Novel melanoma treatment: Preliminary study shows high response rates, regression of metastatic lesions

Key Points

National report - Melanoma treatment may take a big leap forward.

Exciting, though preliminary, results are available for the novel compound PLX4032 (Plexxikon) in patients with the V600E BRAF mutation. High response rates and regression of metastatic lesions were observed in a heavily pretreated population receiving the experimental agent in a phase 1 dose-finding study led by Keith Flaherty, M.D., assistant professor, University of Pennsylvania Medical Center, Philadelphia.

Activating mutations in BRAF are found in 50 percent to 60 percent of melanoma patients. PLX4032 is a small molecule inhibitor with strong selectivity for V600E BRAF in vitro and in vivo. In preclinical studies, the compound demonstrated selective regression of V600E tumors.

Among the 16 patients with V600E BRAF mutation, nine partial responses were observed, and many patients demonstrated regression of liver, lung and bone lesions. One patient had 85 percent shrinkage in visceral lesions.

The interim progression-free survival was approximately six months, "with many patients still on treatment," says co-investigator Keith Nolop, M.D., of Plexxikon. There was no treatment effect on patients lacking the BRAF mutation.

In addition, many patients experienced an improvement in symptoms, including reductions in tumor-related and joint pain, night sweats, swallowing difficulties and need for narcotics.

The drug was well-tolerated, with nearly all adverse events mild and transient in doses up to 720 mg twice daily. The most frequent side effect was a slight rash.

Investigators are evaluating 960 mg twice daily as the maximum tolerated dose in larger studies that will begin accruing this year.

Prolonged survival

Meanwhile, a treatment that paired the investigational peptide gp100:209-217(210M) with high-dose interleukin-2 (IL-2) resulted in prolonged disease-free survival and a trend toward improved overall survival in a multi-institutional phase 3 trial, according to Douglas Schwartzentruber, M.D., F.A.C.S., medical director, Goshen Center for Cancer Care, Goshen, Ind.

Antoni Ribas, M.D., associate professor, University of California, Los Angeles, characterizes the findings as "a rare positive study" in the field of metastatic melanoma. The vaccine, which consists of part of the gp100 molecule found on the surface of melanoma cells, is delivered prior to IL-2.

Ten years ago, a small phase 2 study by the National Cancer Institute found a 42 percent response rate with the vaccine, but in subsequent phase 2 trials using gp100 plus varying schedules of IL-2, response rates ranged from 12.5 percent to 23.8 percent, Dr. Schwartzentruber says. This is the first phase 3 controlled trial to show positive results.

The tandem therapy approach is based on the assumption that the vaccine induces antitumor T cells, while IL-2 induces T-cell proliferation and sensitizes cells to tumor antigen.

The 21-center study randomized 185 patients with stage III locally advanced or metastatic melanoma to IL-2 alone or IL-2 preceded by the vaccine, which is administered subcutaneously.

Overall response rate was 22.1 percent in the vaccine arm, compared with 9.7 percent in the IL-2 arm (P = .022). Progression-free survival was 2.9 months compared with 1.6 months, respectively (P = .01). Median overall survival also favored the vaccine - 17.6 months compared with 12.8 - but the difference was not statistically significant, Dr. Schwartzentruber says.

"The findings are definitely very promising for a very poor-prognosis group of patients," says Sonali Smith, M.D., associate professor, University of Chicago Medical Center, Chicago. While they are far from being clinically applicable, they could act as a "platform" for more refined and potent vaccines.