Encorafenib–binimetinib a new option for BRAF-mutated melanoma
medwireNews: The combination of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib has favorable efficacy and tolerability relative to either encorafenib or vemurafenib alone in patients with advanced melanoma harboring BRAF mutations, phase III trial findings indicate.
The COLUMBUS trial recruited 577 patients with locally advanced (stage IIIB, IIIC, or IV), unresectable, or metastatic melanoma of the skin or of unknown origin that was positive for a BRAF V600E or V600K mutation. Participants were randomly assigned to receive one of three treatment options, namely, oral encorafenib 450 mg/day alongside oral binimetinib 45 mg twice a day, encorafenib 300 mg/day, or vemurafenib 960 mg twice daily.
Over a median follow-up of 16.6 months, progression-free survival (PFS) was significantly longer with the combination than with vemurafenib monotherapy, at a median of 14.9 and 7.3 months, respectively, giving a hazard ratio of 0.54.
Treatment with the combination also improved PFS relative to encorafenib alone, where the median PFS for the latter group was 9.6 months, but this improvement was not statistically significant.
The main question with the combination of encorafenib plus binimetinib is whether this combination will offer a major benefit in overall survival...
And more patients in the encorafenib plus binimetinib study arm achieved an overall response, as assessed by independent central review, compared with those in the encorafenib or vemurafenib groups, with rates of 63% versus 51% and 40%, respectively.
Lead author Reinhard Dummer (University Hospital Zürich, Switzerland) and colleagues also report a more favorable toxicity and tolerability profile for the combination. Specifically, grade 3 or 4 adverse events occurred in 58% of combination-treated patients versus 66% of encorafenib- and 63% of vemurafenib-treated patients.
Moreover, patients in the combination group were more likely to achieve a higher dose intensity and longer median exposure, and were less likely to discontinue treatment as a result of side effects than their counterparts in either monotherapy arm.
The researchers also note that the incidence of pyrexia and photosensitivity – adverse events known to occur with the dabrafenib–trametinib and vemurafenib–cobimetinib combinations, respectively – were “infrequent” with encorafenib and binimetinib.
“Overall survival data and long-term safety data will provide additional insights into the efficacy and tolerability of this combination,” Dummer et al write in The Lancet Oncology.
But they believe that “[e]ncorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma.”
Writing in an accompanying commentary, Jean Jacques Grob (Hôpital de la Timone, Marseille, France) wonders whether this new combination is “too late an addition” to the armamentarium against BRAF-mutated melanoma, given that immunotherapy seems to be taking center stage in this setting.
But he points out that “clinicians should keep in mind that survival of many patients with metastatic melanoma is still dependent on a long-term treatment with BRAF–MEK inhibitor combinations.”
And the commentator concludes: “If confirmed, the attractive tolerability profile of encorafenib–binimetinib would be an advantage in first-line prescription, for reintroduction after immunotherapy failure, for patients with a persistent poor tolerance for BRAF-MEK inhibitor combinations who might benefit from a switch to encorafenib–binimetinib, in facilitating combinations with immunotherapy in triplets, and for extending the scope of adjuvant treatment to less advanced melanoma.”
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