Final BRIM-3 data confirm vemurafenib survival benefit over dacarbazine
medwireNews: Final data from the BRIM-3 trial show that overall survival (OS) remains significantly better with vemurafenib than with dacarbazine when given to treatment-naïve patients with BRAFV600 mutation–positive metastatic melanoma.
However, the researchers warn that “the benefits need to be balanced against toxicities,” because more patients in the vemurafenib group experienced serious adverse events.
During 2010, BRIM-3 participants were randomly assigned to receive vemurafenib (960 mg twice daily; n=337) or dacarbazine (1000 mg/m2 every 3 weeks; n=338).
At the end of data collection, in 2015, all patients in both treatment arms had discontinued study treatment, primarily because of disease progression, with median follow-up durations of 13.4 and 9.2 months in the vemurafenib and dacarbazine arms, respectively.
Without censoring data for the 84 patients who crossed over from dacarbazine to vemurafenib, median OS was significantly longer in the vemurafenib group than in the dacarbazine group, at 13.6 versus 10.3 months.
Similarly, when the patients who crossed over were excluded, corresponding median OS was 13.6 versus 9.7 months. And in both analyses, patients who received vemurafenib had a significant 19% reduced risk for death compared with those who received dacarbazine.
Estimated OS rates at 1, 2, 3 and 4 years were 55.7% versus 46.0%, 30.2% versus 24.5%, 20.8% versus 18.9% and 17.0% versus 15.6% for vemurafenib versus dacarbazine, respectively.
Paul Chapman (Memorial Sloan Kettering Cancer Center, New York, USA) and colleagues point out that the OS curves converged and stabilized at around 3 years, which they suggest is a result of “crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies.”
However, they also say that the extent of crossover and subsequent treatment (given to around 50% of participants) makes it “difficult to determine the contribution of vemurafenib to long-term OS outcomes in subsets of patients defined by known prognostic factors for survival.”
But the team did find that patients with poor prognostic factors, including age 65 years and older, stage M1c disease, elevated baseline lactate dehydrogenase level, Eastern Cooperative Oncology Group performance status of 1, and no prior adjuvant therapy, derived the greatest benefit from vemurafenib.
In terms of safety, the researchers report that adverse event (AE) profiles were consistent with the primary analysis.
Serious AEs were reported by 49% of patients who received vemurafenib (including those who crossed over) and 18% of those who received dacarbazine. These included squamous cell carcinoma of the skin (20 vs <1%), keratoacanthoma (11 vs 1%), basal cell carcinoma (3 vs <1%), and malignant melanoma (2 vs 0%).
Writing in the Annals of Oncology, Chapman et al say: “The BRIM-3 trial ushered in the era of targeted therapy against mutated BRAF in melanoma.”
They add that ”[s]ince the approval of vemurafenib monotherapy in 2011, the treatment landscape for BRAF-mutated metastatic melanoma has changed considerably,” with combinations of dabrafenib plus trametinib and cobimetinib plus vemurafenib now approved first-line therapies.
“Long-term OS results for these combinations are not yet available, but it is anticipated that the plateau in the OS curves will be higher than the plateau seen in this first monotherapy trial with a BRAF inhibitor,” the researchers conclude.
By Laura Cowen
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