of remissions,” he said.

“Thus far, with a median of 21 months of follow-up for overall survival, the results are encouraging but longer follow-up is needed,” he added.

“Further trials are needed in a broader large B-cell lymphoma population as this trial was limited to DLBCL not otherwise specified, so did not include patients with transformed lymphoma, primary mediastinal B-cell lymphoma, high grade B-cell lymphoma, etc.” 
 

Is Chemo Necessary?

Commenting on the findings, Jonathan W. Friedberg, MD, director of the Wilmot Cancer Institute, University of Rochester School of Medicine, in Rochester, New York, underscored that, “given the overall survival benefit, these findings are clearly clinically significant.”

Noting that “these results add to evidence of high activity of bispecific antibodies in this disease,” Dr. Friedberg speculated on the role of chemotherapy with the therapy.

“Indeed, an important question in this study is whether the addition of chemotherapy to glofitamab is necessary, as high response rates with durable responses in patients who achieve complete remission have been demonstrated with single agent bispecific antibody therapy,” he said. 

With the durability of CAR T therapy shown in long-term follow-up of trials to exceed 5 years, Dr. Friedberg added that “it is not known how bispecific antibody therapy, with or without chemotherapy, compares to CAR T-cell therapy and how to sequence CAR T and bispecific antibody therapy.”

Dr. Friedberg agreed that longer-term results are needed get a clearer, fuller picture of the therapy’s effects.

“I have no doubt that the overall survival benefit will endure, but in DLBCL our goal should be cure, and whether glofitamab cures as many patients as CAR T-cell therapy is not currently known and will require further follow-up of this and other trials.”

The study was sponsored by F. Hoffman-La Roche Ltd. Dr. Abramson reported ties with AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, BMS, Cellectar, Caribou Biosciences, Celgene, Genentech, Gilead, Incyte, Interius, Janssen, Lilly, Novartis, F. Hoffmann-La Roche Ltd, Seagen, and Takeda. Dr. Friedberg had no disclosures.

CHICAGO — Prominent Chinese oncologist Tony Shu-Kam Mok, MD, who presented as first author of a phase 3 non–small cell lung cancer study at ASCO 2024, made a dramatic swerve in his career path at age 36.

After 20 years in Canada — 7 spent practicing community oncology near Toronto — Dr. Mok was visiting family in his native Hong Kong back in 1996 when a job offer there enabled him to revive his early dream of doing academic research. Dr. Mok and his family moved back home just before the former British colony was returned to China in 1997.

courtesy of Dr. Tony Mok

That leap of faith helped Dr. Mok play a role in the global paradigm shift on treating lung cancer. He chairs the department of clinical oncology at the Chinese University of Hong Kong. A leader in ushering in targeted therapies and personalized medicine in China and globally, he has helped advance the goal of transforming lung cancer from a death sentence to a chronic disease.

Among Dr. Mok’s other accomplishments, he has published eight books and more than 200 journal articles. Since 2006, he has been writing a twice-weekly column in the Hong Kong Economic Times. At the annual meeting of the American Society of Clinical Oncology (ASCO), Dr. Mok sat down with this news organization to discuss his latest findings, his career path, and China’s ever-growing presence in multinational clinical trials, pharmaceuticals, and cancer research in general.
 

Question: At ASCO 2024 in Chicago, you presented as first author of the KRYSTAL-12 study. Can you give a short “elevator speech” summarizing those findings?

Dr. Mok: KRYSTAL-12 is a randomized phase 3 study comparing adagrasib with docetaxel in patients with previously treated advanced/metastatic non–small cell lung cancer harboring a KRAS G12C-mutation. And the findings are positive, with a median progression free survival of 5.5 months vs 3.8 months, with a significant hazard ratio [of 0.58]. And then there are also differences in their response rates of 32% versus 9%, and that gives you an [odds] ratio of 4.86. So yes, it’s significant.

Question: Now that you’ve given this presentation and perhaps taken some good, meaningful questions about it, are there any further points you’d like to make — anything you’d like to add?

Dr. Mok: You have to understand that whatever I said has been scrutinized by the pharmaceutical company, but now I can say whatever I like. I think the key point is that we actually have made the first so-called achievement in the KRAS G12C space. But this is only the beginning.

I want to note that the median progression-free survival is different, but not the best. The median 5.5 months result is good, but not good enough. So, we still have to work hard to answer the question: How can we best deliver care to patients with KRAS G12C?
 

Question: Speaking more generally about the challenges of targeting KRAS, what issues arise in terms of biomarker testing for KRAS mutations in the clinic? Dr. Mok: In colorectal cancer, there has been testing for KRAS [mutations] for a long, long time. So, most of the laboratories, as long as they are well equipped, will be able to test for KRAS. Usually, the cheaper way is to buy PCR [polymerase chain reaction]. However, these days it’s getting trendier to use NGS [next-generation sequencing]. So, one way or another, specificity is very high. I don’t think we have too much of a problem. The only difference between colorectal cancer and lung cancer is that the tissue sample may not be as good for lung cancer with a small biopsy, but otherwise testing is not an issue.

Question: What clinical trials should oncologist be watching to come into this space?Dr. Mok: There are a lot. Right now, there is the so-called first-line study that’s coming up. So, I can cite you some examples for the KRYSTAL-7 trial, which is the combination of pembrolizumab together with adagrasib in the PD-L1 Tumor Proportion Score ≥ 50%.

That’s one example. And then there is the CodeBreaK 202 trial, which is actually the combination of chemotherapy with sotorasib versus chemotherapy and I-O [immune-oncology]. That is also an ongoing study.
 

Question: I also want to ask you some background questions about yourself. Back in the day, you lived in Canada and were a community oncologist. Then you made a very big change in your life and moved back home to Hong Kong in 1996, on the eve of its return to China the following year.

Dr. Mok: Well, I was born and raised in Hong Kong, but I left for Canada for education when I was 16 and kind of stayed there and got medical school oncology training and then started my practice. At that time, I never imagined myself going back. But 1996 was a big year. Incidentally, I went back to Hong Kong then to visit my friends and was offered a job at the Chinese University of Hong Kong. Then 1997 was coming. I found it very exciting that we could work with China. So that’s why I decided to return. And this was probably one of my best decisions I ever made in my life.

Question: And you went from being a community oncologist to academic research?

Dr. Mok: Here’s a personal thing that I can share with you: When I finished my oncology training at Princess Margaret Hospital in Toronto, I thought of going into research and becoming an academic. However, my son was born. Household costs went up, and I didn’t want to be a low-income, poor PhD student, so I decided that I may as well go into private practice. Returning to Hong Kong [in 1996] gave me a second chance. I went from being a community oncologist for seven years in Canada to a totally new environment in Hong Kong, where I started my academic work at age 36. It has been a good journey.

Question: Why do you say that was the best decision you ever made?Dr. Mok: At that time, it took me about 2 weeks to make this important decision. Basically: I had to give up my big house and my big car in Canada and move back to a small apartment in Hong Kong. That was a tough decision to make. However, it was a matter of certainty versus uncertainty.

In Canada, I actually had a very stable situation. I had a big practice in the Scarborough area [of Toronto], with a lot of Chinese patients, so I had a better, more comfortable life. It was predictable. But then I asked myself what I would be like in 10 years if I stayed in Canada versus Hong Kong. My answer is that I had no idea what would happen to me 10 years later in Hong Kong. In certain parts of life, you have to decide between certainty and uncertainty. And this time, uncertainty brought me great adventure. I definitely would not have done the things I’ve done if I’d stayed in Canada.



Question: At this ASCO, you’ve spoken primarily about your latest research on non–small cell lung cancer with KRAS G12C mutation.Dr. Mok: Actually, my research has been mostly on targeted therapy. My first break was on the EGFR [epidermal growth factor receptor] mutation. I was one of the first to help define personalized medicine according to the EGFR mutation in the IPASS study [2009]. That’s how I started my academic career.



Question: I read some quotes from your writing some years back about “living with imperfection,” and where you wrote about the whole continuum of cancer research. Years ago, you noted that lung cancer was moving from being a death sentence to becoming a chronic condition.

Dr. Mok: The objective is this: A lot of cancer patients, especially lung cancer patients, had a very short survival, but now we are able to identify a subgroup of patients with a driver oncogene.

And with that, we can use a tyrosine kinase inhibitor — which although it has toxicity, it’s manageable toxicity — such that you can take one pill a day and continue to live a normal life. So that would be not so different from diabetes or hypertension: You live with the disease. So that’s what we like to see: the conversion of a fatal disease into a chronic disease.
 

Question: So many countries now, including the United States and many others, are facing the challenges of cancer care in rural versus urban areas. Is this a topic you’d be willing to address? Dr. Mok: Well, in Hong Kong we don’t have rural areas! But in China, this is a major problem. There most of the cancer care is focused on the so-called three major cities [Shanghai, Beijing, Guangzhou]. And after that, there are second-tier cities that also have reasonably good care. But when you filter down to the third and fourth layer, the oncology care actually deteriorates. So that’s why we end up with a lot of people from the more rural areas moving and going to the city looking for care and consultation. So yes, the disparity is significant.

But China is a growing country. It takes time to change. Right now, we can see at ASCO this year, there are a lot of investigators from China sharing their new findings, which is a major development, compared to 10 years ago. Therefore, I think that when you have this type of proliferative development, eventually the good care, the high-quality care will filter down to more rural areas. So, at this moment, I think there is still a lot of work to do.
 

Question: You’ve talked about how oncologists from China are coming up in the field, and this year they have an even greater presence at ASCO, as well as oncologists from elsewhere in Asia, including South Korea, Japan, and Vietnam. You’ve been coming to ASCO for many years. Can you talk about the factors behind China’s increasing presence? Dr. Mok: I think it’s a combination of factors. First of all, I had the honor of working with lung cancer researchers from China from way back, 25 years ago. At that time, we all had nothing. Then with the development of multitargeted therapies, they managed to build up a very good infrastructure for clinical trials. And then, based on that good infrastructure, they were able to do international collaborative studies and provide a supply of patient resources and high-quality data. So, they’ve learned the trick, done a good job, but they cannot have so-called independence until there is a development of pharmaceuticals in China.

And then over the past 10 years, there’s been a proliferation — actually an explosion I would even say — of high-quality pharmaceutical companies in China. First, they’ve got the resources to build the companies. Second, they’ve got the talent resources returning from the United States. So, putting all that together, these were able to go from start-ups to full-fledged functional companies in a very short time.

And with that, they actually sponsored a lot of trials within China. And you can see that putting all the components together: you’ve got high-quality researchers, you’ve got the infrastructure, and now you’ve got your drugs and the money to do the trials. As a result, you’ve got a lot of good data coming from China.
 

Question: There’s also a population with these mutations.Dr. Mok: That for one, but most have multitargeted therapies, but they also have immunotherapies that have nothing to do with the high incidence. But I think in a sense, in the beginning, they were doing `me-too’ compounds, but now I think they are starting to do ‘me-better’ compounds.

Question: Is there anything you want to say about some of the other presentations that have your name on them at ASCO this year?Dr. Mok: I think the most important one I was engaged in is the CROWN study. The CROWN study is actually a phase 3 study that compares lorlatinib versus crizotinib in patients with advanced, ALK-positive non–small cell lung cancer.

This is a 5-year follow-up, and we were actually able to report an outrageously encouraging 5-year progression-free rate at 60%, meaning that the patient is walking in the door 5 years later when they are on the drug, and 60% of them actually do not have progression, not death, just not progression, just staying on the same pill—which is quite outrageously good for lung cancer.

CHICAGO — Prominent Chinese oncologist Tony Shu-Kam Mok, MD, who presented as first author of a phase 3 non–small cell lung cancer study at ASCO 2024, made a dramatic swerve in his career path at age 36.

After 20 years in Canada — 7 spent practicing community oncology near Toronto — Dr. Mok was visiting family in his native Hong Kong back in 1996 when a job offer there enabled him to revive his early dream of doing academic research. Dr. Mok and his family moved back home just before the former British colony was returned to China in 1997.

courtesy of Dr. Tony Mok

That leap of faith helped Dr. Mok play a role in the global paradigm shift on treating lung cancer. He chairs the department of clinical oncology at the Chinese University of Hong Kong. A leader in ushering in targeted therapies and personalized medicine in China and globally, he has helped advance the goal of transforming lung cancer from a death sentence to a chronic disease.

Among Dr. Mok’s other accomplishments, he has published eight books and more than 200 journal articles. Since 2006, he has been writing a twice-weekly column in the Hong Kong Economic Times. At the annual meeting of the American Society of Clinical Oncology (ASCO), Dr. Mok sat down with this news organization to discuss his latest findings, his career path, and China’s ever-growing presence in multinational clinical trials, pharmaceuticals, and cancer research in general.
 

Question: At ASCO 2024 in Chicago, you presented as first author of the KRYSTAL-12 study. Can you give a short “elevator speech” summarizing those findings?

Dr. Mok: KRYSTAL-12 is a randomized phase 3 study comparing adagrasib with docetaxel in patients with previously treated advanced/metastatic non–small cell lung cancer harboring a KRAS G12C-mutation. And the findings are positive, with a median progression free survival of 5.5 months vs 3.8 months, with a significant hazard ratio [of 0.58]. And then there are also differences in their response rates of 32% versus 9%, and that gives you an [odds] ratio of 4.86. So yes, it’s significant.

Question: Now that you’ve given this presentation and perhaps taken some good, meaningful questions about it, are there any further points you’d like to make — anything you’d like to add?

Dr. Mok: You have to understand that whatever I said has been scrutinized by the pharmaceutical company, but now I can say whatever I like. I think the key point is that we actually have made the first so-called achievement in the KRAS G12C space. But this is only the beginning.

I want to note that the median progression-free survival is different, but not the best. The median 5.5 months result is good, but not good enough. So, we still have to work hard to answer the question: How can we best deliver care to patients with KRAS G12C?
 

Question: Speaking more generally about the challenges of targeting KRAS, what issues arise in terms of biomarker testing for KRAS mutations in the clinic? Dr. Mok: In colorectal cancer, there has been testing for KRAS [mutations] for a long, long time. So, most of the laboratories, as long as they are well equipped, will be able to test for KRAS. Usually, the cheaper way is to buy PCR [polymerase chain reaction]. However, these days it’s getting trendier to use NGS [next-generation sequencing]. So, one way or another, specificity is very high. I don’t think we have too much of a problem. The only difference between colorectal cancer and lung cancer is that the tissue sample may not be as good for lung cancer with a small biopsy, but otherwise testing is not an issue.

Question: What clinical trials should oncologist be watching to come into this space?Dr. Mok: There are a lot. Right now, there is the so-called first-line study that’s coming up. So, I can cite you some examples for the KRYSTAL-7 trial, which is the combination of pembrolizumab together with adagrasib in the PD-L1 Tumor Proportion Score ≥ 50%.

That’s one example. And then there is the CodeBreaK 202 trial, which is actually the combination of chemotherapy with sotorasib versus chemotherapy and I-O [immune-oncology]. That is also an ongoing study.
 

Question: I also want to ask you some background questions about yourself. Back in the day, you lived in Canada and were a community oncologist. Then you made a very big change in your life and moved back home to Hong Kong in 1996, on the eve of its return to China the following year.

Dr. Mok: Well, I was born and raised in Hong Kong, but I left for Canada for education when I was 16 and kind of stayed there and got medical school oncology training and then started my practice. At that time, I never imagined myself going back. But 1996 was a big year. Incidentally, I went back to Hong Kong then to visit my friends and was offered a job at the Chinese University of Hong Kong. Then 1997 was coming. I found it very exciting that we could work with China. So that’s why I decided to return. And this was probably one of my best decisions I ever made in my life.

Question: And you went from being a community oncologist to academic research?

Dr. Mok: Here’s a personal thing that I can share with you: When I finished my oncology training at Princess Margaret Hospital in Toronto, I thought of going into research and becoming an academic. However, my son was born. Household costs went up, and I didn’t want to be a low-income, poor PhD student, so I decided that I may as well go into private practice. Returning to Hong Kong [in 1996] gave me a second chance. I went from being a community oncologist for seven years in Canada to a totally new environment in Hong Kong, where I started my academic work at age 36. It has been a good journey.

Question: Why do you say that was the best decision you ever made?Dr. Mok: At that time, it took me about 2 weeks to make this important decision. Basically: I had to give up my big house and my big car in Canada and move back to a small apartment in Hong Kong. That was a tough decision to make. However, it was a matter of certainty versus uncertainty.

In Canada, I actually had a very stable situation. I had a big practice in the Scarborough area [of Toronto], with a lot of Chinese patients, so I had a better, more comfortable life. It was predictable. But then I asked myself what I would be like in 10 years if I stayed in Canada versus Hong Kong. My answer is that I had no idea what would happen to me 10 years later in Hong Kong. In certain parts of life, you have to decide between certainty and uncertainty. And this time, uncertainty brought me great adventure. I definitely would not have done the things I’ve done if I’d stayed in Canada.



Question: At this ASCO, you’ve spoken primarily about your latest research on non–small cell lung cancer with KRAS G12C mutation.Dr. Mok: Actually, my research has been mostly on targeted therapy. My first break was on the EGFR [epidermal growth factor receptor] mutation. I was one of the first to help define personalized medicine according to the EGFR mutation in the IPASS study [2009]. That’s how I started my academic career.



Question: I read some quotes from your writing some years back about “living with imperfection,” and where you wrote about the whole continuum of cancer research. Years ago, you noted that lung cancer was moving from being a death sentence to becoming a chronic condition.

Dr. Mok: The objective is this: A lot of cancer patients, especially lung cancer patients, had a very short survival, but now we are able to identify a subgroup of patients with a driver oncogene.

And with that, we can use a tyrosine kinase inhibitor — which although it has toxicity, it’s manageable toxicity — such that you can take one pill a day and continue to live a normal life. So that would be not so different from diabetes or hypertension: You live with the disease. So that’s what we like to see: the conversion of a fatal disease into a chronic disease.
 

Question: So many countries now, including the United States and many others, are facing the challenges of cancer care in rural versus urban areas. Is this a topic you’d be willing to address? Dr. Mok: Well, in Hong Kong we don’t have rural areas! But in China, this is a major problem. There most of the cancer care is focused on the so-called three major cities [Shanghai, Beijing, Guangzhou]. And after that, there are second-tier cities that also have reasonably good care. But when you filter down to the third and fourth layer, the oncology care actually deteriorates. So that’s why we end up with a lot of people from the more rural areas moving and going to the city looking for care and consultation. So yes, the disparity is significant.

But China is a growing country. It takes time to change. Right now, we can see at ASCO this year, there are a lot of investigators from China sharing their new findings, which is a major development, compared to 10 years ago. Therefore, I think that when you have this type of proliferative development, eventually the good care, the high-quality care will filter down to more rural areas. So, at this moment, I think there is still a lot of work to do.
 

Question: You’ve talked about how oncologists from China are coming up in the field, and this year they have an even greater presence at ASCO, as well as oncologists from elsewhere in Asia, including South Korea, Japan, and Vietnam. You’ve been coming to ASCO for many years. Can you talk about the factors behind China’s increasing presence? Dr. Mok: I think it’s a combination of factors. First of all, I had the honor of working with lung cancer researchers from China from way back, 25 years ago. At that time, we all had nothing. Then with the development of multitargeted therapies, they managed to build up a very good infrastructure for clinical trials. And then, based on that good infrastructure, they were able to do international collaborative studies and provide a supply of patient resources and high-quality data. So, they’ve learned the trick, done a good job, but they cannot have so-called independence until there is a development of pharmaceuticals in China.

And then over the past 10 years, there’s been a proliferation — actually an explosion I would even say — of high-quality pharmaceutical companies in China. First, they’ve got the resources to build the companies. Second, they’ve got the talent resources returning from the United States. So, putting all that together, these were able to go from start-ups to full-fledged functional companies in a very short time.

And with that, they actually sponsored a lot of trials within China. And you can see that putting all the components together: you’ve got high-quality researchers, you’ve got the infrastructure, and now you’ve got your drugs and the money to do the trials. As a result, you’ve got a lot of good data coming from China.
 

Question: There’s also a population with these mutations.Dr. Mok: That for one, but most have multitargeted therapies, but they also have immunotherapies that have nothing to do with the high incidence. But I think in a sense, in the beginning, they were doing `me-too’ compounds, but now I think they are starting to do ‘me-better’ compounds.

Question: Is there anything you want to say about some of the other presentations that have your name on them at ASCO this year?Dr. Mok: I think the most important one I was engaged in is the CROWN study. The CROWN study is actually a phase 3 study that compares lorlatinib versus crizotinib in patients with advanced, ALK-positive non–small cell lung cancer.

This is a 5-year follow-up, and we were actually able to report an outrageously encouraging 5-year progression-free rate at 60%, meaning that the patient is walking in the door 5 years later when they are on the drug, and 60% of them actually do not have progression, not death, just not progression, just staying on the same pill—which is quite outrageously good for lung cancer.

CHICAGO — Prominent Chinese oncologist Tony Shu-Kam Mok, MD, who presented as first author of a phase 3 non–small cell lung cancer study at ASCO 2024, made a dramatic swerve in his career path at age 36.

After 20 years in Canada — 7 spent practicing community oncology near Toronto — Dr. Mok was visiting family in his native Hong Kong back in 1996 when a job offer there enabled him to revive his early dream of doing academic research. Dr. Mok and his family moved back home just before the former British colony was returned to China in 1997.

courtesy of Dr. Tony Mok

That leap of faith helped Dr. Mok play a role in the global paradigm shift on treating lung cancer. He chairs the department of clinical oncology at the Chinese University of Hong Kong. A leader in ushering in targeted therapies and personalized medicine in China and globally, he has helped advance the goal of transforming lung cancer from a death sentence to a chronic disease.

Among Dr. Mok’s other accomplishments, he has published eight books and more than 200 journal articles. Since 2006, he has been writing a twice-weekly column in the Hong Kong Economic Times. At the annual meeting of the American Society of Clinical Oncology (ASCO), Dr. Mok sat down with this news organization to discuss his latest findings, his career path, and China’s ever-growing presence in multinational clinical trials, pharmaceuticals, and cancer research in general.
 

Question: At ASCO 2024 in Chicago, you presented as first author of the KRYSTAL-12 study. Can you give a short “elevator speech” summarizing those findings?

Dr. Mok: KRYSTAL-12 is a randomized phase 3 study comparing adagrasib with docetaxel in patients with previously treated advanced/metastatic non–small cell lung cancer harboring a KRAS G12C-mutation. And the findings are positive, with a median progression free survival of 5.5 months vs 3.8 months, with a significant hazard ratio [of 0.58]. And then there are also differences in their response rates of 32% versus 9%, and that gives you an [odds] ratio of 4.86. So yes, it’s significant.

Question: Now that you’ve given this presentation and perhaps taken some good, meaningful questions about it, are there any further points you’d like to make — anything you’d like to add?

Dr. Mok: You have to understand that whatever I said has been scrutinized by the pharmaceutical company, but now I can say whatever I like. I think the key point is that we actually have made the first so-called achievement in the KRAS G12C space. But this is only the beginning.

I want to note that the median progression-free survival is different, but not the best. The median 5.5 months result is good, but not good enough. So, we still have to work hard to answer the question: How can we best deliver care to patients with KRAS G12C?
 

Question: Speaking more generally about the challenges of targeting KRAS, what issues arise in terms of biomarker testing for KRAS mutations in the clinic? Dr. Mok: In colorectal cancer, there has been testing for KRAS [mutations] for a long, long time. So, most of the laboratories, as long as they are well equipped, will be able to test for KRAS. Usually, the cheaper way is to buy PCR [polymerase chain reaction]. However, these days it’s getting trendier to use NGS [next-generation sequencing]. So, one way or another, specificity is very high. I don’t think we have too much of a problem. The only difference between colorectal cancer and lung cancer is that the tissue sample may not be as good for lung cancer with a small biopsy, but otherwise testing is not an issue.

Question: What clinical trials should oncologist be watching to come into this space?Dr. Mok: There are a lot. Right now, there is the so-called first-line study that’s coming up. So, I can cite you some examples for the KRYSTAL-7 trial, which is the combination of pembrolizumab together with adagrasib in the PD-L1 Tumor Proportion Score ≥ 50%.

That’s one example. And then there is the CodeBreaK 202 trial, which is actually the combination of chemotherapy with sotorasib versus chemotherapy and I-O [immune-oncology]. That is also an ongoing study.
 

Question: I also want to ask you some background questions about yourself. Back in the day, you lived in Canada and were a community oncologist. Then you made a very big change in your life and moved back home to Hong Kong in 1996, on the eve of its return to China the following year.

Dr. Mok: Well, I was born and raised in Hong Kong, but I left for Canada for education when I was 16 and kind of stayed there and got medical school oncology training and then started my practice. At that time, I never imagined myself going back. But 1996 was a big year. Incidentally, I went back to Hong Kong then to visit my friends and was offered a job at the Chinese University of Hong Kong. Then 1997 was coming. I found it very exciting that we could work with China. So that’s why I decided to return. And this was probably one of my best decisions I ever made in my life.

Question: And you went from being a community oncologist to academic research?

Dr. Mok: Here’s a personal thing that I can share with you: When I finished my oncology training at Princess Margaret Hospital in Toronto, I thought of going into research and becoming an academic. However, my son was born. Household costs went up, and I didn’t want to be a low-income, poor PhD student, so I decided that I may as well go into private practice. Returning to Hong Kong [in 1996] gave me a second chance. I went from being a community oncologist for seven years in Canada to a totally new environment in Hong Kong, where I started my academic work at age 36. It has been a good journey.

Question: Why do you say that was the best decision you ever made?Dr. Mok: At that time, it took me about 2 weeks to make this important decision. Basically: I had to give up my big house and my big car in Canada and move back to a small apartment in Hong Kong. That was a tough decision to make. However, it was a matter of certainty versus uncertainty.

In Canada, I actually had a very stable situation. I had a big practice in the Scarborough area [of Toronto], with a lot of Chinese patients, so I had a better, more comfortable life. It was predictable. But then I asked myself what I would be like in 10 years if I stayed in Canada versus Hong Kong. My answer is that I had no idea what would happen to me 10 years later in Hong Kong. In certain parts of life, you have to decide between certainty and uncertainty. And this time, uncertainty brought me great adventure. I definitely would not have done the things I’ve done if I’d stayed in Canada.



Question: At this ASCO, you’ve spoken primarily about your latest research on non–small cell lung cancer with KRAS G12C mutation.Dr. Mok: Actually, my research has been mostly on targeted therapy. My first break was on the EGFR [epidermal growth factor receptor] mutation. I was one of the first to help define personalized medicine according to the EGFR mutation in the IPASS study [2009]. That’s how I started my academic career.



Question: I read some quotes from your writing some years back about “living with imperfection,” and where you wrote about the whole continuum of cancer research. Years ago, you noted that lung cancer was moving from being a death sentence to becoming a chronic condition.

Dr. Mok: The objective is this: A lot of cancer patients, especially lung cancer patients, had a very short survival, but now we are able to identify a subgroup of patients with a driver oncogene.

And with that, we can use a tyrosine kinase inhibitor — which although it has toxicity, it’s manageable toxicity — such that you can take one pill a day and continue to live a normal life. So that would be not so different from diabetes or hypertension: You live with the disease. So that’s what we like to see: the conversion of a fatal disease into a chronic disease.
 

Question: So many countries now, including the United States and many others, are facing the challenges of cancer care in rural versus urban areas. Is this a topic you’d be willing to address? Dr. Mok: Well, in Hong Kong we don’t have rural areas! But in China, this is a major problem. There most of the cancer care is focused on the so-called three major cities [Shanghai, Beijing, Guangzhou]. And after that, there are second-tier cities that also have reasonably good care. But when you filter down to the third and fourth layer, the oncology care actually deteriorates. So that’s why we end up with a lot of people from the more rural areas moving and going to the city looking for care and consultation. So yes, the disparity is significant.

But China is a growing country. It takes time to change. Right now, we can see at ASCO this year, there are a lot of investigators from China sharing their new findings, which is a major development, compared to 10 years ago. Therefore, I think that when you have this type of proliferative development, eventually the good care, the high-quality care will filter down to more rural areas. So, at this moment, I think there is still a lot of work to do.
 

Question: You’ve talked about how oncologists from China are coming up in the field, and this year they have an even greater presence at ASCO, as well as oncologists from elsewhere in Asia, including South Korea, Japan, and Vietnam. You’ve been coming to ASCO for many years. Can you talk about the factors behind China’s increasing presence? Dr. Mok: I think it’s a combination of factors. First of all, I had the honor of working with lung cancer researchers from China from way back, 25 years ago. At that time, we all had nothing. Then with the development of multitargeted therapies, they managed to build up a very good infrastructure for clinical trials. And then, based on that good infrastructure, they were able to do international collaborative studies and provide a supply of patient resources and high-quality data. So, they’ve learned the trick, done a good job, but they cannot have so-called independence until there is a development of pharmaceuticals in China.

And then over the past 10 years, there’s been a proliferation — actually an explosion I would even say — of high-quality pharmaceutical companies in China. First, they’ve got the resources to build the companies. Second, they’ve got the talent resources returning from the United States. So, putting all that together, these were able to go from start-ups to full-fledged functional companies in a very short time.

And with that, they actually sponsored a lot of trials within China. And you can see that putting all the components together: you’ve got high-quality researchers, you’ve got the infrastructure, and now you’ve got your drugs and the money to do the trials. As a result, you’ve got a lot of good data coming from China.
 

Question: There’s also a population with these mutations.Dr. Mok: That for one, but most have multitargeted therapies, but they also have immunotherapies that have nothing to do with the high incidence. But I think in a sense, in the beginning, they were doing `me-too’ compounds, but now I think they are starting to do ‘me-better’ compounds.

Question: Is there anything you want to say about some of the other presentations that have your name on them at ASCO this year?Dr. Mok: I think the most important one I was engaged in is the CROWN study. The CROWN study is actually a phase 3 study that compares lorlatinib versus crizotinib in patients with advanced, ALK-positive non–small cell lung cancer.

This is a 5-year follow-up, and we were actually able to report an outrageously encouraging 5-year progression-free rate at 60%, meaning that the patient is walking in the door 5 years later when they are on the drug, and 60% of them actually do not have progression, not death, just not progression, just staying on the same pill—which is quite outrageously good for lung cancer.

The chemotherapy-free combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) that is standard in treating low-risk acute promyelocytic leukemia (APL) also shows superior benefits in the high-risk APL population, suggesting the regimen should become the standard in those patients as well, new research shows.

“First-line therapy with ATRA-ATO with two initial doses of idarubicin results in superior event-free survival, compared to conventional ATRA-chemotherapy in patients with high-risk APL,” said first author Uwe Platzbecker, MD, of the University Hospital Leipzig, department for hematology, cellular therapy, hemostaseology, and infectious diseases, in Leipzig, Germany, at the annual meeting of the European Hematology Association (EHA) in Madrid, Spain.

“We believe that the trial may support the implementation of this regimen as a new standard of care in all patients with high-risk APL,” he said.

In the treatment of low and intermediate risk APL, a subtype of acute myeloid leukemia (AML), the combination of ATRA and ATO has become standard since being shown in a pivotal 2013 study to be superior versus ATRA and chemotherapy. The approach is approved by the Food and Drug Administration in the treatment of adults with newly diagnosed low-risk APL.

Importantly, the improved survival with ATRA/ATO approach may result from “reduced severe hematologic toxicity together with similar antileukemic efficacy,” compared with the regimen that include chemotherapy, the authors of the 2013 study speculated.

However, the treatment regimen has not been evaluated in randomized trials in patients with high-risk APL, defined as having a white blood cell count of more than 10,000 cells per μL.

For those patients, the conventional treatment remains ATRA with a chemotherapy backbone, Dr. Platzbecker explained.

To evaluate if the improvements extend to high-risk APL patients without compromising safety, Dr. Platzbecker and colleagues conducted the open-label, prospective APOLLO trial, involving newly diagnosed high-risk APL who were enrolled between 2016 and 2022 at 143 sites in six European countries.

The patients were randomized into one of two groups: ATRA/ATO, involving treatment consisting of two doses of idarubicin (12 mg/m²) on days 1 and 3 at the time of induction therapy, in addition to ATO 0.15 mg/kg and ATRA 45 mg/m², daily until complete remission, or the ATRA-chemotherapy arm, involving standard ATRA also with idarubicin induction, followed by three cycles of chemotherapy-based consolidation as well as 2 years of maintenance treatment.

While the study was prematurely discontinued in August 2022 because of COVID-19–related recruitment delays and expiration of the study drug, the maintenance and observational periods are ongoing.

Of 131 patients with high-risk APL who were evaluable for the outcome analysis, 68 were in the ATRA/ATO group and 63 in the ATRA-chemotherapy arm.

Overall, participants had a mean age of 46, 50% were female, their median Eastern Cooperative Oncology Group score was 1. Their median white blood cell count was 36 × 10⁹/L, with 39% having a white blood cell count greater than 50 × 10⁹/L.

Molecular resistance occurred in 1.7% in the ATRA/ATO arm vs 5.5% in the ATRA chemotherapy arm, which was not statistically significant (P = .268); however, the incidence of molecular relapse was much lower without chemotherapy, at 1.6% with ATRA/ATO vs 14% with ATRA and chemotherapy.

For the primary endpoint, with a median follow-up of 31 months, the 2-year rate of event-free survival those in the ATRA/ATO arm was 88% vs 70% in the ATRA plus chemotherapy regimen (P = .02). The 5-year event-free survival continued to favor ATRA-ATO (87% vs 55%; P = .0034).

The estimated 5-year overall survival was 93% vs 82% for ATRA/ATO vs ATRA-chemotherapy, respectively, which was not significantly different (P = .17).

There were no significant differences between the arms in complete response (93% with ATRA/ATO vs 91% with ATRA-chemotherapy; P = .65), and rates of early death (within the first 30 days) were also similar across arms, at 7% vs 10%, respectively.

Death while in complete remission occurred in zero patients in the ATRA/ATO arm and three in the ATRA chemotherapy arm.

In terms of toxicities, the ATRA/ATO group had significantly lower rates of hematologic toxicity versus ATRA-chemotherapy, including rates of thrombocytopenia grade 1-4 and neutropenia grade 3-4 (P < .001), while there were no significant differences between the groups in hepatic toxicities (11.8% and 14.3%, respectively; P = .08) or differentiation syndrome (1.5% vs 4.8%; P = .27).

QTc prolongation grade 3-4 occurred in 4.4 patients receiving ATRA/ATO, compared with 0 in the ATRA-chemotherapy group; however, Dr. Platzbecker said the cases had no clinical implications.

Asked to elaborate on the regimens’ toxicities in the press briefing, Dr. Platzbecker noted that “what is very important especially for patients, is [lower rates] of issues such as hair loss and constipation that are much less common with the ATRO/ATO regimen.”

“In addition, we know from the early experiences with this that younger patients are being cured by this regimen,” hence improving pregnancy prospects for women.

A take-home message from the overall results is that the ATRO/ATO regimen for high-risk APL patients should represent “a new treatment paradigm” that will “hopefully soon” be reflected in guideline recommendations, Dr. Platzbecker said in an interview.
 

Concerns Included Relapse, Differentiation Syndrome

Commenting on the research, Mikkael A. Sekeres, MD, explained that, while the “less is more” non-chemotherapy approach was adopted in widespread utilization in low-risk APL because of superior outcomes, a variety of concerns surrounded its use in high-risk patients.

“In high-risk patients, there were concerns that a durable response would be lower and that relapse would be higher for patients receiving ATRA and ATO than those receiving standard chemotherapy,” Dr. Sekeres, who is chief of the division of hematology, department of medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, said in an interview.

“In addition, it was theoretically possible that patients receiving the differentiating agents ATRA and ATO could suffer higher rates of differentiation syndrome, which could contribute to early death,” he explained. “These fears were simply not realized in the trial.”

Caveats of the trial “include the relatively small sample size and that the trial was stopped prematurely due to low enrollment during the COVID pandemic,” he noted.

Another limitation was the median follow-up of about 2.5 years.

However, Dr. Sekeres said he agreed that, “with further follow-up and continued superiority of the idarubicin, ATRA, and ATO combination, this could become a new standard of care for high-risk patients with APL.”

Dr. Platzbecker’s disclosures include ties with Teva, BMS, Curis, Janssen, AbbVie, and Takeda. Dr. Sekeres had no disclosures.

The chemotherapy-free combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) that is standard in treating low-risk acute promyelocytic leukemia (APL) also shows superior benefits in the high-risk APL population, suggesting the regimen should become the standard in those patients as well, new research shows.

“First-line therapy with ATRA-ATO with two initial doses of idarubicin results in superior event-free survival, compared to conventional ATRA-chemotherapy in patients with high-risk APL,” said first author Uwe Platzbecker, MD, of the University Hospital Leipzig, department for hematology, cellular therapy, hemostaseology, and infectious diseases, in Leipzig, Germany, at the annual meeting of the European Hematology Association (EHA) in Madrid, Spain.

“We believe that the trial may support the implementation of this regimen as a new standard of care in all patients with high-risk APL,” he said.

In the treatment of low and intermediate risk APL, a subtype of acute myeloid leukemia (AML), the combination of ATRA and ATO has become standard since being shown in a pivotal 2013 study to be superior versus ATRA and chemotherapy. The approach is approved by the Food and Drug Administration in the treatment of adults with newly diagnosed low-risk APL.

Importantly, the improved survival with ATRA/ATO approach may result from “reduced severe hematologic toxicity together with similar antileukemic efficacy,” compared with the regimen that include chemotherapy, the authors of the 2013 study speculated.

However, the treatment regimen has not been evaluated in randomized trials in patients with high-risk APL, defined as having a white blood cell count of more than 10,000 cells per μL.

For those patients, the conventional treatment remains ATRA with a chemotherapy backbone, Dr. Platzbecker explained.

To evaluate if the improvements extend to high-risk APL patients without compromising safety, Dr. Platzbecker and colleagues conducted the open-label, prospective APOLLO trial, involving newly diagnosed high-risk APL who were enrolled between 2016 and 2022 at 143 sites in six European countries.

The patients were randomized into one of two groups: ATRA/ATO, involving treatment consisting of two doses of idarubicin (12 mg/m²) on days 1 and 3 at the time of induction therapy, in addition to ATO 0.15 mg/kg and ATRA 45 mg/m², daily until complete remission, or the ATRA-chemotherapy arm, involving standard ATRA also with idarubicin induction, followed by three cycles of chemotherapy-based consolidation as well as 2 years of maintenance treatment.

While the study was prematurely discontinued in August 2022 because of COVID-19–related recruitment delays and expiration of the study drug, the maintenance and observational periods are ongoing.

Of 131 patients with high-risk APL who were evaluable for the outcome analysis, 68 were in the ATRA/ATO group and 63 in the ATRA-chemotherapy arm.

Overall, participants had a mean age of 46, 50% were female, their median Eastern Cooperative Oncology Group score was 1. Their median white blood cell count was 36 × 10⁹/L, with 39% having a white blood cell count greater than 50 × 10⁹/L.

Molecular resistance occurred in 1.7% in the ATRA/ATO arm vs 5.5% in the ATRA chemotherapy arm, which was not statistically significant (P = .268); however, the incidence of molecular relapse was much lower without chemotherapy, at 1.6% with ATRA/ATO vs 14% with ATRA and chemotherapy.

For the primary endpoint, with a median follow-up of 31 months, the 2-year rate of event-free survival those in the ATRA/ATO arm was 88% vs 70% in the ATRA plus chemotherapy regimen (P = .02). The 5-year event-free survival continued to favor ATRA-ATO (87% vs 55%; P = .0034).

The estimated 5-year overall survival was 93% vs 82% for ATRA/ATO vs ATRA-chemotherapy, respectively, which was not significantly different (P = .17).

There were no significant differences between the arms in complete response (93% with ATRA/ATO vs 91% with ATRA-chemotherapy; P = .65), and rates of early death (within the first 30 days) were also similar across arms, at 7% vs 10%, respectively.

Death while in complete remission occurred in zero patients in the ATRA/ATO arm and three in the ATRA chemotherapy arm.

In terms of toxicities, the ATRA/ATO group had significantly lower rates of hematologic toxicity versus ATRA-chemotherapy, including rates of thrombocytopenia grade 1-4 and neutropenia grade 3-4 (P < .001), while there were no significant differences between the groups in hepatic toxicities (11.8% and 14.3%, respectively; P = .08) or differentiation syndrome (1.5% vs 4.8%; P = .27).

QTc prolongation grade 3-4 occurred in 4.4 patients receiving ATRA/ATO, compared with 0 in the ATRA-chemotherapy group; however, Dr. Platzbecker said the cases had no clinical implications.

Asked to elaborate on the regimens’ toxicities in the press briefing, Dr. Platzbecker noted that “what is very important especially for patients, is [lower rates] of issues such as hair loss and constipation that are much less common with the ATRO/ATO regimen.”

“In addition, we know from the early experiences with this that younger patients are being cured by this regimen,” hence improving pregnancy prospects for women.

A take-home message from the overall results is that the ATRO/ATO regimen for high-risk APL patients should represent “a new treatment paradigm” that will “hopefully soon” be reflected in guideline recommendations, Dr. Platzbecker said in an interview.
 

Concerns Included Relapse, Differentiation Syndrome

Commenting on the research, Mikkael A. Sekeres, MD, explained that, while the “less is more” non-chemotherapy approach was adopted in widespread utilization in low-risk APL because of superior outcomes, a variety of concerns surrounded its use in high-risk patients.

“In high-risk patients, there were concerns that a durable response would be lower and that relapse would be higher for patients receiving ATRA and ATO than those receiving standard chemotherapy,” Dr. Sekeres, who is chief of the division of hematology, department of medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, said in an interview.

“In addition, it was theoretically possible that patients receiving the differentiating agents ATRA and ATO could suffer higher rates of differentiation syndrome, which could contribute to early death,” he explained. “These fears were simply not realized in the trial.”

Caveats of the trial “include the relatively small sample size and that the trial was stopped prematurely due to low enrollment during the COVID pandemic,” he noted.

Another limitation was the median follow-up of about 2.5 years.

However, Dr. Sekeres said he agreed that, “with further follow-up and continued superiority of the idarubicin, ATRA, and ATO combination, this could become a new standard of care for high-risk patients with APL.”

Dr. Platzbecker’s disclosures include ties with Teva, BMS, Curis, Janssen, AbbVie, and Takeda. Dr. Sekeres had no disclosures.

The chemotherapy-free combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) that is standard in treating low-risk acute promyelocytic leukemia (APL) also shows superior benefits in the high-risk APL population, suggesting the regimen should become the standard in those patients as well, new research shows.

“First-line therapy with ATRA-ATO with two initial doses of idarubicin results in superior event-free survival, compared to conventional ATRA-chemotherapy in patients with high-risk APL,” said first author Uwe Platzbecker, MD, of the University Hospital Leipzig, department for hematology, cellular therapy, hemostaseology, and infectious diseases, in Leipzig, Germany, at the annual meeting of the European Hematology Association (EHA) in Madrid, Spain.

“We believe that the trial may support the implementation of this regimen as a new standard of care in all patients with high-risk APL,” he said.

In the treatment of low and intermediate risk APL, a subtype of acute myeloid leukemia (AML), the combination of ATRA and ATO has become standard since being shown in a pivotal 2013 study to be superior versus ATRA and chemotherapy. The approach is approved by the Food and Drug Administration in the treatment of adults with newly diagnosed low-risk APL.

Importantly, the improved survival with ATRA/ATO approach may result from “reduced severe hematologic toxicity together with similar antileukemic efficacy,” compared with the regimen that include chemotherapy, the authors of the 2013 study speculated.

However, the treatment regimen has not been evaluated in randomized trials in patients with high-risk APL, defined as having a white blood cell count of more than 10,000 cells per μL.

For those patients, the conventional treatment remains ATRA with a chemotherapy backbone, Dr. Platzbecker explained.

To evaluate if the improvements extend to high-risk APL patients without compromising safety, Dr. Platzbecker and colleagues conducted the open-label, prospective APOLLO trial, involving newly diagnosed high-risk APL who were enrolled between 2016 and 2022 at 143 sites in six European countries.

The patients were randomized into one of two groups: ATRA/ATO, involving treatment consisting of two doses of idarubicin (12 mg/m²) on days 1 and 3 at the time of induction therapy, in addition to ATO 0.15 mg/kg and ATRA 45 mg/m², daily until complete remission, or the ATRA-chemotherapy arm, involving standard ATRA also with idarubicin induction, followed by three cycles of chemotherapy-based consolidation as well as 2 years of maintenance treatment.

While the study was prematurely discontinued in August 2022 because of COVID-19–related recruitment delays and expiration of the study drug, the maintenance and observational periods are ongoing.

Of 131 patients with high-risk APL who were evaluable for the outcome analysis, 68 were in the ATRA/ATO group and 63 in the ATRA-chemotherapy arm.

Overall, participants had a mean age of 46, 50% were female, their median Eastern Cooperative Oncology Group score was 1. Their median white blood cell count was 36 × 10⁹/L, with 39% having a white blood cell count greater than 50 × 10⁹/L.

Molecular resistance occurred in 1.7% in the ATRA/ATO arm vs 5.5% in the ATRA chemotherapy arm, which was not statistically significant (P = .268); however, the incidence of molecular relapse was much lower without chemotherapy, at 1.6% with ATRA/ATO vs 14% with ATRA and chemotherapy.

For the primary endpoint, with a median follow-up of 31 months, the 2-year rate of event-free survival those in the ATRA/ATO arm was 88% vs 70% in the ATRA plus chemotherapy regimen (P = .02). The 5-year event-free survival continued to favor ATRA-ATO (87% vs 55%; P = .0034).

The estimated 5-year overall survival was 93% vs 82% for ATRA/ATO vs ATRA-chemotherapy, respectively, which was not significantly different (P = .17).

There were no significant differences between the arms in complete response (93% with ATRA/ATO vs 91% with ATRA-chemotherapy; P = .65), and rates of early death (within the first 30 days) were also similar across arms, at 7% vs 10%, respectively.

Death while in complete remission occurred in zero patients in the ATRA/ATO arm and three in the ATRA chemotherapy arm.

In terms of toxicities, the ATRA/ATO group had significantly lower rates of hematologic toxicity versus ATRA-chemotherapy, including rates of thrombocytopenia grade 1-4 and neutropenia grade 3-4 (P < .001), while there were no significant differences between the groups in hepatic toxicities (11.8% and 14.3%, respectively; P = .08) or differentiation syndrome (1.5% vs 4.8%; P = .27).

QTc prolongation grade 3-4 occurred in 4.4 patients receiving ATRA/ATO, compared with 0 in the ATRA-chemotherapy group; however, Dr. Platzbecker said the cases had no clinical implications.

Asked to elaborate on the regimens’ toxicities in the press briefing, Dr. Platzbecker noted that “what is very important especially for patients, is [lower rates] of issues such as hair loss and constipation that are much less common with the ATRO/ATO regimen.”

“In addition, we know from the early experiences with this that younger patients are being cured by this regimen,” hence improving pregnancy prospects for women.

A take-home message from the overall results is that the ATRO/ATO regimen for high-risk APL patients should represent “a new treatment paradigm” that will “hopefully soon” be reflected in guideline recommendations, Dr. Platzbecker said in an interview.
 

Concerns Included Relapse, Differentiation Syndrome

Commenting on the research, Mikkael A. Sekeres, MD, explained that, while the “less is more” non-chemotherapy approach was adopted in widespread utilization in low-risk APL because of superior outcomes, a variety of concerns surrounded its use in high-risk patients.

“In high-risk patients, there were concerns that a durable response would be lower and that relapse would be higher for patients receiving ATRA and ATO than those receiving standard chemotherapy,” Dr. Sekeres, who is chief of the division of hematology, department of medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, said in an interview.

“In addition, it was theoretically possible that patients receiving the differentiating agents ATRA and ATO could suffer higher rates of differentiation syndrome, which could contribute to early death,” he explained. “These fears were simply not realized in the trial.”

Caveats of the trial “include the relatively small sample size and that the trial was stopped prematurely due to low enrollment during the COVID pandemic,” he noted.

Another limitation was the median follow-up of about 2.5 years.

However, Dr. Sekeres said he agreed that, “with further follow-up and continued superiority of the idarubicin, ATRA, and ATO combination, this could become a new standard of care for high-risk patients with APL.”

Dr. Platzbecker’s disclosures include ties with Teva, BMS, Curis, Janssen, AbbVie, and Takeda. Dr. Sekeres had no disclosures.

VIENNA — The investigational interleukin (IL)-17 inhibitor izokibep hit its mark when it came to improving overall disease activity in people with active psoriatic arthritis (PsA) in a phase 2b/3 trial, but it was no better than placebo at reducing inflammation of the entheses. 

This apparent and unexpected lack of effect in the entheses was a key talking point after Philip J. Mease, MD, presented the late-breaking trial findings at the annual European Congress of Rheumatology.

Sara Freeman/Medscape Medical News

At just 18.6 kilodaltons in size, izokibep is just “one tenth the size of a standard monoclonal antibody” and is classed as a small protein therapeutic, Dr. Mease said. It has a “very tight” binding affinity for IL-17A, and because it also binds to albumin, it has a prolonged half-life compared with other IL-17 inhibitors. Potentially, it should be able to “penetrate into difficult areas,” such as the entheses, he said.
 

Prespecified Enthesitis Analysis

However, results of a prespecified secondary analysis conducted in 209 of the 343 trial participants who had received treatment showed no significant difference in the proportions with enthesis resolution at 16 weeks, defined as a Leeds Enthesitis Index (LEI) of 0.

Comparing two dosing regimens of izokibep 160 mg once weekly (QW) vs every other week (Q2W) with placebo, enthesitis resolution was seen in 45%, 56%, and 47%, respectively, of patients.

The LEI is “sometimes subject to problems with evaluation because of placebo response, which is what we see here,” noted Dr. Mease, director of rheumatology research at the Providence Swedish Medical Center and a rheumatology professor at the University of Washington School of Medicine in Seattle.

An exploratory analysis showed that there was a better response for izokibep vs placebo if the analysis included only patients with higher LEI scores at baseline, at 8.0% (n = 12) for placebo, 22.0% (n = 9) for izokibep 160 mg QW, and 50.0% (n = 12) for izokibep 160 mg Q2W.
 

Main Efficacy Data

The primary endpoint for the trial was the proportion of patients who had 50% improvement in American College of Rheumatology response criteria (ACR50) at 16 weeks. This showed a clear advantage for treatment with izokibep 160 QW and Q2W compared with placebo, with a respective 40%, 43%, and 15% of patients meeting this endpoint.

Corresponding ACR20 response rates were 59%, 64%, and 35%, respectively; ACR70 response rates were a respective 25%, 23%, and 5%.

In addition to ACR70, izokibep 160 QW and Q2W met a number of other “high hurdle” efficacy endpoints better than did placebo, Dr. Mease reported. A 90% reduction from baseline in the Psoriasis Area and Severity Index (PASI90) was achieved by a respective 64%, 58%, and 12% of patients, and a 100% reduction in this index (PASI100) was achieved by a respective 51%, 47%, and 12%. And 41%, 42%, and 14% of patients, respectively, met the criteria for minimal disease activity.
 

Patient Population

Mease pointed out during his presentation that the trial included patients with adult-onset PsA that had been ongoing for ≥ 6 months. Patients had to have at least three tender or swollen joints and an inadequate response, intolerance, or contraindication to commonly used front-line therapies such as nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and tumor necrosis factor inhibitors (TNFi).

In fact, around half of the participants across the three treatment arms had received prior csDMARDs, and almost a quarter had received a TNFi.

The mean duration of disease was around 7 years, the average age was about 50 years, and the majority of the participants were White individuals. There were more women than men in the placebo vs the izokibep arms (43.4% vs about 60.0%).
 

Adverse Events

Injection site reactions were the most common adverse events, most of which were mild to moderate. Very few (< 1% to 4%) led to any need to discontinue the drug.

Serious adverse events occurred at low rates in all study arms: 0.8% for placebo, 2.7% for izokibep QW, and 1.8% for izokibep Q2W.

One patient each (0.9%) in the izokibep arms developed ulcerative colitis, whereas none in the placebo group did. Only two patients developed candidiasis. One was in the placebo group and had a skin infection, and the other was an oral infection in the QW izokibep arm.

There were no cases of uveitis, suicidal ideation, or deaths reported.
 

Comments on the Study

During the discussion that followed the presentation, Walter P. Maksymowych, MBChB, of the University of Alberta in Edmonton, Alberta, Canada, addressed the dosing regimens used.

“Looking at the side effect profile and then looking at the response rate, comparing the weekly dosing and every 2 weeks, do you think, in hindsight, you might be remiss that there wasn’t an additional dosing on a monthly basis, especially since this is a construct that is meant to prolong the half-life of the molecule?” he asked, adding that perhaps this should be something to consider in future studies.

Mease responded that there had been a fourth dosing arm in the trial — izokibep 80 mg once a month — but because there were only eight patients, the data were not sufficiently robust to analyze. 

Commenting on the study, Laura C. Coates, MBChB, PhD, said: “It’s a pretty standard phase 2b/3 study,” and the outcomes were not wildly different from what has been seen with other IL-17A inhibitors.

“In phase 2, the enthesitis data looked really good; in phase 3, the enthesitis data looks the same as for any other IL-17 inhibitor,” Dr. Coates said.

A version of this article appeared on Medscape.com.

VIENNA — The investigational interleukin (IL)-17 inhibitor izokibep hit its mark when it came to improving overall disease activity in people with active psoriatic arthritis (PsA) in a phase 2b/3 trial, but it was no better than placebo at reducing inflammation of the entheses. 

This apparent and unexpected lack of effect in the entheses was a key talking point after Philip J. Mease, MD, presented the late-breaking trial findings at the annual European Congress of Rheumatology.

Sara Freeman/Medscape Medical News

At just 18.6 kilodaltons in size, izokibep is just “one tenth the size of a standard monoclonal antibody” and is classed as a small protein therapeutic, Dr. Mease said. It has a “very tight” binding affinity for IL-17A, and because it also binds to albumin, it has a prolonged half-life compared with other IL-17 inhibitors. Potentially, it should be able to “penetrate into difficult areas,” such as the entheses, he said.
 

Prespecified Enthesitis Analysis

However, results of a prespecified secondary analysis conducted in 209 of the 343 trial participants who had received treatment showed no significant difference in the proportions with enthesis resolution at 16 weeks, defined as a Leeds Enthesitis Index (LEI) of 0.

Comparing two dosing regimens of izokibep 160 mg once weekly (QW) vs every other week (Q2W) with placebo, enthesitis resolution was seen in 45%, 56%, and 47%, respectively, of patients.

The LEI is “sometimes subject to problems with evaluation because of placebo response, which is what we see here,” noted Dr. Mease, director of rheumatology research at the Providence Swedish Medical Center and a rheumatology professor at the University of Washington School of Medicine in Seattle.

An exploratory analysis showed that there was a better response for izokibep vs placebo if the analysis included only patients with higher LEI scores at baseline, at 8.0% (n = 12) for placebo, 22.0% (n = 9) for izokibep 160 mg QW, and 50.0% (n = 12) for izokibep 160 mg Q2W.
 

Main Efficacy Data

The primary endpoint for the trial was the proportion of patients who had 50% improvement in American College of Rheumatology response criteria (ACR50) at 16 weeks. This showed a clear advantage for treatment with izokibep 160 QW and Q2W compared with placebo, with a respective 40%, 43%, and 15% of patients meeting this endpoint.

Corresponding ACR20 response rates were 59%, 64%, and 35%, respectively; ACR70 response rates were a respective 25%, 23%, and 5%.

In addition to ACR70, izokibep 160 QW and Q2W met a number of other “high hurdle” efficacy endpoints better than did placebo, Dr. Mease reported. A 90% reduction from baseline in the Psoriasis Area and Severity Index (PASI90) was achieved by a respective 64%, 58%, and 12% of patients, and a 100% reduction in this index (PASI100) was achieved by a respective 51%, 47%, and 12%. And 41%, 42%, and 14% of patients, respectively, met the criteria for minimal disease activity.
 

Patient Population

Mease pointed out during his presentation that the trial included patients with adult-onset PsA that had been ongoing for ≥ 6 months. Patients had to have at least three tender or swollen joints and an inadequate response, intolerance, or contraindication to commonly used front-line therapies such as nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and tumor necrosis factor inhibitors (TNFi).

In fact, around half of the participants across the three treatment arms had received prior csDMARDs, and almost a quarter had received a TNFi.

The mean duration of disease was around 7 years, the average age was about 50 years, and the majority of the participants were White individuals. There were more women than men in the placebo vs the izokibep arms (43.4% vs about 60.0%).
 

Adverse Events

Injection site reactions were the most common adverse events, most of which were mild to moderate. Very few (< 1% to 4%) led to any need to discontinue the drug.

Serious adverse events occurred at low rates in all study arms: 0.8% for placebo, 2.7% for izokibep QW, and 1.8% for izokibep Q2W.

One patient each (0.9%) in the izokibep arms developed ulcerative colitis, whereas none in the placebo group did. Only two patients developed candidiasis. One was in the placebo group and had a skin infection, and the other was an oral infection in the QW izokibep arm.

There were no cases of uveitis, suicidal ideation, or deaths reported.
 

Comments on the Study

During the discussion that followed the presentation, Walter P. Maksymowych, MBChB, of the University of Alberta in Edmonton, Alberta, Canada, addressed the dosing regimens used.

“Looking at the side effect profile and then looking at the response rate, comparing the weekly dosing and every 2 weeks, do you think, in hindsight, you might be remiss that there wasn’t an additional dosing on a monthly basis, especially since this is a construct that is meant to prolong the half-life of the molecule?” he asked, adding that perhaps this should be something to consider in future studies.

Mease responded that there had been a fourth dosing arm in the trial — izokibep 80 mg once a month — but because there were only eight patients, the data were not sufficiently robust to analyze. 

Commenting on the study, Laura C. Coates, MBChB, PhD, said: “It’s a pretty standard phase 2b/3 study,” and the outcomes were not wildly different from what has been seen with other IL-17A inhibitors.

“In phase 2, the enthesitis data looked really good; in phase 3, the enthesitis data looks the same as for any other IL-17 inhibitor,” Dr. Coates said.

A version of this article appeared on Medscape.com.

VIENNA — The investigational interleukin (IL)-17 inhibitor izokibep hit its mark when it came to improving overall disease activity in people with active psoriatic arthritis (PsA) in a phase 2b/3 trial, but it was no better than placebo at reducing inflammation of the entheses. 

This apparent and unexpected lack of effect in the entheses was a key talking point after Philip J. Mease, MD, presented the late-breaking trial findings at the annual European Congress of Rheumatology.

Sara Freeman/Medscape Medical News

At just 18.6 kilodaltons in size, izokibep is just “one tenth the size of a standard monoclonal antibody” and is classed as a small protein therapeutic, Dr. Mease said. It has a “very tight” binding affinity for IL-17A, and because it also binds to albumin, it has a prolonged half-life compared with other IL-17 inhibitors. Potentially, it should be able to “penetrate into difficult areas,” such as the entheses, he said.
 

Prespecified Enthesitis Analysis

However, results of a prespecified secondary analysis conducted in 209 of the 343 trial participants who had received treatment showed no significant difference in the proportions with enthesis resolution at 16 weeks, defined as a Leeds Enthesitis Index (LEI) of 0.

Comparing two dosing regimens of izokibep 160 mg once weekly (QW) vs every other week (Q2W) with placebo, enthesitis resolution was seen in 45%, 56%, and 47%, respectively, of patients.

The LEI is “sometimes subject to problems with evaluation because of placebo response, which is what we see here,” noted Dr. Mease, director of rheumatology research at the Providence Swedish Medical Center and a rheumatology professor at the University of Washington School of Medicine in Seattle.

An exploratory analysis showed that there was a better response for izokibep vs placebo if the analysis included only patients with higher LEI scores at baseline, at 8.0% (n = 12) for placebo, 22.0% (n = 9) for izokibep 160 mg QW, and 50.0% (n = 12) for izokibep 160 mg Q2W.
 

Main Efficacy Data

The primary endpoint for the trial was the proportion of patients who had 50% improvement in American College of Rheumatology response criteria (ACR50) at 16 weeks. This showed a clear advantage for treatment with izokibep 160 QW and Q2W compared with placebo, with a respective 40%, 43%, and 15% of patients meeting this endpoint.

Corresponding ACR20 response rates were 59%, 64%, and 35%, respectively; ACR70 response rates were a respective 25%, 23%, and 5%.

In addition to ACR70, izokibep 160 QW and Q2W met a number of other “high hurdle” efficacy endpoints better than did placebo, Dr. Mease reported. A 90% reduction from baseline in the Psoriasis Area and Severity Index (PASI90) was achieved by a respective 64%, 58%, and 12% of patients, and a 100% reduction in this index (PASI100) was achieved by a respective 51%, 47%, and 12%. And 41%, 42%, and 14% of patients, respectively, met the criteria for minimal disease activity.
 

Patient Population

Mease pointed out during his presentation that the trial included patients with adult-onset PsA that had been ongoing for ≥ 6 months. Patients had to have at least three tender or swollen joints and an inadequate response, intolerance, or contraindication to commonly used front-line therapies such as nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and tumor necrosis factor inhibitors (TNFi).

In fact, around half of the participants across the three treatment arms had received prior csDMARDs, and almost a quarter had received a TNFi.

The mean duration of disease was around 7 years, the average age was about 50 years, and the majority of the participants were White individuals. There were more women than men in the placebo vs the izokibep arms (43.4% vs about 60.0%).
 

Adverse Events

Injection site reactions were the most common adverse events, most of which were mild to moderate. Very few (< 1% to 4%) led to any need to discontinue the drug.

Serious adverse events occurred at low rates in all study arms: 0.8% for placebo, 2.7% for izokibep QW, and 1.8% for izokibep Q2W.

One patient each (0.9%) in the izokibep arms developed ulcerative colitis, whereas none in the placebo group did. Only two patients developed candidiasis. One was in the placebo group and had a skin infection, and the other was an oral infection in the QW izokibep arm.

There were no cases of uveitis, suicidal ideation, or deaths reported.
 

Comments on the Study

During the discussion that followed the presentation, Walter P. Maksymowych, MBChB, of the University of Alberta in Edmonton, Alberta, Canada, addressed the dosing regimens used.

“Looking at the side effect profile and then looking at the response rate, comparing the weekly dosing and every 2 weeks, do you think, in hindsight, you might be remiss that there wasn’t an additional dosing on a monthly basis, especially since this is a construct that is meant to prolong the half-life of the molecule?” he asked, adding that perhaps this should be something to consider in future studies.

Mease responded that there had been a fourth dosing arm in the trial — izokibep 80 mg once a month — but because there were only eight patients, the data were not sufficiently robust to analyze. 

Commenting on the study, Laura C. Coates, MBChB, PhD, said: “It’s a pretty standard phase 2b/3 study,” and the outcomes were not wildly different from what has been seen with other IL-17A inhibitors.

“In phase 2, the enthesitis data looked really good; in phase 3, the enthesitis data looks the same as for any other IL-17 inhibitor,” Dr. Coates said.

A version of this article appeared on Medscape.com.

VIENNA — The highly selective oral Janus kinase (JAK) inhibitor SHR0302 (ivarmacitinib) enables more patients with active rheumatoid arthritis to meet American College of Rheumatology (ACR) response criteria than placebo, the results of a phase 3 trial showed.

After 24 weeks of daily treatment, the primary endpoint of an ACR20 response was met by 40.4% of those who had been given placebo, 70.4% who had received a 4-mg dose, and 75.1% given an 8-mg dose. At the same time point, ACR50 responses were a respective 15.4%, 46.0%, and 57.1%, and ACR70 responses were 6.9%, 22.2%, and 31.7%. All analyses comparing SHR0302 vs placebo were highly significant (P < .0001).
 

First Phase 3 Trial in China

“This is the first highly selective JAK inhibitor originally developed, and a phase 3 clinical trial conducted, [exclusively] in China,” Jinjing Liu, from the department of rheumatology at Peking Union Medical College Hospital in Beijing, China, said in an interview.

Sara Freeman/Medscape Medical News

Ms. Liu presented the results at the European Alliance of Associations for Rheumatology (EULAR) 2024 Annual Meeting, during the Abstract Plenary, which highlights the best-scored abstracts of the meeting.

“We are working our best to provide more choices for Chinese patients,” Ms. Liu said, which includes lowering the financial cost of treatments. A locally developed JAK inhibitor could potentially be a much cheaper option than other alternatives that are currently available, she said.

But it is more than that, Ms. Liu said. “The selectivity of SHR0302 for JAK 1 is nine times greater than for JAK 2, so it surpasses either tofacitinib or baricitinib.” The theory is that this higher selectivity for JAK 1 over JAK 2 could lead to fewer adverse events (AEs).

“Maybe it will result in lower JAK 2–associated hematologic side effects,” Ms. Liu said.

“We have noticed that, throughout the clinical trial, the most commonly reported AEs in the drug groups were upper extremity infection [21.7%-22.8% vs 13.8% for placebo] and hyperlipidemia [12.2%-15.3% vs 5.3%].” And for the control group, she said that anemia was the second highest reported AE, at 11.7% vs 6.3% and 7.4% for SHR0302 4 and 8 mg, respectively.
 

Standard Design

The trial design was typical for a phase 3 study: Multicenter, randomized, placebo controlled, and double blind for the first 24 weeks, followed by an extension period out to 52 weeks. For inclusion in the study, patients had to be aged 18-75 years and have active rheumatoid arthritis and an inadequate response to previous treatment with conventional synthetic disease-modifying antirheumatic drugs.

Of 1085 patients who were initially screened, 566 were randomly allocated to receive placebo (n = 188), SHR0302 4 mg (n = 189), or SHR0302 8 mg (n = 189). The average age of patients was 51 years, and 13.3% of patients were older than 65 years.
 

Additional Results

Alongside improvements in ACR responses, Ms Liu reported that a significantly higher proportion of patients treated with SHR0302 vs placebo achieved a Disease Activity Score in 28 joints based on C-reactive protein less than 2.6 (29.6% with 4 mg and 39.2% with 8 mg vs 4.2% with placebo; both P < .0001) and at least 3.2 (57.1% and 46.0% vs 15.4%; both P < .0001) at 24 weeks.

There were also greater improvements seen in Health Assessment Questionnaire-Disability Index, 36-item Short-Form (SF36) physical component summary, and SF36 mental component summary scores for active vs placebo treatment.

As for AEs, there were no surprises. During the main 24-week trial period, 81.5%, 90.5%, and 79.3% of patients treated with SHR0302 4 and 8 mg and placebo, respectively, experienced any AE.

Infection-related treatment-emergent adverse effects occurred slightly more often in the SHR0302-treated groups (40.2% for 4 mg and 40.7% for 8 mg) than in the placebo group (34.0%). There was a single case of serious infection that required treatment in the SHR0302 8 mg–treated group but no cases of systemic opportunistic infection.

There was one thromboembolic event and one major cardiovascular event in the 24-week period, both occurring in patients treated with SHR0302 8 mg. There were also single cases of each reported during the extension phase of the trial, but both were in the placebo arm.

Two cases of liver function abnormality — one each in the SHR0302 4- and 8-mg groups — were recorded during the main part of the trial and two cases — both in the SHR0302 4-mg group — during the extension phase.

As for malignancy, there was a single, newly diagnosed case in the SHR0302 4 mg group in the first part of the trial and two cases, both in the SHR0302 4-mg group, during the extension phase.

“We hope this [JAK inhibitor] will be for everybody. But, you know, if it’s for patients, globally, more clinical trials would be required,” Ms. Liu said in an interview. The future, she added, was to start accumulating some real-world data and perhaps do a trial comparing SHR0302 with another JAK inhibitor or a tumor necrosis factor inhibitor.
 

Another JAK in the Box?

Following her presentation, Ms. Liu at EULAR 2024 was quizzed as to why there were so many screening failures. She responded that she did not have the full data to answer the question but noted that some patients in her center had been worried about being randomized to a placebo. This trial has also been conducted during the COVID-19 pandemic, so that may have been a contributing factor with patients unable to get to their follow-up appointments.

Iain B. McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary & Life Sciences at the University of Glasgow, Glasgow, Scotland, commented on the study, saying: “The JAK field is in evolution. We need to understand the broader toxicities. There is an unexplained mechanism driving potential cardiovascular and malignant risk in a small proportion of patients receiving the drugs.”

Dr. McInnes added, “It’s really unclear whether the solution is going to be greater selectivity and potency, or whether we need to think really about selecting the right patients for a JAK inhibitor.”

The study was funded by Jiangsu Hengrui Pharmaceuticals. Two of the 18 authors of the abstract were employees of the sponsoring company, but Ms. Liu reported having no conflicts of interest. Dr. McInnes reported serving on speaker’s bureaus for AbbVie and UCB; receiving consulting fees received from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Causeway Therapeutics, Cabaletta Bio, Compugen, Eli Lilly, Evelo, Gilead, Janssen, Novartis, MoonLake Immunotherapeutics, Pfizer, Sanofi Regeneron, and UCB; and receiving grant/research support from GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, and UCB.

A version of this article appeared on Medscape.com.

VIENNA — The highly selective oral Janus kinase (JAK) inhibitor SHR0302 (ivarmacitinib) enables more patients with active rheumatoid arthritis to meet American College of Rheumatology (ACR) response criteria than placebo, the results of a phase 3 trial showed.

After 24 weeks of daily treatment, the primary endpoint of an ACR20 response was met by 40.4% of those who had been given placebo, 70.4% who had received a 4-mg dose, and 75.1% given an 8-mg dose. At the same time point, ACR50 responses were a respective 15.4%, 46.0%, and 57.1%, and ACR70 responses were 6.9%, 22.2%, and 31.7%. All analyses comparing SHR0302 vs placebo were highly significant (P < .0001).
 

First Phase 3 Trial in China

“This is the first highly selective JAK inhibitor originally developed, and a phase 3 clinical trial conducted, [exclusively] in China,” Jinjing Liu, from the department of rheumatology at Peking Union Medical College Hospital in Beijing, China, said in an interview.

Sara Freeman/Medscape Medical News

Ms. Liu presented the results at the European Alliance of Associations for Rheumatology (EULAR) 2024 Annual Meeting, during the Abstract Plenary, which highlights the best-scored abstracts of the meeting.

“We are working our best to provide more choices for Chinese patients,” Ms. Liu said, which includes lowering the financial cost of treatments. A locally developed JAK inhibitor could potentially be a much cheaper option than other alternatives that are currently available, she said.

But it is more than that, Ms. Liu said. “The selectivity of SHR0302 for JAK 1 is nine times greater than for JAK 2, so it surpasses either tofacitinib or baricitinib.” The theory is that this higher selectivity for JAK 1 over JAK 2 could lead to fewer adverse events (AEs).

“Maybe it will result in lower JAK 2–associated hematologic side effects,” Ms. Liu said.

“We have noticed that, throughout the clinical trial, the most commonly reported AEs in the drug groups were upper extremity infection [21.7%-22.8% vs 13.8% for placebo] and hyperlipidemia [12.2%-15.3% vs 5.3%].” And for the control group, she said that anemia was the second highest reported AE, at 11.7% vs 6.3% and 7.4% for SHR0302 4 and 8 mg, respectively.
 

Standard Design

The trial design was typical for a phase 3 study: Multicenter, randomized, placebo controlled, and double blind for the first 24 weeks, followed by an extension period out to 52 weeks. For inclusion in the study, patients had to be aged 18-75 years and have active rheumatoid arthritis and an inadequate response to previous treatment with conventional synthetic disease-modifying antirheumatic drugs.

Of 1085 patients who were initially screened, 566 were randomly allocated to receive placebo (n = 188), SHR0302 4 mg (n = 189), or SHR0302 8 mg (n = 189). The average age of patients was 51 years, and 13.3% of patients were older than 65 years.
 

Additional Results

Alongside improvements in ACR responses, Ms Liu reported that a significantly higher proportion of patients treated with SHR0302 vs placebo achieved a Disease Activity Score in 28 joints based on C-reactive protein less than 2.6 (29.6% with 4 mg and 39.2% with 8 mg vs 4.2% with placebo; both P < .0001) and at least 3.2 (57.1% and 46.0% vs 15.4%; both P < .0001) at 24 weeks.

There were also greater improvements seen in Health Assessment Questionnaire-Disability Index, 36-item Short-Form (SF36) physical component summary, and SF36 mental component summary scores for active vs placebo treatment.

As for AEs, there were no surprises. During the main 24-week trial period, 81.5%, 90.5%, and 79.3% of patients treated with SHR0302 4 and 8 mg and placebo, respectively, experienced any AE.

Infection-related treatment-emergent adverse effects occurred slightly more often in the SHR0302-treated groups (40.2% for 4 mg and 40.7% for 8 mg) than in the placebo group (34.0%). There was a single case of serious infection that required treatment in the SHR0302 8 mg–treated group but no cases of systemic opportunistic infection.

There was one thromboembolic event and one major cardiovascular event in the 24-week period, both occurring in patients treated with SHR0302 8 mg. There were also single cases of each reported during the extension phase of the trial, but both were in the placebo arm.

Two cases of liver function abnormality — one each in the SHR0302 4- and 8-mg groups — were recorded during the main part of the trial and two cases — both in the SHR0302 4-mg group — during the extension phase.

As for malignancy, there was a single, newly diagnosed case in the SHR0302 4 mg group in the first part of the trial and two cases, both in the SHR0302 4-mg group, during the extension phase.

“We hope this [JAK inhibitor] will be for everybody. But, you know, if it’s for patients, globally, more clinical trials would be required,” Ms. Liu said in an interview. The future, she added, was to start accumulating some real-world data and perhaps do a trial comparing SHR0302 with another JAK inhibitor or a tumor necrosis factor inhibitor.
 

Another JAK in the Box?

Following her presentation, Ms. Liu at EULAR 2024 was quizzed as to why there were so many screening failures. She responded that she did not have the full data to answer the question but noted that some patients in her center had been worried about being randomized to a placebo. This trial has also been conducted during the COVID-19 pandemic, so that may have been a contributing factor with patients unable to get to their follow-up appointments.

Iain B. McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary & Life Sciences at the University of Glasgow, Glasgow, Scotland, commented on the study, saying: “The JAK field is in evolution. We need to understand the broader toxicities. There is an unexplained mechanism driving potential cardiovascular and malignant risk in a small proportion of patients receiving the drugs.”

Dr. McInnes added, “It’s really unclear whether the solution is going to be greater selectivity and potency, or whether we need to think really about selecting the right patients for a JAK inhibitor.”

The study was funded by Jiangsu Hengrui Pharmaceuticals. Two of the 18 authors of the abstract were employees of the sponsoring company, but Ms. Liu reported having no conflicts of interest. Dr. McInnes reported serving on speaker’s bureaus for AbbVie and UCB; receiving consulting fees received from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Causeway Therapeutics, Cabaletta Bio, Compugen, Eli Lilly, Evelo, Gilead, Janssen, Novartis, MoonLake Immunotherapeutics, Pfizer, Sanofi Regeneron, and UCB; and receiving grant/research support from GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, and UCB.

A version of this article appeared on Medscape.com.

VIENNA — The highly selective oral Janus kinase (JAK) inhibitor SHR0302 (ivarmacitinib) enables more patients with active rheumatoid arthritis to meet American College of Rheumatology (ACR) response criteria than placebo, the results of a phase 3 trial showed.

After 24 weeks of daily treatment, the primary endpoint of an ACR20 response was met by 40.4% of those who had been given placebo, 70.4% who had received a 4-mg dose, and 75.1% given an 8-mg dose. At the same time point, ACR50 responses were a respective 15.4%, 46.0%, and 57.1%, and ACR70 responses were 6.9%, 22.2%, and 31.7%. All analyses comparing SHR0302 vs placebo were highly significant (P < .0001).
 

First Phase 3 Trial in China

“This is the first highly selective JAK inhibitor originally developed, and a phase 3 clinical trial conducted, [exclusively] in China,” Jinjing Liu, from the department of rheumatology at Peking Union Medical College Hospital in Beijing, China, said in an interview.

Sara Freeman/Medscape Medical News

Ms. Liu presented the results at the European Alliance of Associations for Rheumatology (EULAR) 2024 Annual Meeting, during the Abstract Plenary, which highlights the best-scored abstracts of the meeting.

“We are working our best to provide more choices for Chinese patients,” Ms. Liu said, which includes lowering the financial cost of treatments. A locally developed JAK inhibitor could potentially be a much cheaper option than other alternatives that are currently available, she said.

But it is more than that, Ms. Liu said. “The selectivity of SHR0302 for JAK 1 is nine times greater than for JAK 2, so it surpasses either tofacitinib or baricitinib.” The theory is that this higher selectivity for JAK 1 over JAK 2 could lead to fewer adverse events (AEs).

“Maybe it will result in lower JAK 2–associated hematologic side effects,” Ms. Liu said.

“We have noticed that, throughout the clinical trial, the most commonly reported AEs in the drug groups were upper extremity infection [21.7%-22.8% vs 13.8% for placebo] and hyperlipidemia [12.2%-15.3% vs 5.3%].” And for the control group, she said that anemia was the second highest reported AE, at 11.7% vs 6.3% and 7.4% for SHR0302 4 and 8 mg, respectively.
 

Standard Design

The trial design was typical for a phase 3 study: Multicenter, randomized, placebo controlled, and double blind for the first 24 weeks, followed by an extension period out to 52 weeks. For inclusion in the study, patients had to be aged 18-75 years and have active rheumatoid arthritis and an inadequate response to previous treatment with conventional synthetic disease-modifying antirheumatic drugs.

Of 1085 patients who were initially screened, 566 were randomly allocated to receive placebo (n = 188), SHR0302 4 mg (n = 189), or SHR0302 8 mg (n = 189). The average age of patients was 51 years, and 13.3% of patients were older than 65 years.
 

Additional Results

Alongside improvements in ACR responses, Ms Liu reported that a significantly higher proportion of patients treated with SHR0302 vs placebo achieved a Disease Activity Score in 28 joints based on C-reactive protein less than 2.6 (29.6% with 4 mg and 39.2% with 8 mg vs 4.2% with placebo; both P < .0001) and at least 3.2 (57.1% and 46.0% vs 15.4%; both P < .0001) at 24 weeks.

There were also greater improvements seen in Health Assessment Questionnaire-Disability Index, 36-item Short-Form (SF36) physical component summary, and SF36 mental component summary scores for active vs placebo treatment.

As for AEs, there were no surprises. During the main 24-week trial period, 81.5%, 90.5%, and 79.3% of patients treated with SHR0302 4 and 8 mg and placebo, respectively, experienced any AE.

Infection-related treatment-emergent adverse effects occurred slightly more often in the SHR0302-treated groups (40.2% for 4 mg and 40.7% for 8 mg) than in the placebo group (34.0%). There was a single case of serious infection that required treatment in the SHR0302 8 mg–treated group but no cases of systemic opportunistic infection.

There was one thromboembolic event and one major cardiovascular event in the 24-week period, both occurring in patients treated with SHR0302 8 mg. There were also single cases of each reported during the extension phase of the trial, but both were in the placebo arm.

Two cases of liver function abnormality — one each in the SHR0302 4- and 8-mg groups — were recorded during the main part of the trial and two cases — both in the SHR0302 4-mg group — during the extension phase.

As for malignancy, there was a single, newly diagnosed case in the SHR0302 4 mg group in the first part of the trial and two cases, both in the SHR0302 4-mg group, during the extension phase.

“We hope this [JAK inhibitor] will be for everybody. But, you know, if it’s for patients, globally, more clinical trials would be required,” Ms. Liu said in an interview. The future, she added, was to start accumulating some real-world data and perhaps do a trial comparing SHR0302 with another JAK inhibitor or a tumor necrosis factor inhibitor.
 

Another JAK in the Box?

Following her presentation, Ms. Liu at EULAR 2024 was quizzed as to why there were so many screening failures. She responded that she did not have the full data to answer the question but noted that some patients in her center had been worried about being randomized to a placebo. This trial has also been conducted during the COVID-19 pandemic, so that may have been a contributing factor with patients unable to get to their follow-up appointments.

Iain B. McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary & Life Sciences at the University of Glasgow, Glasgow, Scotland, commented on the study, saying: “The JAK field is in evolution. We need to understand the broader toxicities. There is an unexplained mechanism driving potential cardiovascular and malignant risk in a small proportion of patients receiving the drugs.”

Dr. McInnes added, “It’s really unclear whether the solution is going to be greater selectivity and potency, or whether we need to think really about selecting the right patients for a JAK inhibitor.”

The study was funded by Jiangsu Hengrui Pharmaceuticals. Two of the 18 authors of the abstract were employees of the sponsoring company, but Ms. Liu reported having no conflicts of interest. Dr. McInnes reported serving on speaker’s bureaus for AbbVie and UCB; receiving consulting fees received from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Causeway Therapeutics, Cabaletta Bio, Compugen, Eli Lilly, Evelo, Gilead, Janssen, Novartis, MoonLake Immunotherapeutics, Pfizer, Sanofi Regeneron, and UCB; and receiving grant/research support from GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, and UCB.

A version of this article appeared on Medscape.com.

NASHVILLE, TENNESSEE — For the first time, the majority of patients with multiple sclerosis (MS) in the United States are, or soon will be, over age 55, a phenomenon that’s driving a shift in priorities including the creation of MS aging centers and a push for more clinical trials aimed at this growing patient population.

Given typical patterns of MS onset and its rate of progression, disease duration has long been thought to be the key variable driving disability, but Jennifer Graves, MD, PhD, director of the neuroimmunology research program at the University of California, San Diego, said she now believes that “patient age is actually more important.”

Brian Hoyle/MDedge News

Speaking at the annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC), Dr. Graves noted that it is well known that key MS symptoms increase over time, particularly during the transition from a relapsing to a progressive phenotype.

However, she maintains that, independent of disease progression, the impact of aging on MS has been underappreciated. She cited research showing that, relative to chronological age, biologic age is more robustly correlated with MS outcomes.

In studies evaluating variables such as telomere length, various markers of senescence, and DNA methylation patterns, Dr. Graves and others have shown that biologic versus chronological aging is more rapid in patients with MS than those without the disease. In addition, within the population with MS, there are also data supporting the premise that disease progression is slower in those with a younger versus older biologic age.

“This raises the question of whether biologic age is a driver of MS and whether we can slow the disease trajectory if we slow [biologic] aging,” Dr. Graves said. While she acknowledged that genetics play an important role in the aging process, she pointed to evidence showing exposure to toxins and other biological stressors, as well as poor lifestyle choices, such as lack of exercise and smoking, are modifiable aging variables.

There are already many avenues of research regarding aging processes and their interaction with MS. Dr. Graves spoke briefly about current research into the relationship between declining ovarian function, declining telomere length, and how this might relate to the transition to progressive MS and advancing disability. To date, her research has revealed a correlation between declining ovarian function and increasing MS disability.
 

Shifting Priorities

The rapid aging of the population with MS in the United States makes research into slowing biologic aging a priority, said Robert Motl, PhD, professor in the department of physical therapy, University of Alabama at Birmingham Multiple Sclerosis Center. He reported he was able to secure funding from the National MS Society for the Healthy Aging through LifesTyle MS Research Center 10 years ago.

“We are the first and, so far, the only research center devoted to the study of aging in MS,” said Dr. Motl, another participant in the CMSC aging symposium. Dr. Motl said he and a colleague have been evaluating specific strategies to meet the varied needs of aging patients with MS with a key focus on physical therapy and preserving function.

Yinan Zhang, MD, an assistant professor of neurology at the Ohio State University Wexner Medical Center in Columbus, recently started a multidisciplinary clinic for the management of older patients with MS and said he hopes these types of clinics will help shed light on the unmet needs of older adults with MS — particularly the need for better therapies to address common types of neurodegeneration in this population.

“We need to move away from immunomodulatory agents [in older patients],” Dr. Zhang said. Older patients are typically excluded from therapeutic MS trials for a number of reasons, not least because trials have been traditionally targeted at relapsing disease, which is less common in older patients with MS. He believes older patients are particularly appropriate candidates for MS therapy trials aimed at progressive neurodegeneration, which is characteristic of late-stage disease. Therapies with the potential to slow, or even reverse, demyelination are among the novel strategies being pursued in progressive MS.
 

Multidisciplinary Approach

Dr. Zhang acknowledged that his recently established MS clinic is still in the early phases and is largely focused on comprehensive care designed to meet the diverse needs of older individuals who often have advanced disabilities and comorbidities.

Currently, each patient that attends the clinic consults with six different types of providers, including a psychologist, a pharmacist, and a physical therapist — all in a single appointment.

Dr. Zhang said his decision to open a clinic was motivated by the increased volume of older patients with MS and was inspired by similar clinics for other disease states in older individuals.

“The need is already strong and growing,” said Dr. Zhang, who speculated that these types of clinics will become widespread as the need for this care is more broadly recognized and accepted.

As the clinic evolves and matures, Dr. Zhang anticipates there will be a research component to better characterize cell senescence and aging processes that might eventually be modifiable or even reversible. He also speculated that aging in MS might eventually become a subspecialty.

Dr. Graves reported financial relationships with Horizon Therapeutics. Dr. Zhang reported no potential conflicts of interest. Dr. Motl reported financial relationships with Bristol-Myers Squibb.

A version of this article appeared on Medscape.com.

NASHVILLE, TENNESSEE — For the first time, the majority of patients with multiple sclerosis (MS) in the United States are, or soon will be, over age 55, a phenomenon that’s driving a shift in priorities including the creation of MS aging centers and a push for more clinical trials aimed at this growing patient population.

Given typical patterns of MS onset and its rate of progression, disease duration has long been thought to be the key variable driving disability, but Jennifer Graves, MD, PhD, director of the neuroimmunology research program at the University of California, San Diego, said she now believes that “patient age is actually more important.”

Brian Hoyle/MDedge News

Speaking at the annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC), Dr. Graves noted that it is well known that key MS symptoms increase over time, particularly during the transition from a relapsing to a progressive phenotype.

However, she maintains that, independent of disease progression, the impact of aging on MS has been underappreciated. She cited research showing that, relative to chronological age, biologic age is more robustly correlated with MS outcomes.

In studies evaluating variables such as telomere length, various markers of senescence, and DNA methylation patterns, Dr. Graves and others have shown that biologic versus chronological aging is more rapid in patients with MS than those without the disease. In addition, within the population with MS, there are also data supporting the premise that disease progression is slower in those with a younger versus older biologic age.

“This raises the question of whether biologic age is a driver of MS and whether we can slow the disease trajectory if we slow [biologic] aging,” Dr. Graves said. While she acknowledged that genetics play an important role in the aging process, she pointed to evidence showing exposure to toxins and other biological stressors, as well as poor lifestyle choices, such as lack of exercise and smoking, are modifiable aging variables.

There are already many avenues of research regarding aging processes and their interaction with MS. Dr. Graves spoke briefly about current research into the relationship between declining ovarian function, declining telomere length, and how this might relate to the transition to progressive MS and advancing disability. To date, her research has revealed a correlation between declining ovarian function and increasing MS disability.
 

Shifting Priorities

The rapid aging of the population with MS in the United States makes research into slowing biologic aging a priority, said Robert Motl, PhD, professor in the department of physical therapy, University of Alabama at Birmingham Multiple Sclerosis Center. He reported he was able to secure funding from the National MS Society for the Healthy Aging through LifesTyle MS Research Center 10 years ago.

“We are the first and, so far, the only research center devoted to the study of aging in MS,” said Dr. Motl, another participant in the CMSC aging symposium. Dr. Motl said he and a colleague have been evaluating specific strategies to meet the varied needs of aging patients with MS with a key focus on physical therapy and preserving function.

Yinan Zhang, MD, an assistant professor of neurology at the Ohio State University Wexner Medical Center in Columbus, recently started a multidisciplinary clinic for the management of older patients with MS and said he hopes these types of clinics will help shed light on the unmet needs of older adults with MS — particularly the need for better therapies to address common types of neurodegeneration in this population.

“We need to move away from immunomodulatory agents [in older patients],” Dr. Zhang said. Older patients are typically excluded from therapeutic MS trials for a number of reasons, not least because trials have been traditionally targeted at relapsing disease, which is less common in older patients with MS. He believes older patients are particularly appropriate candidates for MS therapy trials aimed at progressive neurodegeneration, which is characteristic of late-stage disease. Therapies with the potential to slow, or even reverse, demyelination are among the novel strategies being pursued in progressive MS.
 

Multidisciplinary Approach

Dr. Zhang acknowledged that his recently established MS clinic is still in the early phases and is largely focused on comprehensive care designed to meet the diverse needs of older individuals who often have advanced disabilities and comorbidities.

Currently, each patient that attends the clinic consults with six different types of providers, including a psychologist, a pharmacist, and a physical therapist — all in a single appointment.

Dr. Zhang said his decision to open a clinic was motivated by the increased volume of older patients with MS and was inspired by similar clinics for other disease states in older individuals.

“The need is already strong and growing,” said Dr. Zhang, who speculated that these types of clinics will become widespread as the need for this care is more broadly recognized and accepted.

As the clinic evolves and matures, Dr. Zhang anticipates there will be a research component to better characterize cell senescence and aging processes that might eventually be modifiable or even reversible. He also speculated that aging in MS might eventually become a subspecialty.

Dr. Graves reported financial relationships with Horizon Therapeutics. Dr. Zhang reported no potential conflicts of interest. Dr. Motl reported financial relationships with Bristol-Myers Squibb.

A version of this article appeared on Medscape.com.

NASHVILLE, TENNESSEE — For the first time, the majority of patients with multiple sclerosis (MS) in the United States are, or soon will be, over age 55, a phenomenon that’s driving a shift in priorities including the creation of MS aging centers and a push for more clinical trials aimed at this growing patient population.

Given typical patterns of MS onset and its rate of progression, disease duration has long been thought to be the key variable driving disability, but Jennifer Graves, MD, PhD, director of the neuroimmunology research program at the University of California, San Diego, said she now believes that “patient age is actually more important.”

Brian Hoyle/MDedge News

Speaking at the annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC), Dr. Graves noted that it is well known that key MS symptoms increase over time, particularly during the transition from a relapsing to a progressive phenotype.

However, she maintains that, independent of disease progression, the impact of aging on MS has been underappreciated. She cited research showing that, relative to chronological age, biologic age is more robustly correlated with MS outcomes.

In studies evaluating variables such as telomere length, various markers of senescence, and DNA methylation patterns, Dr. Graves and others have shown that biologic versus chronological aging is more rapid in patients with MS than those without the disease. In addition, within the population with MS, there are also data supporting the premise that disease progression is slower in those with a younger versus older biologic age.

“This raises the question of whether biologic age is a driver of MS and whether we can slow the disease trajectory if we slow [biologic] aging,” Dr. Graves said. While she acknowledged that genetics play an important role in the aging process, she pointed to evidence showing exposure to toxins and other biological stressors, as well as poor lifestyle choices, such as lack of exercise and smoking, are modifiable aging variables.

There are already many avenues of research regarding aging processes and their interaction with MS. Dr. Graves spoke briefly about current research into the relationship between declining ovarian function, declining telomere length, and how this might relate to the transition to progressive MS and advancing disability. To date, her research has revealed a correlation between declining ovarian function and increasing MS disability.
 

Shifting Priorities

The rapid aging of the population with MS in the United States makes research into slowing biologic aging a priority, said Robert Motl, PhD, professor in the department of physical therapy, University of Alabama at Birmingham Multiple Sclerosis Center. He reported he was able to secure funding from the National MS Society for the Healthy Aging through LifesTyle MS Research Center 10 years ago.

“We are the first and, so far, the only research center devoted to the study of aging in MS,” said Dr. Motl, another participant in the CMSC aging symposium. Dr. Motl said he and a colleague have been evaluating specific strategies to meet the varied needs of aging patients with MS with a key focus on physical therapy and preserving function.

Yinan Zhang, MD, an assistant professor of neurology at the Ohio State University Wexner Medical Center in Columbus, recently started a multidisciplinary clinic for the management of older patients with MS and said he hopes these types of clinics will help shed light on the unmet needs of older adults with MS — particularly the need for better therapies to address common types of neurodegeneration in this population.

“We need to move away from immunomodulatory agents [in older patients],” Dr. Zhang said. Older patients are typically excluded from therapeutic MS trials for a number of reasons, not least because trials have been traditionally targeted at relapsing disease, which is less common in older patients with MS. He believes older patients are particularly appropriate candidates for MS therapy trials aimed at progressive neurodegeneration, which is characteristic of late-stage disease. Therapies with the potential to slow, or even reverse, demyelination are among the novel strategies being pursued in progressive MS.
 

Multidisciplinary Approach

Dr. Zhang acknowledged that his recently established MS clinic is still in the early phases and is largely focused on comprehensive care designed to meet the diverse needs of older individuals who often have advanced disabilities and comorbidities.

Currently, each patient that attends the clinic consults with six different types of providers, including a psychologist, a pharmacist, and a physical therapist — all in a single appointment.

Dr. Zhang said his decision to open a clinic was motivated by the increased volume of older patients with MS and was inspired by similar clinics for other disease states in older individuals.

“The need is already strong and growing,” said Dr. Zhang, who speculated that these types of clinics will become widespread as the need for this care is more broadly recognized and accepted.

As the clinic evolves and matures, Dr. Zhang anticipates there will be a research component to better characterize cell senescence and aging processes that might eventually be modifiable or even reversible. He also speculated that aging in MS might eventually become a subspecialty.

Dr. Graves reported financial relationships with Horizon Therapeutics. Dr. Zhang reported no potential conflicts of interest. Dr. Motl reported financial relationships with Bristol-Myers Squibb.

A version of this article appeared on Medscape.com.