CHICAGO—For the first time in decades, the treatment of advanced melanoma has taken a positive turn, according to studies presented at the 2011 annual meeting of the American Society of Clinical Oncology that showed a survival benefit with 2 experimental agents.
Paul Chapman, MD, presented the results of an international phase 3 trial evaluating vemurafenib (PLX4032), a drug targeting the BRAF gene mutation. The demonstration of improved survival is “really a huge step toward personalized care in melanoma,” said Chapman, of the Melanoma and Sarcoma Service at Memorial Sloan-Kettering Cancer Center, New York, who noted the limited treatment options for this group of patients.
The study compared vemurafenib with standard treatment with dacarbazine in 675 patients with inoperable, previously treated stage IIIc or IV metastatic melanoma who had a V600E mutation in the BRAF gene—which is present in about half of all melanoma patients.
Patients receiving vemurafenib had a 63% reduction in risk of death, compared with those receiving dacarbazine (P <.0001), and a 74% reduction in the risk of tumor progression (P <.0001). Response rates were also substantially higher at 48.4% and 5.5%, respectively.
At the plenary session, where he presented the results, Chapman noted, “Vemurafenib is the first single drug for melanoma to improve response rate, progression-free survival, and overall survival compared with standard chemotherapy. …it is a promising new therapy for patients with metastatic V600EBRAF-mutated melanoma and a foundation upon which to build combination therapies.”
Immunotherapy Drug Also Improved Survival
The CTLA-4 blocking monoclonal antibody ipilimumab was approved in March for the second-line treatment of metastatic melanoma. A phase 3 randomized trial also presented at the plenary session validated its benefit in the first-line setting as well.
The international Study 024 included 502 untreated metastatic melanoma patients randomized to ipilimumab plus dacarbazine or dacarbazine alone. Median overall survival in the combination group was 11.2 months compared with 9.1 months in the single-agent group, which was a highly significant difference (P = .0009) reflecting a 28% reduction in the risk of death, reported Jedd Wolchok, MD, PhD, also of Melanoma and Sarcoma Service at Memorial Sloan-Kettering Cancer Center, New York.
At 1 year, 47.3% of the ipilimumab/dacarbazine group was alive, compared with 36.3% of the control group. The survival rate at 2 years was 28.5% versus 17.9%, and at 3 years was 20.8% versus 12.2%, respectively.
The durability of these responses is one of the benefits of this drug, according to Wolchok. “This is one of the advantages of immunotherapy. The immune system is a ‘living drug,’ able to adapt itself to changes in the tumor that might otherwise lead to resistance when treated with chemotherapy or a pathway inhibitor,” he said.
These treatments were not without side effects, however, notably hepatotoxicity with the ipilimumab/dacarbazine combination and cutaneous toxicity, photosensitivity, gastrointestinal upset, and arthralgia with vemurafenib. Kim Margolin, MD, of the University of Washington Fred Hutchinson Cancer Research Center in Seattle, the invited discussant of the 2 presentations, said that in addition to learning how to select patients for these therapies, healthcare providers and patients will need to be vigilant for adverse events and proactive in the management of side effects.
Future investigations will evaluate the combination of vemurafenib and ipilimumab.