COMBO300 Shows Benefit Without Severe Toxicity in Advanced BRAF V600+ Melanoma

Keith T. Flaherty, MD

The BRAF/MEK inhibitor combination of encorafenib (Braftovi) and binimetinib (Mektovi; COMBO300) demonstrated improvement in progression-free survival (PFS), objective response rate (ORR), and was more tolerable in patients with advanced BRAFV600-mutant melanoma, compared with vemurafenib (Zelboraf) plus encorafenib (ENC300), according to findings from the phase 3 COLUMBUS trial (NCT01909453).¹

This research, which was published in the Journal of Clinical Oncology, proposes the maximization of BRAF inhibition in BRAF/MEK inhibitor combinations improves efficacy and limits toxicity, according to the study investigators led by Paolo A. Ascierto, MD.

“This manuscript updates the outcome data for COLUMBUS. Compared to the primary publication of the positive phase 3 trial, this and prior updates confirm those findings regarding prolongation of progression-free survival and excellent tolerability,” said Keith T. Flaherty, MD, director of clinical research, Massachusetts General Hospital Cancer Center and investigator of the COLUMBUS trial, told Targeted Oncology™.

“With each of these follow-up publications we describe the fraction of patients who remain progression-free (with durable responses) for several years and counting,” he added. “These data reinforce the current view and clinical practice that encorafenib/binimetinib has the best therapeutic index of the approved BRAF/MEK combinations.”

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It was previously shown that adding binimetinib, a selective MEK 1/2 inhibitor, may be able to offset treatment toxicity that led to treatment interruption.² Specifically, adding this drug to encorafenib, a BRAF inhibitor, which has dose-dependent efficacy, was predicted to be beneficial for patients.³

COLUMBUS is a 2-part, phase 3, randomized, open-label, multicenter study. Part 1 included 244 patients, 258 of whom were treated with COMBO300 at 450 mg once daily for encorafenib and 45 mg twice daily for binimetinib. The ENCO300 arm included 86 patients who received either 300 mg of encorafenib once daily or 960 mg of vemurafenib twice daily, and combined part 1 and 2 results that were reported from this study arm.¹

At a median follow-up of 54.4 months in the COMBO300 arm, vs 43.5 months in the ENCO300 arm, the median PFS by blinded independent review committee was 12.9 months (95% CI, 10.9-14.9) vs 9.2 months (95% CI, 7.4-11.1), respectively. The estimated reduction in the risk of disease progression or death with COMBO300 compared with ENCO300 was 26% (HR, 0.74; 95% CI, 0.60-0.92; stratified log-rank, 2-sided P = .003). The PFS results by investigator assessment was similar (HR, 0.60; 95% CI, 0.45-0.80; stratifies log-rank, 2-sided P < .001).

Results for the secondary end point showed that with COMBO300, the ORR by BIRC was 67.8% (95% CI, 61.8%-73.5%). Responses to COMBO300 included complete responses (CRs) in 12.0% of patients, partial responses (PRs) in 55.8%, stable disease (SD) in 22.9%, and progressive disease in 9.3%, for a disease control rate (DCR) of 90.7% (95% CI, 86.5%-93.9%). In comparison, patients treated with ENCO300 had an ORR of 90.7% by BICR (95% CI, 86.5%-93.9%). Response to ENCO300 included 7.9% of patients with a CR, PRs in 43.6% of patients, SD in 31.3%, and PD in 17.5%. The DCR in the ENCO300 arm was 82.5% (95% CI, 77.5%-86.8%).

The median duration of confirmed response to therapy was 15.4 months (95% CI, 11.8-20.6) in the COMBO300 arm compared with 14.8 months (95% CI, 11.0-21.2 months) with ENCO300.

The safety analysis population include 533 patients total, which was inclusive of 84 patients in the ENCO300 arm who were treated in part 2 of the study. The most common adverse events (AEs) in the COMBO300 arm were diarrhea (35.4%), arthralgia (29.6), and nausea (28.8%). The most common grade 3/4 AEs were blood CPK increase and arthralgia (2.3% each). In the ENCO300 arm, the most common AEs were arthralgia (49.3%) and nausea (36.6%).

Discontinuation of COMBO300 due to AEs occurred in 12% of patients compared with an 11% discontinuation rate in the ENCO300 arm. Treatment interruptions or modifications caused by any-grade AEs occurred in 38% of the COMBO300 arm and 63% of the ENCO300 arm.

According to Ascierto et al, these findings provide additional evidence of how binimetinib contributes to the treatment of BRAF-mutant, advanced, unresectable melanoma.

_REFERENCES:

_{1. Ascierto PA, Dunner R, Gogas HJ, et al. Contribution of MEK inhibition to BRAF/MEK inhibitor combination treatment of BRAF-mutant melanoma: Part 2 of the randomized, open-label, phase III COLUMBUS trial. J Clin Oncol. Published July 28, 2023. doi:10.1200/JCO.22.02322}

_{2. Ascierto PA, Schadendorf D, Berking C, et al: MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: A non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14(3)249-256. doi:10.1016/S1470-2045(13)70024-X}

_{3. Stuart DD, Li N, Poon DJ, et al. Preclinical profile of LGX818: A potent and selective RAF kinase inhibitor. Cancer Res. 2012;72(suppl 8):3790. doi:10.1158/1538-7445.AM2012-3790}