Vemurafenib Treatment Beyond Progression Is Safe and Highly Effective in Patients with Metastatic Melanoma

Patients with metastatic melanoma receiving vemurafenib following disease progression showed similar or better overall response to patients without progressive disease, according to findings from an analysis reported at the 11th International Congress of the Society for Melanoma Research on November 15, 2014.

Vemurafenib is an inhibitor of BRAF enzyme activity that is used in patients with advanced melanoma who cannot be surgically treated; however benefit from treatment in patients experiencing disease progression remains controversial.

“Although most patients treated with vemurafenib experience tumor regression during treatment, about 50% of responding patients experience disease progression within 6 to 7 months,” said Christian U. Blank MD, PhD, Netherlands Cancer Institute, Anthoni van Leeuwenhook Hospital, Amsterdam, Netherlands.

He explained further, “Previously reported subgroup analyses of patients treated with vemurafenib have suggested an overall survival benefit for patients who continue to receive BRAF inhibition following progression, but this is contrasted by preclinical models showing that vemurafenib resistant cell lines are dependent on vemurafenib for growth and that withdrawal can induce tumor regression.”

This analysis included data from 3222 patients with BRAFV600 mutation-positive metastatic melanoma who had participated in a global safety study. Both previously-treated and treatment-naïve patients were included and all received oral vemurafenib at 960 mg, twice a day.

At the 3rd interim analysis, 2409 (74.8%) patients demonstrated a best overall response of complete response (CR), partial response (PR), or stable disease (SD). From this cohort, a subgroup of 217 (9.0%) patients was identified that had received vemurafenib for 4 or more weeks following disease progression. The analysis presented here compared the clinical outcome of patients in this subgroup to that of the overall cohort of responders.

No statistically significant differences were seen between the groups regarding patient characteristics, including elevated lactate dehydrogenase (LDH), ECOG performance status, or the baseline melanoma disease stage.

A comparison of best observed response with vemurafenib between the groups showed that 1.4%, 37.3% %, and 61.3% of patients treated following progression achieved CR, PR, and SD versus 3.7%, 34.4%, and 61.9% of patients in the overall population, respectively.

Patients receiving vemurafenib after disease progression achieved median progression-free survival of 6.3 months (95% CI 5.6, 6.7) compared with 6.4 months (95% CI 6.2, 6.5) for the overall population. The respective median overall survival was 15.2 months (95% CI 14.1, 17.9) versus 14.2 months (95% CI 13.2, 15.2) for patients with progressive disease and the overall population.

Median response duration was shorter in patients treated following progress at 5.6 months compared to 7.3 months in patients overall.

Vemurafenib was well-tolerated by patients treated beyond progression; Grade 3/4 adverse events (AEs) occurred slightly more frequently in patients treated beyond progression, with 116 (53%) patients in this cohort reporting grade 3/4 AEs compared to 1480 (46%) patients in the overall population. The most frequently reported grade 3/4 AEs were squamous cell cancer, rash, and liver function abnormalities.

“The slightly higher rate of AEs in patients who continued treatment after progression could possibly be due to the longer exposure to vemurafenib,” explained Dr Blank.

Dr Blank summarized, “ Efficacy outcomes were similar in the overall population and in patients receiving vemurafenib after disease progression, who seemed to have slightly longer median overall survival.”

Funding from F. Hoffman-La Roche was reported.