February 22, 2012 — The oral targeted therapy vemurafenib (Zelboraf, Plexxikon/Roche) for advanced melanoma provides a median survival of nearly 16 months, according to a report publishedin the February 23 issue of the New England Journal of Medicine.
The length of survival compares favorably to historic data on metastatic melanoma patients, who typically survive 6 to 10 months, say study authors, led by Jeffrey A. Sosman, MD, from the Vanderbilt–Ingram Cancer Center in Nashville, Tennessee.
Vemurafenib was approved for use in Europe just this week, and was approved in the United States in August 2011. It is also approved in Brazil, Canada, Israel, and New Zealand.
These new survival findings come from the longest-term dataset on the practice-changing drug — an open-label phase 2 trial of 132 patients with previously treated advanced melanoma who tested positive for the BRAFmutation.
"The long follow-up period in our study provides critical information on long-term overall survival not yet shown in the phase 3 trial comparing vemurafenib with dacarbazine," write Dr. Sosman and his coauthors.
Overall survival was one of the secondary end points of the phase 2 trial, which was conducted at 10 centers in the United States and 3 in Australia. The primary end point was the overall response rate (ascertained by an independent review committee).
The overall response rate was 53% (complete response, 6%; partial response, 47%; 95% confidence interval [CI], 44 to 62).
The response rates, which confirm earlier phase 1 findings, were first presented at the 2010 International Melanoma Research Congress of the Society for Melanoma Research, held in Sydney, Australia, as reported byMedscape Medical News.
"These response rates are amazing," said coauthor Antoni Ribas, MD, from the Jonsson Comprehensive Cancer Center at the University of California in Los Angeles, at the time.
Although the overall response rates have stayed the same since that 2010 meeting, the overall survival data have matured.
The authors now report that, of the 132 patients enrolled in the study, 62 (47%) were alive as of July 1, 2011, and the median overall survival was 15.9 months (95% CI, 11.6 to 18.3).
They also report that the overall survival rate at 6 months was 77% and at 12 months was 58%; it is estimated to be 43% at 18 months.
The survival data are especially impressive, the authors explain, because the patients had more advanced disease than in previous studies.
"The patients did not have favorable baseline characteristics (61% with stage M1c disease and 49% with elevated [lactate dehydrogenase] level) as compared with those in other large, phase 2 and phase 3 studies of melanoma," they write.
Dr. Sosman and his coauthors point out that patients with the BRAF mutation are at a survival disadvantage. The mutation "has been associated with shortened survival in patients with metastatic disease," they say.
Notably, some of the patients in the study received additional treatment during the follow-up period (now a median of 12.9 months). A total of 32 patients (24%) received ipilimumab after progressing while on vemurafenib. However, the study authors report that treatment with this targeted therapy, which is also approved for advanced melanoma, did not bolster their survival data.
In an unplanned post hoc analysis that excluded these 32 patients, median overall survival remained at 15.9 months (95% CI, 8.0 to not reached).
"The long median overall survival was not simply due to postprogression ipilimumab use in some patients, because exclusion of these patients from the analysis did not change the median overall survival," write Dr. Sosman and colleagues.
Other Skin Cancers as Adverse Effects
In the study, patients received a median dose of 1740 mg/day, which represents 91% of the study's intended dose of 1920 mg/day.
As has been reported previously, the responses to vemurafenib are unfortunately not durable. The authors now report that the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1).
The loss of response indicates resistance to the drug, which means that these patients will need to be treated with other drugs. Thus, the phase 2 trial design was altered to include ipilimumab after it was approved by the United States Food and Drug Administration.
The study authors highlight the fact that some patients had a response after receiving vemurafenib for more than 6 months. But this was exceptional; "most responses were rapid," they write.
The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia.
Cutaneous squamous cell carcinomas were diagnosed in 26% of patients, typically consisting of 1 lesion (20 patients) or 2 lesions (6 patients). On central pathologic review, 39 of 43 cutaneous squamous cell carcinoma lesions were either keratoacanthoma or mixed keratoacanthoma type; the remaining 4 were invasive cutaneous squamous cell carcinoma. Eight cases of basal cell carcinoma were also identified.
The median time to development of the first cutaneous squamous cell carcinoma or keratoacanthoma lesion was 8 weeks (range, 2 to 36).
These secondary skin tumors are relatively benign, compared with melanoma, and are no reason to discontinue vemurafenib, according to an editorial published last month in the New England Journal of Medicine.
However, patients treated with vemurafenib should be tested for RAS mutations, which frequently occur in these secondary skin tumors that develop in vemurafenib-treated patients, according to a study that accompanied the editorial.
The testing will alert clinicians to which patients have RAS-driven secondary tumors. The testing is important because patients with RAS mutations could also develop secondary cancers in organs beyond the skin, such as the lungs. However, to date there is no evidence that vemurafenib triggers RAS-driven tumors in other organs.
The study was funded by Roche. Multiple authors report financial relationships with industry, including Roche, or are employees of Roche or its subsidiaries.
N Engl J Med. 2012;366:707-714. Abstract
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