Immunotherapy

NATIONAL HARBOR, MD. – The folate-binding protein vaccine E39+GM-CSF was well tolerated and exhibited a statistically significant, dose-dependent effect on recurrence and disease-free survival among patients with remitted primary ovarian or endometrial cancer, according to the results of a small prospective controlled phase I/IIa trial.

After a median follow-up of 12 months, cancer recurred in 41% of all vaccine recipients and 55% of controls (P = .41), G. Larry Maxwell, MD, reported at the annual meeting of the Society of Gynecologic Oncology. However, cancer recurred in only 13% of patients who received the highest (1,000 mcg) dose of peptide in the vaccine (P = .01 compared with the control group). A closer look showed that this survival benefit was limited to patients with primary disease, indicating that this vaccine has potential as an adjuvant to standard therapy for primary endometrial or ovarian cancer, he added.

Mortality from these cancers continues to rise in the United States despite conventional treatment with chemotherapy and radiation, noted Dr. Maxwell, who is chairman of the department of obstetrics and gynecology of Inova Fairfax Hospital in Annandale, Va.

“Targeted therapies have been evaluated, but durable response remains limited. Novel agents are needed,” he emphasized. He and his coinvestigators have focused on folate-binding protein, which is overexpressed by 20- to 80-fold in endometrial and ovarian tumors, compared with healthy tissue. To develop the vaccine, they combined E39, an immunogenic peptide of folate receptor 1 that amplifies the lymphocytic tumor response, with the immune adjuvant, granulocyte macrophage-colony stimulating factor (GM-CSF).

The trial included 51 patients, of whom 40 had primary ovarian or endometrial cancer and 11 had recurrent cancer. The 29 patients who were HLA-A2 positive were allocated to the vaccine group, receiving six intradermal inoculations of either 100-mcg, 500-mcg, or 1,000-mcg E39 plus 250-mcg GM-CSF, spaced by 21-28 days. Fifteen of these patients received 1,000-mcg E39, while 14 received 500- or 100-mcg doses. The treatment group also received two booster vaccines spaced 6 months apart. The 22 HLA-A2–negative patients were followed as controls. The intervention and control groups resembled each other clinically and demographically, Dr. Maxwell said.

Estimated rates of 2-year disease-free survival were 77% for patients in the 1,000 mcg–dose group, 44% for controls (P = .05), and 23% for patients who received less than 1,000 mcg vaccine (P = .005). Adverse events mainly included grade 1 or grade 2 myalgias, headaches, or reactions at the vaccination site. Mild adverse events were significantly more common at the 1,000-mcg E39 dose than at lower doses (P = .04). There was one grade 3 toxicity, and no grade 4 or 5 adverse events.

Delayed-type hypersensitivity reactions were more pronounced after vaccination, compared with baseline (5.7 ± 1.5 mm versus 10.3 ± 3.0 mm; P = .06), particularly in the 1,000-mcg group (3.8 ± 2.0 mm vs. 9.5 ± 3.5 mm, P = .03), Dr. Maxwell reported. Among patients whose cancer did not recur, delayed-type hypersensitivity was markedly higher after vaccination than at baseline (P = .06). “Our functional immunologic data show that vaccination is associated with delayed type hypersensitivity, but more important, it is associated with clinical outcome,” Dr. Maxwell said.

Low levels of folate-binding protein expression correlated with better disease-free survival, he also reported. “Possibly, this is because high levels of expression are associated with disease aggressiveness, which may outpace the immune response,” he said.

A phase Ib trial of the E39 folate-binding protein peptide vaccine is underway. Dr. Maxwell did not cite external funding sources and reported having no conflicts of interest.

NATIONAL HARBOR, MD. – The folate-binding protein vaccine E39+GM-CSF was well tolerated and exhibited a statistically significant, dose-dependent effect on recurrence and disease-free survival among patients with remitted primary ovarian or endometrial cancer, according to the results of a small prospective controlled phase I/IIa trial.

After a median follow-up of 12 months, cancer recurred in 41% of all vaccine recipients and 55% of controls (P = .41), G. Larry Maxwell, MD, reported at the annual meeting of the Society of Gynecologic Oncology. However, cancer recurred in only 13% of patients who received the highest (1,000 mcg) dose of peptide in the vaccine (P = .01 compared with the control group). A closer look showed that this survival benefit was limited to patients with primary disease, indicating that this vaccine has potential as an adjuvant to standard therapy for primary endometrial or ovarian cancer, he added.

Mortality from these cancers continues to rise in the United States despite conventional treatment with chemotherapy and radiation, noted Dr. Maxwell, who is chairman of the department of obstetrics and gynecology of Inova Fairfax Hospital in Annandale, Va.

“Targeted therapies have been evaluated, but durable response remains limited. Novel agents are needed,” he emphasized. He and his coinvestigators have focused on folate-binding protein, which is overexpressed by 20- to 80-fold in endometrial and ovarian tumors, compared with healthy tissue. To develop the vaccine, they combined E39, an immunogenic peptide of folate receptor 1 that amplifies the lymphocytic tumor response, with the immune adjuvant, granulocyte macrophage-colony stimulating factor (GM-CSF).

The trial included 51 patients, of whom 40 had primary ovarian or endometrial cancer and 11 had recurrent cancer. The 29 patients who were HLA-A2 positive were allocated to the vaccine group, receiving six intradermal inoculations of either 100-mcg, 500-mcg, or 1,000-mcg E39 plus 250-mcg GM-CSF, spaced by 21-28 days. Fifteen of these patients received 1,000-mcg E39, while 14 received 500- or 100-mcg doses. The treatment group also received two booster vaccines spaced 6 months apart. The 22 HLA-A2–negative patients were followed as controls. The intervention and control groups resembled each other clinically and demographically, Dr. Maxwell said.

Estimated rates of 2-year disease-free survival were 77% for patients in the 1,000 mcg–dose group, 44% for controls (P = .05), and 23% for patients who received less than 1,000 mcg vaccine (P = .005). Adverse events mainly included grade 1 or grade 2 myalgias, headaches, or reactions at the vaccination site. Mild adverse events were significantly more common at the 1,000-mcg E39 dose than at lower doses (P = .04). There was one grade 3 toxicity, and no grade 4 or 5 adverse events.

Delayed-type hypersensitivity reactions were more pronounced after vaccination, compared with baseline (5.7 ± 1.5 mm versus 10.3 ± 3.0 mm; P = .06), particularly in the 1,000-mcg group (3.8 ± 2.0 mm vs. 9.5 ± 3.5 mm, P = .03), Dr. Maxwell reported. Among patients whose cancer did not recur, delayed-type hypersensitivity was markedly higher after vaccination than at baseline (P = .06). “Our functional immunologic data show that vaccination is associated with delayed type hypersensitivity, but more important, it is associated with clinical outcome,” Dr. Maxwell said.

Low levels of folate-binding protein expression correlated with better disease-free survival, he also reported. “Possibly, this is because high levels of expression are associated with disease aggressiveness, which may outpace the immune response,” he said.

A phase Ib trial of the E39 folate-binding protein peptide vaccine is underway. Dr. Maxwell did not cite external funding sources and reported having no conflicts of interest.

NATIONAL HARBOR, MD. – The folate-binding protein vaccine E39+GM-CSF was well tolerated and exhibited a statistically significant, dose-dependent effect on recurrence and disease-free survival among patients with remitted primary ovarian or endometrial cancer, according to the results of a small prospective controlled phase I/IIa trial.

After a median follow-up of 12 months, cancer recurred in 41% of all vaccine recipients and 55% of controls (P = .41), G. Larry Maxwell, MD, reported at the annual meeting of the Society of Gynecologic Oncology. However, cancer recurred in only 13% of patients who received the highest (1,000 mcg) dose of peptide in the vaccine (P = .01 compared with the control group). A closer look showed that this survival benefit was limited to patients with primary disease, indicating that this vaccine has potential as an adjuvant to standard therapy for primary endometrial or ovarian cancer, he added.

Mortality from these cancers continues to rise in the United States despite conventional treatment with chemotherapy and radiation, noted Dr. Maxwell, who is chairman of the department of obstetrics and gynecology of Inova Fairfax Hospital in Annandale, Va.

“Targeted therapies have been evaluated, but durable response remains limited. Novel agents are needed,” he emphasized. He and his coinvestigators have focused on folate-binding protein, which is overexpressed by 20- to 80-fold in endometrial and ovarian tumors, compared with healthy tissue. To develop the vaccine, they combined E39, an immunogenic peptide of folate receptor 1 that amplifies the lymphocytic tumor response, with the immune adjuvant, granulocyte macrophage-colony stimulating factor (GM-CSF).

The trial included 51 patients, of whom 40 had primary ovarian or endometrial cancer and 11 had recurrent cancer. The 29 patients who were HLA-A2 positive were allocated to the vaccine group, receiving six intradermal inoculations of either 100-mcg, 500-mcg, or 1,000-mcg E39 plus 250-mcg GM-CSF, spaced by 21-28 days. Fifteen of these patients received 1,000-mcg E39, while 14 received 500- or 100-mcg doses. The treatment group also received two booster vaccines spaced 6 months apart. The 22 HLA-A2–negative patients were followed as controls. The intervention and control groups resembled each other clinically and demographically, Dr. Maxwell said.

Estimated rates of 2-year disease-free survival were 77% for patients in the 1,000 mcg–dose group, 44% for controls (P = .05), and 23% for patients who received less than 1,000 mcg vaccine (P = .005). Adverse events mainly included grade 1 or grade 2 myalgias, headaches, or reactions at the vaccination site. Mild adverse events were significantly more common at the 1,000-mcg E39 dose than at lower doses (P = .04). There was one grade 3 toxicity, and no grade 4 or 5 adverse events.

Delayed-type hypersensitivity reactions were more pronounced after vaccination, compared with baseline (5.7 ± 1.5 mm versus 10.3 ± 3.0 mm; P = .06), particularly in the 1,000-mcg group (3.8 ± 2.0 mm vs. 9.5 ± 3.5 mm, P = .03), Dr. Maxwell reported. Among patients whose cancer did not recur, delayed-type hypersensitivity was markedly higher after vaccination than at baseline (P = .06). “Our functional immunologic data show that vaccination is associated with delayed type hypersensitivity, but more important, it is associated with clinical outcome,” Dr. Maxwell said.

Low levels of folate-binding protein expression correlated with better disease-free survival, he also reported. “Possibly, this is because high levels of expression are associated with disease aggressiveness, which may outpace the immune response,” he said.

A phase Ib trial of the E39 folate-binding protein peptide vaccine is underway. Dr. Maxwell did not cite external funding sources and reported having no conflicts of interest.

For the first time, new-onset connective tissue disease has been reported in patients who were treated with anti-PD1/PDL-1 agents, according to findings published in the Annals of the Rheumatic Diseases.

In a cohort of 447 cancer patients who received therapy with immune checkpoint inhibitors (ICIs), Sébastien Le Burel, MD, of the Bicêtre Hospital in Le Kremlin-Bicêtre, France, and his colleagues described four patients who developed a connective tissue disease (CTD). There were two cases of Sjögren’s syndrome in patients taking an anti–programmed cell death 1 (anti-PD1) drug, one case of cryoglobulinemic vasculitis as a complication of suspected Sjögren’s syndrome in a patient taking an anti–programmed cell death ligand 1 (PDL-1) agent, and a case of a patient with antinuclear antibody positive myositis who was taking an anti-PDL-1 drug (Ann Rheum Dis. 2017 Feb 27. doi: 10.1136/annrheumdis-2016-210820).

“While the onset of systemic autoimmune disease after ICI treatment remains uncommon, greater awareness of these conditions should enable physicians to provide more effective patient care,” the investigators wrote. “This underlines the need for close collaboration within a network of oncologists and other specialist physicians in the new era of immunotherapy.”

The investigators discovered the cases by screening the French prospective, multicenter, academic REISAMIC registry for reports of CTD among patients being treated with anti-PD1 or anti-PDL-1 agents.

All four of the patients who developed a CTD had metastatic cancer, and their mean age was 62 years. Two patients had been treated with anti-PD1 agents and two with anti-PDL-1 agents. None of the four patients had presented with symptoms of CTD before they began treatment.

The mean time interval between the first treatment dose and the first symptom of CTD was 60 days (range, 24-72), and the mean time interval between the first symptom and subsequent diagnosis of CTD was 40 days (range, 10-74).

Three patients discontinued the ICI agent, and two patients were treated with steroids (1 mg/kg/day).

The estimated prevalence of CTD was 0.7% in the REISAMIC registry, and the authors emphasize that the high proportion of cases of Sjögren’s syndrome is noteworthy, with two of the patients fulfilling the recent American College of Rheumatology/European League Against Rheumatism criteria for Sjögren’s syndrome.

A limitation of the study is that some patients presenting with milder symptoms might not have been investigated by their oncologist.

The findings raise the question of whether asymptomatic patients taking ICIs who are at risk for immune-related adverse events should be screened and monitored closely, the authors explained.

One of the study authors received research funding from Novartis and Pfizer for the current paper. Several authors report relationships with industry.

[email protected]

For the first time, new-onset connective tissue disease has been reported in patients who were treated with anti-PD1/PDL-1 agents, according to findings published in the Annals of the Rheumatic Diseases.

In a cohort of 447 cancer patients who received therapy with immune checkpoint inhibitors (ICIs), Sébastien Le Burel, MD, of the Bicêtre Hospital in Le Kremlin-Bicêtre, France, and his colleagues described four patients who developed a connective tissue disease (CTD). There were two cases of Sjögren’s syndrome in patients taking an anti–programmed cell death 1 (anti-PD1) drug, one case of cryoglobulinemic vasculitis as a complication of suspected Sjögren’s syndrome in a patient taking an anti–programmed cell death ligand 1 (PDL-1) agent, and a case of a patient with antinuclear antibody positive myositis who was taking an anti-PDL-1 drug (Ann Rheum Dis. 2017 Feb 27. doi: 10.1136/annrheumdis-2016-210820).

“While the onset of systemic autoimmune disease after ICI treatment remains uncommon, greater awareness of these conditions should enable physicians to provide more effective patient care,” the investigators wrote. “This underlines the need for close collaboration within a network of oncologists and other specialist physicians in the new era of immunotherapy.”

The investigators discovered the cases by screening the French prospective, multicenter, academic REISAMIC registry for reports of CTD among patients being treated with anti-PD1 or anti-PDL-1 agents.

All four of the patients who developed a CTD had metastatic cancer, and their mean age was 62 years. Two patients had been treated with anti-PD1 agents and two with anti-PDL-1 agents. None of the four patients had presented with symptoms of CTD before they began treatment.

The mean time interval between the first treatment dose and the first symptom of CTD was 60 days (range, 24-72), and the mean time interval between the first symptom and subsequent diagnosis of CTD was 40 days (range, 10-74).

Three patients discontinued the ICI agent, and two patients were treated with steroids (1 mg/kg/day).

The estimated prevalence of CTD was 0.7% in the REISAMIC registry, and the authors emphasize that the high proportion of cases of Sjögren’s syndrome is noteworthy, with two of the patients fulfilling the recent American College of Rheumatology/European League Against Rheumatism criteria for Sjögren’s syndrome.

A limitation of the study is that some patients presenting with milder symptoms might not have been investigated by their oncologist.

The findings raise the question of whether asymptomatic patients taking ICIs who are at risk for immune-related adverse events should be screened and monitored closely, the authors explained.

One of the study authors received research funding from Novartis and Pfizer for the current paper. Several authors report relationships with industry.

[email protected]

For the first time, new-onset connective tissue disease has been reported in patients who were treated with anti-PD1/PDL-1 agents, according to findings published in the Annals of the Rheumatic Diseases.

In a cohort of 447 cancer patients who received therapy with immune checkpoint inhibitors (ICIs), Sébastien Le Burel, MD, of the Bicêtre Hospital in Le Kremlin-Bicêtre, France, and his colleagues described four patients who developed a connective tissue disease (CTD). There were two cases of Sjögren’s syndrome in patients taking an anti–programmed cell death 1 (anti-PD1) drug, one case of cryoglobulinemic vasculitis as a complication of suspected Sjögren’s syndrome in a patient taking an anti–programmed cell death ligand 1 (PDL-1) agent, and a case of a patient with antinuclear antibody positive myositis who was taking an anti-PDL-1 drug (Ann Rheum Dis. 2017 Feb 27. doi: 10.1136/annrheumdis-2016-210820).

“While the onset of systemic autoimmune disease after ICI treatment remains uncommon, greater awareness of these conditions should enable physicians to provide more effective patient care,” the investigators wrote. “This underlines the need for close collaboration within a network of oncologists and other specialist physicians in the new era of immunotherapy.”

The investigators discovered the cases by screening the French prospective, multicenter, academic REISAMIC registry for reports of CTD among patients being treated with anti-PD1 or anti-PDL-1 agents.

All four of the patients who developed a CTD had metastatic cancer, and their mean age was 62 years. Two patients had been treated with anti-PD1 agents and two with anti-PDL-1 agents. None of the four patients had presented with symptoms of CTD before they began treatment.

The mean time interval between the first treatment dose and the first symptom of CTD was 60 days (range, 24-72), and the mean time interval between the first symptom and subsequent diagnosis of CTD was 40 days (range, 10-74).

Three patients discontinued the ICI agent, and two patients were treated with steroids (1 mg/kg/day).

The estimated prevalence of CTD was 0.7% in the REISAMIC registry, and the authors emphasize that the high proportion of cases of Sjögren’s syndrome is noteworthy, with two of the patients fulfilling the recent American College of Rheumatology/European League Against Rheumatism criteria for Sjögren’s syndrome.

A limitation of the study is that some patients presenting with milder symptoms might not have been investigated by their oncologist.

The findings raise the question of whether asymptomatic patients taking ICIs who are at risk for immune-related adverse events should be screened and monitored closely, the authors explained.

One of the study authors received research funding from Novartis and Pfizer for the current paper. Several authors report relationships with industry.

[email protected]

SAN FRANCISCO – Nivolumab was associated with durable responses in heavily pretreated patients with advanced hepatocellular carcinoma in the dose-escalation and dose-expansion phases of the CheckMate 040 study.

Further, the safety profile of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), was consistent with that observed in other solid tumors; events were manageable, and no new safety signals were detected, Ignacio Melero, MD, of Clinica Universidad de Navarra, Pamplona, Spain, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.

Sharon Worcester/Frontline Medical News

[email protected]

SAN FRANCISCO – Nivolumab was associated with durable responses in heavily pretreated patients with advanced hepatocellular carcinoma in the dose-escalation and dose-expansion phases of the CheckMate 040 study.

Further, the safety profile of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), was consistent with that observed in other solid tumors; events were manageable, and no new safety signals were detected, Ignacio Melero, MD, of Clinica Universidad de Navarra, Pamplona, Spain, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.

Sharon Worcester/Frontline Medical News

[email protected]

SAN FRANCISCO – Nivolumab was associated with durable responses in heavily pretreated patients with advanced hepatocellular carcinoma in the dose-escalation and dose-expansion phases of the CheckMate 040 study.

Further, the safety profile of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), was consistent with that observed in other solid tumors; events were manageable, and no new safety signals were detected, Ignacio Melero, MD, of Clinica Universidad de Navarra, Pamplona, Spain, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.

Sharon Worcester/Frontline Medical News

[email protected]

VIENNA – The oncologic immunotherapy drug nivolumab works by binding PD-1 receptors, but PD-L1 ligand levels in lung cancers do not predict how responsive patients are to the drug.

“While enhanced clinical activity with nivolumab correlates with increasing tumor PD-L1 expression, nivolumab-treated patients with little or no PD-L1 expression have a comparable probability of response, more durable responses, comparable overall survival, and fewer treatment-related adverse events, compared with patients treated with docetaxel,” Solange Peters, MD, said at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

VIENNA – The oncologic immunotherapy drug nivolumab works by binding PD-1 receptors, but PD-L1 ligand levels in lung cancers do not predict how responsive patients are to the drug.

“While enhanced clinical activity with nivolumab correlates with increasing tumor PD-L1 expression, nivolumab-treated patients with little or no PD-L1 expression have a comparable probability of response, more durable responses, comparable overall survival, and fewer treatment-related adverse events, compared with patients treated with docetaxel,” Solange Peters, MD, said at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

VIENNA – The oncologic immunotherapy drug nivolumab works by binding PD-1 receptors, but PD-L1 ligand levels in lung cancers do not predict how responsive patients are to the drug.

“While enhanced clinical activity with nivolumab correlates with increasing tumor PD-L1 expression, nivolumab-treated patients with little or no PD-L1 expression have a comparable probability of response, more durable responses, comparable overall survival, and fewer treatment-related adverse events, compared with patients treated with docetaxel,” Solange Peters, MD, said at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

SAN FRANCISCO – The human monoclonal IgG4 antibody nivolumab was safe and effective as a salvage treatment for patients in a randomized phase III trial who failed standard chemotherapy for advanced gastric or gastroesophageal junction cancer.

Nivolumab, which blocks the human programmed cell death-1 receptor, was superior to placebo with respect to overall survival, progression-free survival, and overall response rate, Yoon-Koo Kang, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

For the study (ONO-4538), 493 patients with ECOG performance status of 0-1 and unresectable advanced or recurrent advanced gastric or gastroesophageal cancer who failed 2 or more prior chemotherapy regimens were randomized to receive placebo or nivolumab in a 2:1 ratio. Nivolumab treatment was associated with significantly improved median overall survival at the time of data cut-off 5.6 months after the last patient was randomized (5.32 months vs. 4.14 months with placebo; hazard ratio, 0.63), said Dr. Kang of Asan Medical Center, University of Ulsan, Seoul, Korea.

The overall survival rate at 12 months was 26.6% vs. 10.9%, respectively, he said.

The overall response rate was 11.2% vs. 0%, and median progression-free survival was 1.61 months vs. 1.45 months (hazard ratio, 0.60) with nivolumab vs. placebo, respectively.

“Median duration of response was 9.53 months,” he said.

Study subjects were adults aged 20 years or older who were enrolled from 49 centers in Japan, Korea, and Taiwan. The 330 patients in the nivolumab group received 3 mg/kg every 2 weeks until toxicity became unacceptable or disease progressed. Treatment-related adverse events occurred in 42.7% vs. 26.7% of nivolumab and placebo group patients, respectively, and grade 3 or greater events occurred in 11.5% vs. 5.5%, respectively.

Grade 3 or 4 events reported in more than 2% of patients were diarrhea, fatigue, decreased appetite, pyrexia, and increased AST and ALT in the treatment group, and fatigue and decreased appetite in the placebo group. The rates of discontinuation of active treatment due to drug-related adverse events were similar at 2.7% and 2.5% in the groups, respectively, he said, noting that the safety profile was consistent with findings in prior studies involving patients with solid tumors.

The findings demonstrate a clinical benefit with nivolumab in pretreated advanced or recurrent gastric cancer, and establish a strong basis for conducting additional studies of the drug in such patients, he concluded.

ONO-4538 was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Kang reported a consulting or advisory role with Lilly/ImClone, Novartis, Ono Pharmaceutical, Roche/Genentech, and Taiho Pharmaceutical, and research funding from Bayer, Novartis, and Roche/Genentech.

[email protected]

SAN FRANCISCO – The human monoclonal IgG4 antibody nivolumab was safe and effective as a salvage treatment for patients in a randomized phase III trial who failed standard chemotherapy for advanced gastric or gastroesophageal junction cancer.

Nivolumab, which blocks the human programmed cell death-1 receptor, was superior to placebo with respect to overall survival, progression-free survival, and overall response rate, Yoon-Koo Kang, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

For the study (ONO-4538), 493 patients with ECOG performance status of 0-1 and unresectable advanced or recurrent advanced gastric or gastroesophageal cancer who failed 2 or more prior chemotherapy regimens were randomized to receive placebo or nivolumab in a 2:1 ratio. Nivolumab treatment was associated with significantly improved median overall survival at the time of data cut-off 5.6 months after the last patient was randomized (5.32 months vs. 4.14 months with placebo; hazard ratio, 0.63), said Dr. Kang of Asan Medical Center, University of Ulsan, Seoul, Korea.

The overall survival rate at 12 months was 26.6% vs. 10.9%, respectively, he said.

The overall response rate was 11.2% vs. 0%, and median progression-free survival was 1.61 months vs. 1.45 months (hazard ratio, 0.60) with nivolumab vs. placebo, respectively.

“Median duration of response was 9.53 months,” he said.

Study subjects were adults aged 20 years or older who were enrolled from 49 centers in Japan, Korea, and Taiwan. The 330 patients in the nivolumab group received 3 mg/kg every 2 weeks until toxicity became unacceptable or disease progressed. Treatment-related adverse events occurred in 42.7% vs. 26.7% of nivolumab and placebo group patients, respectively, and grade 3 or greater events occurred in 11.5% vs. 5.5%, respectively.

Grade 3 or 4 events reported in more than 2% of patients were diarrhea, fatigue, decreased appetite, pyrexia, and increased AST and ALT in the treatment group, and fatigue and decreased appetite in the placebo group. The rates of discontinuation of active treatment due to drug-related adverse events were similar at 2.7% and 2.5% in the groups, respectively, he said, noting that the safety profile was consistent with findings in prior studies involving patients with solid tumors.

The findings demonstrate a clinical benefit with nivolumab in pretreated advanced or recurrent gastric cancer, and establish a strong basis for conducting additional studies of the drug in such patients, he concluded.

ONO-4538 was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Kang reported a consulting or advisory role with Lilly/ImClone, Novartis, Ono Pharmaceutical, Roche/Genentech, and Taiho Pharmaceutical, and research funding from Bayer, Novartis, and Roche/Genentech.

[email protected]

SAN FRANCISCO – The human monoclonal IgG4 antibody nivolumab was safe and effective as a salvage treatment for patients in a randomized phase III trial who failed standard chemotherapy for advanced gastric or gastroesophageal junction cancer.

Nivolumab, which blocks the human programmed cell death-1 receptor, was superior to placebo with respect to overall survival, progression-free survival, and overall response rate, Yoon-Koo Kang, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

For the study (ONO-4538), 493 patients with ECOG performance status of 0-1 and unresectable advanced or recurrent advanced gastric or gastroesophageal cancer who failed 2 or more prior chemotherapy regimens were randomized to receive placebo or nivolumab in a 2:1 ratio. Nivolumab treatment was associated with significantly improved median overall survival at the time of data cut-off 5.6 months after the last patient was randomized (5.32 months vs. 4.14 months with placebo; hazard ratio, 0.63), said Dr. Kang of Asan Medical Center, University of Ulsan, Seoul, Korea.

The overall survival rate at 12 months was 26.6% vs. 10.9%, respectively, he said.

The overall response rate was 11.2% vs. 0%, and median progression-free survival was 1.61 months vs. 1.45 months (hazard ratio, 0.60) with nivolumab vs. placebo, respectively.

“Median duration of response was 9.53 months,” he said.

Study subjects were adults aged 20 years or older who were enrolled from 49 centers in Japan, Korea, and Taiwan. The 330 patients in the nivolumab group received 3 mg/kg every 2 weeks until toxicity became unacceptable or disease progressed. Treatment-related adverse events occurred in 42.7% vs. 26.7% of nivolumab and placebo group patients, respectively, and grade 3 or greater events occurred in 11.5% vs. 5.5%, respectively.

Grade 3 or 4 events reported in more than 2% of patients were diarrhea, fatigue, decreased appetite, pyrexia, and increased AST and ALT in the treatment group, and fatigue and decreased appetite in the placebo group. The rates of discontinuation of active treatment due to drug-related adverse events were similar at 2.7% and 2.5% in the groups, respectively, he said, noting that the safety profile was consistent with findings in prior studies involving patients with solid tumors.

The findings demonstrate a clinical benefit with nivolumab in pretreated advanced or recurrent gastric cancer, and establish a strong basis for conducting additional studies of the drug in such patients, he concluded.

ONO-4538 was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Kang reported a consulting or advisory role with Lilly/ImClone, Novartis, Ono Pharmaceutical, Roche/Genentech, and Taiho Pharmaceutical, and research funding from Bayer, Novartis, and Roche/Genentech.

[email protected]

VIENNA – Patients with metastatic non–small-cell lung cancer with high levels of PD-L1 who received first-line pembrolizumab treatment had clinically meaningful improvement in their quality of life, compared with patients randomized to chemotherapy, in a prespecified secondary analysis of data from the drug’s pivotal trial.

This boost in quality of life as well as other measures of health status add to the pivotal trial’s primary finding of significantly increased progression-free survival compared with chemotherapy, as well as previously-reported secondary findings of superior overall survival, objective response rate, and safety with pembrolizumab compared with chemotherapy (N Engl J Med. 2016 Nov 10;375[19]:1823-33), Julie R. Brahmer, MD, said at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

The primary endpoint of the Study of Pembrolizumab Compared to Platinum-Based Chemotherapies in Participants With Metastatic Non–Small Cell Lung Cancer (KEYNOTE-024) showed an average 4.3-month increase in progression-free survival with pembrolizumab immunotherapy, compared with a standard chemotherapy regimen.

Improved quality of life on top of improved efficacy and safety is an important added benefit from pembrolizumab that should further spur its widespread adoption as first-line treatment for approved patients, Dr. Brahmer said in a video interview.

“When you talk about improving efficacy by months, patients and physicians want to also see improved quality of life,” said Dr. Brahmer, director of thoracic oncology at the Johns Hopkins Kimmel Cancer Center in Baltimore. “If symptoms are not improved or there are a ton of side effects with the treatment then use might be low.”

Based on its performance in KEYNOTE-024, pembrolizumab (Keytruda) received Food and Drug Administration approval on Oct. 24, 2016, as first-line treatment for patients with metastatic non–small-cell lung cancer that has a tumor proportion score of at least 50% for programmed death ligand 1 (PD-L1). Pembrolizumab is a monoclonal antibody that binds and blocks PD-1, the immune-cell receptor that tumor-cell PD-L1 binds to make immune cells less active. Other new immune checkpoint inhibitor drugs that act by blocking PD-1 or PD-L1 have shown similar quality of life benefits, she noted.

Routine availability of pembrolizumab as initial treatment for patients who have tumors with this level of PD-L1 expression (and also have no EGFR or ALK genomic aberrations) is shifting practice, Dr. Brahmer said.

“It’s catching on. The limitation right now is making sure patients get tested” for their PD-L1 tumor proportion score at the time they are first diagnosed. “Medical oncologists need to educate pathologists that we need this testing automatically, upfront. It’s not there yet,” she said.

Patients also are enthused. “There is a lot of chemo-exhaustion among patients. They are looking for something different, and something that uses their immune system makes sense.” But only about one quarter of patients have tumors with this level of PD-L1 expression; the others must start chemotherapy first before trying immunotherapy, unless they have an EGFR mutation. Out-of-pocket cost for pembrolizumab is also a major issues for many patients, she said.

KEYNOTE-024 randomized 305 patients at 102 international sites and followed patients for a median of 11 months. Dr. Brahmer and her associates made two primary analyses of patient-reported outcomes. One was measurement of global health status at 15 weeks after the start of treatment using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire designed to assess quality of life. Weighted averaging of the EORTC QCQ-C30 scores showed a mean improvement of 7.8 points (P = .002) in the pembrolizumab patients compared with the chemotherapy patients, a difference Dr. Brahmer called “clinically meaningful” as well as statistically significant.

A second analysis of patient-reported outcomes used a second EORTC instrument, the QLC-LC13, which combines assessment of cough, chest pain, and dyspnea. Treatment with pembrolizumab significantly reduced the time to deterioration as measured by this questionnaire by a relative 34%, (P = .029).

A third analysis looked at 15 individual function or symptom domains that make up the QLQ-C30. In general, these showed more improvements with pembrolizumab than with chemotherapy. One notable subcategory was fatigue, which showed significant improvement with pembrolizumab compared with a small worsening with chemotherapy.

[email protected]

On Twitter @mitchelzoler

VIENNA – Patients with metastatic non–small-cell lung cancer with high levels of PD-L1 who received first-line pembrolizumab treatment had clinically meaningful improvement in their quality of life, compared with patients randomized to chemotherapy, in a prespecified secondary analysis of data from the drug’s pivotal trial.

This boost in quality of life as well as other measures of health status add to the pivotal trial’s primary finding of significantly increased progression-free survival compared with chemotherapy, as well as previously-reported secondary findings of superior overall survival, objective response rate, and safety with pembrolizumab compared with chemotherapy (N Engl J Med. 2016 Nov 10;375[19]:1823-33), Julie R. Brahmer, MD, said at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

The primary endpoint of the Study of Pembrolizumab Compared to Platinum-Based Chemotherapies in Participants With Metastatic Non–Small Cell Lung Cancer (KEYNOTE-024) showed an average 4.3-month increase in progression-free survival with pembrolizumab immunotherapy, compared with a standard chemotherapy regimen.

Improved quality of life on top of improved efficacy and safety is an important added benefit from pembrolizumab that should further spur its widespread adoption as first-line treatment for approved patients, Dr. Brahmer said in a video interview.

“When you talk about improving efficacy by months, patients and physicians want to also see improved quality of life,” said Dr. Brahmer, director of thoracic oncology at the Johns Hopkins Kimmel Cancer Center in Baltimore. “If symptoms are not improved or there are a ton of side effects with the treatment then use might be low.”

Based on its performance in KEYNOTE-024, pembrolizumab (Keytruda) received Food and Drug Administration approval on Oct. 24, 2016, as first-line treatment for patients with metastatic non–small-cell lung cancer that has a tumor proportion score of at least 50% for programmed death ligand 1 (PD-L1). Pembrolizumab is a monoclonal antibody that binds and blocks PD-1, the immune-cell receptor that tumor-cell PD-L1 binds to make immune cells less active. Other new immune checkpoint inhibitor drugs that act by blocking PD-1 or PD-L1 have shown similar quality of life benefits, she noted.

Routine availability of pembrolizumab as initial treatment for patients who have tumors with this level of PD-L1 expression (and also have no EGFR or ALK genomic aberrations) is shifting practice, Dr. Brahmer said.

“It’s catching on. The limitation right now is making sure patients get tested” for their PD-L1 tumor proportion score at the time they are first diagnosed. “Medical oncologists need to educate pathologists that we need this testing automatically, upfront. It’s not there yet,” she said.

Patients also are enthused. “There is a lot of chemo-exhaustion among patients. They are looking for something different, and something that uses their immune system makes sense.” But only about one quarter of patients have tumors with this level of PD-L1 expression; the others must start chemotherapy first before trying immunotherapy, unless they have an EGFR mutation. Out-of-pocket cost for pembrolizumab is also a major issues for many patients, she said.

KEYNOTE-024 randomized 305 patients at 102 international sites and followed patients for a median of 11 months. Dr. Brahmer and her associates made two primary analyses of patient-reported outcomes. One was measurement of global health status at 15 weeks after the start of treatment using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire designed to assess quality of life. Weighted averaging of the EORTC QCQ-C30 scores showed a mean improvement of 7.8 points (P = .002) in the pembrolizumab patients compared with the chemotherapy patients, a difference Dr. Brahmer called “clinically meaningful” as well as statistically significant.

A second analysis of patient-reported outcomes used a second EORTC instrument, the QLC-LC13, which combines assessment of cough, chest pain, and dyspnea. Treatment with pembrolizumab significantly reduced the time to deterioration as measured by this questionnaire by a relative 34%, (P = .029).

A third analysis looked at 15 individual function or symptom domains that make up the QLQ-C30. In general, these showed more improvements with pembrolizumab than with chemotherapy. One notable subcategory was fatigue, which showed significant improvement with pembrolizumab compared with a small worsening with chemotherapy.

[email protected]

On Twitter @mitchelzoler

VIENNA – Patients with metastatic non–small-cell lung cancer with high levels of PD-L1 who received first-line pembrolizumab treatment had clinically meaningful improvement in their quality of life, compared with patients randomized to chemotherapy, in a prespecified secondary analysis of data from the drug’s pivotal trial.

This boost in quality of life as well as other measures of health status add to the pivotal trial’s primary finding of significantly increased progression-free survival compared with chemotherapy, as well as previously-reported secondary findings of superior overall survival, objective response rate, and safety with pembrolizumab compared with chemotherapy (N Engl J Med. 2016 Nov 10;375[19]:1823-33), Julie R. Brahmer, MD, said at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

The primary endpoint of the Study of Pembrolizumab Compared to Platinum-Based Chemotherapies in Participants With Metastatic Non–Small Cell Lung Cancer (KEYNOTE-024) showed an average 4.3-month increase in progression-free survival with pembrolizumab immunotherapy, compared with a standard chemotherapy regimen.

Improved quality of life on top of improved efficacy and safety is an important added benefit from pembrolizumab that should further spur its widespread adoption as first-line treatment for approved patients, Dr. Brahmer said in a video interview.

“When you talk about improving efficacy by months, patients and physicians want to also see improved quality of life,” said Dr. Brahmer, director of thoracic oncology at the Johns Hopkins Kimmel Cancer Center in Baltimore. “If symptoms are not improved or there are a ton of side effects with the treatment then use might be low.”

Based on its performance in KEYNOTE-024, pembrolizumab (Keytruda) received Food and Drug Administration approval on Oct. 24, 2016, as first-line treatment for patients with metastatic non–small-cell lung cancer that has a tumor proportion score of at least 50% for programmed death ligand 1 (PD-L1). Pembrolizumab is a monoclonal antibody that binds and blocks PD-1, the immune-cell receptor that tumor-cell PD-L1 binds to make immune cells less active. Other new immune checkpoint inhibitor drugs that act by blocking PD-1 or PD-L1 have shown similar quality of life benefits, she noted.

Routine availability of pembrolizumab as initial treatment for patients who have tumors with this level of PD-L1 expression (and also have no EGFR or ALK genomic aberrations) is shifting practice, Dr. Brahmer said.

“It’s catching on. The limitation right now is making sure patients get tested” for their PD-L1 tumor proportion score at the time they are first diagnosed. “Medical oncologists need to educate pathologists that we need this testing automatically, upfront. It’s not there yet,” she said.

Patients also are enthused. “There is a lot of chemo-exhaustion among patients. They are looking for something different, and something that uses their immune system makes sense.” But only about one quarter of patients have tumors with this level of PD-L1 expression; the others must start chemotherapy first before trying immunotherapy, unless they have an EGFR mutation. Out-of-pocket cost for pembrolizumab is also a major issues for many patients, she said.

KEYNOTE-024 randomized 305 patients at 102 international sites and followed patients for a median of 11 months. Dr. Brahmer and her associates made two primary analyses of patient-reported outcomes. One was measurement of global health status at 15 weeks after the start of treatment using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire designed to assess quality of life. Weighted averaging of the EORTC QCQ-C30 scores showed a mean improvement of 7.8 points (P = .002) in the pembrolizumab patients compared with the chemotherapy patients, a difference Dr. Brahmer called “clinically meaningful” as well as statistically significant.

A second analysis of patient-reported outcomes used a second EORTC instrument, the QLC-LC13, which combines assessment of cough, chest pain, and dyspnea. Treatment with pembrolizumab significantly reduced the time to deterioration as measured by this questionnaire by a relative 34%, (P = .029).

A third analysis looked at 15 individual function or symptom domains that make up the QLQ-C30. In general, these showed more improvements with pembrolizumab than with chemotherapy. One notable subcategory was fatigue, which showed significant improvement with pembrolizumab compared with a small worsening with chemotherapy.

[email protected]

On Twitter @mitchelzoler

NATIONAL HARBOR, MD – For patients with non-muscle invasive bladder cancer, intravesicular administration of an oncolytic virus was both feasible and safe, and in a small study was associated with at least one complete tumor response, investigators reported.

Instillation into the bladder of coxsackievirus A21 (CVA21; Cavatak), alone or in combination with low-dose mitomycin C, was associated with increases in immune cell filtrates and ramped-up expression of the programmed death-1 ligand (PD-L1) in the tumor microenvironment, reported Nicola Annels, PhD, a research fellow at the University of Surrey in England.

Neil Osterweil/Frontline Medical News

NATIONAL HARBOR, MD – For patients with non-muscle invasive bladder cancer, intravesicular administration of an oncolytic virus was both feasible and safe, and in a small study was associated with at least one complete tumor response, investigators reported.

Instillation into the bladder of coxsackievirus A21 (CVA21; Cavatak), alone or in combination with low-dose mitomycin C, was associated with increases in immune cell filtrates and ramped-up expression of the programmed death-1 ligand (PD-L1) in the tumor microenvironment, reported Nicola Annels, PhD, a research fellow at the University of Surrey in England.

Neil Osterweil/Frontline Medical News

NATIONAL HARBOR, MD – For patients with non-muscle invasive bladder cancer, intravesicular administration of an oncolytic virus was both feasible and safe, and in a small study was associated with at least one complete tumor response, investigators reported.

Instillation into the bladder of coxsackievirus A21 (CVA21; Cavatak), alone or in combination with low-dose mitomycin C, was associated with increases in immune cell filtrates and ramped-up expression of the programmed death-1 ligand (PD-L1) in the tumor microenvironment, reported Nicola Annels, PhD, a research fellow at the University of Surrey in England.

Neil Osterweil/Frontline Medical News

NATIONAL HARBOR, MD. – To date, checkpoint inhibitors have shown little clinical activity as single agents against metastatic, castration-resistant prostate cancer, but a combination of a DNA vaccine and a programmed-death 1 inhibitor shows promise for enhancing anti-tumor immune responses, report investigators in a phase I trial.

“If you vaccinate animals, PD-1 expression transiently goes up, and if you block it at that point you get a better anti-tumor response, and that was in models where anti PD-1 therapy alone didn’t do anything. So we thought this could be a good approach for prostate cancer,” Douglas G. McNeel, MD, PhD, of the University of Wisconsin, Madison, said in an interview at the annual meeting of the Society for Immunotherapy of Cancer.

Neil Osterweil/Frontline Medical News

Vaccine ramps up PD-1 expression

The investigators had previously shown that patients immunized with a DNA vaccine encoding PAP (pTVG-HP; currently in phase II clinical trials) developed PD-1-regulated, PAP-specific T cells and had increased PD-L1 expression in circulating tumor cells. They also demonstrated in preclinical studies with mouse models that increased PD-1 expression on vaccine-induced CD8-positive T cells led to inferior anti-tumor immune responses, and that blocking PD-1 at the time of T-cell activation with vaccine improved anti-tumor responses.

“The current pilot trial was designed to evaluate whether delivery of PD-1 blockade after immunization (when PD-1-regulated T cells are elicited and when PD-L1 expression is induced with vaccination on tumor cells) or with immunization (when PD-1 expression increases on antigen-specific CD8+ T cells with activation) results in anti-tumor responses in patients with advanced, metastatic, castration-resistant prostate cancer,” Dr. McNeel and his colleagues wrote.

They reported preliminary impressions of the efficacy and safety of the combination in 12 patients with mCRPC. The patients all had evidence of progressive disease and were at least 6 months out from chemotherapy. Patients could have previously been treated with enzalutamide (Xtandi) or abiraterone (Zytiga), but were excluded if they had received sipuleucel-T vaccine.

Patients in the ongoing trial are randomized to receive six doses of pTVG-HP over 10 weeks with either four doses of concurrent pembrolizumab, or four doses of pembrolizumab delivered every 3 weeks beginning 2 weeks after the last vaccine dose.

The authors reported that treatment with the combination evokes changes in serum prostate-specific antigen (PSA) that are associated with objective radiographic changes, and “elicits robust and persistent PAP-specific Th1-based immunity.”

They also found evidence to suggest that concurrent administration of the vaccine and the PD-1 inhibitor may be more effective than sequential administration, based on differences in serum PSA and PAP.

Adverse events were generally mild and similar to those seen in other studies of pembrolizumab and DNA vaccine, with only three grade 3 events and no grade 4 events.

The investigators hope to expand the pilot study beyond the 12 weeks originally scheduled, and plan to explore potential biomarkers for vaccine response based on T-cell proliferation in tumors and in regional lymph nodes as seen on imaging modalities.

The study is funded by a 2014 Movember Prostate Cancer Foundation Challenge Award and Madison Vaccines Inc. Dr. McNeel reports an ownership interest and funding support from Madison Vaccines. All other coauthors reported no conflicts of interest.

NATIONAL HARBOR, MD. – To date, checkpoint inhibitors have shown little clinical activity as single agents against metastatic, castration-resistant prostate cancer, but a combination of a DNA vaccine and a programmed-death 1 inhibitor shows promise for enhancing anti-tumor immune responses, report investigators in a phase I trial.

“If you vaccinate animals, PD-1 expression transiently goes up, and if you block it at that point you get a better anti-tumor response, and that was in models where anti PD-1 therapy alone didn’t do anything. So we thought this could be a good approach for prostate cancer,” Douglas G. McNeel, MD, PhD, of the University of Wisconsin, Madison, said in an interview at the annual meeting of the Society for Immunotherapy of Cancer.

Neil Osterweil/Frontline Medical News

Vaccine ramps up PD-1 expression

The investigators had previously shown that patients immunized with a DNA vaccine encoding PAP (pTVG-HP; currently in phase II clinical trials) developed PD-1-regulated, PAP-specific T cells and had increased PD-L1 expression in circulating tumor cells. They also demonstrated in preclinical studies with mouse models that increased PD-1 expression on vaccine-induced CD8-positive T cells led to inferior anti-tumor immune responses, and that blocking PD-1 at the time of T-cell activation with vaccine improved anti-tumor responses.

“The current pilot trial was designed to evaluate whether delivery of PD-1 blockade after immunization (when PD-1-regulated T cells are elicited and when PD-L1 expression is induced with vaccination on tumor cells) or with immunization (when PD-1 expression increases on antigen-specific CD8+ T cells with activation) results in anti-tumor responses in patients with advanced, metastatic, castration-resistant prostate cancer,” Dr. McNeel and his colleagues wrote.

They reported preliminary impressions of the efficacy and safety of the combination in 12 patients with mCRPC. The patients all had evidence of progressive disease and were at least 6 months out from chemotherapy. Patients could have previously been treated with enzalutamide (Xtandi) or abiraterone (Zytiga), but were excluded if they had received sipuleucel-T vaccine.

Patients in the ongoing trial are randomized to receive six doses of pTVG-HP over 10 weeks with either four doses of concurrent pembrolizumab, or four doses of pembrolizumab delivered every 3 weeks beginning 2 weeks after the last vaccine dose.

The authors reported that treatment with the combination evokes changes in serum prostate-specific antigen (PSA) that are associated with objective radiographic changes, and “elicits robust and persistent PAP-specific Th1-based immunity.”

They also found evidence to suggest that concurrent administration of the vaccine and the PD-1 inhibitor may be more effective than sequential administration, based on differences in serum PSA and PAP.

Adverse events were generally mild and similar to those seen in other studies of pembrolizumab and DNA vaccine, with only three grade 3 events and no grade 4 events.

The investigators hope to expand the pilot study beyond the 12 weeks originally scheduled, and plan to explore potential biomarkers for vaccine response based on T-cell proliferation in tumors and in regional lymph nodes as seen on imaging modalities.

The study is funded by a 2014 Movember Prostate Cancer Foundation Challenge Award and Madison Vaccines Inc. Dr. McNeel reports an ownership interest and funding support from Madison Vaccines. All other coauthors reported no conflicts of interest.

NATIONAL HARBOR, MD. – To date, checkpoint inhibitors have shown little clinical activity as single agents against metastatic, castration-resistant prostate cancer, but a combination of a DNA vaccine and a programmed-death 1 inhibitor shows promise for enhancing anti-tumor immune responses, report investigators in a phase I trial.

“If you vaccinate animals, PD-1 expression transiently goes up, and if you block it at that point you get a better anti-tumor response, and that was in models where anti PD-1 therapy alone didn’t do anything. So we thought this could be a good approach for prostate cancer,” Douglas G. McNeel, MD, PhD, of the University of Wisconsin, Madison, said in an interview at the annual meeting of the Society for Immunotherapy of Cancer.

Neil Osterweil/Frontline Medical News

Vaccine ramps up PD-1 expression

The investigators had previously shown that patients immunized with a DNA vaccine encoding PAP (pTVG-HP; currently in phase II clinical trials) developed PD-1-regulated, PAP-specific T cells and had increased PD-L1 expression in circulating tumor cells. They also demonstrated in preclinical studies with mouse models that increased PD-1 expression on vaccine-induced CD8-positive T cells led to inferior anti-tumor immune responses, and that blocking PD-1 at the time of T-cell activation with vaccine improved anti-tumor responses.

“The current pilot trial was designed to evaluate whether delivery of PD-1 blockade after immunization (when PD-1-regulated T cells are elicited and when PD-L1 expression is induced with vaccination on tumor cells) or with immunization (when PD-1 expression increases on antigen-specific CD8+ T cells with activation) results in anti-tumor responses in patients with advanced, metastatic, castration-resistant prostate cancer,” Dr. McNeel and his colleagues wrote.

They reported preliminary impressions of the efficacy and safety of the combination in 12 patients with mCRPC. The patients all had evidence of progressive disease and were at least 6 months out from chemotherapy. Patients could have previously been treated with enzalutamide (Xtandi) or abiraterone (Zytiga), but were excluded if they had received sipuleucel-T vaccine.

Patients in the ongoing trial are randomized to receive six doses of pTVG-HP over 10 weeks with either four doses of concurrent pembrolizumab, or four doses of pembrolizumab delivered every 3 weeks beginning 2 weeks after the last vaccine dose.

The authors reported that treatment with the combination evokes changes in serum prostate-specific antigen (PSA) that are associated with objective radiographic changes, and “elicits robust and persistent PAP-specific Th1-based immunity.”

They also found evidence to suggest that concurrent administration of the vaccine and the PD-1 inhibitor may be more effective than sequential administration, based on differences in serum PSA and PAP.

Adverse events were generally mild and similar to those seen in other studies of pembrolizumab and DNA vaccine, with only three grade 3 events and no grade 4 events.

The investigators hope to expand the pilot study beyond the 12 weeks originally scheduled, and plan to explore potential biomarkers for vaccine response based on T-cell proliferation in tumors and in regional lymph nodes as seen on imaging modalities.

The study is funded by a 2014 Movember Prostate Cancer Foundation Challenge Award and Madison Vaccines Inc. Dr. McNeel reports an ownership interest and funding support from Madison Vaccines. All other coauthors reported no conflicts of interest.

Background Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. It is challenging to deliver standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy in the very elderly or elderly with comorbidities because of age-related changes in metabolism and performance.

Objectives To describe outcomes of a unique approach to the delivery of standard R-CHOP chemotherapy in split-doses for the treatment of elderly DLBCL patients.

Methods We performed a single center, retrospective analysis of all patients with DLBCL treated with split-dose R-CHOP during January 2007-April 2015. The patients received R-CHOP at a 50% dose reduction on days 1 and 15 of each 28-day cycle (split dose), with full dose rituximab on day 1 for up to 6 cycles. The total amount of chemotherapy delivered during each 28-day cycle of split-dose R-CHOP was equivalent to the cumulative dose in each 21-day cycle of standard R-CHOP.

Results We identified 22 patients who had been treated with split-dose R-CHOP (median age, 81 years). 10 patients had a Charlson Comorbidity Index score of 2 or more, and 13 were aged 80 or older. 12 patients completed their prescribed treatments, and 10 required further de-escalation or early termination owing to toxicity. All of the patients who completed therapy were in a complete remission at the end of treatment. The median overall survival for the entire cohort was 47 months, and median progression-free survival was 43 months.

Limitations Retrospective, single institution study, small cohort Conclusions Split-dose R-CHOP allowed administration of curative-intent therapy in an elderly population with encouraging outcomes.

Conclusions Split-dose R-CHOP allowed administration of curative-intent therapy in an elderly population with encouraging outcomes.

Funding/sponsorship Cancer Center Research Training Program, NCI 5-T32 CA09615-25 (fellowship funding for Dr Shah).
 

Click on the PDF icon at the top of this introduction to read the full article.
 

Background Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. It is challenging to deliver standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy in the very elderly or elderly with comorbidities because of age-related changes in metabolism and performance.

Objectives To describe outcomes of a unique approach to the delivery of standard R-CHOP chemotherapy in split-doses for the treatment of elderly DLBCL patients.

Methods We performed a single center, retrospective analysis of all patients with DLBCL treated with split-dose R-CHOP during January 2007-April 2015. The patients received R-CHOP at a 50% dose reduction on days 1 and 15 of each 28-day cycle (split dose), with full dose rituximab on day 1 for up to 6 cycles. The total amount of chemotherapy delivered during each 28-day cycle of split-dose R-CHOP was equivalent to the cumulative dose in each 21-day cycle of standard R-CHOP.

Results We identified 22 patients who had been treated with split-dose R-CHOP (median age, 81 years). 10 patients had a Charlson Comorbidity Index score of 2 or more, and 13 were aged 80 or older. 12 patients completed their prescribed treatments, and 10 required further de-escalation or early termination owing to toxicity. All of the patients who completed therapy were in a complete remission at the end of treatment. The median overall survival for the entire cohort was 47 months, and median progression-free survival was 43 months.

Limitations Retrospective, single institution study, small cohort Conclusions Split-dose R-CHOP allowed administration of curative-intent therapy in an elderly population with encouraging outcomes.

Conclusions Split-dose R-CHOP allowed administration of curative-intent therapy in an elderly population with encouraging outcomes.

Funding/sponsorship Cancer Center Research Training Program, NCI 5-T32 CA09615-25 (fellowship funding for Dr Shah).
 

Click on the PDF icon at the top of this introduction to read the full article.
 

Background Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. It is challenging to deliver standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy in the very elderly or elderly with comorbidities because of age-related changes in metabolism and performance.

Objectives To describe outcomes of a unique approach to the delivery of standard R-CHOP chemotherapy in split-doses for the treatment of elderly DLBCL patients.

Methods We performed a single center, retrospective analysis of all patients with DLBCL treated with split-dose R-CHOP during January 2007-April 2015. The patients received R-CHOP at a 50% dose reduction on days 1 and 15 of each 28-day cycle (split dose), with full dose rituximab on day 1 for up to 6 cycles. The total amount of chemotherapy delivered during each 28-day cycle of split-dose R-CHOP was equivalent to the cumulative dose in each 21-day cycle of standard R-CHOP.

Results We identified 22 patients who had been treated with split-dose R-CHOP (median age, 81 years). 10 patients had a Charlson Comorbidity Index score of 2 or more, and 13 were aged 80 or older. 12 patients completed their prescribed treatments, and 10 required further de-escalation or early termination owing to toxicity. All of the patients who completed therapy were in a complete remission at the end of treatment. The median overall survival for the entire cohort was 47 months, and median progression-free survival was 43 months.

Limitations Retrospective, single institution study, small cohort Conclusions Split-dose R-CHOP allowed administration of curative-intent therapy in an elderly population with encouraging outcomes.

Conclusions Split-dose R-CHOP allowed administration of curative-intent therapy in an elderly population with encouraging outcomes.

Funding/sponsorship Cancer Center Research Training Program, NCI 5-T32 CA09615-25 (fellowship funding for Dr Shah).
 

Click on the PDF icon at the top of this introduction to read the full article.
 

It is amazing to see how many new drugs are being developed and approved for patients with cancer. In 2015 alone, the US Food and Drug Administration approved 45 new cancer drugs – a significant jump from the average 26 approvals annually from 2006 to 2014. This major shift in the number of approvals is due to many factors, including the intensified efforts by scientists and clinicians to develop new drugs, especially novel immunotherapies, and changes in the FDA’s drug approval process under the leadership of Dr Richard Pazdur.

Click on the PDF icon at the top of this introduction to read the full article. 

It is amazing to see how many new drugs are being developed and approved for patients with cancer. In 2015 alone, the US Food and Drug Administration approved 45 new cancer drugs – a significant jump from the average 26 approvals annually from 2006 to 2014. This major shift in the number of approvals is due to many factors, including the intensified efforts by scientists and clinicians to develop new drugs, especially novel immunotherapies, and changes in the FDA’s drug approval process under the leadership of Dr Richard Pazdur.

Click on the PDF icon at the top of this introduction to read the full article. 

It is amazing to see how many new drugs are being developed and approved for patients with cancer. In 2015 alone, the US Food and Drug Administration approved 45 new cancer drugs – a significant jump from the average 26 approvals annually from 2006 to 2014. This major shift in the number of approvals is due to many factors, including the intensified efforts by scientists and clinicians to develop new drugs, especially novel immunotherapies, and changes in the FDA’s drug approval process under the leadership of Dr Richard Pazdur.

Click on the PDF icon at the top of this introduction to read the full article.