Vemurafenib Improves Outcomes in BRAF-mutated Melanoma
Vemurafenib was associated with improvements in overall survival (OS) and progression-free survival (PFS) compared with dacarbazine in patients with previously untreated melanoma with a mutation in the BRAF gene (Abstract LBA4), announced Paul B. Chapman, MD, of Memorial Sloan-Kettering Cancer Center, at Sunday’s Plenary Session.
A planned interim analysis in the phase III BRAF Inhibitor in Melanoma (BRIM3) trial found that treatment with vemurafenib was associated with a 63% decrease in the hazard of death (p < 0.0001) and a 74% decrease in the hazard of tumor progression (p < 0.0001) in patients with the BRAFV600E mutation, which is present in 40% to 60% of melanomas.
A benefit of vemurafenib was seen in all subgroups in the trial, including patients with metastatic disease (stage M1c) and high levels of lactate dehydrogenase, conditions that are usually associated with poor prognosis.
Vemurafenib had a "manageable" safety profile and there were few drug-related discontinuations from the trial, noted Dr. Chapman.
"Vemurafenib is the first single drug for melanoma to improve response rate, PFS, and OS compared with standard chemotherapy," he said. "It is a promising new therapy for patients with metastatic BRAFV600E-mutated melanoma and a foundation upon which to build combination therapies in the future."
Patients with previously untreated, unresectable stage IIIC or IV melanoma who tested positive for the BRAFV600E mutation on a real-time polymerase chain reaction assay were randomly assigned to twice-daily 60 mg oral vemurafenib or standard chemotherapy with dacarbazine for 3 weeks. Of the patients screened, 47% were mutation positive.
Dr. Chapman explained that, as the trial enrollment was proceeding in 2010, emerging data from a phase II study made it clear that the phase III trial design, as originally conceived, had underestimated the treatment effect of vemurafenib. A revised statistical plan was established in October 2010 before any data in the trial were analyzed.
When the study’s independent Data and Safety Monitoring Board (DSMB) reviewed the data in January 2011, it determined that there was compelling evidence of vemurafenib’s treatment benefit over dacarbazine. The DSMB recommended that patients in the chemotherapy arm be allowed to cross over to treatment with vemurafenib and this change was quickly implemented, explained Dr. Chapman.
The revised statistical plan included two primary endpoints: OS, with a lower number of required events than originally planned (196, reduced from 468), and PFS. The revised plan called for one interim analysis at 50% of the number of deaths needed for final analysis, and the data announced on Sunday were from this analysis.
Of the 675 patients enrolled at 104 centers worldwide, 337 received vemurafenib and 338 received dacarbazine. At the planned interim analysis, the hazard ratio for OS was 0.37 (95% CI [0.26, 0.55]; p < 0.0001) and the hazard ratio for PFS was 0.26 (95% CI [0.20, 0.33]; p < 0.0001), both were in favor of vemurafenib (Fig. 1).
Estimated 6-month survival was 84% for vemurafenib and 64% for dacarbazine. In the 65% of patients who were evaluable, the overall response rate was 48.4% for vemurafenib and 5.5% for dacarbazine.
The most frequent adverse events in patients receiving vemurafenib included arthralgia, rash, and diarrhea. Dr. Chapman noted that cutaneous squamous cell carcinomas and other cutaneous tumors, which are associated with vemurafenib and other drugs in its class, were seen in the patients receiving the drug and all of them were excised by dermatologists. None of the lesions were associated with metastases.
During a discussion of the study, Kim Margolin, MD, of the University of Washington and the Fred Hutchinson Cancer Research Center, praised the "excellent early results of a challenging but transformative study." She said the work was "based on a rational approach to molecular biology and therapeutic drug development" and showed "a strong survival benefit of vemurafenib over dacarbazine" in patients with melanoma whose tumor had the BRAFV600E mutation.
Dr. Margolin said the drug is already being made available through an expanded access program to patients with qualifying BRAF mutations, and it is anticipated that it may be approved by the U.S. Food and Drug Administration later this year.
Dr. Margolin said the drug’s rapid relief for symptomatic patients was "something melanoma specialists have never been able to offer," and she is excited by the implications of this development. She noted, however, that the median progression-free duration in the study was 7 months, and that the nature of relapse from this form of molecularly targeted therapy is still being investigated.
Discussing the cutaneous lesions seen with vemurafenib use in the study, Dr. Margolin commented that the biology of the lesions is "particularly nonthreatening and quite amenable to surgical excision." Furthermore, she explained, the absence of squamous metaplasia from these lesions is encouraging.