Vemurafenib improved OS, PFS in V600EBRAF mutated melanoma

2011 ASCO Annual Meeting

CHICAGO — Treating patients with advanced melanoma with vemurafenib resulted in a 63% decrease in the risk for death, according to phase 3 trial data presented here today.

“This is the first single drug, by itself, to improve response, PFS and OS compared with a chemotherapy regimen,” Paul Chapman, MD, of Memorial Sloan-Kettering Cancer Center, said in a press conference. “And it’s a promising new therapy for patients whose tumors have this mutation, and it’s a foundation which our field can build upon to develop even more effective combinations.”

Between January 2010 and December 2010, Chapman and colleagues enrolled 675 patients with V600EBRAF mutated, unresectable, stage IIIC or IV melanoma and no prior treatment. Patients were randomly assigned 1:1 to vemurafenib or dacarbazine. Co-primary endpoints were OS and PFS in the intent-to-treat population; secondary endpoints were response rate, duration of response and safety.

At the planned 3-month interim analysis, patients in the vemurafenib arm had a 63% reduction in the risk for death compared with the dacarbazine arm (HR=0.37; P<.0001). In addition, the risk for progression in the vemurafenib arm was reduced by 74% compared with dacarbazine (HR=0.26; P<.0001). The response rate was 48.4% in patients assigned to vemurafenib vs. 5.5% in those assigned to dacarbazine.

According to Chapman, the incidence of common grade 3 or 4 adverse events was uncommon in either arm (<10% in the vemurafenib arm). The most common side effects in the vemurafenib group were arthralgia (3%), cutaneous squamous cell carcinoma (12%), keratocanthoma (6%), photosensitivity (3%), increased liver enzymes (7%) and rash (8%).

Based on these data, crossover is allowed for patients in the dacarbazine group. – by Stacey L. Fisher

For more information:

• Chapman P. #LBA4. Presented at: 2011 ASCO Annual Meeting; Chicago; June 3-7, 2011.

Disclosure: Dr. Chapman holds a consultant/advisory role and receives research funding from Roche.

Wen-Jen Hwu, MD, PhD

Major breakthroughs in the treatment of metastatic melanoma were reported in the 2011 ASCO Plenary Session. Considerable excitement has been generated by two new antitumor agents, vemurafenib and ipilimumab. In patients with late-stage melanoma, vemurafenib demonstrated dramatic clinical responses and ipilimumab showed significantly improved survival as a single agent or in combination with chemotherapy (dacarbazine). Both agents were developed to target relevant molecular targets, either in the signal transduction pathway (vemurafenib) or tumor immunity barriers (ipilimumab). These major breakthroughs result from the great success in translational research from bench to bedside. Small-molecule vemurafenib targeting BRAF V600E mutation was developed based on the identification of genetic mutations of various components of signal pathways involving melanoma initiation and progression. Humanized monoclonal antibody ipilimumab targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) was developed based on the emerging insights into the mechanisms of activation and regulation of tumor immunity.

The treatment of metastatic melanoma is changing rapidly due to the new targeted therapy approach. However, there are many hurdles to overcome in order to optimize the targeted therapy. The mechanisms of rapid development of drug resistance to vemurafenib remain largely unknown. The safety and management of serious autoimmune toxicities induced by ipilimumab require intense education and training of oncologists. Thus, further improvement in the targeted therapy and translational research from bedside to bench is warranted.

- Wen-Jen Hwu, MD, PhD
HemOnc Today Editorial Board member

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