'Time to Celebrate'; New Metastatic Melanoma Agent Wows ASCO

But Data Only Short Term

Nick Mulcahy

June 06, 2011

June 6, 2011 (Chicago, Illinois) — In a study that has been accompanied by much praise and grand declarations, the targeted therapy vemurafenib (also known as PLX4032; Plexxicon/Roche), dramatically improved progression-free and overall survival, compared with standard chemotherapy, in patients with advanced melanoma with no previous treatment.

The 675-patient phase 3 study, which has only short follow-up at this point, was presented here at the American Society of Clinical Oncology (ASCO) 2011 Annual Meeting.

Vemurafenib targets the V600E mutations in the BRAF gene. An estimated 40% to 60% of melanoma patients have this type of BRAF mutation, which does not occur in normal cells, said lead author Paul Chapman, MD, from Memorial Sloan-Kettering Cancer Center in New York City, at a meeting press conference.

At 6 months, estimated overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. There is no median overall survival in the study yet because the data are not mature enough, Dr. Chapman explained. "It's unprecedented to report a trial this early," he said, adding that the dacarbazine patients have been allowed to cross over to vemurafenib treatment.

Although the trial is ongoing, the findings for progression-free survival are final; patients receiving vemurafenib had a 74% reduction in the risk for progression (or death), compared with patients receiving dacarbazine chemotherapy (hazard ratio [HR], 0.26; P < .001). Mean progression-free survival was 5.3 months in the vemurafenib group, compared with 1.6 months in the dacarbazine group, said Dr. Chapman.

The progression-free survival data constitute "an unprecedented level of difference," said Dr. Chapman.

Furthermore, a planned interim analysis for overall survival revealed that patients receiving vemurafenib had a 63% reduction in risk for death (HR, 0.37; P < .001).

The median follow-up for the interim analysis was 3.8 months in the vemurafenib group and 2.3 months in the dacarbazine group.

After reviewing the interim analysis, an independent data and safety monitoring board recommended that patients receiving dacarbazine cross over to vemurafenib, Dr. Chapman explained about the study known as BRAF Inhibitor in Melanoma (BRIM)-3. The study results were published online June 5 in the New England Journal of Medicine to coincide with their presentation here at ASCO.

Response rates were 48% for vemurafenib and 5% for dacarbazine (P < .001).

Enthusiasms

This study is "practice changing," said Lynn Schuchter, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, who moderated the press conference.

Responses with the new oral therapy can be dramatic — patients can have improvement within 72 hours of treatment, she said.

With 2 agents — vemurafenib and ipilimumab (which is approved by the US Food and Drug Administration) — emerging as effective treatments for metastatic melanoma in the past year, it is a "time for celebration for our patients," said Dr. Schuchter — "a time for hope."

"The results of the BRIM-3 study represent a major shift in the way we think about and treat melanoma," writes Marc Ernstoff, MD, in an editorial that accompanies the published study. He is from the Dartmouth Medical School and Norris Cotton Cancer Center in Lebanon, New Hampshire.

Melanoma is a collection of heterogeneous tumors that are differentiated by means of molecular markers, says Dr. Ernstoff, and "each molecularly defined subgroup will probably have a different treatment algorithm."

For patients with metastatic melanoma and the BRAF V600E mutation, "the availability of vemurafenib is a major defining moment that will have an important effect on survival and quality of life," he summarizes.

"These are definitely absolutely remarkable results," said Petra Rietschel, MD, PhD, from the Montefiore Einstein Center for Cancer Care in the Bronx, New York. "As soon as it is on the market, I will most certainly be using it in my clinic for patients with V600E BRAF mutations," she told Medscape Medical News.

Vemurafenib has been continuing to impress since data were first revealed at ASCO in 2009, which showed — in a phase 1 dose-escalation proof-of-concept study — that more than half of metastatic melanoma patients with a BRAF mutation who received high doses of PLX4032 had tumor shrinkage.

Resistance and Combinations

Despite being a member of the chorus of vemurafenib enthusiasts, Dr. Ernstoff, in his editorial, sounds notes of caution about the agent. "The final estimate of survival outcomes is still to be determined," he writes.

Also, the study, which was sponsored by Hoffman-La Roche, had the investigators report responses, not an independent response review board, "which could bias the rates of response and progression-free survival," he points out.

Dr. Ernstoff also highlights the fact that the complete response rate in the study was "low" — just 0.9% (n = 2) of the 219 patients receiving vemurafenib whose tumor response was evaluated.

Another melanoma expert also wants to see the final overall survival benefit.

"The results of the final analysis will be necessary for the true reduction in risk of death," said Kari Kendra, MD, from Ohio State University in Columbus.

"This is an interim analysis, with 66% of the vemurafenib and 25% of the dacarbazine patients still undergoing treatment," she pointed out.

Still, Dr. Kendra is impressed. "The interim analysis does demonstrate an excellent response in this targeted population," she told Medscape Medical News.

Dr. Ernstoff, despite his reservations, calls for the testing of vemurafenib in earlier-stage disease.

"It is now reasonable to consider testing adjuvant vemurafenib in patients with high-risk stage II or III melanoma with the BRAF V600E mutation on the basis of the findings in the BRIM-3 study," he said.

Dr. Ernstoff also contributes, in print, to the considerable amount of talk at ASCO about the use of vemurafenib in combination with other agents.

He cites resistance to BRAF inhibitors as one of the reasons combination therapy is needed.

"Mechanisms of resistance to BRAF V600E kinase inhibitors include upstream and downstream events and activation of alternative pathways that are therapeutic targets," he writes.

"Tumor regrowth occurs in many of the patients," wrote a pair of Plexxicon staff members in a 2010 study about resistance.

"To combine targeted therapies is the wave of the future," said Dr. Schuchter, who lamented the resistance.

A phase 1 trial has already begun with vemurafenib and ipilimumab, reported Dr. Chapman.

In addition, a phase 1 study presented here indicated that combining 2 oral targeted therapies, the MEK inhibitor GSK212 and the BRAF inhibitor GSK436, was safe and had preliminary antitumor activity in patients with advanced melanoma.

Study Details, Adverse Events

The trial participants were patients with previously untreated, inoperable stage IIIc or stage IV metastatic melanoma and a V600E mutation in the BRAF gene. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 of body-surface area intravenously every 3 weeks).

The coprimary end points were rates of overall and progression-free survival, report the authors of the multicenter trial conducted at 104 centers in 12 countries. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths.

Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea. Notably, 38% of patients required dose modification because of toxic effects.

Less than 10% of patients who received vemurafenib experienced problems with high levels of toxicity (grade 3 or worse). The most common adverse effects were skin rashes, photosensitivity, and joint pain.

The investigators also reported that 12% of patients in the vemurafenib group developed grade 3 or worse cutaneous squamous cell carcinoma, compared with less than 1% in the dacarbazine group.

The study was sponsored by Hoffman-La Roche. Dr. Chapman reports serving as a consultant/advisor for and receiving research funding from Roche. Other coauthors report financial relationships with industry, including Roche, or are employees of Roche.

N Engl J Med. Published online June 5, 2011. Abstract, Editorial

American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting: Abstract LBA4. Presented June 6, 2011.

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