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Encorafenib plus binimetinib prolongs OS for advanced BRAF-mutated melanoma
CHICAGO — Combination therapy with encorafenib plus binimetinib significantly improved OS compared with vemurafenib or encorafenib alone for patients with advanced BRAF-mutated melanoma, according to phase 3 results from the COLUMBUS trial presented at ASCO Annual Meeting.
Encorafenib (LGX818, Array BioPharma) plus binimetinib (MEK162, Array BioPharma) — a BRAF/MEK inhibitor combination — conferred a best-in-class median PFS of 14.9 months and median OS of 33.6 months. In comparison, vemurafenib (Zelboraf, Genentech) monotherapy conferred a median PFS of 7.3 months and median OS of 16.9 months, and encorafenib monotherapy conferred a median PFS of 9.6 months and median OS of 23.5 months.
“Encorafenib plus binimetinib combination therapy provides a new efficacy benchmark for targeted therapy and it is a promising treatment option for patients with BRAFV600-mutant melanoma,” Reinhard Dummer, MD, from the department of dermatology at University of Zurich Hospital in Zurich, Switzerland, said during his presentation.
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 BRAFV600E or BRAFV600K 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: 450 mg once-daily oral encorafenib plus 45 mg twice-daily oral binimetinib (n = 192), monotherapy with 300 mg oral encorafenib once daily (n = 194), or 960 mg twice-daily oral vemurafenib (n = 191).
An earlier primary analysis showed median PFS was 14.9 months with the combination vs .7.3 compared with vemurafenib (HR = 0.54; P < .001).
In the current analysis, researchers analyzed OS, a secondary endpoint. Median follow-up across arms was 21.5 months.
The median duration of exposure was 51 weeks for the combination group, 31 weeks in the encorafenib group and 26 weeks in the vemurafenib group.
The overall response rate was 64% per central review and 76% per local review among patients treated with the combination; 52% per central review and 58% per local review among patients treated with encorafenib; and 41% per central review and 49% per local review among patients treated with vemurafenib.
The median duration of response was 18.6 months (12.7-24.1) per central review and 16.2 months (11.1-24.1) per local review among patients in the combination group; 15.2 months (11.1-27.6) per central review and 14.8 (11-16.6) per local review among patients treated with encorafenib; and 12.3 months (6.9-14.5) per central review and 7.7 months (5.8-11) per local review among patients treated with vemurafenib.
Median OS was 33.6 months (95% CI, 24.4-39.2) with the combination, 23.5 months (95% CI, 19.6-33.6) with encorafenib, and 16.9 months (95% CI, 14.0-24.5) with vemurafenib.
The combination significantly reduced risk for death compared with vemurafenib (HR = 0.61, 95% CI, 0.47-0.79).
The combination appeared to prolong OS compared with encorafenib monotherapy, but the difference did not reach statistical significance (HR = 0.81; 95% CI, 0.61-1.06). However, encorafenib monotherapy showed a benefit over vemurafenib (HR = 0.76; 95% CI, 0.58-0.98).
Updated median PFS reached 14.9 months (95% CI, 11-20.2) with the combination, 9.6 months (95% CI, 7.4-14.8) with encorafenib, and 7.3 months (95% CI, 5.6-7.9) with vemurafenib. PFS appeared significantly longer with the combination vs. vemurafenib (HR = 0.51; 95% CI, 0.39-0.67).
The combination also showed a PFS benefit over encorafenib (HR = 0.77; 95% CI, 0.59-1), as did encorafenib over vemurafenib (HR = 0.68; 95% CI, 0.52-0.88).
Adverse events occurred among 98% of patients in the combination group, 99% in the encorafenib group and 100% in the vemurafenib group. Grade 3 or 4 events were more common in the encorafenib (67%) and vemurafenib (66%) groups than the combination group (64%). Approximately 53% of patients in the combination group underwent dose reduction or interruption compared with 71% in the encorafenib group and 62% in the vemurafenib group.
“The updated results are consistent to data that have been reported on other clinical trials,” Dummer said. – by Melinda Stevens
Reference:
Dummer R, et al. Abstract 9504. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
Disclosures: Dummer reports honoraria from Amgen, Bristol-Myers Squibb, Merck, Novartis, Pierre Fabre, Roche, Sun Pharma and Takeda; consultant/advisory roles with Amgen, Bristol-Myers Squibb, Merck, Novartis, Pierre Fabre, Roche, Sun Pharma and Takeda; and research funding to his institution from Amgen, Bristol-Myers Squibb, Merck, Novartis and Roche. Please see the abstract for all other authors’ relevant financial disclosures.
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This combination of encorafenib plus binimetinib is the third combination, which we call BRAF-plus-MEK protein inhibitors, to be presented in a randomized phase 3 trial against BRAF inhibition alone. What is newsworthy is that this combination of encorafenib plus binimetinib demonstrates a longer PFS and OS than the previous combinations. The abstract alluded to this as best in class, with this combination of BRAF plus MEK having the longest progression-free interval and OS. That makes those of us in the melanoma field excited to use encorafenib plus binimetinib rather than feeling blasé about a new-generation combination.
Previously, the OS with combination BRAF plus MEK inhibitors approximated 2 years with a PFS of 11.4 to 12.3 months. Encorafenib plus binimetinib has an OS of 33.6 months, with a median PFS of 14.9 months. So, this combination is adding on several months to the progression-free period and OS.
We should use caution when interpreting OS, as the combination treatment may not be directly responsible for a patient’s survival —it’s what they get treated with next. The landscape for melanoma has really changed such that there are even more effective treatments. The therapies that these patients receive after progression do impact the OS.
The toxicity of this combination may actually be better tolerated than previous BRAF plus MEK treatments. Previous combos had more pyrexia and photosensitivity; encorafenib plus binimetinib may need closer monitoring for ocular toxicities — serous retinopathy. Less constitutional and dermatological side effects may make it not only easier for patients to take the treatment, but, also, as the data are showing, they may take it longer for the duration of benefit.
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