ASCO: String of Lackluster Results in ECOG Melanoma Trials

CHICAGO – A string of disappointing melanoma trials from the Eastern Cooperative Oncology Group left some seeing the proverbial glass as half empty, others as half full in an oral abstract session at the annual meeting of the American Society for Clinical Oncology.

No Benefit from GM-CSF
Updated data from the E4697 phase III cooperative trial in resected stage III and IV melanoma show only a hint of benefit for granulocyte-macrophage colony-stimulating factor (GM-CSF) in the adjuvant setting. The study was unblinded in April 2009, and an analysis reported later that year showed a significant improvement in disease-free survival for GM-CSF vs. placebo (P = .03), but no difference in overall survival.

In the updated analysis, with 86% of full data reported, the difference in disease-free survival at 9.2 months in 375 patients who were given placebo and 11.5 months in 368 patients who received GM-CSF was no longer significant (P = .14), Dr. David Lawson said. Again, there was no difference in overall survival.

GM-CSF also had no significant effect on either survival outcome in HLA A2–positive patients who also received peptide vaccination, said Dr. Lawson of Emory University in Atlanta.

A subset analysis that was stratified by disease stage, however, showed that GM-CSF did significantly improve disease-free survival in 258 patients with stage IV disease (hazard ratio 0.74, P = .04) but not overall survival (HR 0.72, P = .07).

Dr. Lawson said the data are worthy of further investigation and discussion. Invited discussant Dr. Michael S. Sabel of the University of Michigan in Ann Arbor said he is more skeptical, and would only go so far as to say that “you can’t take away the fact that there is some sort of immunologic effect potentially to these cytokines.”

Outcome Unchanged by Helper Peptides
Adding melanoma helper peptides to a multiepitope melanoma vaccination stimulated CD4+ and CD8+ T-cell responses, but did little to improve clinical outcome in the four-arm, phase II E1602 trial.

Patients with stage IV melanoma were vaccinated with 12 class I restricted melanoma peptides (arm A), plus either a tetanus peptide (arm B) or a mixture of six class II melanoma helper peptides (arm C), or with six class II melanoma helper peptides alone. Arm C was stopped early because of a lack of clinical response or disease stabilization.

The best overall response was partial response in 4% of 136 evaluable patients, said Dr. Craig L. Slingluff Jr., head of the surgical oncology division at the University of Virginia in Charlottesville. After a median follow-up of 21.4 months, median overall survival was 11.4 months, with no statistical differences between groups.

The trial can be viewed in two ways: as a success because it met the primary end point of stimulating T cells, but also as a requiem for peptide vaccines because “despite creating this army of antigen-specific T cells, the tumor continues to progress in the great majority of patients,” said invited discussant Dr. Antoni Ribas of the University of California, Los Angeles.

Adding Sorafenib Disappoints
There was little interpretation over the seventh and final analysis of the phase III E2603 trial of sorafenib (Nexavar) in combination with chemotherapy. Sorafenib does not improve overall survival, progression-free survival, or response rate when combined with carboplatin and paclitaxel in metastatic melanoma, reported Dr. Kevin Flaherty of Massachusetts General Hospital in Boston, who just 4 years ago set tongues wagging over sorafenib when he reported an 85% disease control rate in 105 melanoma patients.

Overall survival was 11.3 months, progression-free survival was 4.1 months, and the response rate was 16% with carboplatin/paclitaxel chemotherapy alone, compared with 11.1 months, 4.9 months, and 18%, respectively, for carboplatin/paclitaxel plus sorafenib. None of the differences was significantly different.

“There seem to be no additive effects, at least in melanoma,” said invited discussant Dr. Dirk Schadendorf, director of dermatology at University Hospital Essen (Germany). “What we have learned from the combination with chemotherapy, especially with carboplatin and paclitaxel, is that the progression-free survival time is around 4-5 months, which is interesting in patients who have rapid tumor progression and where you need a regimen to stop disease progression.”

Dr. Lawson reported a consultant/advisory role with Genzyme Corp. Dr. Slingluff reported a consultant/advisory role with and honoraria from Immatics Biotechnologies GmbH, research funding from Berlex Inc./Genzyme and GlaxoSmithKline, and other remuneration from the University of Virginia Patent Foundation. Dr. Ribas reported honoraria from Amgen Inc. and Roche. Dr. Flaherty disclosed no conflicts. Dr. Sabel reported a consultant/advisory role, honoraria, and research funding from Schering-Plough/Merck. Dr. Schadendorf disclosed consultant or advisory roles with AstraZeneca, Bristol-Myers Squibb Co., Plexxikon Inc., Roche, and Schering-Plough Corp., and research funding from Schering-Plough and Bayer-Schering.

CHICAGO – A string of disappointing melanoma trials from the Eastern Cooperative Oncology Group left some seeing the proverbial glass as half empty, others as half full in an oral abstract session at the annual meeting of the American Society for Clinical Oncology.

No Benefit from GM-CSF
Updated data from the E4697 phase III cooperative trial in resected stage III and IV melanoma show only a hint of benefit for granulocyte-macrophage colony-stimulating factor (GM-CSF) in the adjuvant setting. The study was unblinded in April 2009, and an analysis reported later that year showed a significant improvement in disease-free survival for GM-CSF vs. placebo (P = .03), but no difference in overall survival.

In the updated analysis, with 86% of full data reported, the difference in disease-free survival at 9.2 months in 375 patients who were given placebo and 11.5 months in 368 patients who received GM-CSF was no longer significant (P = .14), Dr. David Lawson said. Again, there was no difference in overall survival.

GM-CSF also had no significant effect on either survival outcome in HLA A2–positive patients who also received peptide vaccination, said Dr. Lawson of Emory University in Atlanta.

A subset analysis that was stratified by disease stage, however, showed that GM-CSF did significantly improve disease-free survival in 258 patients with stage IV disease (hazard ratio 0.74, P = .04) but not overall survival (HR 0.72, P = .07).

Dr. Lawson said the data are worthy of further investigation and discussion. Invited discussant Dr. Michael S. Sabel of the University of Michigan in Ann Arbor said he is more skeptical, and would only go so far as to say that “you can’t take away the fact that there is some sort of immunologic effect potentially to these cytokines.”

Outcome Unchanged by Helper Peptides
Adding melanoma helper peptides to a multiepitope melanoma vaccination stimulated CD4+ and CD8+ T-cell responses, but did little to improve clinical outcome in the four-arm, phase II E1602 trial.

Patients with stage IV melanoma were vaccinated with 12 class I restricted melanoma peptides (arm A), plus either a tetanus peptide (arm B) or a mixture of six class II melanoma helper peptides (arm C), or with six class II melanoma helper peptides alone. Arm C was stopped early because of a lack of clinical response or disease stabilization.

The best overall response was partial response in 4% of 136 evaluable patients, said Dr. Craig L. Slingluff Jr., head of the surgical oncology division at the University of Virginia in Charlottesville. After a median follow-up of 21.4 months, median overall survival was 11.4 months, with no statistical differences between groups.

The trial can be viewed in two ways: as a success because it met the primary end point of stimulating T cells, but also as a requiem for peptide vaccines because “despite creating this army of antigen-specific T cells, the tumor continues to progress in the great majority of patients,” said invited discussant Dr. Antoni Ribas of the University of California, Los Angeles.

Adding Sorafenib Disappoints
There was little interpretation over the seventh and final analysis of the phase III E2603 trial of sorafenib (Nexavar) in combination with chemotherapy. Sorafenib does not improve overall survival, progression-free survival, or response rate when combined with carboplatin and paclitaxel in metastatic melanoma, reported Dr. Kevin Flaherty of Massachusetts General Hospital in Boston, who just 4 years ago set tongues wagging over sorafenib when he reported an 85% disease control rate in 105 melanoma patients.

Overall survival was 11.3 months, progression-free survival was 4.1 months, and the response rate was 16% with carboplatin/paclitaxel chemotherapy alone, compared with 11.1 months, 4.9 months, and 18%, respectively, for carboplatin/paclitaxel plus sorafenib. None of the differences was significantly different.

“There seem to be no additive effects, at least in melanoma,” said invited discussant Dr. Dirk Schadendorf, director of dermatology at University Hospital Essen (Germany). “What we have learned from the combination with chemotherapy, especially with carboplatin and paclitaxel, is that the progression-free survival time is around 4-5 months, which is interesting in patients who have rapid tumor progression and where you need a regimen to stop disease progression.”

Dr. Lawson reported a consultant/advisory role with Genzyme Corp. Dr. Slingluff reported a consultant/advisory role with and honoraria from Immatics Biotechnologies GmbH, research funding from Berlex Inc./Genzyme and GlaxoSmithKline, and other remuneration from the University of Virginia Patent Foundation. Dr. Ribas reported honoraria from Amgen Inc. and Roche. Dr. Flaherty disclosed no conflicts. Dr. Sabel reported a consultant/advisory role, honoraria, and research funding from Schering-Plough/Merck. Dr. Schadendorf disclosed consultant or advisory roles with AstraZeneca, Bristol-Myers Squibb Co., Plexxikon Inc., Roche, and Schering-Plough Corp., and research funding from Schering-Plough and Bayer-Schering.

CHICAGO – A string of disappointing melanoma trials from the Eastern Cooperative Oncology Group left some seeing the proverbial glass as half empty, others as half full in an oral abstract session at the annual meeting of the American Society for Clinical Oncology.

No Benefit from GM-CSF
Updated data from the E4697 phase III cooperative trial in resected stage III and IV melanoma show only a hint of benefit for granulocyte-macrophage colony-stimulating factor (GM-CSF) in the adjuvant setting. The study was unblinded in April 2009, and an analysis reported later that year showed a significant improvement in disease-free survival for GM-CSF vs. placebo (P = .03), but no difference in overall survival.

In the updated analysis, with 86% of full data reported, the difference in disease-free survival at 9.2 months in 375 patients who were given placebo and 11.5 months in 368 patients who received GM-CSF was no longer significant (P = .14), Dr. David Lawson said. Again, there was no difference in overall survival.

GM-CSF also had no significant effect on either survival outcome in HLA A2–positive patients who also received peptide vaccination, said Dr. Lawson of Emory University in Atlanta.

A subset analysis that was stratified by disease stage, however, showed that GM-CSF did significantly improve disease-free survival in 258 patients with stage IV disease (hazard ratio 0.74, P = .04) but not overall survival (HR 0.72, P = .07).

Dr. Lawson said the data are worthy of further investigation and discussion. Invited discussant Dr. Michael S. Sabel of the University of Michigan in Ann Arbor said he is more skeptical, and would only go so far as to say that “you can’t take away the fact that there is some sort of immunologic effect potentially to these cytokines.”

Outcome Unchanged by Helper Peptides
Adding melanoma helper peptides to a multiepitope melanoma vaccination stimulated CD4+ and CD8+ T-cell responses, but did little to improve clinical outcome in the four-arm, phase II E1602 trial.

Patients with stage IV melanoma were vaccinated with 12 class I restricted melanoma peptides (arm A), plus either a tetanus peptide (arm B) or a mixture of six class II melanoma helper peptides (arm C), or with six class II melanoma helper peptides alone. Arm C was stopped early because of a lack of clinical response or disease stabilization.

The best overall response was partial response in 4% of 136 evaluable patients, said Dr. Craig L. Slingluff Jr., head of the surgical oncology division at the University of Virginia in Charlottesville. After a median follow-up of 21.4 months, median overall survival was 11.4 months, with no statistical differences between groups.

The trial can be viewed in two ways: as a success because it met the primary end point of stimulating T cells, but also as a requiem for peptide vaccines because “despite creating this army of antigen-specific T cells, the tumor continues to progress in the great majority of patients,” said invited discussant Dr. Antoni Ribas of the University of California, Los Angeles.

Adding Sorafenib Disappoints
There was little interpretation over the seventh and final analysis of the phase III E2603 trial of sorafenib (Nexavar) in combination with chemotherapy. Sorafenib does not improve overall survival, progression-free survival, or response rate when combined with carboplatin and paclitaxel in metastatic melanoma, reported Dr. Kevin Flaherty of Massachusetts General Hospital in Boston, who just 4 years ago set tongues wagging over sorafenib when he reported an 85% disease control rate in 105 melanoma patients.

Overall survival was 11.3 months, progression-free survival was 4.1 months, and the response rate was 16% with carboplatin/paclitaxel chemotherapy alone, compared with 11.1 months, 4.9 months, and 18%, respectively, for carboplatin/paclitaxel plus sorafenib. None of the differences was significantly different.

“There seem to be no additive effects, at least in melanoma,” said invited discussant Dr. Dirk Schadendorf, director of dermatology at University Hospital Essen (Germany). “What we have learned from the combination with chemotherapy, especially with carboplatin and paclitaxel, is that the progression-free survival time is around 4-5 months, which is interesting in patients who have rapid tumor progression and where you need a regimen to stop disease progression.”

Dr. Lawson reported a consultant/advisory role with Genzyme Corp. Dr. Slingluff reported a consultant/advisory role with and honoraria from Immatics Biotechnologies GmbH, research funding from Berlex Inc./Genzyme and GlaxoSmithKline, and other remuneration from the University of Virginia Patent Foundation. Dr. Ribas reported honoraria from Amgen Inc. and Roche. Dr. Flaherty disclosed no conflicts. Dr. Sabel reported a consultant/advisory role, honoraria, and research funding from Schering-Plough/Merck. Dr. Schadendorf disclosed consultant or advisory roles with AstraZeneca, Bristol-Myers Squibb Co., Plexxikon Inc., Roche, and Schering-Plough Corp., and research funding from Schering-Plough and Bayer-Schering.