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ASCO: BRAF Inhibitor Cuts Death Risk in Advanced Melanoma
Major Finding: Survival estimates at a median 3 months' of follow-up suggest 84% of patients treated with vemurafenib would be alive at 6 months...
CHICAGO –More good news on ipilimumab for metastatic melanoma emerged from the results of a trial reported at the annual meeting of the American Society of Clinical Oncology.
In a double-blind, randomized, phase III study, nearly 21% of 250 metastatic melanoma patients who underwent first-line treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) in combination with dacarbazine were alive after 3 years, compared with 12% of 252 patients given placebo and dacarbazine, Dr. Jedd Wolchok reported during a plenary session at the meeting.
Overall survival was 11.2 months in the ipilimumab plus dacarbazine group and 9.1 months in the placebo plus dacarbazine group. The study was simultaneously published in the New England Journal of Medicine (2011 June 5;doi:10.1056/NEJMoa1104621).
A divergence in the survival curve was evident at 1 year, with 47% survival in the ipilimumab plus dacarbazine group, compared with 36% in the placebo plus dacarbazine group; at 2 years, the survival rates were 28% and 18%, respectively. The hazard ratio was 0.72, or 28% reduction in death.
At last year’s ASCO meeting, ipilimumab monotherapy was shown to prolong survival in previously treated metastatic melanoma patients. The drug was approved earlier this year as a first-line monotherapy treatment at a dosage of 3 mg/kg.
This is the first trial to show efficacy and safety of combining immunotherapy and chemotherapy in metastatic melanoma, said Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York. The next step for ipilimumab combination therapy is to look to other combination therapies, such as the investigational agent vemurafenib (PLX4032), as well as other targeted agents and immune-modifying agents.
Dr. Wolchok cautioned that ipilimumab is approved only as a monotherapy and should only be used at the approved dose. Any use in combination therapy should be conducted as part of a clinical trial, several of which are ongoing or about to get underway.
In another plenary presentation at ASCO, Dr. Paul Chapman, also of Memorial Sloan-Kettering, reported a 63% reduction in risk of death with vemurafenib, compared with dacarbazine alone, in metastatic melanoma patients with BRAF mutations. Vemurafenib is an investigational oral drug that inhibits BRAF kinase.
In Dr. Wolchok’s study, progression-free survival was not significantly different between the two treatment groups. Ipilimumab, a monoclonal antibody that blocks CTLA-4 and augments T-cell activation, may improve survival by re-establishing an immuno-equilibrium that allows patients to survive despite the presence of tumors, he said. "The immune system is a ‘living drug,’ able to adapt itself to changes in the tumor ... overall survival is a more accurate way to gauge treatment effectiveness than progression-free survival."
In the trial, patients received either ipilimumab (10 mg/kg, three times per week for 4 weeks) plus dacarbazine (850 mg/m2, three times per week for 8 weeks) or placebo plus dacarbazine at the same dose and schedule. More than half of the patients in the study had MC1 disease.
Tumors were assessed at weeks 1, 12, and 24 in the protocol. For the maintenance therapy section of the trial, placebo or ipilimumab at 10 mg/kg once every 12 weeks was given until the disease progressed or patients had toxic effects.
Treatment discontinuations due to disease progression and adverse events were higher in the ipilimumab plus dacarbazine group; 92 patients received all four doses, compared with 165 patients in the placebo plus dacarbazine group.
Most discontinuations were due to disease progression, which occurred in 46% of the ipilimumab plus dacarbazine group and in 77% of the placebo plus dacarbazine group.
Of those who received at least one dose of therapy, 89 of 247 patients in the ipilimumab plus dacarbazine group and 10 of 251 patients given dacarbazine plus placebo discontinued. In the ipilimumab plus dacarbazine group, 85 of 247 discontinued after the induction phase because of a drug-related adverse event as did 10 of 251 in the placebo plus dacarbazine group.
After the maintenance dose, 4 of 43 in the dacarbazine plus ipilimumab group and none of the 53 in the placebo plus dacarbazine group discontinued therapy after receiving the maintenance dose.
The only treatment-related death occurred in the placebo plus dacarbazine group. Immune-related adverse events were seen in 78% of the ipilimumab plus dacarbazine group and in 38% of the placebo plus dacarbazine group. Grade 3 and 4 adverse events occurred in 38% of the ipilimumab plus dacarbazine group and in 4.4% of the placebo plus dacarbazine group. Liver function abnormalities were the most common immune-mediated adverse event. Most of the patients received steroids and their liver function normalized.
The study was funded by Bristol-Myers Squibb, the maker of ipilimumab. Dr. Wolchok is a consultant/advisor to Bristol-Myers Squibb.