Head & Neck/Thyroid Cancers

A small molecule can provide a “clinically meaningful reduction” in severe oral mucositis without affecting tumor control in head and neck cancer, according to an investigator from a phase 2 trial.

The molecule, GC4419 (avasopasem manganese), is designed to convert superoxide to hydrogen peroxide and oxygen, thereby protecting normal tissue from damage associated with radiotherapy.

Investigators tested GC4419 in a phase 2 trial of patients with locally advanced oral cavity or oropharynx cancer who received intensity-modulated radiotherapy plus cisplatin. Initial results from this trial were published in December (J Clin Oncol. 2019 Dec 1;37[34]:3256-65).

Carryn M. Anderson, MD, of University of Iowa Hospitals & Clinics in Iowa City, presented updated results at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

The trial (NCT02508389) enrolled 223 patients scheduled to be treated with intensity-modulated radiotherapy (60-72 Gy or greater than 50 Gy to more than two oral sites) plus cisplatin (weekly or every 3 weeks).

The patients were randomized to receive 30 mg of GC4419 (n = 73), 90 mg of GC4419 (n = 76), or placebo (n = 74) intravenously over 60 minutes prior to each radiotherapy fraction. Baseline patient and tumor characteristics were well balanced among the treatment arms.
 

Efficacy and safety

The study’s primary endpoint was the duration of severe oral mucositis. When compared with placebo, the 90-mg dose of GC4419 conferred a 92% reduction in median days of severe oral mucositis (P = .024).

The 90-mg dose of GC4419 also reduced the incidence of severe oral mucositis by 34% (P = .009) and the rate of grade 4 oral mucositis by 47% (P = .045) when compared with placebo.

“GC4419, particularly the 90-mg dosage, provides a clinically meaningful reduction in severe oral mucositis duration, incidence, and severity,” Dr. Anderson noted.

“Safety was comparable across study arms,” she added. “The most frequent adverse events were those already expected with cisplatin and radiation, and those were not worsened in any way by the addition of this drug.”

Adverse events expected with GC4419 were “mild and transient,” according to Dr. Anderson. These events included syncope, hypotension/orthostasis, and oral/facial paresthesia.

Grade 3 syncope occurred in 4% of patients in the placebo arm, 4% in the 30-mg arm, and 6% in the 90-mg arm. Grade 3 hypotension/orthostasis occurred in 6%, 4%, and 4%, respectively. Grade 1 oral/facial paresthesia occurred in 15%, 10%, and 19%, respectively.
 

Long-term outcomes

“The 1- and 2-year tumor control is similar with utilization of [GC4419], and this is consistent with the drug’s known mechanism and previous animal models,” Dr. Anderson said.

At 1 and 2 years, there were no significant differences between the treatment arms with regard to locoregional control, distant metastasis, progression-free survival, or overall survival.

The 1-year progression-free survival was 82% in the placebo arm, 86% in the 30-mg arm, and 80% in the 90-mg arm. The 1-year overall survival was 93%, 91%, and 88%, respectively.

The 2-year progression-free survival was 77% in the placebo arm, 76% in the 30-mg arm, and 77% in the 90-mg arm. The 1-year overall survival was 87%, 85%, and 86%, respectively.
 

From trials to practice

Despite the favorable results of this trial, meeting attendees expressed concerns that the administration of GC4419 may not be feasible in real-life because it is labor- and resource-intensive.

“Methodologically, the study was excellent,” said attendee Shahid Iqbal, MBBS, a consultant clinical oncologist at Newcastle upon Tyne Hospitals NHS Foundation Trust in the United Kingdom, who was not involved in this trial.

Dr. Iqbal noted that this placebo-controlled trial had a “very reasonable number of patients in each arm,” the 90-mg dose of GC4419 was “effective,” and the drug had “no adverse impact on survival.”

“However, in my personal opinion, this intravenous infusion on a daily basis is not feasible in real life,” Dr. Iqbal said. “I cannot see this becoming a standard of care in National Health Service UK. This is simply not cost-effective at all.”

Although she didn’t address costs, Dr. Anderson did acknowledge that administering GC4419 is labor intensive.

“But we are hopeful that, if this drug ultimately makes it to [Food and Drug Administration] approval, the efficacy benefits we are showing will make the work flow changes worthwhile,” she said. “We certainly have shown that, in this study, 44 institutions could make that happen. At the University of Iowa, we found it easiest to institute an infusion space within the department of radiation oncology rather than relying on our medical oncology colleagues to let us borrow a chair.”

GC4419 is now under investigation in a phase 3 trial (NCT03689712) and has received fast track and breakthrough therapy designations from the FDA.

The phase 2 trial was sponsored by Galera Therapeutics. Dr. Anderson is an uncompensated research adviser to the company. Dr. Iqbal has no relevant conflicts of interest.

[email protected]

SOURCE: Anderson CM et al. Head and Neck Cancer Symposium. Abstract LBA 2.

A small molecule can provide a “clinically meaningful reduction” in severe oral mucositis without affecting tumor control in head and neck cancer, according to an investigator from a phase 2 trial.

The molecule, GC4419 (avasopasem manganese), is designed to convert superoxide to hydrogen peroxide and oxygen, thereby protecting normal tissue from damage associated with radiotherapy.

Investigators tested GC4419 in a phase 2 trial of patients with locally advanced oral cavity or oropharynx cancer who received intensity-modulated radiotherapy plus cisplatin. Initial results from this trial were published in December (J Clin Oncol. 2019 Dec 1;37[34]:3256-65).

Carryn M. Anderson, MD, of University of Iowa Hospitals & Clinics in Iowa City, presented updated results at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

The trial (NCT02508389) enrolled 223 patients scheduled to be treated with intensity-modulated radiotherapy (60-72 Gy or greater than 50 Gy to more than two oral sites) plus cisplatin (weekly or every 3 weeks).

The patients were randomized to receive 30 mg of GC4419 (n = 73), 90 mg of GC4419 (n = 76), or placebo (n = 74) intravenously over 60 minutes prior to each radiotherapy fraction. Baseline patient and tumor characteristics were well balanced among the treatment arms.
 

Efficacy and safety

The study’s primary endpoint was the duration of severe oral mucositis. When compared with placebo, the 90-mg dose of GC4419 conferred a 92% reduction in median days of severe oral mucositis (P = .024).

The 90-mg dose of GC4419 also reduced the incidence of severe oral mucositis by 34% (P = .009) and the rate of grade 4 oral mucositis by 47% (P = .045) when compared with placebo.

“GC4419, particularly the 90-mg dosage, provides a clinically meaningful reduction in severe oral mucositis duration, incidence, and severity,” Dr. Anderson noted.

“Safety was comparable across study arms,” she added. “The most frequent adverse events were those already expected with cisplatin and radiation, and those were not worsened in any way by the addition of this drug.”

Adverse events expected with GC4419 were “mild and transient,” according to Dr. Anderson. These events included syncope, hypotension/orthostasis, and oral/facial paresthesia.

Grade 3 syncope occurred in 4% of patients in the placebo arm, 4% in the 30-mg arm, and 6% in the 90-mg arm. Grade 3 hypotension/orthostasis occurred in 6%, 4%, and 4%, respectively. Grade 1 oral/facial paresthesia occurred in 15%, 10%, and 19%, respectively.
 

Long-term outcomes

“The 1- and 2-year tumor control is similar with utilization of [GC4419], and this is consistent with the drug’s known mechanism and previous animal models,” Dr. Anderson said.

At 1 and 2 years, there were no significant differences between the treatment arms with regard to locoregional control, distant metastasis, progression-free survival, or overall survival.

The 1-year progression-free survival was 82% in the placebo arm, 86% in the 30-mg arm, and 80% in the 90-mg arm. The 1-year overall survival was 93%, 91%, and 88%, respectively.

The 2-year progression-free survival was 77% in the placebo arm, 76% in the 30-mg arm, and 77% in the 90-mg arm. The 1-year overall survival was 87%, 85%, and 86%, respectively.
 

From trials to practice

Despite the favorable results of this trial, meeting attendees expressed concerns that the administration of GC4419 may not be feasible in real-life because it is labor- and resource-intensive.

“Methodologically, the study was excellent,” said attendee Shahid Iqbal, MBBS, a consultant clinical oncologist at Newcastle upon Tyne Hospitals NHS Foundation Trust in the United Kingdom, who was not involved in this trial.

Dr. Iqbal noted that this placebo-controlled trial had a “very reasonable number of patients in each arm,” the 90-mg dose of GC4419 was “effective,” and the drug had “no adverse impact on survival.”

“However, in my personal opinion, this intravenous infusion on a daily basis is not feasible in real life,” Dr. Iqbal said. “I cannot see this becoming a standard of care in National Health Service UK. This is simply not cost-effective at all.”

Although she didn’t address costs, Dr. Anderson did acknowledge that administering GC4419 is labor intensive.

“But we are hopeful that, if this drug ultimately makes it to [Food and Drug Administration] approval, the efficacy benefits we are showing will make the work flow changes worthwhile,” she said. “We certainly have shown that, in this study, 44 institutions could make that happen. At the University of Iowa, we found it easiest to institute an infusion space within the department of radiation oncology rather than relying on our medical oncology colleagues to let us borrow a chair.”

GC4419 is now under investigation in a phase 3 trial (NCT03689712) and has received fast track and breakthrough therapy designations from the FDA.

The phase 2 trial was sponsored by Galera Therapeutics. Dr. Anderson is an uncompensated research adviser to the company. Dr. Iqbal has no relevant conflicts of interest.

[email protected]

SOURCE: Anderson CM et al. Head and Neck Cancer Symposium. Abstract LBA 2.

A small molecule can provide a “clinically meaningful reduction” in severe oral mucositis without affecting tumor control in head and neck cancer, according to an investigator from a phase 2 trial.

The molecule, GC4419 (avasopasem manganese), is designed to convert superoxide to hydrogen peroxide and oxygen, thereby protecting normal tissue from damage associated with radiotherapy.

Investigators tested GC4419 in a phase 2 trial of patients with locally advanced oral cavity or oropharynx cancer who received intensity-modulated radiotherapy plus cisplatin. Initial results from this trial were published in December (J Clin Oncol. 2019 Dec 1;37[34]:3256-65).

Carryn M. Anderson, MD, of University of Iowa Hospitals & Clinics in Iowa City, presented updated results at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

The trial (NCT02508389) enrolled 223 patients scheduled to be treated with intensity-modulated radiotherapy (60-72 Gy or greater than 50 Gy to more than two oral sites) plus cisplatin (weekly or every 3 weeks).

The patients were randomized to receive 30 mg of GC4419 (n = 73), 90 mg of GC4419 (n = 76), or placebo (n = 74) intravenously over 60 minutes prior to each radiotherapy fraction. Baseline patient and tumor characteristics were well balanced among the treatment arms.
 

Efficacy and safety

The study’s primary endpoint was the duration of severe oral mucositis. When compared with placebo, the 90-mg dose of GC4419 conferred a 92% reduction in median days of severe oral mucositis (P = .024).

The 90-mg dose of GC4419 also reduced the incidence of severe oral mucositis by 34% (P = .009) and the rate of grade 4 oral mucositis by 47% (P = .045) when compared with placebo.

“GC4419, particularly the 90-mg dosage, provides a clinically meaningful reduction in severe oral mucositis duration, incidence, and severity,” Dr. Anderson noted.

“Safety was comparable across study arms,” she added. “The most frequent adverse events were those already expected with cisplatin and radiation, and those were not worsened in any way by the addition of this drug.”

Adverse events expected with GC4419 were “mild and transient,” according to Dr. Anderson. These events included syncope, hypotension/orthostasis, and oral/facial paresthesia.

Grade 3 syncope occurred in 4% of patients in the placebo arm, 4% in the 30-mg arm, and 6% in the 90-mg arm. Grade 3 hypotension/orthostasis occurred in 6%, 4%, and 4%, respectively. Grade 1 oral/facial paresthesia occurred in 15%, 10%, and 19%, respectively.
 

Long-term outcomes

“The 1- and 2-year tumor control is similar with utilization of [GC4419], and this is consistent with the drug’s known mechanism and previous animal models,” Dr. Anderson said.

At 1 and 2 years, there were no significant differences between the treatment arms with regard to locoregional control, distant metastasis, progression-free survival, or overall survival.

The 1-year progression-free survival was 82% in the placebo arm, 86% in the 30-mg arm, and 80% in the 90-mg arm. The 1-year overall survival was 93%, 91%, and 88%, respectively.

The 2-year progression-free survival was 77% in the placebo arm, 76% in the 30-mg arm, and 77% in the 90-mg arm. The 1-year overall survival was 87%, 85%, and 86%, respectively.
 

From trials to practice

Despite the favorable results of this trial, meeting attendees expressed concerns that the administration of GC4419 may not be feasible in real-life because it is labor- and resource-intensive.

“Methodologically, the study was excellent,” said attendee Shahid Iqbal, MBBS, a consultant clinical oncologist at Newcastle upon Tyne Hospitals NHS Foundation Trust in the United Kingdom, who was not involved in this trial.

Dr. Iqbal noted that this placebo-controlled trial had a “very reasonable number of patients in each arm,” the 90-mg dose of GC4419 was “effective,” and the drug had “no adverse impact on survival.”

“However, in my personal opinion, this intravenous infusion on a daily basis is not feasible in real life,” Dr. Iqbal said. “I cannot see this becoming a standard of care in National Health Service UK. This is simply not cost-effective at all.”

Although she didn’t address costs, Dr. Anderson did acknowledge that administering GC4419 is labor intensive.

“But we are hopeful that, if this drug ultimately makes it to [Food and Drug Administration] approval, the efficacy benefits we are showing will make the work flow changes worthwhile,” she said. “We certainly have shown that, in this study, 44 institutions could make that happen. At the University of Iowa, we found it easiest to institute an infusion space within the department of radiation oncology rather than relying on our medical oncology colleagues to let us borrow a chair.”

GC4419 is now under investigation in a phase 3 trial (NCT03689712) and has received fast track and breakthrough therapy designations from the FDA.

The phase 2 trial was sponsored by Galera Therapeutics. Dr. Anderson is an uncompensated research adviser to the company. Dr. Iqbal has no relevant conflicts of interest.

[email protected]

SOURCE: Anderson CM et al. Head and Neck Cancer Symposium. Abstract LBA 2.

The combination of radiotherapy plus pembrolizumab (Keytruda, Merck) leads to good disease control in recurrent or metastatic head and neck squamous cell cancer (HNSCC) in patients for whom cisplatin would prove to be too toxic, a phase 2 trial suggests.

“There are convincing arguments that radiation sensitizes patients to immunotherapy and can enhance its effects,” Jared Weiss, MD, associate professor of medicine, UNC Lineberger Comprehensive Cancer, Chapel Hill, North Carolina, said in a statement.

“And the opposite direction also seems to be true – radiation therapy needs a functional immune system to work. Our hope was that pembrolizumab might be a radiation sensitizer for these patients,” he said.

The study was presented at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

Both modalities have had some outstanding results in the past, observed Weiss. “If you look back to the historic studies, radiation alone often cures patients with this disease, while some of the first patients treated with pembrolizumab for recurrent/metastatic cancer are still alive many years out, with no evidence of disease,” he said.

“Our concept was that, in addition to whatever synergy the immunotherapy might provide with radiation, we also conceived of it as a ‘second shot on goal’ towards a cure, because there is durable control with drug alone,” he added.

Single-arm trial

The single-arm trial included 29 patients with locally advanced HNSCC.

Only about 10% of patients were current smokers, but more than half of the study group had a history of smoking. Of those, more than 55% had a history of 10 pack-years or more.

In slightly more than one third of patients, the primary site of the cancer was the base of the tongue. The tonsils were the primary site in slightly more than one third.

Platinum ineligibility was defined by provider and standard measures.

More than two thirds of patients were ineligible to receive cisplatin because of preexisting otopathy, including hearing impairment and tinnitus.

The combination of cisplatin and definitive-dose radiotherapy is standard treatment for locally advanced head and neck cancer, but contraindications to cisplatin are common in everyday clinical practice. Weiss noted that contraindications are present in about one third of his patients.

“We replaced standard, every-3-week cisplatin with pembrolizumab every 3 weeks,” Weiss explained, “and we hypothesized that with the ongoing effects of radiation therapy after completion, that additional adjuvant cycles could further sensitize patients [to the effects of radiation] without impairing recovery, so we added three adjuvant cycles as well,” he added.

With six cycles of an every-3-week drug, patients received 18 weeks of pembrolizumab in total.

Echoing results from the previously reported KEYNOTE-48 trial, pembrolizumab given with radiotherapy instead of chemotherapy led to an overall progression-free survival (PFS) rate of 76% at 1 year and an estimated PFS of 71% at 2 years.

At 1 year, 86% of patients were still alive, and at 2 years, an estimated 75% of patients were still alive, Weiss added.

For patients with human papillomavirus 16–positive cancer, rates of PFS and overall survival were slightly better, at 88% and 94%, respectively.

With regard to toxicities, “For the most part, this [treatment regimen] looks like radiation alone with one very notable exception, which was lymphopenia,” Weiss observed. Grade 3-4 lymphopenia affected 59% of patients.

Lymphocyte count hit bottom at week 4, he added, with only partial recovery at week 20 and no further recovery at 40 weeks. Lymphocyte count alone or any change in it was not predictive of early progression.

However, in comparing patients who experienced early disease progression to patients who did not experience progression, levels of baseline naive B cells in peripheral blood were higher and levels of circulating marginal zone B cells were lower in patients with progressive disease, Weiss reported.

Patient-reported outcomes indicated that common symptoms of treatment peaked at week 10, and there was relative recovery by week 20.

As reflected by Functional Assessment of Cancer Therapy (FACT) scores, which include social, emotional, and functional well-being, as well as the head and neck cancer scale, “we again see a nadir at 10 weeks with relative recovery at 20 weeks,” Weiss noted.

“We found that concurrent pembrolizumab with radiotherapy is a safe and feasible option for locally advanced head and neck cancer patients with cisplatin ineligibility,” Weiss concluded.

More research is being conducted in this area, and multiple ongoing studies will further elucidate the value of PD-1 or PD-L1 checkpoint blockade with definitive radiation therapy, he added.

The study was funded by Merck & Co. Weiss’ institution has received research funding from Celgene, Pfizer, Merck, AZ/Medimmmune, Amgen, Carefusion, G1 Therapeutics, Immunicum, Loxo/Lilly, and the Jimmy V Foundation. Weiss has received honoraria for consulting from AstraZeneca, EMD Serono, Genentech, Inivata, Celgene, G1 Therapeutics, Jounce Therapeutics, Abbvie, Rakuten, Nanobiotix, Azitra, Loxo/Lilly, Pfizer, and Blueprint had has stock in Nektar and Vesselon.

This article first appeared on Medscape.com.

The combination of radiotherapy plus pembrolizumab (Keytruda, Merck) leads to good disease control in recurrent or metastatic head and neck squamous cell cancer (HNSCC) in patients for whom cisplatin would prove to be too toxic, a phase 2 trial suggests.

“There are convincing arguments that radiation sensitizes patients to immunotherapy and can enhance its effects,” Jared Weiss, MD, associate professor of medicine, UNC Lineberger Comprehensive Cancer, Chapel Hill, North Carolina, said in a statement.

“And the opposite direction also seems to be true – radiation therapy needs a functional immune system to work. Our hope was that pembrolizumab might be a radiation sensitizer for these patients,” he said.

The study was presented at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

Both modalities have had some outstanding results in the past, observed Weiss. “If you look back to the historic studies, radiation alone often cures patients with this disease, while some of the first patients treated with pembrolizumab for recurrent/metastatic cancer are still alive many years out, with no evidence of disease,” he said.

“Our concept was that, in addition to whatever synergy the immunotherapy might provide with radiation, we also conceived of it as a ‘second shot on goal’ towards a cure, because there is durable control with drug alone,” he added.

Single-arm trial

The single-arm trial included 29 patients with locally advanced HNSCC.

Only about 10% of patients were current smokers, but more than half of the study group had a history of smoking. Of those, more than 55% had a history of 10 pack-years or more.

In slightly more than one third of patients, the primary site of the cancer was the base of the tongue. The tonsils were the primary site in slightly more than one third.

Platinum ineligibility was defined by provider and standard measures.

More than two thirds of patients were ineligible to receive cisplatin because of preexisting otopathy, including hearing impairment and tinnitus.

The combination of cisplatin and definitive-dose radiotherapy is standard treatment for locally advanced head and neck cancer, but contraindications to cisplatin are common in everyday clinical practice. Weiss noted that contraindications are present in about one third of his patients.

“We replaced standard, every-3-week cisplatin with pembrolizumab every 3 weeks,” Weiss explained, “and we hypothesized that with the ongoing effects of radiation therapy after completion, that additional adjuvant cycles could further sensitize patients [to the effects of radiation] without impairing recovery, so we added three adjuvant cycles as well,” he added.

With six cycles of an every-3-week drug, patients received 18 weeks of pembrolizumab in total.

Echoing results from the previously reported KEYNOTE-48 trial, pembrolizumab given with radiotherapy instead of chemotherapy led to an overall progression-free survival (PFS) rate of 76% at 1 year and an estimated PFS of 71% at 2 years.

At 1 year, 86% of patients were still alive, and at 2 years, an estimated 75% of patients were still alive, Weiss added.

For patients with human papillomavirus 16–positive cancer, rates of PFS and overall survival were slightly better, at 88% and 94%, respectively.

With regard to toxicities, “For the most part, this [treatment regimen] looks like radiation alone with one very notable exception, which was lymphopenia,” Weiss observed. Grade 3-4 lymphopenia affected 59% of patients.

Lymphocyte count hit bottom at week 4, he added, with only partial recovery at week 20 and no further recovery at 40 weeks. Lymphocyte count alone or any change in it was not predictive of early progression.

However, in comparing patients who experienced early disease progression to patients who did not experience progression, levels of baseline naive B cells in peripheral blood were higher and levels of circulating marginal zone B cells were lower in patients with progressive disease, Weiss reported.

Patient-reported outcomes indicated that common symptoms of treatment peaked at week 10, and there was relative recovery by week 20.

As reflected by Functional Assessment of Cancer Therapy (FACT) scores, which include social, emotional, and functional well-being, as well as the head and neck cancer scale, “we again see a nadir at 10 weeks with relative recovery at 20 weeks,” Weiss noted.

“We found that concurrent pembrolizumab with radiotherapy is a safe and feasible option for locally advanced head and neck cancer patients with cisplatin ineligibility,” Weiss concluded.

More research is being conducted in this area, and multiple ongoing studies will further elucidate the value of PD-1 or PD-L1 checkpoint blockade with definitive radiation therapy, he added.

The study was funded by Merck & Co. Weiss’ institution has received research funding from Celgene, Pfizer, Merck, AZ/Medimmmune, Amgen, Carefusion, G1 Therapeutics, Immunicum, Loxo/Lilly, and the Jimmy V Foundation. Weiss has received honoraria for consulting from AstraZeneca, EMD Serono, Genentech, Inivata, Celgene, G1 Therapeutics, Jounce Therapeutics, Abbvie, Rakuten, Nanobiotix, Azitra, Loxo/Lilly, Pfizer, and Blueprint had has stock in Nektar and Vesselon.

This article first appeared on Medscape.com.

The combination of radiotherapy plus pembrolizumab (Keytruda, Merck) leads to good disease control in recurrent or metastatic head and neck squamous cell cancer (HNSCC) in patients for whom cisplatin would prove to be too toxic, a phase 2 trial suggests.

“There are convincing arguments that radiation sensitizes patients to immunotherapy and can enhance its effects,” Jared Weiss, MD, associate professor of medicine, UNC Lineberger Comprehensive Cancer, Chapel Hill, North Carolina, said in a statement.

“And the opposite direction also seems to be true – radiation therapy needs a functional immune system to work. Our hope was that pembrolizumab might be a radiation sensitizer for these patients,” he said.

The study was presented at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

Both modalities have had some outstanding results in the past, observed Weiss. “If you look back to the historic studies, radiation alone often cures patients with this disease, while some of the first patients treated with pembrolizumab for recurrent/metastatic cancer are still alive many years out, with no evidence of disease,” he said.

“Our concept was that, in addition to whatever synergy the immunotherapy might provide with radiation, we also conceived of it as a ‘second shot on goal’ towards a cure, because there is durable control with drug alone,” he added.

Single-arm trial

The single-arm trial included 29 patients with locally advanced HNSCC.

Only about 10% of patients were current smokers, but more than half of the study group had a history of smoking. Of those, more than 55% had a history of 10 pack-years or more.

In slightly more than one third of patients, the primary site of the cancer was the base of the tongue. The tonsils were the primary site in slightly more than one third.

Platinum ineligibility was defined by provider and standard measures.

More than two thirds of patients were ineligible to receive cisplatin because of preexisting otopathy, including hearing impairment and tinnitus.

The combination of cisplatin and definitive-dose radiotherapy is standard treatment for locally advanced head and neck cancer, but contraindications to cisplatin are common in everyday clinical practice. Weiss noted that contraindications are present in about one third of his patients.

“We replaced standard, every-3-week cisplatin with pembrolizumab every 3 weeks,” Weiss explained, “and we hypothesized that with the ongoing effects of radiation therapy after completion, that additional adjuvant cycles could further sensitize patients [to the effects of radiation] without impairing recovery, so we added three adjuvant cycles as well,” he added.

With six cycles of an every-3-week drug, patients received 18 weeks of pembrolizumab in total.

Echoing results from the previously reported KEYNOTE-48 trial, pembrolizumab given with radiotherapy instead of chemotherapy led to an overall progression-free survival (PFS) rate of 76% at 1 year and an estimated PFS of 71% at 2 years.

At 1 year, 86% of patients were still alive, and at 2 years, an estimated 75% of patients were still alive, Weiss added.

For patients with human papillomavirus 16–positive cancer, rates of PFS and overall survival were slightly better, at 88% and 94%, respectively.

With regard to toxicities, “For the most part, this [treatment regimen] looks like radiation alone with one very notable exception, which was lymphopenia,” Weiss observed. Grade 3-4 lymphopenia affected 59% of patients.

Lymphocyte count hit bottom at week 4, he added, with only partial recovery at week 20 and no further recovery at 40 weeks. Lymphocyte count alone or any change in it was not predictive of early progression.

However, in comparing patients who experienced early disease progression to patients who did not experience progression, levels of baseline naive B cells in peripheral blood were higher and levels of circulating marginal zone B cells were lower in patients with progressive disease, Weiss reported.

Patient-reported outcomes indicated that common symptoms of treatment peaked at week 10, and there was relative recovery by week 20.

As reflected by Functional Assessment of Cancer Therapy (FACT) scores, which include social, emotional, and functional well-being, as well as the head and neck cancer scale, “we again see a nadir at 10 weeks with relative recovery at 20 weeks,” Weiss noted.

“We found that concurrent pembrolizumab with radiotherapy is a safe and feasible option for locally advanced head and neck cancer patients with cisplatin ineligibility,” Weiss concluded.

More research is being conducted in this area, and multiple ongoing studies will further elucidate the value of PD-1 or PD-L1 checkpoint blockade with definitive radiation therapy, he added.

The study was funded by Merck & Co. Weiss’ institution has received research funding from Celgene, Pfizer, Merck, AZ/Medimmmune, Amgen, Carefusion, G1 Therapeutics, Immunicum, Loxo/Lilly, and the Jimmy V Foundation. Weiss has received honoraria for consulting from AstraZeneca, EMD Serono, Genentech, Inivata, Celgene, G1 Therapeutics, Jounce Therapeutics, Abbvie, Rakuten, Nanobiotix, Azitra, Loxo/Lilly, Pfizer, and Blueprint had has stock in Nektar and Vesselon.

This article first appeared on Medscape.com.

Everolimus, a safe, cheap and well-tolerated drug, prolonged progression-free survival (PFS) compared with placebo during the year patients with advanced head and neck squamous cell carcinoma (HNSCC) were on it, a phase 2 study indicates.

Advanced HNSCC

The investigator-initiated trial randomly assigned 28 patients with advanced HNSCC to everolimus 10 mg orally once daily or placebo for a maximum of 1 year or until disease progression, whichever came first.

Patients had stage IV HNSCC but had to be disease-free clinically and radiologically following definitive treatment with chemoradiation or surgery followed by chemoradiation. There was no difference in the type of definitive treatment received prior to the intervention between the two groups.

Adjuvant therapy was initiated between 8 and 16 weeks after completing definitive therapy.

If patients had HPV-positive oropharyngeal cancer, they had to have a minimum of 10 pack-years of smoking history.

“The primary endpoint was PFS at 2 years; the secondary endpoint was toxicity,” Nathan observed.

Oral mucositis and leukopenia were common but only 7% of patients developed grade 3 mucositis or leukopenia.

Other grade 3 or greater toxicities were reported in 16 patients and were similar to the adverse events (AEs) noted in other trials with everolimus. Only two patients developed serious AEs possibly related to the drug.

At 1 year, 81% of patients on everolimus were disease-free compared with 57% of patients on placebo (P = .04), Nathan reported.

However, at 2 years, PFS – although continuing to favor those treated with adjuvant therapy – was no longer significant even though it was clear that during the year patients were receiving treatment, “there was a consistent, protective effect of everolimus,” Nathan suggested.
 

Special effect among TP53-mutated patients?

Targeted exon sequencing was also carried out, the results from which showed that TP53 was the most commonly mutated gene.

“As expected, HPV-negative tumors were more likely to be mutated for TP53,” Nathan observed. Approximately 80% of HPV-negative smoking-related HNSCC tumors carry the TP53 mutation.

Interestingly, survival rates were significantly higher in TP53-mutated patients treated with everolimus: 70% of the patients were still alive at 2 years compared with only 22% of placebo controls (P = .026), she said.

This is a surprising finding, Nathan suggested, as patients with TP53 mutations traditionally have worse survival than those without, suggesting that these patients in particular appear to benefit from adjuvant everolimus.

“Everolimus is used for patients with breast cancer or renal cell cancer for extended periods without major side effects and there is potential for patients with TP53-mutated head and neck disease to see a survival benefit as well,” Nathan speculated.

However, additional trials are needed to confirm the link between the TP53 mutation and survival and to assess the safety of keeping patients with HNSCC on an mTOR inhibitor for longer than 1 year.

The study was funded by Novartis. Nathan has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Everolimus, a safe, cheap and well-tolerated drug, prolonged progression-free survival (PFS) compared with placebo during the year patients with advanced head and neck squamous cell carcinoma (HNSCC) were on it, a phase 2 study indicates.

Advanced HNSCC

The investigator-initiated trial randomly assigned 28 patients with advanced HNSCC to everolimus 10 mg orally once daily or placebo for a maximum of 1 year or until disease progression, whichever came first.

Patients had stage IV HNSCC but had to be disease-free clinically and radiologically following definitive treatment with chemoradiation or surgery followed by chemoradiation. There was no difference in the type of definitive treatment received prior to the intervention between the two groups.

Adjuvant therapy was initiated between 8 and 16 weeks after completing definitive therapy.

If patients had HPV-positive oropharyngeal cancer, they had to have a minimum of 10 pack-years of smoking history.

“The primary endpoint was PFS at 2 years; the secondary endpoint was toxicity,” Nathan observed.

Oral mucositis and leukopenia were common but only 7% of patients developed grade 3 mucositis or leukopenia.

Other grade 3 or greater toxicities were reported in 16 patients and were similar to the adverse events (AEs) noted in other trials with everolimus. Only two patients developed serious AEs possibly related to the drug.

At 1 year, 81% of patients on everolimus were disease-free compared with 57% of patients on placebo (P = .04), Nathan reported.

However, at 2 years, PFS – although continuing to favor those treated with adjuvant therapy – was no longer significant even though it was clear that during the year patients were receiving treatment, “there was a consistent, protective effect of everolimus,” Nathan suggested.
 

Special effect among TP53-mutated patients?

Targeted exon sequencing was also carried out, the results from which showed that TP53 was the most commonly mutated gene.

“As expected, HPV-negative tumors were more likely to be mutated for TP53,” Nathan observed. Approximately 80% of HPV-negative smoking-related HNSCC tumors carry the TP53 mutation.

Interestingly, survival rates were significantly higher in TP53-mutated patients treated with everolimus: 70% of the patients were still alive at 2 years compared with only 22% of placebo controls (P = .026), she said.

This is a surprising finding, Nathan suggested, as patients with TP53 mutations traditionally have worse survival than those without, suggesting that these patients in particular appear to benefit from adjuvant everolimus.

“Everolimus is used for patients with breast cancer or renal cell cancer for extended periods without major side effects and there is potential for patients with TP53-mutated head and neck disease to see a survival benefit as well,” Nathan speculated.

However, additional trials are needed to confirm the link between the TP53 mutation and survival and to assess the safety of keeping patients with HNSCC on an mTOR inhibitor for longer than 1 year.

The study was funded by Novartis. Nathan has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Everolimus, a safe, cheap and well-tolerated drug, prolonged progression-free survival (PFS) compared with placebo during the year patients with advanced head and neck squamous cell carcinoma (HNSCC) were on it, a phase 2 study indicates.

Advanced HNSCC

The investigator-initiated trial randomly assigned 28 patients with advanced HNSCC to everolimus 10 mg orally once daily or placebo for a maximum of 1 year or until disease progression, whichever came first.

Patients had stage IV HNSCC but had to be disease-free clinically and radiologically following definitive treatment with chemoradiation or surgery followed by chemoradiation. There was no difference in the type of definitive treatment received prior to the intervention between the two groups.

Adjuvant therapy was initiated between 8 and 16 weeks after completing definitive therapy.

If patients had HPV-positive oropharyngeal cancer, they had to have a minimum of 10 pack-years of smoking history.

“The primary endpoint was PFS at 2 years; the secondary endpoint was toxicity,” Nathan observed.

Oral mucositis and leukopenia were common but only 7% of patients developed grade 3 mucositis or leukopenia.

Other grade 3 or greater toxicities were reported in 16 patients and were similar to the adverse events (AEs) noted in other trials with everolimus. Only two patients developed serious AEs possibly related to the drug.

At 1 year, 81% of patients on everolimus were disease-free compared with 57% of patients on placebo (P = .04), Nathan reported.

However, at 2 years, PFS – although continuing to favor those treated with adjuvant therapy – was no longer significant even though it was clear that during the year patients were receiving treatment, “there was a consistent, protective effect of everolimus,” Nathan suggested.
 

Special effect among TP53-mutated patients?

Targeted exon sequencing was also carried out, the results from which showed that TP53 was the most commonly mutated gene.

“As expected, HPV-negative tumors were more likely to be mutated for TP53,” Nathan observed. Approximately 80% of HPV-negative smoking-related HNSCC tumors carry the TP53 mutation.

Interestingly, survival rates were significantly higher in TP53-mutated patients treated with everolimus: 70% of the patients were still alive at 2 years compared with only 22% of placebo controls (P = .026), she said.

This is a surprising finding, Nathan suggested, as patients with TP53 mutations traditionally have worse survival than those without, suggesting that these patients in particular appear to benefit from adjuvant everolimus.

“Everolimus is used for patients with breast cancer or renal cell cancer for extended periods without major side effects and there is potential for patients with TP53-mutated head and neck disease to see a survival benefit as well,” Nathan speculated.

However, additional trials are needed to confirm the link between the TP53 mutation and survival and to assess the safety of keeping patients with HNSCC on an mTOR inhibitor for longer than 1 year.

The study was funded by Novartis. Nathan has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Adding cetuximab to radiotherapy and cisplatin does not improve outcomes in patients with locoregionally advanced head and neck carcinoma, according to 10-year follow-up from a phase 3 trial.

The addition of cetuximab did not reduce local-regional failure or distant metastasis, and it did not improve progression-free or overall survival.

“With a median follow-up of over 10 years, this updated report confirms the addition of cetuximab to radiation/cisplatin did not improve any measured outcome in the entire cohort or when stratifying by p16 status,” said Jimmy J. Caudell, MD, of Moffitt Cancer Center in Tampa, Fla.

Dr. Caudell presented this update at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

Dr. Caudell noted that cisplatin plus radiotherapy or cetuximab plus radiotherapy have been shown to improve overall survival in patients with locoregionally advanced head and neck carcinoma. Researchers conducted this phase 3 trial, RTOG 0522 (NCT00265941), to determine if adding cetuximab to radiotherapy and cisplatin would improve progression-free survival.

The trial included 891 evaluable patients with stage T2 N2a-3 M0 or T3-4 N0-3 M0 disease. They were randomized to receive radiotherapy and cisplatin without cetuximab (n = 447) or with cetuximab (n = 444). Most patients were assigned to intensity-modulated radiotherapy (86.8% in the radiotherapy/cisplatin arm and 89.2% in the cetuximab arm) rather than 3-D conformal radiotherapy (13.2% and 10.8%, respectively).

Baseline characteristics were balanced between the treatment arms. The median age was 57 years (range, 31-79 years) in the radiotherapy/cisplatin arm and 58 years (range, 34-76 years) in the cetuximab arm. Nearly 90% of patients in both arms were men, and the oropharynx was the primary site of disease in about 70% of patients in both arms.

More patients were p16-positive (35.7% in the radiotherapy/cisplatin arm and 39.4% in the cetuximab arm) than were p16-negative (14.4% and 13.1%, respectively). However, p16 status was unknown for about half of patients in each arm.
 

Long-term efficacy

At a median follow-up of 10.1 years, 452 patients were still alive.

The rate of local-regional failure was 28.5% in the radiotherapy/cisplatin arm and 34.8% in the cetuximab arm (hazard ratio, 1.21; P = .94). The rate of distant metastases was 15% and 11.8%, respectively (HR, 0.79; P = .10).

The 10-year progression-free survival rate was 43.6% in the radiotherapy/cisplatin arm and 40.2% in the cetuximab arm (HR, 1.06; P = .74). The 10-year overall survival rate was 49.9% and 50%, respectively (HR, 0.97; P = .36)

“As might be expected, patients who were p16-positive had a substantially improved progression-free survival as well as overall survival,” Dr. Caudell said. “Patients who had p16-negative oropharyngeal cancer or nonoropharyngeal cancer had equivalent progression-free survival and overall survival.”

However, the addition of cetuximab did not improve progression-free or overall survival in patients with p16-positive, p16-negative oropharyngeal, or nonoropharyngeal cancers.

“[These results] have proven conclusively that the addition of cetuximab to concurrent cisplatin and radiation therapy does not improve outcomes in stage III-IV head and neck cancer, regardless of the primary tumor site and p16 status,” said Kartik Sehgal, MD, of Beth Israel Deaconess Medical Center in Boston, who was not involved in this study.
 

Late toxicity

Dr. Caudell noted that late toxicity was “substantial” in both treatment arms. Late toxicity was defined as adverse events occurring greater than 90 days from the start of radiotherapy.

The incidence of grade 3/4 late toxicity was 57.4% in the radiotherapy/cisplatin arm and 61.3% in the cetuximab arm (P = .26). The most common grade 3/4 late adverse event was dysphagia, occurring in 39.6% of patients in the radiotherapy/cisplatin arm and 38.2% of those in the cetuximab arm.

Other late grade 3/4 events (in the radiotherapy/cisplatin and cetuximab arms, respectively) included dry mouth (3% and 5%), radiation mucositis (5.3% and 7%), weight decrease (7.6% and 8.7%), hearing impairment (6% and 5%), pharynx mucositis/stomatitis (4.9% and 6%), and osteonecrosis (6% and 4.8%).

Feeding tube use was similar in both treatment arms over time. At 10 years, 14.3% of patients in the radiotherapy/cisplatin arm and 11% of those in the cetuximab arm used a feeding tube (P = .53).

“Despite the use of intensity-modulated radiotherapy, there was a high incidence of late grade 3 and higher toxicities, primarily related to dysphagia, which have substantial effects on the quality of life of our patients,” Dr. Sehgal noted. “These findings need to be considered carefully while designing future studies.

“Future directions for the management of locoregionally advanced head and neck cancer include evaluation of benefits from the addition of immune checkpoint inhibitors to cisplatin with concurrent radiation therapy (e.g., JAVELIN with avelumab [NCT01772004], KEYNOTE-412 with pembrolizumab [NCT03040999], and NCT03349710 with nivolumab) and whether immune checkpoint inhibitors can substitute for cisplatin in those being treated concurrently with radiation therapy (e.g., REACH trial comparing avelumab, cetuximab, and radiation therapy versus cisplatin plus radiation therapy [NCT02999087]).”

The current study was sponsored by the Radiation Therapy Oncology Group, the National Cancer Institute, NRG Oncology, and Eli Lilly. Dr. Caudell disclosed grants and fees from Varian Medical Systems. Dr. Sehgal had no conflicts of interest to disclose.

[email protected]

SOURCE: Caudell J et al. Head and Neck Cancers Symposium 2020, Abstract 6.

Adding cetuximab to radiotherapy and cisplatin does not improve outcomes in patients with locoregionally advanced head and neck carcinoma, according to 10-year follow-up from a phase 3 trial.

The addition of cetuximab did not reduce local-regional failure or distant metastasis, and it did not improve progression-free or overall survival.

“With a median follow-up of over 10 years, this updated report confirms the addition of cetuximab to radiation/cisplatin did not improve any measured outcome in the entire cohort or when stratifying by p16 status,” said Jimmy J. Caudell, MD, of Moffitt Cancer Center in Tampa, Fla.

Dr. Caudell presented this update at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

Dr. Caudell noted that cisplatin plus radiotherapy or cetuximab plus radiotherapy have been shown to improve overall survival in patients with locoregionally advanced head and neck carcinoma. Researchers conducted this phase 3 trial, RTOG 0522 (NCT00265941), to determine if adding cetuximab to radiotherapy and cisplatin would improve progression-free survival.

The trial included 891 evaluable patients with stage T2 N2a-3 M0 or T3-4 N0-3 M0 disease. They were randomized to receive radiotherapy and cisplatin without cetuximab (n = 447) or with cetuximab (n = 444). Most patients were assigned to intensity-modulated radiotherapy (86.8% in the radiotherapy/cisplatin arm and 89.2% in the cetuximab arm) rather than 3-D conformal radiotherapy (13.2% and 10.8%, respectively).

Baseline characteristics were balanced between the treatment arms. The median age was 57 years (range, 31-79 years) in the radiotherapy/cisplatin arm and 58 years (range, 34-76 years) in the cetuximab arm. Nearly 90% of patients in both arms were men, and the oropharynx was the primary site of disease in about 70% of patients in both arms.

More patients were p16-positive (35.7% in the radiotherapy/cisplatin arm and 39.4% in the cetuximab arm) than were p16-negative (14.4% and 13.1%, respectively). However, p16 status was unknown for about half of patients in each arm.
 

Long-term efficacy

At a median follow-up of 10.1 years, 452 patients were still alive.

The rate of local-regional failure was 28.5% in the radiotherapy/cisplatin arm and 34.8% in the cetuximab arm (hazard ratio, 1.21; P = .94). The rate of distant metastases was 15% and 11.8%, respectively (HR, 0.79; P = .10).

The 10-year progression-free survival rate was 43.6% in the radiotherapy/cisplatin arm and 40.2% in the cetuximab arm (HR, 1.06; P = .74). The 10-year overall survival rate was 49.9% and 50%, respectively (HR, 0.97; P = .36)

“As might be expected, patients who were p16-positive had a substantially improved progression-free survival as well as overall survival,” Dr. Caudell said. “Patients who had p16-negative oropharyngeal cancer or nonoropharyngeal cancer had equivalent progression-free survival and overall survival.”

However, the addition of cetuximab did not improve progression-free or overall survival in patients with p16-positive, p16-negative oropharyngeal, or nonoropharyngeal cancers.

“[These results] have proven conclusively that the addition of cetuximab to concurrent cisplatin and radiation therapy does not improve outcomes in stage III-IV head and neck cancer, regardless of the primary tumor site and p16 status,” said Kartik Sehgal, MD, of Beth Israel Deaconess Medical Center in Boston, who was not involved in this study.
 

Late toxicity

Dr. Caudell noted that late toxicity was “substantial” in both treatment arms. Late toxicity was defined as adverse events occurring greater than 90 days from the start of radiotherapy.

The incidence of grade 3/4 late toxicity was 57.4% in the radiotherapy/cisplatin arm and 61.3% in the cetuximab arm (P = .26). The most common grade 3/4 late adverse event was dysphagia, occurring in 39.6% of patients in the radiotherapy/cisplatin arm and 38.2% of those in the cetuximab arm.

Other late grade 3/4 events (in the radiotherapy/cisplatin and cetuximab arms, respectively) included dry mouth (3% and 5%), radiation mucositis (5.3% and 7%), weight decrease (7.6% and 8.7%), hearing impairment (6% and 5%), pharynx mucositis/stomatitis (4.9% and 6%), and osteonecrosis (6% and 4.8%).

Feeding tube use was similar in both treatment arms over time. At 10 years, 14.3% of patients in the radiotherapy/cisplatin arm and 11% of those in the cetuximab arm used a feeding tube (P = .53).

“Despite the use of intensity-modulated radiotherapy, there was a high incidence of late grade 3 and higher toxicities, primarily related to dysphagia, which have substantial effects on the quality of life of our patients,” Dr. Sehgal noted. “These findings need to be considered carefully while designing future studies.

“Future directions for the management of locoregionally advanced head and neck cancer include evaluation of benefits from the addition of immune checkpoint inhibitors to cisplatin with concurrent radiation therapy (e.g., JAVELIN with avelumab [NCT01772004], KEYNOTE-412 with pembrolizumab [NCT03040999], and NCT03349710 with nivolumab) and whether immune checkpoint inhibitors can substitute for cisplatin in those being treated concurrently with radiation therapy (e.g., REACH trial comparing avelumab, cetuximab, and radiation therapy versus cisplatin plus radiation therapy [NCT02999087]).”

The current study was sponsored by the Radiation Therapy Oncology Group, the National Cancer Institute, NRG Oncology, and Eli Lilly. Dr. Caudell disclosed grants and fees from Varian Medical Systems. Dr. Sehgal had no conflicts of interest to disclose.

[email protected]

SOURCE: Caudell J et al. Head and Neck Cancers Symposium 2020, Abstract 6.

Adding cetuximab to radiotherapy and cisplatin does not improve outcomes in patients with locoregionally advanced head and neck carcinoma, according to 10-year follow-up from a phase 3 trial.

The addition of cetuximab did not reduce local-regional failure or distant metastasis, and it did not improve progression-free or overall survival.

“With a median follow-up of over 10 years, this updated report confirms the addition of cetuximab to radiation/cisplatin did not improve any measured outcome in the entire cohort or when stratifying by p16 status,” said Jimmy J. Caudell, MD, of Moffitt Cancer Center in Tampa, Fla.

Dr. Caudell presented this update at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

Dr. Caudell noted that cisplatin plus radiotherapy or cetuximab plus radiotherapy have been shown to improve overall survival in patients with locoregionally advanced head and neck carcinoma. Researchers conducted this phase 3 trial, RTOG 0522 (NCT00265941), to determine if adding cetuximab to radiotherapy and cisplatin would improve progression-free survival.

The trial included 891 evaluable patients with stage T2 N2a-3 M0 or T3-4 N0-3 M0 disease. They were randomized to receive radiotherapy and cisplatin without cetuximab (n = 447) or with cetuximab (n = 444). Most patients were assigned to intensity-modulated radiotherapy (86.8% in the radiotherapy/cisplatin arm and 89.2% in the cetuximab arm) rather than 3-D conformal radiotherapy (13.2% and 10.8%, respectively).

Baseline characteristics were balanced between the treatment arms. The median age was 57 years (range, 31-79 years) in the radiotherapy/cisplatin arm and 58 years (range, 34-76 years) in the cetuximab arm. Nearly 90% of patients in both arms were men, and the oropharynx was the primary site of disease in about 70% of patients in both arms.

More patients were p16-positive (35.7% in the radiotherapy/cisplatin arm and 39.4% in the cetuximab arm) than were p16-negative (14.4% and 13.1%, respectively). However, p16 status was unknown for about half of patients in each arm.
 

Long-term efficacy

At a median follow-up of 10.1 years, 452 patients were still alive.

The rate of local-regional failure was 28.5% in the radiotherapy/cisplatin arm and 34.8% in the cetuximab arm (hazard ratio, 1.21; P = .94). The rate of distant metastases was 15% and 11.8%, respectively (HR, 0.79; P = .10).

The 10-year progression-free survival rate was 43.6% in the radiotherapy/cisplatin arm and 40.2% in the cetuximab arm (HR, 1.06; P = .74). The 10-year overall survival rate was 49.9% and 50%, respectively (HR, 0.97; P = .36)

“As might be expected, patients who were p16-positive had a substantially improved progression-free survival as well as overall survival,” Dr. Caudell said. “Patients who had p16-negative oropharyngeal cancer or nonoropharyngeal cancer had equivalent progression-free survival and overall survival.”

However, the addition of cetuximab did not improve progression-free or overall survival in patients with p16-positive, p16-negative oropharyngeal, or nonoropharyngeal cancers.

“[These results] have proven conclusively that the addition of cetuximab to concurrent cisplatin and radiation therapy does not improve outcomes in stage III-IV head and neck cancer, regardless of the primary tumor site and p16 status,” said Kartik Sehgal, MD, of Beth Israel Deaconess Medical Center in Boston, who was not involved in this study.
 

Late toxicity

Dr. Caudell noted that late toxicity was “substantial” in both treatment arms. Late toxicity was defined as adverse events occurring greater than 90 days from the start of radiotherapy.

The incidence of grade 3/4 late toxicity was 57.4% in the radiotherapy/cisplatin arm and 61.3% in the cetuximab arm (P = .26). The most common grade 3/4 late adverse event was dysphagia, occurring in 39.6% of patients in the radiotherapy/cisplatin arm and 38.2% of those in the cetuximab arm.

Other late grade 3/4 events (in the radiotherapy/cisplatin and cetuximab arms, respectively) included dry mouth (3% and 5%), radiation mucositis (5.3% and 7%), weight decrease (7.6% and 8.7%), hearing impairment (6% and 5%), pharynx mucositis/stomatitis (4.9% and 6%), and osteonecrosis (6% and 4.8%).

Feeding tube use was similar in both treatment arms over time. At 10 years, 14.3% of patients in the radiotherapy/cisplatin arm and 11% of those in the cetuximab arm used a feeding tube (P = .53).

“Despite the use of intensity-modulated radiotherapy, there was a high incidence of late grade 3 and higher toxicities, primarily related to dysphagia, which have substantial effects on the quality of life of our patients,” Dr. Sehgal noted. “These findings need to be considered carefully while designing future studies.

“Future directions for the management of locoregionally advanced head and neck cancer include evaluation of benefits from the addition of immune checkpoint inhibitors to cisplatin with concurrent radiation therapy (e.g., JAVELIN with avelumab [NCT01772004], KEYNOTE-412 with pembrolizumab [NCT03040999], and NCT03349710 with nivolumab) and whether immune checkpoint inhibitors can substitute for cisplatin in those being treated concurrently with radiation therapy (e.g., REACH trial comparing avelumab, cetuximab, and radiation therapy versus cisplatin plus radiation therapy [NCT02999087]).”

The current study was sponsored by the Radiation Therapy Oncology Group, the National Cancer Institute, NRG Oncology, and Eli Lilly. Dr. Caudell disclosed grants and fees from Varian Medical Systems. Dr. Sehgal had no conflicts of interest to disclose.

[email protected]

SOURCE: Caudell J et al. Head and Neck Cancers Symposium 2020, Abstract 6.

Preoperative nivolumab, with or without ipilimumab, appeared safe and effective in a phase 2 trial of patients with oral cavity squamous cell carcinoma (OCSCC).

“We found that nivolumab, with or without ipilimumab, was feasible prior to surgery in patients with oral cavity cancers, with no delays in surgery observed,” said Jonathan D. Schoenfeld, MD, of the Dana-Farber/Brigham and Women’s Cancer Center in Boston.

“We did observe promising rates of volumetric and pathologic response, with near-complete and complete responses observed, particularly in the nivo-ipi arm.”

Dr. Schoenfeld presented these results at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

“The rationale behind evaluation of neoadjuvant immunotherapy is the potential of tumor downstaging, converting unresectable disease to resectable and inducing durable immunological memory as a result of exposure to the full breadth of tumor antigens preoperatively,” said Kartik Sehgal, MD, of Beth Israel Deaconess Medical Center in Boston, who was not involved in this study.

“This randomized, phase 2 window study ... found that treatment with two neoadjuvant cycles of nivolumab alone or along with ipilimumab during the first cycle was feasible from an adverse events perspective and led to volumetric responses in approximately 50% of patients.”
 

Patients and treatment

The trial (NCT02919683) enrolled 30 patients with OCSCC, but 1 patient was excluded due to metastases at baseline. Patients had T2 (n = 20) or greater (n = 9) disease at baseline, and 58% of patients (n = 17) had node-positive disease.

The patients were randomized to two cycles of nivolumab (3 mg/kg) or nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg with the first cycle). Patients underwent surgery 3-7 days after completing cycle 2.

In the nivolumab monotherapy arm (n = 14), the median age was 64.4 years (range, 39.1-81 years), and 71.4% of patients were men. Oral tongue was the primary tumor site in 50% of patients, and 50% of patients had stage IV disease.

In the nivolumab-ipilimumab arm (n = 15), the median age was 65.2 years (range, 32.5-78.4 years), and 53.3% of patients were men. Oral tongue was the primary tumor site in 60% of patients, and 73.3% of patients had stage IV disease.
 

Safety and tolerability

Six patients did not receive the full cycle 2 dose of immunotherapy, two in the nivolumab arm and four in the nivolumab-ipilimumab arm. This was most commonly due to an infusion reaction during cycle 2, Dr. Schoenfeld said.

There were no cases in which surgery was delayed. However, one patient did have surgery moved to an earlier date after cycle 1 because of concerns about progression.

There were three severe immune-related adverse events. In the nivolumab-ipilimumab arm, there was a case of grade 3 pneumonitis and a case of grade 3 colitis. Both of these events were reversible with treatment.

In the nivolumab monotherapy arm, one patient had grade 4 new-onset diabetes with diabetic ketoacidosis. This patient is still insulin dependent.

Perioperative adverse events in both arms included pulmonary embolism, postoperative hematoma, and flap failures (n = 2). One patient with flap failure also had a perioperative stroke, experienced progressive clinical decline, and ultimately died.
 

Response and survival

In the nivolumab monotherapy arm, 50% of patients (n = 7) had a volumetric response, and 8% (n = 1) had a pathologic complete response.

In the nivolumab-ipilimumab arm, 53% of patients (n = 8) had a volumetric response, and 20% (n = 3) had a pathologic complete response.

“In general, we found that our response metrics were concordant; that is, patients with volumetric responses tended more frequently to have pathologic responses,” Dr. Schoenfeld said. “There were a couple notable cases where there were volumetric increases and significant pathologic responses.”

To identify factors associated with response, Dr. Schoenfeld and colleagues performed correlative multiplex immunofluorescence on 21 patient specimens prior to treatment.

“We did not identify any differences in baseline levels of PD-L1 expression in tumor cells between the two arms,” Dr. Schoenfeld noted. “We found that CD4-positive T cells in the pretreatment specimens correlated with pathologic response [P = .016]. Interestingly, this association was only significant in patients treated with nivo-ipi [P = .008] but not nivolumab alone [P = .83].”

Ten patients went on to receive radiation, and nine received chemoradiation. One patient presented to the operating room but did not undergo surgery because he was thought to require total glossectomy. This patient received chemoradiotherapy, achieved a complete response, and is still disease free after more than 3 years of follow-up.

The median follow-up for the entire cohort was 14 months. At 12 months, the progression-free survival rate was 85%, and the overall survival rate was 89%.

Dr. Schoenfeld noted that this study was not powered to assess survival or to directly compare nivolumab monotherapy and nivolumab plus ipilimumab.
 

‘Encouraging’ results, but what’s next?

“We were very encouraged by the toxicity data ... [and] the impressive pathologic responses in both arms, but particularly in the nivo-ipi arm,” Dr. Schoenfeld said. “I think the real question is, ‘Does this translate into a significant progression-free or overall survival advantage?’ So I think that would be something worthy of further study.”

“These results are encouraging for management of patients with oral cavity cancers who remain at high risk for recurrence with the current standard of care but will need validation in larger prospective studies,” Dr. Sehgal noted. “Multiple clinical trials are currently ongoing to evaluate the role of neoadjuvant immunotherapy for disease-specific outcomes, notable being phase 2 NCT02296684 and phase 3 KEYNOTE-689 (NCT03765918) with pembrolizumab and phase 3 IMSTAR-HN (NCT03700905) with nivolumab alone or along with ipilimumab.”

The current study was funded by Bristol-Myers Squibb. Dr. Schoenfeld disclosed relationships with Bristol-Myers Squibb and other companies. Dr. Sehgal had no relevant conflicts to disclose.

[email protected]

SOURCE: Schoenfeld J et al. Head and Neck Cancers Symposium 2020, Abstract 1.

Preoperative nivolumab, with or without ipilimumab, appeared safe and effective in a phase 2 trial of patients with oral cavity squamous cell carcinoma (OCSCC).

“We found that nivolumab, with or without ipilimumab, was feasible prior to surgery in patients with oral cavity cancers, with no delays in surgery observed,” said Jonathan D. Schoenfeld, MD, of the Dana-Farber/Brigham and Women’s Cancer Center in Boston.

“We did observe promising rates of volumetric and pathologic response, with near-complete and complete responses observed, particularly in the nivo-ipi arm.”

Dr. Schoenfeld presented these results at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

“The rationale behind evaluation of neoadjuvant immunotherapy is the potential of tumor downstaging, converting unresectable disease to resectable and inducing durable immunological memory as a result of exposure to the full breadth of tumor antigens preoperatively,” said Kartik Sehgal, MD, of Beth Israel Deaconess Medical Center in Boston, who was not involved in this study.

“This randomized, phase 2 window study ... found that treatment with two neoadjuvant cycles of nivolumab alone or along with ipilimumab during the first cycle was feasible from an adverse events perspective and led to volumetric responses in approximately 50% of patients.”
 

Patients and treatment

The trial (NCT02919683) enrolled 30 patients with OCSCC, but 1 patient was excluded due to metastases at baseline. Patients had T2 (n = 20) or greater (n = 9) disease at baseline, and 58% of patients (n = 17) had node-positive disease.

The patients were randomized to two cycles of nivolumab (3 mg/kg) or nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg with the first cycle). Patients underwent surgery 3-7 days after completing cycle 2.

In the nivolumab monotherapy arm (n = 14), the median age was 64.4 years (range, 39.1-81 years), and 71.4% of patients were men. Oral tongue was the primary tumor site in 50% of patients, and 50% of patients had stage IV disease.

In the nivolumab-ipilimumab arm (n = 15), the median age was 65.2 years (range, 32.5-78.4 years), and 53.3% of patients were men. Oral tongue was the primary tumor site in 60% of patients, and 73.3% of patients had stage IV disease.
 

Safety and tolerability

Six patients did not receive the full cycle 2 dose of immunotherapy, two in the nivolumab arm and four in the nivolumab-ipilimumab arm. This was most commonly due to an infusion reaction during cycle 2, Dr. Schoenfeld said.

There were no cases in which surgery was delayed. However, one patient did have surgery moved to an earlier date after cycle 1 because of concerns about progression.

There were three severe immune-related adverse events. In the nivolumab-ipilimumab arm, there was a case of grade 3 pneumonitis and a case of grade 3 colitis. Both of these events were reversible with treatment.

In the nivolumab monotherapy arm, one patient had grade 4 new-onset diabetes with diabetic ketoacidosis. This patient is still insulin dependent.

Perioperative adverse events in both arms included pulmonary embolism, postoperative hematoma, and flap failures (n = 2). One patient with flap failure also had a perioperative stroke, experienced progressive clinical decline, and ultimately died.
 

Response and survival

In the nivolumab monotherapy arm, 50% of patients (n = 7) had a volumetric response, and 8% (n = 1) had a pathologic complete response.

In the nivolumab-ipilimumab arm, 53% of patients (n = 8) had a volumetric response, and 20% (n = 3) had a pathologic complete response.

“In general, we found that our response metrics were concordant; that is, patients with volumetric responses tended more frequently to have pathologic responses,” Dr. Schoenfeld said. “There were a couple notable cases where there were volumetric increases and significant pathologic responses.”

To identify factors associated with response, Dr. Schoenfeld and colleagues performed correlative multiplex immunofluorescence on 21 patient specimens prior to treatment.

“We did not identify any differences in baseline levels of PD-L1 expression in tumor cells between the two arms,” Dr. Schoenfeld noted. “We found that CD4-positive T cells in the pretreatment specimens correlated with pathologic response [P = .016]. Interestingly, this association was only significant in patients treated with nivo-ipi [P = .008] but not nivolumab alone [P = .83].”

Ten patients went on to receive radiation, and nine received chemoradiation. One patient presented to the operating room but did not undergo surgery because he was thought to require total glossectomy. This patient received chemoradiotherapy, achieved a complete response, and is still disease free after more than 3 years of follow-up.

The median follow-up for the entire cohort was 14 months. At 12 months, the progression-free survival rate was 85%, and the overall survival rate was 89%.

Dr. Schoenfeld noted that this study was not powered to assess survival or to directly compare nivolumab monotherapy and nivolumab plus ipilimumab.
 

‘Encouraging’ results, but what’s next?

“We were very encouraged by the toxicity data ... [and] the impressive pathologic responses in both arms, but particularly in the nivo-ipi arm,” Dr. Schoenfeld said. “I think the real question is, ‘Does this translate into a significant progression-free or overall survival advantage?’ So I think that would be something worthy of further study.”

“These results are encouraging for management of patients with oral cavity cancers who remain at high risk for recurrence with the current standard of care but will need validation in larger prospective studies,” Dr. Sehgal noted. “Multiple clinical trials are currently ongoing to evaluate the role of neoadjuvant immunotherapy for disease-specific outcomes, notable being phase 2 NCT02296684 and phase 3 KEYNOTE-689 (NCT03765918) with pembrolizumab and phase 3 IMSTAR-HN (NCT03700905) with nivolumab alone or along with ipilimumab.”

The current study was funded by Bristol-Myers Squibb. Dr. Schoenfeld disclosed relationships with Bristol-Myers Squibb and other companies. Dr. Sehgal had no relevant conflicts to disclose.

[email protected]

SOURCE: Schoenfeld J et al. Head and Neck Cancers Symposium 2020, Abstract 1.

Preoperative nivolumab, with or without ipilimumab, appeared safe and effective in a phase 2 trial of patients with oral cavity squamous cell carcinoma (OCSCC).

“We found that nivolumab, with or without ipilimumab, was feasible prior to surgery in patients with oral cavity cancers, with no delays in surgery observed,” said Jonathan D. Schoenfeld, MD, of the Dana-Farber/Brigham and Women’s Cancer Center in Boston.

“We did observe promising rates of volumetric and pathologic response, with near-complete and complete responses observed, particularly in the nivo-ipi arm.”

Dr. Schoenfeld presented these results at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

“The rationale behind evaluation of neoadjuvant immunotherapy is the potential of tumor downstaging, converting unresectable disease to resectable and inducing durable immunological memory as a result of exposure to the full breadth of tumor antigens preoperatively,” said Kartik Sehgal, MD, of Beth Israel Deaconess Medical Center in Boston, who was not involved in this study.

“This randomized, phase 2 window study ... found that treatment with two neoadjuvant cycles of nivolumab alone or along with ipilimumab during the first cycle was feasible from an adverse events perspective and led to volumetric responses in approximately 50% of patients.”
 

Patients and treatment

The trial (NCT02919683) enrolled 30 patients with OCSCC, but 1 patient was excluded due to metastases at baseline. Patients had T2 (n = 20) or greater (n = 9) disease at baseline, and 58% of patients (n = 17) had node-positive disease.

The patients were randomized to two cycles of nivolumab (3 mg/kg) or nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg with the first cycle). Patients underwent surgery 3-7 days after completing cycle 2.

In the nivolumab monotherapy arm (n = 14), the median age was 64.4 years (range, 39.1-81 years), and 71.4% of patients were men. Oral tongue was the primary tumor site in 50% of patients, and 50% of patients had stage IV disease.

In the nivolumab-ipilimumab arm (n = 15), the median age was 65.2 years (range, 32.5-78.4 years), and 53.3% of patients were men. Oral tongue was the primary tumor site in 60% of patients, and 73.3% of patients had stage IV disease.
 

Safety and tolerability

Six patients did not receive the full cycle 2 dose of immunotherapy, two in the nivolumab arm and four in the nivolumab-ipilimumab arm. This was most commonly due to an infusion reaction during cycle 2, Dr. Schoenfeld said.

There were no cases in which surgery was delayed. However, one patient did have surgery moved to an earlier date after cycle 1 because of concerns about progression.

There were three severe immune-related adverse events. In the nivolumab-ipilimumab arm, there was a case of grade 3 pneumonitis and a case of grade 3 colitis. Both of these events were reversible with treatment.

In the nivolumab monotherapy arm, one patient had grade 4 new-onset diabetes with diabetic ketoacidosis. This patient is still insulin dependent.

Perioperative adverse events in both arms included pulmonary embolism, postoperative hematoma, and flap failures (n = 2). One patient with flap failure also had a perioperative stroke, experienced progressive clinical decline, and ultimately died.
 

Response and survival

In the nivolumab monotherapy arm, 50% of patients (n = 7) had a volumetric response, and 8% (n = 1) had a pathologic complete response.

In the nivolumab-ipilimumab arm, 53% of patients (n = 8) had a volumetric response, and 20% (n = 3) had a pathologic complete response.

“In general, we found that our response metrics were concordant; that is, patients with volumetric responses tended more frequently to have pathologic responses,” Dr. Schoenfeld said. “There were a couple notable cases where there were volumetric increases and significant pathologic responses.”

To identify factors associated with response, Dr. Schoenfeld and colleagues performed correlative multiplex immunofluorescence on 21 patient specimens prior to treatment.

“We did not identify any differences in baseline levels of PD-L1 expression in tumor cells between the two arms,” Dr. Schoenfeld noted. “We found that CD4-positive T cells in the pretreatment specimens correlated with pathologic response [P = .016]. Interestingly, this association was only significant in patients treated with nivo-ipi [P = .008] but not nivolumab alone [P = .83].”

Ten patients went on to receive radiation, and nine received chemoradiation. One patient presented to the operating room but did not undergo surgery because he was thought to require total glossectomy. This patient received chemoradiotherapy, achieved a complete response, and is still disease free after more than 3 years of follow-up.

The median follow-up for the entire cohort was 14 months. At 12 months, the progression-free survival rate was 85%, and the overall survival rate was 89%.

Dr. Schoenfeld noted that this study was not powered to assess survival or to directly compare nivolumab monotherapy and nivolumab plus ipilimumab.
 

‘Encouraging’ results, but what’s next?

“We were very encouraged by the toxicity data ... [and] the impressive pathologic responses in both arms, but particularly in the nivo-ipi arm,” Dr. Schoenfeld said. “I think the real question is, ‘Does this translate into a significant progression-free or overall survival advantage?’ So I think that would be something worthy of further study.”

“These results are encouraging for management of patients with oral cavity cancers who remain at high risk for recurrence with the current standard of care but will need validation in larger prospective studies,” Dr. Sehgal noted. “Multiple clinical trials are currently ongoing to evaluate the role of neoadjuvant immunotherapy for disease-specific outcomes, notable being phase 2 NCT02296684 and phase 3 KEYNOTE-689 (NCT03765918) with pembrolizumab and phase 3 IMSTAR-HN (NCT03700905) with nivolumab alone or along with ipilimumab.”

The current study was funded by Bristol-Myers Squibb. Dr. Schoenfeld disclosed relationships with Bristol-Myers Squibb and other companies. Dr. Sehgal had no relevant conflicts to disclose.

[email protected]

SOURCE: Schoenfeld J et al. Head and Neck Cancers Symposium 2020, Abstract 1.

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

CHICAGO – Overall survival for patients with anaplastic thyroid cancer was boosted when their care facilitated a rapid work-up, comprehensive treatment planning, and integrated implementation of multimodal therapies.

Median survival for participants in a specialized program who have been able to benefit from targeted therapy and immunotherapy now stands at 16 months, with 43% of patients surviving 2 years or more, said Anastasios Maniakas, MD, at the annual meeting of the American Thyroid Association.

Median survival was 8 months during 2000-2013, before the program, dubbed FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment), was initiated at the University of Texas MD Anderson Cancer Center, Houston.

These increased survival rates were driven primarily by better targeting of mutation-specific therapy and by immunotherapy, said Dr. Maniakas, a fellow in head and neck surgery at the center. This targeting, in turn, was facilitated by timely staging and genetic work-up, as well as appropriate clinical trial enrollment.

As word has spread about the program, referrals went up by 44%, said Dr. Maniakas. Members of the FAST team include representatives from oncologic endocrinology, head and neck surgery, radiation oncology, pathology, and basic science.

Historically, anaplastic thyroid cancer (ATC) has had a 12-month overall survival rate of less than 30% for patients who have advanced disease, said Dr. Maniakas, citing a recent analysis showing that, in 1,567 ATC cases, the median survival was just 4 months, and the 6-month survival rate was 35%.

The FAST team’s engagement starts with rapid intake whereby patients see a physician within 3-5 days of initial contact with the center, explained Dr. Maniakas. A prescheduled work-up is completed within another 3-7 days. It includes basic lab work, cell-free DNA testing, BRAF immunohistochemistry, and molecular testing. Additional consults and appropriate medical imaging for staging are also included in the initial work-up.

With these data in hand, physicians meet again with patients in a treatment-planning clinic to assess eligibility for participation in a clinical trial. Patients will otherwise receive standard-of-care therapy that may include surgery or BRAF-directed therapy. However, said Dr. Maniakas, the FAST approach has resulted in a boost of more than 30% in clinical trial participation by ATC patients. Adjunctive therapies are also tailored to patients under the care of the FAST team, which may include stereotactic body-radiation therapy, surgery, and immunotherapy.

The team is tracking a cohort of patients who received surgery with or without radiation therapy, preceded by neoadjuvant BRAF/MEK inhibitor therapy – an approach used since 2017. Of 20 patients who were positive for BRAF-V600E, 16 are still alive at a median 1.21 years of follow-up since diagnosis, said Dr. Maniakas. The median survival time for those who did not receive surgery is 0.8 years, whereas the median survival has not been reached for those who also had surgery.

Molecular testing and initial screening of ATC patients is an essential component of the cancer center’s precision medicine approach, said Dr. Maniakas. “Genetic profiling has become a key player in ATC management and survival.”

In looking at outcomes at the cancer center, Dr. Maniakas and his collaborators divided the patients into three groups. The first included 227 patients seen during 2000-2013, before the program was initiated. The 100 participants in the second group initiated treatment sometime during 2014-2016, after the program was launched but before the targeted therapy and immunotherapy trial was fully implemented. Since 2017, 152 participants in the third group have had the opportunity to participate in the clinical trial, as well as receiving surgery with or without radiation therapy after neoadjuvant immunotherapy.

Since 2017, 97% of ATC patients have had genetic profiling done. Most patients are receiving rapid determination of BRAF-V600E status with immunohistochemistry, with results available in a few days, followed by liquid biopsy (available in about 2 weeks), and then next-generation sequencing. Results for the latter, considered the gold standard, can take up to 3 weeks.

Patients participating in the program were aged a mean 65 years at diagnosis, and just over half were men. The number of patients receiving targeted therapy has continued to rise, said Dr. Maniakas. From 2000 to 2013, just 9% of patients received targeted therapy; from 2014 to 2016, that figure rose to 43%; and since 2017, 61% of patients have received targeted therapy (P less than .001).

“Landmark changes in the management of ATC patients as a whole have had a direct impact to the significant increase in overall survival,” said Dr. Maniakas.

He added that the cancer center’s experience could inform future ATC guidelines. Patients with this deadliest of thyroid cancers should all have rapid molecular testing, followed by timely, targeted therapy. Clinical trial eligibility should be considered for all patients. Finally, guideline authors should take note of the ongoing favorable survival rates seen for patients receiving surgery after neoadjuvant therapy.

Dr. Maniakas reported no outside sources of funding and that he had no relevant disclosures.
 

SOURCE: Maniakas A et al. ATA 2019, Short Call Oral Abstract 9.

CHICAGO – Overall survival for patients with anaplastic thyroid cancer was boosted when their care facilitated a rapid work-up, comprehensive treatment planning, and integrated implementation of multimodal therapies.

Median survival for participants in a specialized program who have been able to benefit from targeted therapy and immunotherapy now stands at 16 months, with 43% of patients surviving 2 years or more, said Anastasios Maniakas, MD, at the annual meeting of the American Thyroid Association.

Median survival was 8 months during 2000-2013, before the program, dubbed FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment), was initiated at the University of Texas MD Anderson Cancer Center, Houston.

These increased survival rates were driven primarily by better targeting of mutation-specific therapy and by immunotherapy, said Dr. Maniakas, a fellow in head and neck surgery at the center. This targeting, in turn, was facilitated by timely staging and genetic work-up, as well as appropriate clinical trial enrollment.

As word has spread about the program, referrals went up by 44%, said Dr. Maniakas. Members of the FAST team include representatives from oncologic endocrinology, head and neck surgery, radiation oncology, pathology, and basic science.

Historically, anaplastic thyroid cancer (ATC) has had a 12-month overall survival rate of less than 30% for patients who have advanced disease, said Dr. Maniakas, citing a recent analysis showing that, in 1,567 ATC cases, the median survival was just 4 months, and the 6-month survival rate was 35%.

The FAST team’s engagement starts with rapid intake whereby patients see a physician within 3-5 days of initial contact with the center, explained Dr. Maniakas. A prescheduled work-up is completed within another 3-7 days. It includes basic lab work, cell-free DNA testing, BRAF immunohistochemistry, and molecular testing. Additional consults and appropriate medical imaging for staging are also included in the initial work-up.

With these data in hand, physicians meet again with patients in a treatment-planning clinic to assess eligibility for participation in a clinical trial. Patients will otherwise receive standard-of-care therapy that may include surgery or BRAF-directed therapy. However, said Dr. Maniakas, the FAST approach has resulted in a boost of more than 30% in clinical trial participation by ATC patients. Adjunctive therapies are also tailored to patients under the care of the FAST team, which may include stereotactic body-radiation therapy, surgery, and immunotherapy.

The team is tracking a cohort of patients who received surgery with or without radiation therapy, preceded by neoadjuvant BRAF/MEK inhibitor therapy – an approach used since 2017. Of 20 patients who were positive for BRAF-V600E, 16 are still alive at a median 1.21 years of follow-up since diagnosis, said Dr. Maniakas. The median survival time for those who did not receive surgery is 0.8 years, whereas the median survival has not been reached for those who also had surgery.

Molecular testing and initial screening of ATC patients is an essential component of the cancer center’s precision medicine approach, said Dr. Maniakas. “Genetic profiling has become a key player in ATC management and survival.”

In looking at outcomes at the cancer center, Dr. Maniakas and his collaborators divided the patients into three groups. The first included 227 patients seen during 2000-2013, before the program was initiated. The 100 participants in the second group initiated treatment sometime during 2014-2016, after the program was launched but before the targeted therapy and immunotherapy trial was fully implemented. Since 2017, 152 participants in the third group have had the opportunity to participate in the clinical trial, as well as receiving surgery with or without radiation therapy after neoadjuvant immunotherapy.

Since 2017, 97% of ATC patients have had genetic profiling done. Most patients are receiving rapid determination of BRAF-V600E status with immunohistochemistry, with results available in a few days, followed by liquid biopsy (available in about 2 weeks), and then next-generation sequencing. Results for the latter, considered the gold standard, can take up to 3 weeks.

Patients participating in the program were aged a mean 65 years at diagnosis, and just over half were men. The number of patients receiving targeted therapy has continued to rise, said Dr. Maniakas. From 2000 to 2013, just 9% of patients received targeted therapy; from 2014 to 2016, that figure rose to 43%; and since 2017, 61% of patients have received targeted therapy (P less than .001).

“Landmark changes in the management of ATC patients as a whole have had a direct impact to the significant increase in overall survival,” said Dr. Maniakas.

He added that the cancer center’s experience could inform future ATC guidelines. Patients with this deadliest of thyroid cancers should all have rapid molecular testing, followed by timely, targeted therapy. Clinical trial eligibility should be considered for all patients. Finally, guideline authors should take note of the ongoing favorable survival rates seen for patients receiving surgery after neoadjuvant therapy.

Dr. Maniakas reported no outside sources of funding and that he had no relevant disclosures.
 

SOURCE: Maniakas A et al. ATA 2019, Short Call Oral Abstract 9.

CHICAGO – Overall survival for patients with anaplastic thyroid cancer was boosted when their care facilitated a rapid work-up, comprehensive treatment planning, and integrated implementation of multimodal therapies.

Median survival for participants in a specialized program who have been able to benefit from targeted therapy and immunotherapy now stands at 16 months, with 43% of patients surviving 2 years or more, said Anastasios Maniakas, MD, at the annual meeting of the American Thyroid Association.

Median survival was 8 months during 2000-2013, before the program, dubbed FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment), was initiated at the University of Texas MD Anderson Cancer Center, Houston.

These increased survival rates were driven primarily by better targeting of mutation-specific therapy and by immunotherapy, said Dr. Maniakas, a fellow in head and neck surgery at the center. This targeting, in turn, was facilitated by timely staging and genetic work-up, as well as appropriate clinical trial enrollment.

As word has spread about the program, referrals went up by 44%, said Dr. Maniakas. Members of the FAST team include representatives from oncologic endocrinology, head and neck surgery, radiation oncology, pathology, and basic science.

Historically, anaplastic thyroid cancer (ATC) has had a 12-month overall survival rate of less than 30% for patients who have advanced disease, said Dr. Maniakas, citing a recent analysis showing that, in 1,567 ATC cases, the median survival was just 4 months, and the 6-month survival rate was 35%.

The FAST team’s engagement starts with rapid intake whereby patients see a physician within 3-5 days of initial contact with the center, explained Dr. Maniakas. A prescheduled work-up is completed within another 3-7 days. It includes basic lab work, cell-free DNA testing, BRAF immunohistochemistry, and molecular testing. Additional consults and appropriate medical imaging for staging are also included in the initial work-up.

With these data in hand, physicians meet again with patients in a treatment-planning clinic to assess eligibility for participation in a clinical trial. Patients will otherwise receive standard-of-care therapy that may include surgery or BRAF-directed therapy. However, said Dr. Maniakas, the FAST approach has resulted in a boost of more than 30% in clinical trial participation by ATC patients. Adjunctive therapies are also tailored to patients under the care of the FAST team, which may include stereotactic body-radiation therapy, surgery, and immunotherapy.

The team is tracking a cohort of patients who received surgery with or without radiation therapy, preceded by neoadjuvant BRAF/MEK inhibitor therapy – an approach used since 2017. Of 20 patients who were positive for BRAF-V600E, 16 are still alive at a median 1.21 years of follow-up since diagnosis, said Dr. Maniakas. The median survival time for those who did not receive surgery is 0.8 years, whereas the median survival has not been reached for those who also had surgery.

Molecular testing and initial screening of ATC patients is an essential component of the cancer center’s precision medicine approach, said Dr. Maniakas. “Genetic profiling has become a key player in ATC management and survival.”

In looking at outcomes at the cancer center, Dr. Maniakas and his collaborators divided the patients into three groups. The first included 227 patients seen during 2000-2013, before the program was initiated. The 100 participants in the second group initiated treatment sometime during 2014-2016, after the program was launched but before the targeted therapy and immunotherapy trial was fully implemented. Since 2017, 152 participants in the third group have had the opportunity to participate in the clinical trial, as well as receiving surgery with or without radiation therapy after neoadjuvant immunotherapy.

Since 2017, 97% of ATC patients have had genetic profiling done. Most patients are receiving rapid determination of BRAF-V600E status with immunohistochemistry, with results available in a few days, followed by liquid biopsy (available in about 2 weeks), and then next-generation sequencing. Results for the latter, considered the gold standard, can take up to 3 weeks.

Patients participating in the program were aged a mean 65 years at diagnosis, and just over half were men. The number of patients receiving targeted therapy has continued to rise, said Dr. Maniakas. From 2000 to 2013, just 9% of patients received targeted therapy; from 2014 to 2016, that figure rose to 43%; and since 2017, 61% of patients have received targeted therapy (P less than .001).

“Landmark changes in the management of ATC patients as a whole have had a direct impact to the significant increase in overall survival,” said Dr. Maniakas.

He added that the cancer center’s experience could inform future ATC guidelines. Patients with this deadliest of thyroid cancers should all have rapid molecular testing, followed by timely, targeted therapy. Clinical trial eligibility should be considered for all patients. Finally, guideline authors should take note of the ongoing favorable survival rates seen for patients receiving surgery after neoadjuvant therapy.

Dr. Maniakas reported no outside sources of funding and that he had no relevant disclosures.
 

SOURCE: Maniakas A et al. ATA 2019, Short Call Oral Abstract 9.

CHICAGO – Many patients with thyroid cancer can be sent home after lateral neck dissections with few or no opioids, in the experience of an institution that made a sea change in opioid prescribing practices.

Kari Oakes/MDedge News

Between 2012 to mid-2019, Oregon Health & Science University (OHSU), Portland, saw 243 patients who received lateral neck dissections for thyroid cancer and were opioid naive. Before a shift in prescribing practices in early 2017, 5.3% of patients were discharged without opioids after lateral neck dissections for thyroid cancer, whereas after the shift, 41.7% of patients went home on an opioid-free regimen, James Y. Lim, MD, an endocrine surgeon and assistant professor at the university, said during a poster presentation at the annual meeting of the American Thyroid Association.

The initiative, led by Maisie L. Shindo, MD, was started at the OHSU Thyroid and Parathyroid Center in late 2016 in an effort to reduce the number of opioid prescriptions in postoperative patients, Dr. Lim explained in an interview after his presentation. Dr. Shindo, coauthor of the study, directs the thyroid and parathyroid surgery department at the university.

“Before the initiative, standard postoperative pain control consisted of opioids. However, it was common for patients to mention that they did not need them at all,” said Dr. Lim. “Our prescribing practices today reflect the ability to maintain patient comfort without having to resort to opioids. We are able to keep more than 90% of our patients comfortable with a multimodal approach to pain,” he said.

Dr. Lim and colleagues used a retrospective record review to tally how many opioids were initially prescribed at discharge after lateral neck dissections for thyroid cancer, along with the number and quantity of refills for opioids after discharge. Opioid doses were converted to morphine milligram equivalents (MME), and dosing patterns were compared for the periods before and after Feb. 1, 2017, when operating surgeons changed opioid prescribing patterns. These two subgroups were termed group 1 and group 2, respectively.

In all, 143 of the total 243 patients included in the study were women, and the mean age at the time of surgery was 47 years. Patients in group 1 had 170 surgeries, and those in group 2 had 103 surgeries.

Group 1 patients received a mean 295.4 MME after surgery, and group 2 patients received a mean 85.89 MME, though there was wide variation in discharge prescribing within each group. The absolute difference between the pre- and postinitiative groups was 209.51 MME (95% confidence interval, 157.8-261.2), for an effect size of 1.08. The MME figures for each group reflected both discharge medication and any refills or rescue prescriptions that were required.

“Decreasing the volume of opioids prescribed at discharge will decrease waste and reduce potential for addiction,” the authors noted.

As far as is known, “this is the first study that seeks to identify the extent of opioid needs after an extensive neck dissection for thyroid cancer operation,” said Dr. Lim, who added that he has been surprised at how well patients do after surgery. He said he and other surgeons had expected patients to have more pain from lateral neck dissections than they seem to experience.

“There have been studies, including from our own institution, that reported the relatively small need for opioids after a central neck procedure, such as a total thyroidectomy,” Dr. Lim said. “Our study showed that those requirements remain low even with more extensive lateral neck dissections. In the last 8 months of the study, more than 70% of patients with lateral neck dissections did not require opioids on discharge.”

Dr. Lim said that he and the rest of the care team advise patients to ramp up nonpharmacologic options, including ibuprofen, acetaminophen, ice packs, and throat lozenges – all of which can make a big difference in postoperative comfort.

Paying attention to how patients fare during an inpatient stay or even same-day procedures can help physicians estimate postdischarge needs, said Dr. Lim: “For our lateral neck dissections, patients usually stay overnight, and we can get a pretty good estimate of how their pain is being managed off opioids. For same-day procedures, it requires evaluating the patient before discharge and reassessing the pain needs at that time.”

Helping patients and their families understand the postoperative course and what level of discomfort they can expect has helped in the effort to minimize opioid use, Dr. Lim said. Overall, patients, family, and staff have received the changes “very well,” he added.

Practices that are considering a move toward opioid-free or opioid-sparing regimens after surgery should know that “it does require buy-in from all members of the medical team as well as the patients,” Dr. Lim emphasized.

“It starts at the initial surgical consultation, with surgeons educating patients on what to expect in terms of postoperative discomfort and pain. Patients are informed that they will have some discomfort and mild pain that is generally controlled with nonopioid, over-the-counter medications and cold therapy to the surgical site,” he explained.

“It requires education of the nurses and residents to encourage moving away from using opioids as a first-line therapy,” but it’s worth the hard work to get to a point where patients are going home with few, or no, opioids, said Dr. Lim. “Ultimately, patients are happier and are often relieved that their pain can be controlled without opioids,” he said.

Dr. Shindo is the senior author of a related study examining opioid reduction in neck dissection for a variety of head and neck cancers. In that study, she and her coauthors found that opioid requirements vary by cancer type. In an upcoming manuscript, the researchers are aiming to characterize typical opioid requirements for commonly performed procedures, to provide surgeons with evidence-based baselines for appropriate, but not excessive, opioid prescribing.

Dr. Lim reported no outside sources of funding. He, Dr. Shindo, and a third author reported that they had no conflicts of interest.

[email protected]

SOURCE: Lim J et al. ATA 2019, Poster 401.

CHICAGO – Many patients with thyroid cancer can be sent home after lateral neck dissections with few or no opioids, in the experience of an institution that made a sea change in opioid prescribing practices.

Kari Oakes/MDedge News

Between 2012 to mid-2019, Oregon Health & Science University (OHSU), Portland, saw 243 patients who received lateral neck dissections for thyroid cancer and were opioid naive. Before a shift in prescribing practices in early 2017, 5.3% of patients were discharged without opioids after lateral neck dissections for thyroid cancer, whereas after the shift, 41.7% of patients went home on an opioid-free regimen, James Y. Lim, MD, an endocrine surgeon and assistant professor at the university, said during a poster presentation at the annual meeting of the American Thyroid Association.

The initiative, led by Maisie L. Shindo, MD, was started at the OHSU Thyroid and Parathyroid Center in late 2016 in an effort to reduce the number of opioid prescriptions in postoperative patients, Dr. Lim explained in an interview after his presentation. Dr. Shindo, coauthor of the study, directs the thyroid and parathyroid surgery department at the university.

“Before the initiative, standard postoperative pain control consisted of opioids. However, it was common for patients to mention that they did not need them at all,” said Dr. Lim. “Our prescribing practices today reflect the ability to maintain patient comfort without having to resort to opioids. We are able to keep more than 90% of our patients comfortable with a multimodal approach to pain,” he said.

Dr. Lim and colleagues used a retrospective record review to tally how many opioids were initially prescribed at discharge after lateral neck dissections for thyroid cancer, along with the number and quantity of refills for opioids after discharge. Opioid doses were converted to morphine milligram equivalents (MME), and dosing patterns were compared for the periods before and after Feb. 1, 2017, when operating surgeons changed opioid prescribing patterns. These two subgroups were termed group 1 and group 2, respectively.

In all, 143 of the total 243 patients included in the study were women, and the mean age at the time of surgery was 47 years. Patients in group 1 had 170 surgeries, and those in group 2 had 103 surgeries.

Group 1 patients received a mean 295.4 MME after surgery, and group 2 patients received a mean 85.89 MME, though there was wide variation in discharge prescribing within each group. The absolute difference between the pre- and postinitiative groups was 209.51 MME (95% confidence interval, 157.8-261.2), for an effect size of 1.08. The MME figures for each group reflected both discharge medication and any refills or rescue prescriptions that were required.

“Decreasing the volume of opioids prescribed at discharge will decrease waste and reduce potential for addiction,” the authors noted.

As far as is known, “this is the first study that seeks to identify the extent of opioid needs after an extensive neck dissection for thyroid cancer operation,” said Dr. Lim, who added that he has been surprised at how well patients do after surgery. He said he and other surgeons had expected patients to have more pain from lateral neck dissections than they seem to experience.

“There have been studies, including from our own institution, that reported the relatively small need for opioids after a central neck procedure, such as a total thyroidectomy,” Dr. Lim said. “Our study showed that those requirements remain low even with more extensive lateral neck dissections. In the last 8 months of the study, more than 70% of patients with lateral neck dissections did not require opioids on discharge.”

Dr. Lim said that he and the rest of the care team advise patients to ramp up nonpharmacologic options, including ibuprofen, acetaminophen, ice packs, and throat lozenges – all of which can make a big difference in postoperative comfort.

Paying attention to how patients fare during an inpatient stay or even same-day procedures can help physicians estimate postdischarge needs, said Dr. Lim: “For our lateral neck dissections, patients usually stay overnight, and we can get a pretty good estimate of how their pain is being managed off opioids. For same-day procedures, it requires evaluating the patient before discharge and reassessing the pain needs at that time.”

Helping patients and their families understand the postoperative course and what level of discomfort they can expect has helped in the effort to minimize opioid use, Dr. Lim said. Overall, patients, family, and staff have received the changes “very well,” he added.

Practices that are considering a move toward opioid-free or opioid-sparing regimens after surgery should know that “it does require buy-in from all members of the medical team as well as the patients,” Dr. Lim emphasized.

“It starts at the initial surgical consultation, with surgeons educating patients on what to expect in terms of postoperative discomfort and pain. Patients are informed that they will have some discomfort and mild pain that is generally controlled with nonopioid, over-the-counter medications and cold therapy to the surgical site,” he explained.

“It requires education of the nurses and residents to encourage moving away from using opioids as a first-line therapy,” but it’s worth the hard work to get to a point where patients are going home with few, or no, opioids, said Dr. Lim. “Ultimately, patients are happier and are often relieved that their pain can be controlled without opioids,” he said.

Dr. Shindo is the senior author of a related study examining opioid reduction in neck dissection for a variety of head and neck cancers. In that study, she and her coauthors found that opioid requirements vary by cancer type. In an upcoming manuscript, the researchers are aiming to characterize typical opioid requirements for commonly performed procedures, to provide surgeons with evidence-based baselines for appropriate, but not excessive, opioid prescribing.

Dr. Lim reported no outside sources of funding. He, Dr. Shindo, and a third author reported that they had no conflicts of interest.

[email protected]

SOURCE: Lim J et al. ATA 2019, Poster 401.

CHICAGO – Many patients with thyroid cancer can be sent home after lateral neck dissections with few or no opioids, in the experience of an institution that made a sea change in opioid prescribing practices.

Kari Oakes/MDedge News

Between 2012 to mid-2019, Oregon Health & Science University (OHSU), Portland, saw 243 patients who received lateral neck dissections for thyroid cancer and were opioid naive. Before a shift in prescribing practices in early 2017, 5.3% of patients were discharged without opioids after lateral neck dissections for thyroid cancer, whereas after the shift, 41.7% of patients went home on an opioid-free regimen, James Y. Lim, MD, an endocrine surgeon and assistant professor at the university, said during a poster presentation at the annual meeting of the American Thyroid Association.

The initiative, led by Maisie L. Shindo, MD, was started at the OHSU Thyroid and Parathyroid Center in late 2016 in an effort to reduce the number of opioid prescriptions in postoperative patients, Dr. Lim explained in an interview after his presentation. Dr. Shindo, coauthor of the study, directs the thyroid and parathyroid surgery department at the university.

“Before the initiative, standard postoperative pain control consisted of opioids. However, it was common for patients to mention that they did not need them at all,” said Dr. Lim. “Our prescribing practices today reflect the ability to maintain patient comfort without having to resort to opioids. We are able to keep more than 90% of our patients comfortable with a multimodal approach to pain,” he said.

Dr. Lim and colleagues used a retrospective record review to tally how many opioids were initially prescribed at discharge after lateral neck dissections for thyroid cancer, along with the number and quantity of refills for opioids after discharge. Opioid doses were converted to morphine milligram equivalents (MME), and dosing patterns were compared for the periods before and after Feb. 1, 2017, when operating surgeons changed opioid prescribing patterns. These two subgroups were termed group 1 and group 2, respectively.

In all, 143 of the total 243 patients included in the study were women, and the mean age at the time of surgery was 47 years. Patients in group 1 had 170 surgeries, and those in group 2 had 103 surgeries.

Group 1 patients received a mean 295.4 MME after surgery, and group 2 patients received a mean 85.89 MME, though there was wide variation in discharge prescribing within each group. The absolute difference between the pre- and postinitiative groups was 209.51 MME (95% confidence interval, 157.8-261.2), for an effect size of 1.08. The MME figures for each group reflected both discharge medication and any refills or rescue prescriptions that were required.

“Decreasing the volume of opioids prescribed at discharge will decrease waste and reduce potential for addiction,” the authors noted.

As far as is known, “this is the first study that seeks to identify the extent of opioid needs after an extensive neck dissection for thyroid cancer operation,” said Dr. Lim, who added that he has been surprised at how well patients do after surgery. He said he and other surgeons had expected patients to have more pain from lateral neck dissections than they seem to experience.

“There have been studies, including from our own institution, that reported the relatively small need for opioids after a central neck procedure, such as a total thyroidectomy,” Dr. Lim said. “Our study showed that those requirements remain low even with more extensive lateral neck dissections. In the last 8 months of the study, more than 70% of patients with lateral neck dissections did not require opioids on discharge.”

Dr. Lim said that he and the rest of the care team advise patients to ramp up nonpharmacologic options, including ibuprofen, acetaminophen, ice packs, and throat lozenges – all of which can make a big difference in postoperative comfort.

Paying attention to how patients fare during an inpatient stay or even same-day procedures can help physicians estimate postdischarge needs, said Dr. Lim: “For our lateral neck dissections, patients usually stay overnight, and we can get a pretty good estimate of how their pain is being managed off opioids. For same-day procedures, it requires evaluating the patient before discharge and reassessing the pain needs at that time.”

Helping patients and their families understand the postoperative course and what level of discomfort they can expect has helped in the effort to minimize opioid use, Dr. Lim said. Overall, patients, family, and staff have received the changes “very well,” he added.

Practices that are considering a move toward opioid-free or opioid-sparing regimens after surgery should know that “it does require buy-in from all members of the medical team as well as the patients,” Dr. Lim emphasized.

“It starts at the initial surgical consultation, with surgeons educating patients on what to expect in terms of postoperative discomfort and pain. Patients are informed that they will have some discomfort and mild pain that is generally controlled with nonopioid, over-the-counter medications and cold therapy to the surgical site,” he explained.

“It requires education of the nurses and residents to encourage moving away from using opioids as a first-line therapy,” but it’s worth the hard work to get to a point where patients are going home with few, or no, opioids, said Dr. Lim. “Ultimately, patients are happier and are often relieved that their pain can be controlled without opioids,” he said.

Dr. Shindo is the senior author of a related study examining opioid reduction in neck dissection for a variety of head and neck cancers. In that study, she and her coauthors found that opioid requirements vary by cancer type. In an upcoming manuscript, the researchers are aiming to characterize typical opioid requirements for commonly performed procedures, to provide surgeons with evidence-based baselines for appropriate, but not excessive, opioid prescribing.

Dr. Lim reported no outside sources of funding. He, Dr. Shindo, and a third author reported that they had no conflicts of interest.

[email protected]

SOURCE: Lim J et al. ATA 2019, Poster 401.