START trial keeps L-BLP25 immunotherapy alive in stage III NSCLC

CHICAGO – Maintenance therapy with the investigational immunotherapy L-BLP25 offered no significant overall survival advantage in stage III unresectable non-small cell lung cancer in the phase III START trial.

In a modified intention-to-treat population of 1,239 patients, median overall survival was 25.6 months with L-BLP25 and 22.3 months with placebo (adjusted hazard ratio, 0.88; P = .123). Median follow-up was 39.9 months and 37.7 months, respectively.

Although the trial failed to meet its primary endpoint, the results were encouraging in patients receiving initial concurrent chemoradiotherapy, the largest subset of patients in the trial, Dr. Charles Butts said at the annual meeting of the American Society of Clinical Oncology.

Median survival in these 806 patients was 10.2 months longer with L-BLP25 (now known as Tecemotide) at 30.8 months vs. 20.6 months with placebo (HR, 0.78; P = .016).

Patients in all subgroups in the preplanned analysis appeared to benefit from maintenance L-BLP25, except those who had initial sequential chemotherapy/radiation therapy (19.4 vs. 24.6 months; HR, 1.12; P .38).

The secondary endpoints also significantly favored L-BLP25 over placebo for time to symptomatic progression (14.2 vs. 11.4 months; HR, 0.85; P = .023) and time to progression (10.0 vs. 8.4 months; HR, 0.87; P = .053), said Dr. Butts of the Cross Cancer Institute, University of Alberta, Edmonton.

"The treatment was well tolerated, and, certainly, further study is required to confirm these results," he said.

In a statement released by the study sponsor, Merck KGaA, Dr. Butts observed that concurrent chemoradiotherapy is the standard of care recommended for unresectable stage III NSCLC in U.S. and European guidelines, and said, "This is the first time that an antigen-specific cancer immunotherapy has shown this effect in a substantial subgroup of NSCLC patients who are usually only observed following chemoradiotherapy."

L-BLP25, formerly known as Stimuvax, targets the mucin1 (MUC1) cell surface–associated antigen, which is overexpressed and aberrantly glycolated in many epithelial tumors, particularly NSCLC. L-BLP25 appeared to confer a survival benefit to patients with localized stage III NSCLC in two earlier phase II trials.

Treatment in the phase III START (Stimulating Targeted Antigenic Responses to NSCLC) trial, however, was suspended for a median of 135 days in 531 patients after the Food and Drug Administration placed a clinical hold in 2010 on all L-BLP25 trials after a case of fatal encephalitis was reported in a patient with multiple myeloma in a phase II study and immune-related causality could not be excluded, Dr. Butts explained.

The primary analysis population was modified to exclude 274 patients randomized within 6 months of the clinical hold – the time period the investigators hypothesized would be needed to receive enough injections to stimulate an immune response. To maintain the power of the trial, these patients were replaced with additional accrual, for a final sample size of 1,513 patients and a modified intention-to-treat population of 1,239, "making it by far, the largest trial in stage III non-small cell lung cancer ever conducted," he said.

As for whether the massive trial brings the promise of vaccine therapy for NSCLC to reality, invited discussant Dr. Johan Vansteenkiste, who is with University Hospitals Leuven, Belgium, said, "I think it starts in START because, yes, START delivers clinically relevant results."

He agreed there is room for a confirmatory trial and said further work is also needed to address the timing of injections, radiotherapy and immunotherapy links, the role inflammation plays in immunotherapy, and the use of biomarkers with MUC1 vaccinations and PD-1 antibodies.

START investigators in 33 countries enrolled patients with unresectable, locally advanced stage III NSCLC who had a response or stable disease after at least two cycles of platinum-based chemoradiotherapy (concurrent or sequential). Patients were randomized within 4-12 weeks of completing initial treatment to a single dose of cyclophosphamide on day 3 followed by weekly injections of L-BLP25 for 8 weeks and then six weekly maintenance injections, or a single dose of saline followed by placebo injections using the same schedule.

One-third of patients had stable disease, 65% had received concurrent chemoradiotherapy, 25% were current smokers, and the median duration of NSCLC from diagnosis was 6 months.

An overall survival analysis of the 274 patients whose treatment was interrupted showed absolutely no treatment effect of L-BLP25 vs. placebo (26.4 vs. 29.1 months; HR, 1.09; P = .66), "suggesting that uninterrupted therapy, particularly in the initial phases of immune therapy, is absolutely critical for any efficacy," Dr. Butts said.

Injection-site reactions occurred in 17.3% of patients given L-BLP25 and in 12% of the placebo group, and grade 3/4 flulike symptoms occurred in less than 2% of each arm. The most frequent adverse events with L-BLP25 and placebo were cough (33% vs. 28%), dyspnea (23.2% vs. 23.5%), fatigue (19.2% vs. 21.4%), back pain (14.3% vs. 11.1%), nausea (13.7% vs. 8.2%), and chest pain (13.2% vs. 9.4%).

Rates of any adverse event leading to death were similar at 4.5% of L-BLP25-treated patients and 7.3% of placebo-treated patients, Dr. Butts said. Grade 3 or 4 potentially immune-related adverse events were low, at just two patients in both groups (0.2% vs. 0.4%).

"There really were no safety concerns seen in the trial," he said.

L-BLP25 is currently being investigated in the similarly designed phase III INSPIRE (L-BLP25 Liposome Vaccine Trial in Asian NSCLC Patients: Stimulating Immune Response) trial in 420 unresectable, locally advanced stage III NSCLC patients in Hong Kong, China, Korea, Singapore, and Taiwan.

START was supported by Merck KGaA. Dr. Butts reported a consultant/advisory role and honoraria from Merck KGaA and Merck Serono. Dr. Vansteenkiste reported a consultant/advisory role with Merck Serono and GlaxoSmithKline, and research support from Eli Lilly and AstraZeneca.

[email protected]

CHICAGO – Maintenance therapy with the investigational immunotherapy L-BLP25 offered no significant overall survival advantage in stage III unresectable non-small cell lung cancer in the phase III START trial.

In a modified intention-to-treat population of 1,239 patients, median overall survival was 25.6 months with L-BLP25 and 22.3 months with placebo (adjusted hazard ratio, 0.88; P = .123). Median follow-up was 39.9 months and 37.7 months, respectively.

Although the trial failed to meet its primary endpoint, the results were encouraging in patients receiving initial concurrent chemoradiotherapy, the largest subset of patients in the trial, Dr. Charles Butts said at the annual meeting of the American Society of Clinical Oncology.

Median survival in these 806 patients was 10.2 months longer with L-BLP25 (now known as Tecemotide) at 30.8 months vs. 20.6 months with placebo (HR, 0.78; P = .016).

Patients in all subgroups in the preplanned analysis appeared to benefit from maintenance L-BLP25, except those who had initial sequential chemotherapy/radiation therapy (19.4 vs. 24.6 months; HR, 1.12; P .38).

The secondary endpoints also significantly favored L-BLP25 over placebo for time to symptomatic progression (14.2 vs. 11.4 months; HR, 0.85; P = .023) and time to progression (10.0 vs. 8.4 months; HR, 0.87; P = .053), said Dr. Butts of the Cross Cancer Institute, University of Alberta, Edmonton.

"The treatment was well tolerated, and, certainly, further study is required to confirm these results," he said.

In a statement released by the study sponsor, Merck KGaA, Dr. Butts observed that concurrent chemoradiotherapy is the standard of care recommended for unresectable stage III NSCLC in U.S. and European guidelines, and said, "This is the first time that an antigen-specific cancer immunotherapy has shown this effect in a substantial subgroup of NSCLC patients who are usually only observed following chemoradiotherapy."

L-BLP25, formerly known as Stimuvax, targets the mucin1 (MUC1) cell surface–associated antigen, which is overexpressed and aberrantly glycolated in many epithelial tumors, particularly NSCLC. L-BLP25 appeared to confer a survival benefit to patients with localized stage III NSCLC in two earlier phase II trials.

Treatment in the phase III START (Stimulating Targeted Antigenic Responses to NSCLC) trial, however, was suspended for a median of 135 days in 531 patients after the Food and Drug Administration placed a clinical hold in 2010 on all L-BLP25 trials after a case of fatal encephalitis was reported in a patient with multiple myeloma in a phase II study and immune-related causality could not be excluded, Dr. Butts explained.

The primary analysis population was modified to exclude 274 patients randomized within 6 months of the clinical hold – the time period the investigators hypothesized would be needed to receive enough injections to stimulate an immune response. To maintain the power of the trial, these patients were replaced with additional accrual, for a final sample size of 1,513 patients and a modified intention-to-treat population of 1,239, "making it by far, the largest trial in stage III non-small cell lung cancer ever conducted," he said.

As for whether the massive trial brings the promise of vaccine therapy for NSCLC to reality, invited discussant Dr. Johan Vansteenkiste, who is with University Hospitals Leuven, Belgium, said, "I think it starts in START because, yes, START delivers clinically relevant results."

He agreed there is room for a confirmatory trial and said further work is also needed to address the timing of injections, radiotherapy and immunotherapy links, the role inflammation plays in immunotherapy, and the use of biomarkers with MUC1 vaccinations and PD-1 antibodies.

START investigators in 33 countries enrolled patients with unresectable, locally advanced stage III NSCLC who had a response or stable disease after at least two cycles of platinum-based chemoradiotherapy (concurrent or sequential). Patients were randomized within 4-12 weeks of completing initial treatment to a single dose of cyclophosphamide on day 3 followed by weekly injections of L-BLP25 for 8 weeks and then six weekly maintenance injections, or a single dose of saline followed by placebo injections using the same schedule.

One-third of patients had stable disease, 65% had received concurrent chemoradiotherapy, 25% were current smokers, and the median duration of NSCLC from diagnosis was 6 months.

An overall survival analysis of the 274 patients whose treatment was interrupted showed absolutely no treatment effect of L-BLP25 vs. placebo (26.4 vs. 29.1 months; HR, 1.09; P = .66), "suggesting that uninterrupted therapy, particularly in the initial phases of immune therapy, is absolutely critical for any efficacy," Dr. Butts said.

Injection-site reactions occurred in 17.3% of patients given L-BLP25 and in 12% of the placebo group, and grade 3/4 flulike symptoms occurred in less than 2% of each arm. The most frequent adverse events with L-BLP25 and placebo were cough (33% vs. 28%), dyspnea (23.2% vs. 23.5%), fatigue (19.2% vs. 21.4%), back pain (14.3% vs. 11.1%), nausea (13.7% vs. 8.2%), and chest pain (13.2% vs. 9.4%).

Rates of any adverse event leading to death were similar at 4.5% of L-BLP25-treated patients and 7.3% of placebo-treated patients, Dr. Butts said. Grade 3 or 4 potentially immune-related adverse events were low, at just two patients in both groups (0.2% vs. 0.4%).

"There really were no safety concerns seen in the trial," he said.

L-BLP25 is currently being investigated in the similarly designed phase III INSPIRE (L-BLP25 Liposome Vaccine Trial in Asian NSCLC Patients: Stimulating Immune Response) trial in 420 unresectable, locally advanced stage III NSCLC patients in Hong Kong, China, Korea, Singapore, and Taiwan.

START was supported by Merck KGaA. Dr. Butts reported a consultant/advisory role and honoraria from Merck KGaA and Merck Serono. Dr. Vansteenkiste reported a consultant/advisory role with Merck Serono and GlaxoSmithKline, and research support from Eli Lilly and AstraZeneca.

[email protected]

CHICAGO – Maintenance therapy with the investigational immunotherapy L-BLP25 offered no significant overall survival advantage in stage III unresectable non-small cell lung cancer in the phase III START trial.

In a modified intention-to-treat population of 1,239 patients, median overall survival was 25.6 months with L-BLP25 and 22.3 months with placebo (adjusted hazard ratio, 0.88; P = .123). Median follow-up was 39.9 months and 37.7 months, respectively.

Although the trial failed to meet its primary endpoint, the results were encouraging in patients receiving initial concurrent chemoradiotherapy, the largest subset of patients in the trial, Dr. Charles Butts said at the annual meeting of the American Society of Clinical Oncology.

Median survival in these 806 patients was 10.2 months longer with L-BLP25 (now known as Tecemotide) at 30.8 months vs. 20.6 months with placebo (HR, 0.78; P = .016).

Patients in all subgroups in the preplanned analysis appeared to benefit from maintenance L-BLP25, except those who had initial sequential chemotherapy/radiation therapy (19.4 vs. 24.6 months; HR, 1.12; P .38).

The secondary endpoints also significantly favored L-BLP25 over placebo for time to symptomatic progression (14.2 vs. 11.4 months; HR, 0.85; P = .023) and time to progression (10.0 vs. 8.4 months; HR, 0.87; P = .053), said Dr. Butts of the Cross Cancer Institute, University of Alberta, Edmonton.

"The treatment was well tolerated, and, certainly, further study is required to confirm these results," he said.

In a statement released by the study sponsor, Merck KGaA, Dr. Butts observed that concurrent chemoradiotherapy is the standard of care recommended for unresectable stage III NSCLC in U.S. and European guidelines, and said, "This is the first time that an antigen-specific cancer immunotherapy has shown this effect in a substantial subgroup of NSCLC patients who are usually only observed following chemoradiotherapy."

L-BLP25, formerly known as Stimuvax, targets the mucin1 (MUC1) cell surface–associated antigen, which is overexpressed and aberrantly glycolated in many epithelial tumors, particularly NSCLC. L-BLP25 appeared to confer a survival benefit to patients with localized stage III NSCLC in two earlier phase II trials.

Treatment in the phase III START (Stimulating Targeted Antigenic Responses to NSCLC) trial, however, was suspended for a median of 135 days in 531 patients after the Food and Drug Administration placed a clinical hold in 2010 on all L-BLP25 trials after a case of fatal encephalitis was reported in a patient with multiple myeloma in a phase II study and immune-related causality could not be excluded, Dr. Butts explained.

The primary analysis population was modified to exclude 274 patients randomized within 6 months of the clinical hold – the time period the investigators hypothesized would be needed to receive enough injections to stimulate an immune response. To maintain the power of the trial, these patients were replaced with additional accrual, for a final sample size of 1,513 patients and a modified intention-to-treat population of 1,239, "making it by far, the largest trial in stage III non-small cell lung cancer ever conducted," he said.

As for whether the massive trial brings the promise of vaccine therapy for NSCLC to reality, invited discussant Dr. Johan Vansteenkiste, who is with University Hospitals Leuven, Belgium, said, "I think it starts in START because, yes, START delivers clinically relevant results."

He agreed there is room for a confirmatory trial and said further work is also needed to address the timing of injections, radiotherapy and immunotherapy links, the role inflammation plays in immunotherapy, and the use of biomarkers with MUC1 vaccinations and PD-1 antibodies.

START investigators in 33 countries enrolled patients with unresectable, locally advanced stage III NSCLC who had a response or stable disease after at least two cycles of platinum-based chemoradiotherapy (concurrent or sequential). Patients were randomized within 4-12 weeks of completing initial treatment to a single dose of cyclophosphamide on day 3 followed by weekly injections of L-BLP25 for 8 weeks and then six weekly maintenance injections, or a single dose of saline followed by placebo injections using the same schedule.

One-third of patients had stable disease, 65% had received concurrent chemoradiotherapy, 25% were current smokers, and the median duration of NSCLC from diagnosis was 6 months.

An overall survival analysis of the 274 patients whose treatment was interrupted showed absolutely no treatment effect of L-BLP25 vs. placebo (26.4 vs. 29.1 months; HR, 1.09; P = .66), "suggesting that uninterrupted therapy, particularly in the initial phases of immune therapy, is absolutely critical for any efficacy," Dr. Butts said.

Injection-site reactions occurred in 17.3% of patients given L-BLP25 and in 12% of the placebo group, and grade 3/4 flulike symptoms occurred in less than 2% of each arm. The most frequent adverse events with L-BLP25 and placebo were cough (33% vs. 28%), dyspnea (23.2% vs. 23.5%), fatigue (19.2% vs. 21.4%), back pain (14.3% vs. 11.1%), nausea (13.7% vs. 8.2%), and chest pain (13.2% vs. 9.4%).

Rates of any adverse event leading to death were similar at 4.5% of L-BLP25-treated patients and 7.3% of placebo-treated patients, Dr. Butts said. Grade 3 or 4 potentially immune-related adverse events were low, at just two patients in both groups (0.2% vs. 0.4%).

"There really were no safety concerns seen in the trial," he said.

L-BLP25 is currently being investigated in the similarly designed phase III INSPIRE (L-BLP25 Liposome Vaccine Trial in Asian NSCLC Patients: Stimulating Immune Response) trial in 420 unresectable, locally advanced stage III NSCLC patients in Hong Kong, China, Korea, Singapore, and Taiwan.

START was supported by Merck KGaA. Dr. Butts reported a consultant/advisory role and honoraria from Merck KGaA and Merck Serono. Dr. Vansteenkiste reported a consultant/advisory role with Merck Serono and GlaxoSmithKline, and research support from Eli Lilly and AstraZeneca.

[email protected]