Novel agent boosts survival in metastatic melanoma patients

July 1, 2011

An investigational melanoma drug that targets a mutation found in about half of tumors reduces the risk of progression in patients with advanced disease by nearly three-fourths, and cuts the risk of dying by 63 percent, new research shows.

Key Points

Promising studies of the orally administered BRAF inhibitor vemurafenib and the immune-stimulator ipilimumab were presented in June at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO).

Both novel treatments promise to extend survival in patients with advanced melanoma, who historically have had essentially no good treatment options.

The finding represents "a huge step toward personalized care in melanoma," Dr. Chapman told reporters. Results were so dramatic that the study was halted so that the control group could receive the treatment.

Study details

Dr. Chapman presented the study's first interim analysis, reporting that median progression-free survival (PFS) was 5.3 months with vemurafenib versus 1.6 months with dacarbazine, for a 74 percent reduced risk of progression (P < 0.0001), and the risk of dying was reduced by 63 percent (P < 0.0001). Estimated overall survival (OS) at six months was 84 percent versus 64 percent, respectively. OS and PFS benefits were observed across all subgroups, he reported.

Vemurafenib also led to significantly higher response rates, 48.4 percent versus 5.5 percent with dacarbazine.

Due to the impressive results, the study was stopped at the planned interim analysis and the control group was allowed to receive vemurafenib.

"Vemurafenib is the first single drug for melanoma to improve response rate, progression-free survival and overall survival compared to standard chemotherapy," Dr. Chapman said. "It is a promising new therapy for patients with metastatic BRAF V600E mutated-melanoma and a foundation upon which to build combination therapies."

Adverse events were generally mild; fewer than 10 percent of toxicities were grade 3 or greater. Side effects were primarily cutaneous toxicity, gastrointestinal upset and arthralgias. Skin toxicities include hyperkeratotic follicular eruption, extreme sun sensitivity, tender calluses of the extremities, and squamous cancers, keratoacanthomas and verrucae - which were easily managed in most cases, he said.

Vemurafenib is now available in an expanded access program, and Food and Drug Administration (FDA) approval is expected for patients with BRAF mutations.

Benefit confirmed

The immune-stimulating CTLA-4 blocker ipilimumab also produced solid results in the first-line metastatic treatment setting. The monoclonal antibody, which augments T-cell activation, was approved by the FDA in March 2011 for second-line treatment.

Study 024 confirmed ipilimumab's activity as a first-line agent for metastatic disease, reported Jedd Wolchok, M.D., of Memorial Sloan-Kettering Cancer Center, New York.

The study included 502 untreated metastatic melanoma patients randomized to dacarbazine (eight cycles) plus ipilimumab (every three weeks for four cycles, then every 12 weeks) or dacarbazine alone. Median OS survival was 11.2 months with ipilimumab/dacarbazine versus 9.1 months with dacarbazine alone, which was a highly significant 28 percent reduction in the risk of dying of melanoma (P = 0.0009).

Survival rates were 47.3 percent with ipilimumab/dacarbazine compared with 36.3 percent with dacarbazine alone, at one year; 28.5 versus 17.9 percent at two years; and 20.8 versus 12.2 percent, respectively, at three years. Median duration of response was 19.3 months with ipilimumab/dacarbazine compared to 8.1 months with dacarbazine.

"This is the second randomized ipilimumab phase 3 trial to show a significant survival improvement in metastatic melanoma," Dr. Wolchok said, emphasizing the durability of many of the responses.

Notable adverse events with ipilimumab were hepatotoxicity, endocrine abnormalities and immune-mediated adverse reactions. Grade 3-4 increases in liver enzymes were observed in approximately 20 percent of patients.

Discussion

"Ipilimumab now shows a survival benefit in first-line therapy, compared with DTIC. ... Checkpoint blockade, i.e., enhancement of autologous antitumor immune responses, works!" said Kim Margolin, M.D., of the University of Washington and Fred Hutchinson Cancer Research Center, Seattle. She was the invited discussant of the studies at ASCO.

"And vemurafenib showed a survival benefit in first-line versus dacarbazine as well," she said. "Regression was seen in over 80 percent of patients. There was rapid relief of symptoms, median PFS of seven months, and an early survival benefit."

But she cautioned that management of side effects with these drugs will be important, and she said she would not use ipilimumab in combination with dacarbazine based on its toxicity and the lack of apparent therapeutic advantage to the chemotherapy component.

Dr. Margolin suggests that the drugs will target different patient profiles. The BRAF inhibitor might be best intended for patients with a high tumor burden and symptoms, as the drug's onset is fairly rapid.

In contrast, ipilimumab works at a slower pace and might be the first option for patients with less tumor burden and fewer symptoms, she says. Future investigations will evaluate the combination of vemurafenib and ipilimumab.