Head and Neck Cancers Symposium 2020

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.

jensmith@mdedge.com

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.

jensmith@mdedge.com

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.

jensmith@mdedge.com

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.

jensmith@mdedge.com

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.

jensmith@mdedge.com

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.

jensmith@mdedge.com

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.

jensmith@mdedge.com

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.

jensmith@mdedge.com

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.

jensmith@mdedge.com

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