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Encorafenib plus binimetinib prolongs PFS in BRAF-mutated advanced melanoma
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Combination therapy with encorafenib plus binimetinib significantly improved PFS compared with vemurafenib for patients with advanced BRAF-mutated melanoma, according to results of the two-part, randomized, open-label phase 3 trial COLUMBUS trial published in The Lancet Oncology.
“We’ve learned in years past that other BRAF-MEK inhibitor combination therapies improve PFS compared [with] BRAF inhibitor monotherapy,” Keith T. Flaherty, MD, professor of medicine at Harvard Medical School, told HemOnc Today. “The degree of improvement here looks to be even greater than in other studies but, of course, no two clinical trials are identical.”
The COLUMBUS study included 577 patients from 162 hospitals in 28 countries with histologically confirmed, locally advanced unresectable or metastatic melanoma, or unknown primary melanoma; a BRAF V600E or BRAF V600K mutation; and an ECOG performance status of either 0 or 1. Patients were treatment naive or progressed following a first-line immunotherapy.
For part 1 of the study, researchers randomly assigned patients 1:1:1 to receive one of three treatments: once-daily oral encorafenib (LGX818, Array BioPharma) at a dose of 450 mg plus 45 mg of twice-daily oral binimetinib (MEK162, Array BioPharma; n = 192); monotherapy with 300 mg oral encorafenib once daily (n = 194); or 960 mg of twice-daily oral vemurafenib (Zelboraf, Genentech; n = 191).
In part 2 — which will be published separately — researchers compared the combination of encorafenib at its monotherapy maximum tolerated dose plus binimetinib with encorafenib monotherapy at the same dose to better characterize the contribution of binimetinib to the combination.
Median follow-up was 16.6 months (95% CI, 14.8-16.9).
Median PFS was 14.9 months (95% CI, 11-18.5) among patients assigned encorafenib plus binimetinib compared with 9.6 months (95% CI, 7.5-14.8) among patients assigned encorafenib monotherapy and 7.3 months (95% CI, 5.6-8.2) among patients assigned vemurafenib.
PFS by blinded independent central review showed a significant reduction in the risk for progression or death with encorafenib plus binimetinib vs. vemurafenib (HR = 0.54, 95% CI 0.41-0.71) and vs. encorafenib (HR 0.75, 95% CI 0.56-1).
PFS analysis by blinded independent central review also favored encorafenib monotherapy over vemurafenib (HR = 0.68; 95% CI, 0.52-0.9).
In the encorafenib-plus-binimetinib group, the most common grade 3 to grade 4 adverse events to occur among more than 5% of patients included increased y-glutamyltransferase (n = 18; 9%), increased creatine phosphokinase (n = 13; 7%) and hypertension (n = 11; 6).
Among patients who received encorafenib alone, the most common adverse events included palmoplantar erythrodysesthesia syndrome (n = 26; 14%), myalgia (n = 19; 10%) and arthralgia (n = 18; 9%).
One treatment-related death occurred in the combination therapy group.
Flaherty pointed out that two toxicities that often occur in other BRAF-MEK inhibitor combination therapies — namely, pyrexia with dabrafenib-trametinib and photosensitivity with vemurafenib-cobimetinib (Cotellic, Genentech) — occurred infrequently in the encorafenib-binimetinib combination group.
“This regimen has shown the biggest impact in median PFS yet observed,” Flaherty said. “This combination reduces the side effect profile while at the same time improving the efficacy profile.” – by Andy Polhamus
For more information:
Keith T. Flaherty, MD, can be reached at kflaherty@partners.org.
Disclosures: Flaherty reports consulting fees from Array BioPharma during this study, as well as consulting fees from Roche and research funding from Novartis outside of the submitted work. Please see the full study for all other authors’ relevant financial disclosures.
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