Treatment options for patients with advanced melanoma are limited.22
Since its discovery in 2002, the BRAF V600E mutant kinase has been considered a promising therapeutic target for this disease. The previously reported phase 1 study with vemurafenib in patients with BRAF V600–mutant metastatic melanoma provided evidence that inhibition of the oncogenic MAPK pathway resulted in significant antitumor activity.15,23
The major objective of the current phase 2 clinical trial was to define, in a larger number of patients, the overall response rate with vemurafenib in advanced melanoma. We report a confirmed response rate of over 50% in patients with previously treated metastatic melanoma bearing the V600E or V600K BRAF mutations. Most responses were rapid, with less than 15% of patients having had disease progression at their first evaluation. Therefore, this trial shows that vemurafenib has clinically evident antitumor activity in metastatic melanoma and that response rates are higher than those associated with previously used treatments.1–8,22
Reanalysis of the response rate in the phase 1 study according to the response criteria used in our phase 2 study yielded a similar overall response rate of 56%. Furthermore, although the median durations of response and progression-free survival were less than 7 months, some responses were delayed, with one fourth of patients remaining progression-free after a median follow-up period of 13 months. The median overall survival was nearly 16 months in this group of patients with melanomas expressing the relevant mutation. The patients did not have favorable baseline characteristics (61% with stage M1c disease and 49% with elevated LDH level) as compared with those in other large, phase 2 and phase 3 studies of melanoma. In fact, the BRAF mutation has been associated with shortened survival in patients with metastatic disease.24
The long median overall survival was not simply due to post-progression ipilimumab use in some patients, because exclusion of these patients from the analysis did not change the median overall survival.
Toxic effects were common but not severe or life-threatening in most instances. Although some patients required dose interruptions or reductions, patients were able to receive most of their intended daily dose. The toxic effects were largely related to the skin. As reported previously, the BRAF inhibitor vemurafenib, as with other RAF inhibitors, is associated with the development of cutaneous squamous-cell carcinoma or keratoacanthoma but not squamous-cell carcinoma derived from other organs.15,25,26
Lesions usually manifested in the first 8 to 12 weeks of treatment and were effectively managed with simple resection without discontinuation of vemurafenib. This suggests differential effects of vemurafenib on cells without oncogenic BRAF. Preclinical models have shown that BRAF inhibitors can paradoxically enhance activation of the MAPK pathway in cancer cells with wild-type BRAF that carry upstream RAS
This mechanism may play a role in the development of cutaneous squamous-cell carcinomas. 30
As with most targeted therapies that block a driver oncogene, cancer cells can develop acquired resistance with continuous dosing. The molecular mechanisms of vemurafenib resistance are under investigation. The currently available data suggest that reactivation of the MAPK pathway through the emergence of truncated hyperactive forms of BRAF,31
secondary mutations in NRAS (the neuroblastoma RAS viral oncogene homologue)32
or MEK (MAP kinase kinase),33
up-regulation of COT (also known as TPL2 or MAP3K8),34
or activation of alternative survival pathways induced by increased expression of receptor tyrosine kinases but not by secondary point mutations in BRAF32,35
are all mechanisms of resistance. Elucidating approaches that can overcome or prevent acquired resistance is critical to further advances in the treatment of melanoma.
In conclusion, this trial shows a high rate of response to vemurafenib in patients with meta-static melanoma and activating BRAF mutations. These results independently confirm the high response rate and response duration shown in a phase 1 trial. 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.19
Targeted therapy aimed at oncogenic BRAF V600 induces responses in half the patients and a median survival of 16 months.