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Weekly UpdatesORLANDO -- At last, some favorable news regarding immunization against melanoma: The addition of a peptide vaccine to high-dose interleukin-2 therapy significantly improved clinical response for patients with metastatic disease in a randomized, prospective, phase III trial.
Investigators at the 21 centers reported a 14% complete response rate (the primary end point) in 86 patients who received the combined therapy vs. just 2% in 93 patients treated only with high-dose IL-2 (P = .003), Dr. Doug J. Schwartzentruber reported at the annual meeting of the American Society of Clinical Oncology. Progression-free survival, the secondary end point, also favored the vaccine plus IL-2 therapy. Immunized patients lived without a recurrence 2.9 months vs. 1.6 months with IL-2 alone after a median follow-up of almost 29 months, another significant difference (P = .01). An equal proportion of each group (8%) had partial responses.
"If you add all responders--complete and partial--you get a 9.7% response vs. a 22.1% with the vaccine added," said Dr. Schwartzentruber, a surgical oncologist and medical director of the Goshen (Ind.) Center for Cancer Care.
"There was more than a doubling of the [overall] response rate, with a highly significant P value of .022," study discussant Dr. Antoni Ribas commented. "This is a clearly positive study any way we look at it, a rare event in this [ASCO melanoma] session."
The positive study follows two fared high-profile melanoma vaccine trials. Last year at ASCO, European Organisation for Research and Treatment of Cancer (EORTC) investigators reported that a ganglioside vaccine was associated with worse survival for patients with stage II melanoma. In 2007, ASCO attendees heard that the international phase III trial of a melanoma vaccine, known as Canvaxin, had been halted in the absence of any overall benefit to patients with stage III or IV disease.
Dr. Schwartzentruber and his associates randomized 185 patients with stage IV or stage III HLA-A2-positive metastatic melanoma to immunization with gp100:2009-217 (210M) peptide in Montanide ISA-51 followed by high-dose (720,000 IU/kg per dose) IL-2, or to high-dose IL-2 alone.
A central laboratory review of pathology and HLA genotyping confirmed the investigators' Findings. The lab reported an 18.6% overall response in the vaccine vs. 6.5% for high-dose IL-2 therapy alone. Although the numbers were smaller, the difference remained statistically significant (P = .013), Dr. Schwartzentruber said. Interestingly, overall response was primarily in M1b patients (those with lung metastases), he noted.
Overall survival was not a prespecified study end point, but there was a nonsignificant trend toward longer overall survival with combination treatment at 17.6 months vs. 12.8 months for IL-2 alone (P = .084).
"We don't know the impact of response rate on overall survival with the IL-2 plus gp100 [treatment]. We need longer follow-up," said Dr. Ribas, a member of the medicine and surgery faculties at University of California, Los Angeles.
Of the 91 patients randomized to the vaccine, 2 were ineligible and 3 withdrew from the study. Of the 94 patients randomized to the infusion of high-dose IL-2 alone every 3 weeks, none was ineligible and 1 withdrew. The six patients who received no treatment were excluded from the response and toxicity analyses but were included in survival calculations as randomized.
Two deaths were attributable to treatment in the vaccine group and one such death occurred in the control arm, Dr. Schwartzentruber said.
The current study raises several questions, Dr. Ribas said, including:
* How does high-dose IL-2 induce tumor regression? "With over 20 years of study, we still don't have an answer."
* How do gp100 peptides improve outcomes of high-dose IL-2?
Dr. Schwartzentruber proposed that the vaccine induces antitumor T-cell activity, and IL-2 causes proliferation of these T cells.
Both groups were well balanced in terms of anatomical site of disease, Dr. Schwartzentruber said. Men accounted for 63% of the vaccine arm and 67% of the control group; mean age was 50 years vs. 47 years; and both cohorts were predominantly white (97% vs. 99%).
All patients were enrolled between 2000 and 2007, and all had HLA-A0201 disease because the vaccine is specific to this HLA type. Dr. Ribas noted that this peptide specificity was responsible for the long enrollment period.
Participants were allowed to continue treatment if they responded. The combination group received 270 total cycles and the IL-2--only group completed 244 total cycles. "Keep this in mind as we look at toxicities," Dr. Schwartzentruber advised.
Arrhythmias were the only significantly different toxicity, with 15 events in the vaccine group vs. 2 events in the control group (P = .002) when adverse events were assessed after two cycles of treatment. "There were no grade 5 toxicities after two cycles; most were grade 3," Dr. Schwartzentruber said. When grade 3-5 toxicities for any cycle were evaluated, arrhythmias affected 19% of the vaccine group vs. 4% of controls. Two other toxicities also were notably higher in the vaccine group: metabolic/laboratory abnormalities (48% vs. 21%) and neurologic toxicity (26% vs. 12%).
"Can this combination be offered to patients in routine practice? That is limited by the availability of the peptides," Dr. Ribas said, noting in response to an audience question that an Investigational New Drug application would need to be approved by the Food and Drug Administration.
Dr. Schwartzentruber said he has had conversations with the Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute. "Clearly, we need to do other studies. I'd like to be able to show a survival advantage in a larger trial," he said.
The gp100 vaccine was provided by CTEP, holder of the Investigational New Drug application. The study was financially supported by the National Cancer Institute, Chiron/Novartis (which is developing the vaccine), Goshen Health System, Goshen Hospital and Healthcare Foundation Inc., and the Luke Brennan Research Fund. Each participating site received grant support from Chiron/Novartis. In addition, one coauthor is on the advisory council and speakers bureau for Chiron / Novartis.
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