Pharmacology

Antibiotic resistance is a major public health problem. Few new molecules are in development, but a new antibiotic called clovibactin brings hope.

This drug, isolated from bacteria that haven’t previously been studied, seems to be capable of combating multidrug-resistant “superbugs” thanks to unusual mechanisms of action.

The drug was discovered and has been studied by scientists from Utrecht University in the Netherlands, the University of Bonn in Germany, the German Center for Infection Research, Northeastern University in Boston, and NovoBiotic Pharmaceuticals in Cambridge, Mass.

Their research was published in Cell.

“Since clovibactin was isolated from bacteria that could not be grown before, pathogenic bacteria have not seen such an antibiotic before and had no time to develop resistance,” Markus Weingarth, MD, PhD, a researcher in Utrecht University’s chemistry department, said in a press release.
 

Microbial “dark matter”

Researchers isolated clovibactin from sandy soil from North Carolina and studied it using the iChip device, which was developed in 2015. This technique allowed them to grow “bacterial dark matter,” so-called unculturable bacteria, which compose a group to which 99% of bacteria belong.

This device also paved the way for the discovery of the antibiotic teixobactin in 2020. Teixobactin is effective against gram-positive bacteria and is one of the first truly new antibiotics in decades. Its mechanism of action is like that of clovibactin.
 

Combats resistant bacteria

In the Cell article, the researchers showed that clovibactin acts via several mechanisms and that it successfully treated mice infected with the superbug Staphylococcus aureus.

Clovibactin exhibited antibacterial activity against a broad range of gram-positive pathogens, including methicillin-resistant S. aureus, daptomycin-resistant and vancomycin-resistant S. aureus strains, and difficult-to-treat vancomycin-resistant Enterococcus faecalis and E faecium (vancomycin-resistant enterococci). Escherichia coli was only marginally affected “compared with an outer membrane deficient E. coli WO153 strain, probably reflecting insufficient penetration of the compound,” the authors wrote.
 

Original mechanism of action

Clovibactin acts not on one but three molecules, all of which are essential to the construction of bacterial walls: C55PP, lipid II, and lipid IIIWTA, which are from different cell wall biosynthetic pathways. Clovibactin binds to the pyrophosphate portion of these precursors.

“Clovibactin wraps around the pyrophosphate like [a] tight glove, like a cage that encloses its target,” said Dr. Weingarth. This is what gives clovibactin its name, which is derived from Greek word klouvi, meaning cage.

The remarkable aspect of clovibactin’s mechanism is that it only binds to the immutable pyrophosphate that is common to cell wall precursors, but it also ignores the variable sugar-peptide part of the targets. The bacteria therefore have a much harder time developing resistance against it. “In fact, we did not observe any resistance to clovibactin in our studies,” Dr. Weingarth confirmed.

Upon binding the target molecules, it self-assembles into large fibrils on the surface of bacterial membranes. These fibrils are stable for a long time and thereby ensure that the target molecules remain sequestered for as long as necessary to kill bacteria.
 

Few side effects

Because of the mechanism of action of the antibiotic, few side effects are predicted. Indeed, clovibactin targets bacteria cells but not human cells.

“Since these fibrils only form on bacterial membranes and not on human membranes, they are presumably also the reason why clovibactin selectively damages bacterial cells but is not toxic to human cells,” said Dr. Weingarth.

Other studies – in particular, studies in humans – are needed before the antibiotic can be considered a potential treatment. In the meantime, regulations regarding the proper use of antibiotics must continue to be applied to limit antibiotic resistance.

In 2019, 4.95 million deaths worldwide were associated with bacterial antimicrobial resistance, including 1.27 million deaths directly attributable to bacterial antimicrobial resistance. If this trend continues without new medicines becoming available to treat bacterial infections, it is estimated that by 2050, 10 million people will die every year from antimicrobial drug resistance.
 

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

Antibiotic resistance is a major public health problem. Few new molecules are in development, but a new antibiotic called clovibactin brings hope.

This drug, isolated from bacteria that haven’t previously been studied, seems to be capable of combating multidrug-resistant “superbugs” thanks to unusual mechanisms of action.

The drug was discovered and has been studied by scientists from Utrecht University in the Netherlands, the University of Bonn in Germany, the German Center for Infection Research, Northeastern University in Boston, and NovoBiotic Pharmaceuticals in Cambridge, Mass.

Their research was published in Cell.

“Since clovibactin was isolated from bacteria that could not be grown before, pathogenic bacteria have not seen such an antibiotic before and had no time to develop resistance,” Markus Weingarth, MD, PhD, a researcher in Utrecht University’s chemistry department, said in a press release.
 

Microbial “dark matter”

Researchers isolated clovibactin from sandy soil from North Carolina and studied it using the iChip device, which was developed in 2015. This technique allowed them to grow “bacterial dark matter,” so-called unculturable bacteria, which compose a group to which 99% of bacteria belong.

This device also paved the way for the discovery of the antibiotic teixobactin in 2020. Teixobactin is effective against gram-positive bacteria and is one of the first truly new antibiotics in decades. Its mechanism of action is like that of clovibactin.
 

Combats resistant bacteria

In the Cell article, the researchers showed that clovibactin acts via several mechanisms and that it successfully treated mice infected with the superbug Staphylococcus aureus.

Clovibactin exhibited antibacterial activity against a broad range of gram-positive pathogens, including methicillin-resistant S. aureus, daptomycin-resistant and vancomycin-resistant S. aureus strains, and difficult-to-treat vancomycin-resistant Enterococcus faecalis and E faecium (vancomycin-resistant enterococci). Escherichia coli was only marginally affected “compared with an outer membrane deficient E. coli WO153 strain, probably reflecting insufficient penetration of the compound,” the authors wrote.
 

Original mechanism of action

Clovibactin acts not on one but three molecules, all of which are essential to the construction of bacterial walls: C55PP, lipid II, and lipid IIIWTA, which are from different cell wall biosynthetic pathways. Clovibactin binds to the pyrophosphate portion of these precursors.

“Clovibactin wraps around the pyrophosphate like [a] tight glove, like a cage that encloses its target,” said Dr. Weingarth. This is what gives clovibactin its name, which is derived from Greek word klouvi, meaning cage.

The remarkable aspect of clovibactin’s mechanism is that it only binds to the immutable pyrophosphate that is common to cell wall precursors, but it also ignores the variable sugar-peptide part of the targets. The bacteria therefore have a much harder time developing resistance against it. “In fact, we did not observe any resistance to clovibactin in our studies,” Dr. Weingarth confirmed.

Upon binding the target molecules, it self-assembles into large fibrils on the surface of bacterial membranes. These fibrils are stable for a long time and thereby ensure that the target molecules remain sequestered for as long as necessary to kill bacteria.
 

Few side effects

Because of the mechanism of action of the antibiotic, few side effects are predicted. Indeed, clovibactin targets bacteria cells but not human cells.

“Since these fibrils only form on bacterial membranes and not on human membranes, they are presumably also the reason why clovibactin selectively damages bacterial cells but is not toxic to human cells,” said Dr. Weingarth.

Other studies – in particular, studies in humans – are needed before the antibiotic can be considered a potential treatment. In the meantime, regulations regarding the proper use of antibiotics must continue to be applied to limit antibiotic resistance.

In 2019, 4.95 million deaths worldwide were associated with bacterial antimicrobial resistance, including 1.27 million deaths directly attributable to bacterial antimicrobial resistance. If this trend continues without new medicines becoming available to treat bacterial infections, it is estimated that by 2050, 10 million people will die every year from antimicrobial drug resistance.
 

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

Antibiotic resistance is a major public health problem. Few new molecules are in development, but a new antibiotic called clovibactin brings hope.

This drug, isolated from bacteria that haven’t previously been studied, seems to be capable of combating multidrug-resistant “superbugs” thanks to unusual mechanisms of action.

The drug was discovered and has been studied by scientists from Utrecht University in the Netherlands, the University of Bonn in Germany, the German Center for Infection Research, Northeastern University in Boston, and NovoBiotic Pharmaceuticals in Cambridge, Mass.

Their research was published in Cell.

“Since clovibactin was isolated from bacteria that could not be grown before, pathogenic bacteria have not seen such an antibiotic before and had no time to develop resistance,” Markus Weingarth, MD, PhD, a researcher in Utrecht University’s chemistry department, said in a press release.
 

Microbial “dark matter”

Researchers isolated clovibactin from sandy soil from North Carolina and studied it using the iChip device, which was developed in 2015. This technique allowed them to grow “bacterial dark matter,” so-called unculturable bacteria, which compose a group to which 99% of bacteria belong.

This device also paved the way for the discovery of the antibiotic teixobactin in 2020. Teixobactin is effective against gram-positive bacteria and is one of the first truly new antibiotics in decades. Its mechanism of action is like that of clovibactin.
 

Combats resistant bacteria

In the Cell article, the researchers showed that clovibactin acts via several mechanisms and that it successfully treated mice infected with the superbug Staphylococcus aureus.

Clovibactin exhibited antibacterial activity against a broad range of gram-positive pathogens, including methicillin-resistant S. aureus, daptomycin-resistant and vancomycin-resistant S. aureus strains, and difficult-to-treat vancomycin-resistant Enterococcus faecalis and E faecium (vancomycin-resistant enterococci). Escherichia coli was only marginally affected “compared with an outer membrane deficient E. coli WO153 strain, probably reflecting insufficient penetration of the compound,” the authors wrote.
 

Original mechanism of action

Clovibactin acts not on one but three molecules, all of which are essential to the construction of bacterial walls: C55PP, lipid II, and lipid IIIWTA, which are from different cell wall biosynthetic pathways. Clovibactin binds to the pyrophosphate portion of these precursors.

“Clovibactin wraps around the pyrophosphate like [a] tight glove, like a cage that encloses its target,” said Dr. Weingarth. This is what gives clovibactin its name, which is derived from Greek word klouvi, meaning cage.

The remarkable aspect of clovibactin’s mechanism is that it only binds to the immutable pyrophosphate that is common to cell wall precursors, but it also ignores the variable sugar-peptide part of the targets. The bacteria therefore have a much harder time developing resistance against it. “In fact, we did not observe any resistance to clovibactin in our studies,” Dr. Weingarth confirmed.

Upon binding the target molecules, it self-assembles into large fibrils on the surface of bacterial membranes. These fibrils are stable for a long time and thereby ensure that the target molecules remain sequestered for as long as necessary to kill bacteria.
 

Few side effects

Because of the mechanism of action of the antibiotic, few side effects are predicted. Indeed, clovibactin targets bacteria cells but not human cells.

“Since these fibrils only form on bacterial membranes and not on human membranes, they are presumably also the reason why clovibactin selectively damages bacterial cells but is not toxic to human cells,” said Dr. Weingarth.

Other studies – in particular, studies in humans – are needed before the antibiotic can be considered a potential treatment. In the meantime, regulations regarding the proper use of antibiotics must continue to be applied to limit antibiotic resistance.

In 2019, 4.95 million deaths worldwide were associated with bacterial antimicrobial resistance, including 1.27 million deaths directly attributable to bacterial antimicrobial resistance. If this trend continues without new medicines becoming available to treat bacterial infections, it is estimated that by 2050, 10 million people will die every year from antimicrobial drug resistance.
 

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

The frequency of medication errors among children who take drugs to treat attention-deficit/hyperactivity disorder reported to U.S. poison control centers increased by nearly 300% over a 22-year period, according to results of a study published in the journal Pediatrics.

The dramatic jump is likely attributable to an increase in the prescribing of ADHD medications for children. According to the study authors, in 2019, nearly 10% of children in the United States had been diagnosed with ADHD, and some 3.3 million – or about 5% of all children in the country – had received a prescription for an ADHD medication.

“Because therapeutic errors are preventable, more attention should be given to patient and caregiver education and development of improved child-resistant medication dispensing and tracking systems,” the authors commented.

The investigators analyzed data from the National Poison Data System from 2000 through 2021 for therapeutic errors associated with ADHD medication among patients younger than 20 years.

“As medicine changes, it’s nice to look back at some of these things and see how some of these problems have changed,” said Natalie I. Rine, PharmD, a coauthor of the study and director of the Central Ohio Poison Center at Nationwide Children’s Hospital in Columbus.

The researchers identified 124,383 such errors reported to U.S. poison centers during the study period. The frequency increased by 299%.

Two-thirds (66.6%) of the exposures involved children aged 6-12 years, three-fourths (76.4%) were among males, and half (50.5%) involved amphetamines and related compounds. Most (79.7%) therapeutic errors were linked to exposure to a single substance. Nearly 83% of patients did not receive treatment at a health care facility; however, 2.3% were admitted to the hospital, and 4.2% had a “serious medical outcome,” the researchers found.

The most common scenarios were “inadvertently took or given medication twice” (53.9%), followed by “inadvertently took or given someone else’s medication” (13.4%) and “wrong medication taken or given” (12.9%), according to the researchers. Two percent involved mistakes by a pharmacist or nurse.
 

Easily preventable

Dr. Rine attributed the errors to simple mistakes and said they were likely the product of busy households and distracted caregivers. She added that the errors are easily avoided by storing the medication properly, keeping a sheet with the medication to document what was taken and when, and using a pillbox or one of many apps that can assist in documenting the dispensing of medications.

“I think the biggest thing is that a lot of these errors are preventable, more than anything else,” Dr. Rine said.

The increase in ADHD diagnoses among children and the subsequent prescribing of medications are reasons for the nearly 300% increase in poison control calls. A 2018 study showed that the estimated prevalence of ADHD diagnoses among U.S. children and adolescents increased from 6.1% in 1997-1998 to 10.2% in 2015-2016. The Centers for Disease Control and Prevention states that 6 million children and adolescents aged 3-17 years have been diagnosed with ADHD, and 62% have received ADHD medication.

Colleen Kraft, MD, a pediatrician at Children’s Hospital Los Angeles, said she was not surprised by the reported increase in errors. In addition to the simple uptick in ADHD diagnoses and prescriptions in the past 2 decades, Dr. Kraft said the growing variety of ADHD medication is a cause for more errors.

“Because we have so many more different types of these medications, it’s easy to confuse them, and it’s easy to make an error when you give this to a child,” she said in an interview.

Dr. Kraft also hypothesized that because ADHD can have a genetic component, some parents with undiagnosed and untreated ADHD are responsible for their child’s medication, a scenario ripe for mistakes.
 

Potential dangers

Not all ADHD medicinal overdosing is created equal, Dr. Kraft pointed out. Doubling up on a stimulant such as methylphenidate (Ritalin) or the combination of amphetamine and dextroamphetamine (Adderall) may cause headaches, suppress appetite, and cause an upset stomach, although those symptoms usually clear up in a few hours.

However, she noted, the use of alpha-1 adrenergic blockers is more concerning. Also used to treat high blood pressure, medications such as guanfacine and clonidine cause sedation. A double dose can cause blood pressure to decrease to dangerous levels.

The study’s primary limitation was bias in self-reporting, which may have led to underreporting of incidences, according to the researchers. Not every case in which an error occurs that involves a child’s taking ADHD medication gets reported to poison control, because some will take a wait-and-see approach and may not call if their child is asymptomatic.

“Our data is only as good as what the callers report to us,” Dr. Rine said.

A version of this article appeared on Medscape.com.

The frequency of medication errors among children who take drugs to treat attention-deficit/hyperactivity disorder reported to U.S. poison control centers increased by nearly 300% over a 22-year period, according to results of a study published in the journal Pediatrics.

The dramatic jump is likely attributable to an increase in the prescribing of ADHD medications for children. According to the study authors, in 2019, nearly 10% of children in the United States had been diagnosed with ADHD, and some 3.3 million – or about 5% of all children in the country – had received a prescription for an ADHD medication.

“Because therapeutic errors are preventable, more attention should be given to patient and caregiver education and development of improved child-resistant medication dispensing and tracking systems,” the authors commented.

The investigators analyzed data from the National Poison Data System from 2000 through 2021 for therapeutic errors associated with ADHD medication among patients younger than 20 years.

“As medicine changes, it’s nice to look back at some of these things and see how some of these problems have changed,” said Natalie I. Rine, PharmD, a coauthor of the study and director of the Central Ohio Poison Center at Nationwide Children’s Hospital in Columbus.

The researchers identified 124,383 such errors reported to U.S. poison centers during the study period. The frequency increased by 299%.

Two-thirds (66.6%) of the exposures involved children aged 6-12 years, three-fourths (76.4%) were among males, and half (50.5%) involved amphetamines and related compounds. Most (79.7%) therapeutic errors were linked to exposure to a single substance. Nearly 83% of patients did not receive treatment at a health care facility; however, 2.3% were admitted to the hospital, and 4.2% had a “serious medical outcome,” the researchers found.

The most common scenarios were “inadvertently took or given medication twice” (53.9%), followed by “inadvertently took or given someone else’s medication” (13.4%) and “wrong medication taken or given” (12.9%), according to the researchers. Two percent involved mistakes by a pharmacist or nurse.
 

Easily preventable

Dr. Rine attributed the errors to simple mistakes and said they were likely the product of busy households and distracted caregivers. She added that the errors are easily avoided by storing the medication properly, keeping a sheet with the medication to document what was taken and when, and using a pillbox or one of many apps that can assist in documenting the dispensing of medications.

“I think the biggest thing is that a lot of these errors are preventable, more than anything else,” Dr. Rine said.

The increase in ADHD diagnoses among children and the subsequent prescribing of medications are reasons for the nearly 300% increase in poison control calls. A 2018 study showed that the estimated prevalence of ADHD diagnoses among U.S. children and adolescents increased from 6.1% in 1997-1998 to 10.2% in 2015-2016. The Centers for Disease Control and Prevention states that 6 million children and adolescents aged 3-17 years have been diagnosed with ADHD, and 62% have received ADHD medication.

Colleen Kraft, MD, a pediatrician at Children’s Hospital Los Angeles, said she was not surprised by the reported increase in errors. In addition to the simple uptick in ADHD diagnoses and prescriptions in the past 2 decades, Dr. Kraft said the growing variety of ADHD medication is a cause for more errors.

“Because we have so many more different types of these medications, it’s easy to confuse them, and it’s easy to make an error when you give this to a child,” she said in an interview.

Dr. Kraft also hypothesized that because ADHD can have a genetic component, some parents with undiagnosed and untreated ADHD are responsible for their child’s medication, a scenario ripe for mistakes.
 

Potential dangers

Not all ADHD medicinal overdosing is created equal, Dr. Kraft pointed out. Doubling up on a stimulant such as methylphenidate (Ritalin) or the combination of amphetamine and dextroamphetamine (Adderall) may cause headaches, suppress appetite, and cause an upset stomach, although those symptoms usually clear up in a few hours.

However, she noted, the use of alpha-1 adrenergic blockers is more concerning. Also used to treat high blood pressure, medications such as guanfacine and clonidine cause sedation. A double dose can cause blood pressure to decrease to dangerous levels.

The study’s primary limitation was bias in self-reporting, which may have led to underreporting of incidences, according to the researchers. Not every case in which an error occurs that involves a child’s taking ADHD medication gets reported to poison control, because some will take a wait-and-see approach and may not call if their child is asymptomatic.

“Our data is only as good as what the callers report to us,” Dr. Rine said.

A version of this article appeared on Medscape.com.

The frequency of medication errors among children who take drugs to treat attention-deficit/hyperactivity disorder reported to U.S. poison control centers increased by nearly 300% over a 22-year period, according to results of a study published in the journal Pediatrics.

The dramatic jump is likely attributable to an increase in the prescribing of ADHD medications for children. According to the study authors, in 2019, nearly 10% of children in the United States had been diagnosed with ADHD, and some 3.3 million – or about 5% of all children in the country – had received a prescription for an ADHD medication.

“Because therapeutic errors are preventable, more attention should be given to patient and caregiver education and development of improved child-resistant medication dispensing and tracking systems,” the authors commented.

The investigators analyzed data from the National Poison Data System from 2000 through 2021 for therapeutic errors associated with ADHD medication among patients younger than 20 years.

“As medicine changes, it’s nice to look back at some of these things and see how some of these problems have changed,” said Natalie I. Rine, PharmD, a coauthor of the study and director of the Central Ohio Poison Center at Nationwide Children’s Hospital in Columbus.

The researchers identified 124,383 such errors reported to U.S. poison centers during the study period. The frequency increased by 299%.

Two-thirds (66.6%) of the exposures involved children aged 6-12 years, three-fourths (76.4%) were among males, and half (50.5%) involved amphetamines and related compounds. Most (79.7%) therapeutic errors were linked to exposure to a single substance. Nearly 83% of patients did not receive treatment at a health care facility; however, 2.3% were admitted to the hospital, and 4.2% had a “serious medical outcome,” the researchers found.

The most common scenarios were “inadvertently took or given medication twice” (53.9%), followed by “inadvertently took or given someone else’s medication” (13.4%) and “wrong medication taken or given” (12.9%), according to the researchers. Two percent involved mistakes by a pharmacist or nurse.
 

Easily preventable

Dr. Rine attributed the errors to simple mistakes and said they were likely the product of busy households and distracted caregivers. She added that the errors are easily avoided by storing the medication properly, keeping a sheet with the medication to document what was taken and when, and using a pillbox or one of many apps that can assist in documenting the dispensing of medications.

“I think the biggest thing is that a lot of these errors are preventable, more than anything else,” Dr. Rine said.

The increase in ADHD diagnoses among children and the subsequent prescribing of medications are reasons for the nearly 300% increase in poison control calls. A 2018 study showed that the estimated prevalence of ADHD diagnoses among U.S. children and adolescents increased from 6.1% in 1997-1998 to 10.2% in 2015-2016. The Centers for Disease Control and Prevention states that 6 million children and adolescents aged 3-17 years have been diagnosed with ADHD, and 62% have received ADHD medication.

Colleen Kraft, MD, a pediatrician at Children’s Hospital Los Angeles, said she was not surprised by the reported increase in errors. In addition to the simple uptick in ADHD diagnoses and prescriptions in the past 2 decades, Dr. Kraft said the growing variety of ADHD medication is a cause for more errors.

“Because we have so many more different types of these medications, it’s easy to confuse them, and it’s easy to make an error when you give this to a child,” she said in an interview.

Dr. Kraft also hypothesized that because ADHD can have a genetic component, some parents with undiagnosed and untreated ADHD are responsible for their child’s medication, a scenario ripe for mistakes.
 

Potential dangers

Not all ADHD medicinal overdosing is created equal, Dr. Kraft pointed out. Doubling up on a stimulant such as methylphenidate (Ritalin) or the combination of amphetamine and dextroamphetamine (Adderall) may cause headaches, suppress appetite, and cause an upset stomach, although those symptoms usually clear up in a few hours.

However, she noted, the use of alpha-1 adrenergic blockers is more concerning. Also used to treat high blood pressure, medications such as guanfacine and clonidine cause sedation. A double dose can cause blood pressure to decrease to dangerous levels.

The study’s primary limitation was bias in self-reporting, which may have led to underreporting of incidences, according to the researchers. Not every case in which an error occurs that involves a child’s taking ADHD medication gets reported to poison control, because some will take a wait-and-see approach and may not call if their child is asymptomatic.

“Our data is only as good as what the callers report to us,” Dr. Rine said.

A version of this article appeared on Medscape.com.

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

A version of this article first appeared on Medscape.com.

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

A version of this article first appeared on Medscape.com.

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

A version of this article first appeared on Medscape.com.

Long-term follow-up from the CheckMate 227 study has revealed lasting benefit from the combination of the CTLA-4 inhibitor ipilimumab (IPI) and the PD-1 inhibitor nivolumab (NIVO) in non-small cell lung cancer. After 6 years, previous tumor response, tumor burden reduction, and baseline health-related quality of life all correlated with overall survival, according to the latest analysis from the study.

“Patients treated with NIVO-IPI versus chemotherapy continue to derive long term durable efficacy benefit in CheckMate 227, regardless of PD-L1 expression. This represents the longest ever reported follow-up across phase three studies of frontline immunotherapy in patients with metastatic non–small cell lung cancer, and this further highlights the clinical benefit of frontline NIVO-IPI as a treatment in these patients with metastatic non–small cell lung cancer, regardless of the PD-L1 expression,” said Solange Peters, MD, PhD, during a presentation of the latest analysis at the annual World Conference on Lung Cancer. Dr. Peters is a professor of oncology at Lausanne (Switzerland) University Hospital.

The combination of nivolumab and ipilimumab has shown long-term survival benefit in other cancer types, including advanced melanoma, advanced renal cell carcinoma, and unresectable pleural mesothelioma.

The same session featured other studies demonstrating positive outcomes of immunotherapy in NSCLC. Serving as a discussant, Ferdinandos Skoulidis MD, PhD, commented, “I would argue that we are now at an inflection point where we can claim that we are altering the natural history of the disease for a subset of patients.” Dr. Skoulidis is an associate professor of thoracic oncology at the University of Texas MD Anderson Cancer Center.
 

Updated results

CheckMate 227 enrolled patients with metastatic or recurrent NSCLC, excluding those with EGFR/ALK alterations. Patients with PD-L1 expression greater than or equal to 1% (PD-L1 positive, n = 1,189) were randomized to NIVO-IPI, NIVO, or chemotherapy. Patients with PD-L1 expression less than 1% (n = 550, PD-L1 negative) were randomized to NIVO-IPI, NIVO plus chemotherapy, or chemotherapy alone. The 5-year landmark analysis, which was published by the National Center for Biotechnology Information, showed overall survival rate of 24% among PD-L1 greater than or equal to 1% patients (PD-L1 positive) and 19% in PD-L1 less than 1% (PD-L1 negative) patients who received IPI-NIVO therapy, compared with 14% and 7%, respectively, in the chemotherapy only groups.

At WCLC, Dr. Peters presented data extending to 6 years of follow-up, as well as exploratory analyses. At 6 years of follow-up, in PD-L1 positive patients, 22% of the NIVO-IPI group remained alive, versus 13% of the chemotherapy group (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91), while there was no significant improvement in OS for nivolumab alone, compared with chemotherapy. In the PD-L1 negative group, 16% were alive at 6 years in the IPI-NIVO group (HR, 0.65; 95% CI, 0.52-0.81), as were 10% in NIVO plus chemotherapy (HR, 0.79; 95% CI, 0.64-0.98) group, versus 5% in the chemotherapy group. The benefit of NIVO-IPI was significant in both squamous and non-squamous tumors for both PDL1-positive and PD-L1 negative patients.

At 6 years follow-up, 27% of PD-L1 positive patients who responded to NIVO-IPI remained in response, versus 22% in the NIVO group and 4% in the chemotherapy only group. Among PD-L1 negative patients, 25% of combination therapy responders remained in response at 6 years, while there were 10% still in response among the NIVO group, and none in the chemotherapy only group.
 

Exploratory analyses

Dr. Peters presented a slide showing tumor burden reductions occurring in responders. “What has to be concluded from this very interesting graph is that there are more, deeper responses in the NIVO-IPI versus chemotherapy. Very importantly, too, this is strongly correlated with survival. In both treatment arms, a high magnitude of tumor burden reduction is correlated with an improved survival,” said Dr. Peters. Specifically, among PD-L1 positive patients with more than 80% tumor reduction, survival was 59% at 6 years (95% CI, 44-71%). The figure was 68% in the NIVO only arm (95% CI, 47-82%), and 42% in the chemotherapy only arm (95% CI, 15-66%).

Among PD-L1 negative patients, “there are more, deeper responses in NIVO-IPI versus chemotherapy. That is very clear. And probably differently from the positive PD-L1 arm, the tumor burden reduction is correlated with survival but really only strongly observed in the NIVO-IPI arm,” said Dr. Peters. The figure was 20% in the nivolumab arm (95% CI, 3-48%) and 0% in the chemotherapy only arm (95% CI, not available). “So really something is correlating the tumor burden reduction with the outcome and specifically correlating it in the negative PD-L1 with the treatment of NIVO-IPI,” said Dr. Peters.

The researchers also noted longer progression-free survival and overall response rate in the NIVO-IPI group than the chemotherapy group in both PD-L1 positive and PD-L1 negative patients.

With respect to health-related quality of life, the researchers found a correlation between higher scores at baseline on the EQ-5D-3L scale and overall survival in the chemotherapy group (HR, 0.61; 95% CI, 0.51-0.74) and a trend in the NIVO-IPI group (HR, 0.83; 95% CI, 0.69-1.01). “So this baseline history, the quality of life, is correlated with the outcome regardless of the treatment you deliver,” said Dr. Peters.
 

Personalizing immunotherapy in NSCLC

In his comments, Dr. Skoulidis highlighted the length of responses. “Most importantly, approximately 50% of these patients that are alive at six years are also disease free, suggesting that we are indeed making a dent on the natural history of the disease for these patients,” he said.

He also made a case for personalizing immunotherapy and suggested that CheckMate 227 could provide some guidance. “Ipilimumab/nivolumab – the CheckMate 227 regimen – appears to be particularly active in terms of inducing long-term, long-lasting responses and overall survival in patients harboring tumors that are negative for PD-L1,” he said.

Dr. Skoulidis also highlighted the 16% six-year overall survival among PD-L1 negative patients who received NIVO-IPI, calling it “impressive.” Of those who responded, 25% continued to respond at 6 years. “This is particularly notable in the subset of patients with squamous histology and lack of PD-L1 expression, where the six year overall survival rate with NIVO-IPI versus chemo was 18% versus 4%. So perhaps in patients with squamous histology and lack of PD-L1 expression, NIVO-IPI might represent a favorable regimen to improve long term outcomes,” said Dr. Skoulidis.

CheckMate 227 was funded by Bristol Myers Sqiubb. Dr. Peters has financial relationships with a wide range of pharmaceutical companies, including Bristol Myers Squibb. Dr. Skoulidis has financial relationships with Moderna, BioNTech, Amgen, Intellisphere, Navire, BeiGene, Medscape, Calithera Biosciences, Tango Therapeutics, Guardant Health, Novartis, AIMM Therapeutics, Mirati Therapeutics, Boehringer Ingelheim, Merck, and Pfizer.

Long-term follow-up from the CheckMate 227 study has revealed lasting benefit from the combination of the CTLA-4 inhibitor ipilimumab (IPI) and the PD-1 inhibitor nivolumab (NIVO) in non-small cell lung cancer. After 6 years, previous tumor response, tumor burden reduction, and baseline health-related quality of life all correlated with overall survival, according to the latest analysis from the study.

“Patients treated with NIVO-IPI versus chemotherapy continue to derive long term durable efficacy benefit in CheckMate 227, regardless of PD-L1 expression. This represents the longest ever reported follow-up across phase three studies of frontline immunotherapy in patients with metastatic non–small cell lung cancer, and this further highlights the clinical benefit of frontline NIVO-IPI as a treatment in these patients with metastatic non–small cell lung cancer, regardless of the PD-L1 expression,” said Solange Peters, MD, PhD, during a presentation of the latest analysis at the annual World Conference on Lung Cancer. Dr. Peters is a professor of oncology at Lausanne (Switzerland) University Hospital.

The combination of nivolumab and ipilimumab has shown long-term survival benefit in other cancer types, including advanced melanoma, advanced renal cell carcinoma, and unresectable pleural mesothelioma.

The same session featured other studies demonstrating positive outcomes of immunotherapy in NSCLC. Serving as a discussant, Ferdinandos Skoulidis MD, PhD, commented, “I would argue that we are now at an inflection point where we can claim that we are altering the natural history of the disease for a subset of patients.” Dr. Skoulidis is an associate professor of thoracic oncology at the University of Texas MD Anderson Cancer Center.
 

Updated results

CheckMate 227 enrolled patients with metastatic or recurrent NSCLC, excluding those with EGFR/ALK alterations. Patients with PD-L1 expression greater than or equal to 1% (PD-L1 positive, n = 1,189) were randomized to NIVO-IPI, NIVO, or chemotherapy. Patients with PD-L1 expression less than 1% (n = 550, PD-L1 negative) were randomized to NIVO-IPI, NIVO plus chemotherapy, or chemotherapy alone. The 5-year landmark analysis, which was published by the National Center for Biotechnology Information, showed overall survival rate of 24% among PD-L1 greater than or equal to 1% patients (PD-L1 positive) and 19% in PD-L1 less than 1% (PD-L1 negative) patients who received IPI-NIVO therapy, compared with 14% and 7%, respectively, in the chemotherapy only groups.

At WCLC, Dr. Peters presented data extending to 6 years of follow-up, as well as exploratory analyses. At 6 years of follow-up, in PD-L1 positive patients, 22% of the NIVO-IPI group remained alive, versus 13% of the chemotherapy group (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91), while there was no significant improvement in OS for nivolumab alone, compared with chemotherapy. In the PD-L1 negative group, 16% were alive at 6 years in the IPI-NIVO group (HR, 0.65; 95% CI, 0.52-0.81), as were 10% in NIVO plus chemotherapy (HR, 0.79; 95% CI, 0.64-0.98) group, versus 5% in the chemotherapy group. The benefit of NIVO-IPI was significant in both squamous and non-squamous tumors for both PDL1-positive and PD-L1 negative patients.

At 6 years follow-up, 27% of PD-L1 positive patients who responded to NIVO-IPI remained in response, versus 22% in the NIVO group and 4% in the chemotherapy only group. Among PD-L1 negative patients, 25% of combination therapy responders remained in response at 6 years, while there were 10% still in response among the NIVO group, and none in the chemotherapy only group.
 

Exploratory analyses

Dr. Peters presented a slide showing tumor burden reductions occurring in responders. “What has to be concluded from this very interesting graph is that there are more, deeper responses in the NIVO-IPI versus chemotherapy. Very importantly, too, this is strongly correlated with survival. In both treatment arms, a high magnitude of tumor burden reduction is correlated with an improved survival,” said Dr. Peters. Specifically, among PD-L1 positive patients with more than 80% tumor reduction, survival was 59% at 6 years (95% CI, 44-71%). The figure was 68% in the NIVO only arm (95% CI, 47-82%), and 42% in the chemotherapy only arm (95% CI, 15-66%).

Among PD-L1 negative patients, “there are more, deeper responses in NIVO-IPI versus chemotherapy. That is very clear. And probably differently from the positive PD-L1 arm, the tumor burden reduction is correlated with survival but really only strongly observed in the NIVO-IPI arm,” said Dr. Peters. The figure was 20% in the nivolumab arm (95% CI, 3-48%) and 0% in the chemotherapy only arm (95% CI, not available). “So really something is correlating the tumor burden reduction with the outcome and specifically correlating it in the negative PD-L1 with the treatment of NIVO-IPI,” said Dr. Peters.

The researchers also noted longer progression-free survival and overall response rate in the NIVO-IPI group than the chemotherapy group in both PD-L1 positive and PD-L1 negative patients.

With respect to health-related quality of life, the researchers found a correlation between higher scores at baseline on the EQ-5D-3L scale and overall survival in the chemotherapy group (HR, 0.61; 95% CI, 0.51-0.74) and a trend in the NIVO-IPI group (HR, 0.83; 95% CI, 0.69-1.01). “So this baseline history, the quality of life, is correlated with the outcome regardless of the treatment you deliver,” said Dr. Peters.
 

Personalizing immunotherapy in NSCLC

In his comments, Dr. Skoulidis highlighted the length of responses. “Most importantly, approximately 50% of these patients that are alive at six years are also disease free, suggesting that we are indeed making a dent on the natural history of the disease for these patients,” he said.

He also made a case for personalizing immunotherapy and suggested that CheckMate 227 could provide some guidance. “Ipilimumab/nivolumab – the CheckMate 227 regimen – appears to be particularly active in terms of inducing long-term, long-lasting responses and overall survival in patients harboring tumors that are negative for PD-L1,” he said.

Dr. Skoulidis also highlighted the 16% six-year overall survival among PD-L1 negative patients who received NIVO-IPI, calling it “impressive.” Of those who responded, 25% continued to respond at 6 years. “This is particularly notable in the subset of patients with squamous histology and lack of PD-L1 expression, where the six year overall survival rate with NIVO-IPI versus chemo was 18% versus 4%. So perhaps in patients with squamous histology and lack of PD-L1 expression, NIVO-IPI might represent a favorable regimen to improve long term outcomes,” said Dr. Skoulidis.

CheckMate 227 was funded by Bristol Myers Sqiubb. Dr. Peters has financial relationships with a wide range of pharmaceutical companies, including Bristol Myers Squibb. Dr. Skoulidis has financial relationships with Moderna, BioNTech, Amgen, Intellisphere, Navire, BeiGene, Medscape, Calithera Biosciences, Tango Therapeutics, Guardant Health, Novartis, AIMM Therapeutics, Mirati Therapeutics, Boehringer Ingelheim, Merck, and Pfizer.

Long-term follow-up from the CheckMate 227 study has revealed lasting benefit from the combination of the CTLA-4 inhibitor ipilimumab (IPI) and the PD-1 inhibitor nivolumab (NIVO) in non-small cell lung cancer. After 6 years, previous tumor response, tumor burden reduction, and baseline health-related quality of life all correlated with overall survival, according to the latest analysis from the study.

“Patients treated with NIVO-IPI versus chemotherapy continue to derive long term durable efficacy benefit in CheckMate 227, regardless of PD-L1 expression. This represents the longest ever reported follow-up across phase three studies of frontline immunotherapy in patients with metastatic non–small cell lung cancer, and this further highlights the clinical benefit of frontline NIVO-IPI as a treatment in these patients with metastatic non–small cell lung cancer, regardless of the PD-L1 expression,” said Solange Peters, MD, PhD, during a presentation of the latest analysis at the annual World Conference on Lung Cancer. Dr. Peters is a professor of oncology at Lausanne (Switzerland) University Hospital.

The combination of nivolumab and ipilimumab has shown long-term survival benefit in other cancer types, including advanced melanoma, advanced renal cell carcinoma, and unresectable pleural mesothelioma.

The same session featured other studies demonstrating positive outcomes of immunotherapy in NSCLC. Serving as a discussant, Ferdinandos Skoulidis MD, PhD, commented, “I would argue that we are now at an inflection point where we can claim that we are altering the natural history of the disease for a subset of patients.” Dr. Skoulidis is an associate professor of thoracic oncology at the University of Texas MD Anderson Cancer Center.
 

Updated results

CheckMate 227 enrolled patients with metastatic or recurrent NSCLC, excluding those with EGFR/ALK alterations. Patients with PD-L1 expression greater than or equal to 1% (PD-L1 positive, n = 1,189) were randomized to NIVO-IPI, NIVO, or chemotherapy. Patients with PD-L1 expression less than 1% (n = 550, PD-L1 negative) were randomized to NIVO-IPI, NIVO plus chemotherapy, or chemotherapy alone. The 5-year landmark analysis, which was published by the National Center for Biotechnology Information, showed overall survival rate of 24% among PD-L1 greater than or equal to 1% patients (PD-L1 positive) and 19% in PD-L1 less than 1% (PD-L1 negative) patients who received IPI-NIVO therapy, compared with 14% and 7%, respectively, in the chemotherapy only groups.

At WCLC, Dr. Peters presented data extending to 6 years of follow-up, as well as exploratory analyses. At 6 years of follow-up, in PD-L1 positive patients, 22% of the NIVO-IPI group remained alive, versus 13% of the chemotherapy group (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91), while there was no significant improvement in OS for nivolumab alone, compared with chemotherapy. In the PD-L1 negative group, 16% were alive at 6 years in the IPI-NIVO group (HR, 0.65; 95% CI, 0.52-0.81), as were 10% in NIVO plus chemotherapy (HR, 0.79; 95% CI, 0.64-0.98) group, versus 5% in the chemotherapy group. The benefit of NIVO-IPI was significant in both squamous and non-squamous tumors for both PDL1-positive and PD-L1 negative patients.

At 6 years follow-up, 27% of PD-L1 positive patients who responded to NIVO-IPI remained in response, versus 22% in the NIVO group and 4% in the chemotherapy only group. Among PD-L1 negative patients, 25% of combination therapy responders remained in response at 6 years, while there were 10% still in response among the NIVO group, and none in the chemotherapy only group.
 

Exploratory analyses

Dr. Peters presented a slide showing tumor burden reductions occurring in responders. “What has to be concluded from this very interesting graph is that there are more, deeper responses in the NIVO-IPI versus chemotherapy. Very importantly, too, this is strongly correlated with survival. In both treatment arms, a high magnitude of tumor burden reduction is correlated with an improved survival,” said Dr. Peters. Specifically, among PD-L1 positive patients with more than 80% tumor reduction, survival was 59% at 6 years (95% CI, 44-71%). The figure was 68% in the NIVO only arm (95% CI, 47-82%), and 42% in the chemotherapy only arm (95% CI, 15-66%).

Among PD-L1 negative patients, “there are more, deeper responses in NIVO-IPI versus chemotherapy. That is very clear. And probably differently from the positive PD-L1 arm, the tumor burden reduction is correlated with survival but really only strongly observed in the NIVO-IPI arm,” said Dr. Peters. The figure was 20% in the nivolumab arm (95% CI, 3-48%) and 0% in the chemotherapy only arm (95% CI, not available). “So really something is correlating the tumor burden reduction with the outcome and specifically correlating it in the negative PD-L1 with the treatment of NIVO-IPI,” said Dr. Peters.

The researchers also noted longer progression-free survival and overall response rate in the NIVO-IPI group than the chemotherapy group in both PD-L1 positive and PD-L1 negative patients.

With respect to health-related quality of life, the researchers found a correlation between higher scores at baseline on the EQ-5D-3L scale and overall survival in the chemotherapy group (HR, 0.61; 95% CI, 0.51-0.74) and a trend in the NIVO-IPI group (HR, 0.83; 95% CI, 0.69-1.01). “So this baseline history, the quality of life, is correlated with the outcome regardless of the treatment you deliver,” said Dr. Peters.
 

Personalizing immunotherapy in NSCLC

In his comments, Dr. Skoulidis highlighted the length of responses. “Most importantly, approximately 50% of these patients that are alive at six years are also disease free, suggesting that we are indeed making a dent on the natural history of the disease for these patients,” he said.

He also made a case for personalizing immunotherapy and suggested that CheckMate 227 could provide some guidance. “Ipilimumab/nivolumab – the CheckMate 227 regimen – appears to be particularly active in terms of inducing long-term, long-lasting responses and overall survival in patients harboring tumors that are negative for PD-L1,” he said.

Dr. Skoulidis also highlighted the 16% six-year overall survival among PD-L1 negative patients who received NIVO-IPI, calling it “impressive.” Of those who responded, 25% continued to respond at 6 years. “This is particularly notable in the subset of patients with squamous histology and lack of PD-L1 expression, where the six year overall survival rate with NIVO-IPI versus chemo was 18% versus 4%. So perhaps in patients with squamous histology and lack of PD-L1 expression, NIVO-IPI might represent a favorable regimen to improve long term outcomes,” said Dr. Skoulidis.

CheckMate 227 was funded by Bristol Myers Sqiubb. Dr. Peters has financial relationships with a wide range of pharmaceutical companies, including Bristol Myers Squibb. Dr. Skoulidis has financial relationships with Moderna, BioNTech, Amgen, Intellisphere, Navire, BeiGene, Medscape, Calithera Biosciences, Tango Therapeutics, Guardant Health, Novartis, AIMM Therapeutics, Mirati Therapeutics, Boehringer Ingelheim, Merck, and Pfizer.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

BACKGROUND

Chimeric antigen receptor T-cell (CAR-T) therapy is a novel treatment for hematologic malignancies, with 6 FDA agents approved for commercial use. The Veterans Affairs (VA) Tennessee Valley Healthcare System (TVHS) is currently the only VA facility accredited to administer these agents and we are reporting the TVHS experience thus far.

METHODS

TVHS became an authorized treatment center for CAR-T therapy in September 2019 and performed its first CAR-T infusion in December 2019. This is a retrospective electronic chart review of all CAR-T veterans referred to TVHS from the program’s inception, December 1, 2019 through July 31, 2022 to evaluate at least one year of post infusion data. The primary objective is to evaluate the outcomes of veterans who received CAR-T therapy at TVHS including overall response rates (ORR), progression free survival (PFS), and overall survival (OS). Secondary objectives include assessment of toxicities, including rates and maximum grades of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

RESULTS

A total of 41 veterans have received CAR-T infusion at TVHS to date. Twenty-nine of these veterans have at least one year post-CAR-T infusion data and are included in this analysis. The majority of veterans were White (72%), male (93%), and were treated for diffuse large B-cell lymphoma (86%). Twenty-eight percent of veterans were under-represented minorities. Average age was 61 years with 62% being 65 years and older and five (17%) veterans being over the age of 74. Day 30 ORR was 90% (45% complete response [CR]). One-year PFS was 55.2% and 1-year OS was 65.5%. Of the 19 veterans who achieved CR by day 100, 79% remain in CR to date. CRS toxicity was observed in 66% of veterans (0% Grade 3 or higher). ICANS was observed in 27.5% of veterans (24% Grade 3 or higher). Only 5 (26%) veterans required transfer to the intensive care unit for additional monitoring.

CONCLUSIONS

CAR-T therapy has become a wellestablished practice at TVHS and is a safe and effective treatment option for veterans with aggressive lymphoid malignancies. Our outcomes are similar to that seen nationally with better access to under-represented minorities in an aging population.

BACKGROUND

Chimeric antigen receptor T-cell (CAR-T) therapy is a novel treatment for hematologic malignancies, with 6 FDA agents approved for commercial use. The Veterans Affairs (VA) Tennessee Valley Healthcare System (TVHS) is currently the only VA facility accredited to administer these agents and we are reporting the TVHS experience thus far.

METHODS

TVHS became an authorized treatment center for CAR-T therapy in September 2019 and performed its first CAR-T infusion in December 2019. This is a retrospective electronic chart review of all CAR-T veterans referred to TVHS from the program’s inception, December 1, 2019 through July 31, 2022 to evaluate at least one year of post infusion data. The primary objective is to evaluate the outcomes of veterans who received CAR-T therapy at TVHS including overall response rates (ORR), progression free survival (PFS), and overall survival (OS). Secondary objectives include assessment of toxicities, including rates and maximum grades of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

RESULTS

A total of 41 veterans have received CAR-T infusion at TVHS to date. Twenty-nine of these veterans have at least one year post-CAR-T infusion data and are included in this analysis. The majority of veterans were White (72%), male (93%), and were treated for diffuse large B-cell lymphoma (86%). Twenty-eight percent of veterans were under-represented minorities. Average age was 61 years with 62% being 65 years and older and five (17%) veterans being over the age of 74. Day 30 ORR was 90% (45% complete response [CR]). One-year PFS was 55.2% and 1-year OS was 65.5%. Of the 19 veterans who achieved CR by day 100, 79% remain in CR to date. CRS toxicity was observed in 66% of veterans (0% Grade 3 or higher). ICANS was observed in 27.5% of veterans (24% Grade 3 or higher). Only 5 (26%) veterans required transfer to the intensive care unit for additional monitoring.

CONCLUSIONS

CAR-T therapy has become a wellestablished practice at TVHS and is a safe and effective treatment option for veterans with aggressive lymphoid malignancies. Our outcomes are similar to that seen nationally with better access to under-represented minorities in an aging population.

BACKGROUND

Chimeric antigen receptor T-cell (CAR-T) therapy is a novel treatment for hematologic malignancies, with 6 FDA agents approved for commercial use. The Veterans Affairs (VA) Tennessee Valley Healthcare System (TVHS) is currently the only VA facility accredited to administer these agents and we are reporting the TVHS experience thus far.

METHODS

TVHS became an authorized treatment center for CAR-T therapy in September 2019 and performed its first CAR-T infusion in December 2019. This is a retrospective electronic chart review of all CAR-T veterans referred to TVHS from the program’s inception, December 1, 2019 through July 31, 2022 to evaluate at least one year of post infusion data. The primary objective is to evaluate the outcomes of veterans who received CAR-T therapy at TVHS including overall response rates (ORR), progression free survival (PFS), and overall survival (OS). Secondary objectives include assessment of toxicities, including rates and maximum grades of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

RESULTS

A total of 41 veterans have received CAR-T infusion at TVHS to date. Twenty-nine of these veterans have at least one year post-CAR-T infusion data and are included in this analysis. The majority of veterans were White (72%), male (93%), and were treated for diffuse large B-cell lymphoma (86%). Twenty-eight percent of veterans were under-represented minorities. Average age was 61 years with 62% being 65 years and older and five (17%) veterans being over the age of 74. Day 30 ORR was 90% (45% complete response [CR]). One-year PFS was 55.2% and 1-year OS was 65.5%. Of the 19 veterans who achieved CR by day 100, 79% remain in CR to date. CRS toxicity was observed in 66% of veterans (0% Grade 3 or higher). ICANS was observed in 27.5% of veterans (24% Grade 3 or higher). Only 5 (26%) veterans required transfer to the intensive care unit for additional monitoring.

CONCLUSIONS

CAR-T therapy has become a wellestablished practice at TVHS and is a safe and effective treatment option for veterans with aggressive lymphoid malignancies. Our outcomes are similar to that seen nationally with better access to under-represented minorities in an aging population.

BACKGROUND

The safety and efficacy of biosimilars are carefully reviewed by the Food and Drug Administration (FDA) to ensure the biosimilar meets the high standards for approval. However, safety concerns from infusion nursing staff prompted a review of rituximab-PVVR and rituximab for any new trends in National VA, primary literature, and facility adverse events.

METHODS

Utilizing the VA ADERS (Veteran’s Affairs Adverse Drug Event Reporting System), data was analyzed from 01/01/21 thru 04/01/23. No clear trends were identified to support an increased reaction rate for Rituximab-PVVR or Rituximab. A total of 104 Rituximab product (both parent and biosimilar products) adverse reactions were reported nationally. Of those reported, about half 56 ADEs (54%) were specifically to Rituximab-PVVR.

RESULTS

Reviewing our facility specific VA ADERS data, Birmingham VA reported 7 ADEs. Similarly other sites reported a range of 0 to 13 Rituximab product ADEs. The total number of unique patients to receive a rituximab product in the Birmingham VA since 2021 is 106, resulting in an overall incidence rate of 6.6%.

DISCUSSION

Based on the recent publication, Safety of switching between rituximab biosimilars in onco-hematology “adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of biosimilars.” This prospective clinical trial published in 2021, reported grade 1 rituximab related infusion events in 7.1% of patients (n=83) which correlates closely to the reported incidence at our facility referenced above (6.6%). Our current pre-medications include acetaminophen, an antihistamine, and steroid 30 minutes prior to infusion. Although our interdisciplinary team deemed this appropriate, to improve and minimize infusion reaction symptoms, the following interventions were instituted including changing ORAL Diphenhydramine to intravenous Diphenhydramine 25mg IV and providing education to infusion nursing staff on the safety and efficacy of the rituximab and biosimilar products.

CONCLUSIONS

Following the intervention (04/07/23), 36 total unique patients received rituximab products with zero incidents reported. Although the results are limited, the data may suggest IV diphenhydramine reduces the severity of ADEs which may alter reporting or show a potential “nocebo” effect could be a factor with any rituximab infusion needing further evaluation.

BACKGROUND

The safety and efficacy of biosimilars are carefully reviewed by the Food and Drug Administration (FDA) to ensure the biosimilar meets the high standards for approval. However, safety concerns from infusion nursing staff prompted a review of rituximab-PVVR and rituximab for any new trends in National VA, primary literature, and facility adverse events.

METHODS

Utilizing the VA ADERS (Veteran’s Affairs Adverse Drug Event Reporting System), data was analyzed from 01/01/21 thru 04/01/23. No clear trends were identified to support an increased reaction rate for Rituximab-PVVR or Rituximab. A total of 104 Rituximab product (both parent and biosimilar products) adverse reactions were reported nationally. Of those reported, about half 56 ADEs (54%) were specifically to Rituximab-PVVR.

RESULTS

Reviewing our facility specific VA ADERS data, Birmingham VA reported 7 ADEs. Similarly other sites reported a range of 0 to 13 Rituximab product ADEs. The total number of unique patients to receive a rituximab product in the Birmingham VA since 2021 is 106, resulting in an overall incidence rate of 6.6%.

DISCUSSION

Based on the recent publication, Safety of switching between rituximab biosimilars in onco-hematology “adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of biosimilars.” This prospective clinical trial published in 2021, reported grade 1 rituximab related infusion events in 7.1% of patients (n=83) which correlates closely to the reported incidence at our facility referenced above (6.6%). Our current pre-medications include acetaminophen, an antihistamine, and steroid 30 minutes prior to infusion. Although our interdisciplinary team deemed this appropriate, to improve and minimize infusion reaction symptoms, the following interventions were instituted including changing ORAL Diphenhydramine to intravenous Diphenhydramine 25mg IV and providing education to infusion nursing staff on the safety and efficacy of the rituximab and biosimilar products.

CONCLUSIONS

Following the intervention (04/07/23), 36 total unique patients received rituximab products with zero incidents reported. Although the results are limited, the data may suggest IV diphenhydramine reduces the severity of ADEs which may alter reporting or show a potential “nocebo” effect could be a factor with any rituximab infusion needing further evaluation.

BACKGROUND

The safety and efficacy of biosimilars are carefully reviewed by the Food and Drug Administration (FDA) to ensure the biosimilar meets the high standards for approval. However, safety concerns from infusion nursing staff prompted a review of rituximab-PVVR and rituximab for any new trends in National VA, primary literature, and facility adverse events.

METHODS

Utilizing the VA ADERS (Veteran’s Affairs Adverse Drug Event Reporting System), data was analyzed from 01/01/21 thru 04/01/23. No clear trends were identified to support an increased reaction rate for Rituximab-PVVR or Rituximab. A total of 104 Rituximab product (both parent and biosimilar products) adverse reactions were reported nationally. Of those reported, about half 56 ADEs (54%) were specifically to Rituximab-PVVR.

RESULTS

Reviewing our facility specific VA ADERS data, Birmingham VA reported 7 ADEs. Similarly other sites reported a range of 0 to 13 Rituximab product ADEs. The total number of unique patients to receive a rituximab product in the Birmingham VA since 2021 is 106, resulting in an overall incidence rate of 6.6%.

DISCUSSION

Based on the recent publication, Safety of switching between rituximab biosimilars in onco-hematology “adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of biosimilars.” This prospective clinical trial published in 2021, reported grade 1 rituximab related infusion events in 7.1% of patients (n=83) which correlates closely to the reported incidence at our facility referenced above (6.6%). Our current pre-medications include acetaminophen, an antihistamine, and steroid 30 minutes prior to infusion. Although our interdisciplinary team deemed this appropriate, to improve and minimize infusion reaction symptoms, the following interventions were instituted including changing ORAL Diphenhydramine to intravenous Diphenhydramine 25mg IV and providing education to infusion nursing staff on the safety and efficacy of the rituximab and biosimilar products.

CONCLUSIONS

Following the intervention (04/07/23), 36 total unique patients received rituximab products with zero incidents reported. Although the results are limited, the data may suggest IV diphenhydramine reduces the severity of ADEs which may alter reporting or show a potential “nocebo” effect could be a factor with any rituximab infusion needing further evaluation.

INTRODUCTION

Gemcitabine is a part of National Comprehensive Cancer Network (NCCN) guidelines as salvage therapy for relapsed/refractory B-cell lymphomas, but its role in chronic lymphocytic leukemia (CLL) remains unclear. We describe a case of relapsed CLL showing complete response while on gemcitabine for another primary malignancy, suggesting a potential curative role of gemcitabine for CLL.

CASE REPORT

A 78-year-old male with relapsed CD38+ CLL with del11q on ibrutinib with partial response, presented with gross hematuria for one week. Of note, he was diagnosed with BRCA-negative Stage Ib pancreatic adenocarcinoma within the previous year, treated with surgery and adjuvant capecitabine-gemcitabine. Physical examination was unremarkable and bloodwork showed a white cell count of 32,000 cells/ mm3 with 1.5% lymphocytes, hemoglobin 9.5 g/dL, and platelets 866,000 cells/mm3. Hematuria remained persistent despite frequent bladder irrigations but resolved within a week of stopping ibrutinib. Eight months later, his white cell count is 6,600 cells/mm3, with 16% lymphocytes, hemoglobin 10.2 g/dL, platelets 519,000/m3, and CT scans show no pathological lymphadenopathy. A recent flow cytometry done for academic purposes showed no clonal B cells.

DISCUSSION

Relapsed CLL has a poor prognosis with no curative treatment. Gemcitabine is a part of NCCN guidelines for relapse/refractory B-cell lymphomas but is not included in guidelines for CLL. A study by Jamie et al in 2001 suggested the pre-clinical effectiveness of gemcitabine for relapsed/refractory CLL and phase II trials conducted in 2005 and 2012 on combination chemotherapy including gemcitabine have shown overall CLL response rates of 50-65%. The resolution of B-cell clonality and improvement in biochemical markers after treatment with gemcitabine for an alternate primary malignancy suggested that gemcitabine played a potential curative role in our patient. Further prospective studies are needed to explore this avenue for the role of gemcitabine as a salvage as well as potentially curative therapy for relapsed CLL with variable cytogenetics and treatment histories.

CONCLUSIONS

Gemcitabine is not part of NCCN guidelines for CLL currently but it is a reasonable treatment option for relapsed/refractory CLL. Further studies are needed to explore its potential curative role for relapsed CLL, and update existing guidelines.

INTRODUCTION

Gemcitabine is a part of National Comprehensive Cancer Network (NCCN) guidelines as salvage therapy for relapsed/refractory B-cell lymphomas, but its role in chronic lymphocytic leukemia (CLL) remains unclear. We describe a case of relapsed CLL showing complete response while on gemcitabine for another primary malignancy, suggesting a potential curative role of gemcitabine for CLL.

CASE REPORT

A 78-year-old male with relapsed CD38+ CLL with del11q on ibrutinib with partial response, presented with gross hematuria for one week. Of note, he was diagnosed with BRCA-negative Stage Ib pancreatic adenocarcinoma within the previous year, treated with surgery and adjuvant capecitabine-gemcitabine. Physical examination was unremarkable and bloodwork showed a white cell count of 32,000 cells/ mm3 with 1.5% lymphocytes, hemoglobin 9.5 g/dL, and platelets 866,000 cells/mm3. Hematuria remained persistent despite frequent bladder irrigations but resolved within a week of stopping ibrutinib. Eight months later, his white cell count is 6,600 cells/mm3, with 16% lymphocytes, hemoglobin 10.2 g/dL, platelets 519,000/m3, and CT scans show no pathological lymphadenopathy. A recent flow cytometry done for academic purposes showed no clonal B cells.

DISCUSSION

Relapsed CLL has a poor prognosis with no curative treatment. Gemcitabine is a part of NCCN guidelines for relapse/refractory B-cell lymphomas but is not included in guidelines for CLL. A study by Jamie et al in 2001 suggested the pre-clinical effectiveness of gemcitabine for relapsed/refractory CLL and phase II trials conducted in 2005 and 2012 on combination chemotherapy including gemcitabine have shown overall CLL response rates of 50-65%. The resolution of B-cell clonality and improvement in biochemical markers after treatment with gemcitabine for an alternate primary malignancy suggested that gemcitabine played a potential curative role in our patient. Further prospective studies are needed to explore this avenue for the role of gemcitabine as a salvage as well as potentially curative therapy for relapsed CLL with variable cytogenetics and treatment histories.

CONCLUSIONS

Gemcitabine is not part of NCCN guidelines for CLL currently but it is a reasonable treatment option for relapsed/refractory CLL. Further studies are needed to explore its potential curative role for relapsed CLL, and update existing guidelines.

INTRODUCTION

Gemcitabine is a part of National Comprehensive Cancer Network (NCCN) guidelines as salvage therapy for relapsed/refractory B-cell lymphomas, but its role in chronic lymphocytic leukemia (CLL) remains unclear. We describe a case of relapsed CLL showing complete response while on gemcitabine for another primary malignancy, suggesting a potential curative role of gemcitabine for CLL.

CASE REPORT

A 78-year-old male with relapsed CD38+ CLL with del11q on ibrutinib with partial response, presented with gross hematuria for one week. Of note, he was diagnosed with BRCA-negative Stage Ib pancreatic adenocarcinoma within the previous year, treated with surgery and adjuvant capecitabine-gemcitabine. Physical examination was unremarkable and bloodwork showed a white cell count of 32,000 cells/ mm3 with 1.5% lymphocytes, hemoglobin 9.5 g/dL, and platelets 866,000 cells/mm3. Hematuria remained persistent despite frequent bladder irrigations but resolved within a week of stopping ibrutinib. Eight months later, his white cell count is 6,600 cells/mm3, with 16% lymphocytes, hemoglobin 10.2 g/dL, platelets 519,000/m3, and CT scans show no pathological lymphadenopathy. A recent flow cytometry done for academic purposes showed no clonal B cells.

DISCUSSION

Relapsed CLL has a poor prognosis with no curative treatment. Gemcitabine is a part of NCCN guidelines for relapse/refractory B-cell lymphomas but is not included in guidelines for CLL. A study by Jamie et al in 2001 suggested the pre-clinical effectiveness of gemcitabine for relapsed/refractory CLL and phase II trials conducted in 2005 and 2012 on combination chemotherapy including gemcitabine have shown overall CLL response rates of 50-65%. The resolution of B-cell clonality and improvement in biochemical markers after treatment with gemcitabine for an alternate primary malignancy suggested that gemcitabine played a potential curative role in our patient. Further prospective studies are needed to explore this avenue for the role of gemcitabine as a salvage as well as potentially curative therapy for relapsed CLL with variable cytogenetics and treatment histories.

CONCLUSIONS

Gemcitabine is not part of NCCN guidelines for CLL currently but it is a reasonable treatment option for relapsed/refractory CLL. Further studies are needed to explore its potential curative role for relapsed CLL, and update existing guidelines.