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Vemurafenib induced responses in previously treated metastatic melanoma
Sosman JA. N Engl J Med. 2012;366:707-714.
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The BRAF inhibitor vemurafenib induced clinical responses in more than half of patients with previously treated V600–mutant metastatic melanoma, according to study results published in The New England Journal of Medicine.
Based on earlier phase 1 trials indicating that vemurafenib (Zelboraf, Hoffmann-La Roche) produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma, researchers designed a multicenter, phase 2 trial to investigate the efficacy of vemurafenib with respect to overall response rate, duration of response and OS.
The study enrolled 132 patients who received oral vemurafenib 960 mg twice daily until the disease progressed or unacceptable toxic effects developed. Patients with disease progression were permitted to continue treatment if the investigator determined that the patient would benefit clinically.
According to study results, 53% of patients exhibited a confirmed overall response (95% CI, 44-62), with 6% exhibiting a complete response and 47% exhibiting a partial response. The median duration of response was 6.7 months (95% CI, 5.6-8.6), and the median PFS was 6.8 months (95% CI, 5.6-8.1). The median OS was 15.9 months (95% CI, 11.6-18.3).
“This study shows that [vemurafenib] changes the natural history of this disease,” researcher Antoni Ribas, MD, PhD, of UCLA’s Jonsson Comprehensive Cancer Center, said in a press release. “This data is beyond what I would have expected. We’re seeing a significant number of patients with durable responses to the drug, and that the whole group of treated patients is living longer. These results tell us that this drug is having a very big impact, and this changes the way we treat metastatic melanoma.”
The most common adverse events included alopecia, fatigue, grade-1 or -2 arthralgia, rash and photosensitivity. Cutaneous squamous cell carcinomas were diagnosed in 26% of patients.
“While the problem of relapse and resistance is great, this study provides evidence that, in some patients, their melanoma is controlled for over 2 years on the medication,” researcher Jeffrey A. Sosman, MD, of the Vanderbilt-Ingram Cancer Center, said in a press release.
Disclosure: The researchers report funding support from Hoffmann-La Roche.
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This multicenter phase 2 trial of vemurafenib has answered two important questions — does vemurafenib induce high responses, and does vemurafenib improve OS in patients with previously treated BRAF V600-mutated metastatic melanoma. The clinical response among 132 patients was 53% (6% complete response and 47% partial response). With a median follow-up of 12.9 months, the median OS was 15.9 months.
Vemurafenib, an oral BRAF targeted therapy, not only induces unprecedented response rates but also significantly improved overall survival in previously treated BRAF V600-mutant metastatic melanoma. The exciting results of BRAF phase 1, 2 and 3 clinical trials (BRIM1, 2, and 3) have made important breakthroughs and are changing the paradigm of treatment of metastatic melanoma. While celebrating this major breakthrough, the next effort should be focused on how to improve the complete response rate and to overcome the rapid emergence of drug resistance.
Wen-Jen Hwu, MD
HemOnc Today Editorial Board member
Disclosure: Dr. Hwu reports no relevant financial disclosures.
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In 2011, a major breakthrough in the therapy of metastatic melanoma was achieved with the approval of vemurafenib as a targeted therapy for the approximately 50% of patients who harbor the BRAF V600E mutation. In a phase 3 trial randomized against dacarbazine, a 48% response rate and an OS of 84% was noted for the vemurafenib treated patients, compared with a 5% response rate and 64% OS for dacarbazine-treated patients at 6 months in an interim analysis [Paul B. N Engl J Med. 2011;364:2507-2516]. Sosman and colleagues report on the more mature data of a phase 2 trial of 132 patients with the BRAF V600E mutation at a median follow up of 12.9 months. This report provides important new information about vemurafenib. The response rate of 53% in patients with previously treated melanoma is impressive and implies that the drug may work equally well whether given first line or after prior therapy, a phenomenon that is unusual and perhaps unprecedented in cancer therapy. The median overall duration of response was 6.7 months and median PFS was 6.8 months, again similar to the first-line phase 3 trial. The OS in this phase 2 trial was 16 months, another highly impressive number, which implies that some patients do achieve a long-term response and survival with this agent. Can clinicians therefore administer immunotherapy as a first-line option even for BRAF-mutant patients with the expectation that they will still respond to vemurafenib if given second line? These impressive results in previously treated disease seem to imply that, but this question will remain unanswered until formal trials of sequencing are completed.
– Sanjiv S. Agarwala, MD
HemOnc Today Editorial Board member,
Course director of the HemOnc Today Melanoma and Cutaneous Malignancies meeting
Disclosure: Dr. Agarwala reports no relevant financial disclosures.
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