Encorafenib/Binimetinib Outperforms BRAF Inhibitor Monotherapy in BRAF V600+ Melanoma

Keith Flaherty, MD

The BRAF/MEK inhibitor combination of encorafenib (Braftovi) and binimetinib (Mekinist) has demonstrated long-term benefits in patients with BRAF V600-mutant melanoma, according to 5-year analysis results from the COLUMBUS study (NCT01909453). The safety profile of the combination was also consistent with prior reports, according to the published findings.¹

“COLUMBUS long-term follow-up data continue to support the short and long-term benefit of this BRAF/MEK regimen for patients who receive this treatment as the first therapy for metastatic melanoma. We knew based on the shorter follow-up data that this regimen is uniquely well-tolerated, and this long-term data reinforces that point, Keith Flaherty, MD, director of clinical research at Massachusetts General Cancer Center and co-investigator of COLUMBUS told Targeted Oncology™, in an interview.

Encorafenib plus binimetinib achieved a median progression-free survival (PFS) of 14.9 months (95% CI, 11.0-20.2 months) vs 7.3 months (95% CI, 11.0-7.9 months) in the vemurafenib monotherapy arm (HR 0.51; 95% CI, 0.40-0.67). In the encorafenib monotherapy arm, the median PFS was 9.6 months (95% CI, 7.4-14.8 months) compared with encorafenib plus binimetinib (HR, 0.79; 95% CI, 0.61-1.02).

In terms of overall survival (OS), a key secondary end point, encorafenib plus binimetinib showed a median of 33.6 months (95% CI, 24.4-39.2 months) vs 16.9 months (95% CI, 14.0-24.5 months) with vemurafenib monotherapy (HR, 0.64; 95% CI, 0.50-0.81). In the encorafenib monotherapy arm, the median OS was 23.5 months (95% CI, 19.6-33.6 months). The HR for the difference between treatment with encorafenib/binimetinib and encorafenib alone was 0.71 (95% CI, 0.56-0.91).

Combing a BRAF and MEK inhibitor to treat locally advanced or metastatic BRAF V6000-mutant melanoma is now the standard treatment strategy, with 3 guideline-recommended combination regimens. The regimens for locally advanced or metastatic BRAF V6000-mutant melanoma include encorafenib plus binimetinib based on a prior analysis of the COLUMBUS trial a prior phase 1/2 study (NCT01543698), as well as the combination of vemurafenib (Zelboraf) plus cobimetinib (Cotellic) and dabrafenib (Tafinlar) plus trametinib (Mektovi).

“Following the development of dabrafenib/trametinib and vemurafenib/cobimetinib combination regimens for BRAF V600-mutant melanoma, there remained room for improvement with regard to both efficacy and safety/tolerability. Based on preclinical evidence, encorafenib was the most potent and selective BRAF inhibitor and had the unique feature of binding tightly to BRAF; maintaining its inhibitory effect longer than other agents,” explained Flaherty. “We had hoped that this would result in better control of the MAP kinase pathway and improve efficacy. The greater selectivity of encorafenib was hoped to improve tolerability,” he added.

In the prior analysis of part 1 of the COLUMBUS study, the combination of encorafenib and binimetinib demonstrated prolonged progression-free survival (PFS at 14.9 months compared with 7.3 months with either vemurafenib monotherapy, or encorafenib monotherapy (HR, 0.51; 95% CI, 0.39-0.67). The median overall survival (OS) observed with encorafenib/binimetinib was 33.6 months vs 16.9 months with monotherapy (HR, 0.61; 95% CI, 0.48-0.79).

Treatment with encorafenib and binimetinib in part 1 of the study was also well-tolerated, and the experimental arm had a lower treatment discontinuation rate (10%) compared with both monotherapy arms (14%). Moreover, quality-of-life measured by the Functional Assessment of Cancer Therapy – Melanoma (FACT- M) and EORTC Core Quality of Life C30 (EORTC QLQ-c30) questionnaires was better with the experimental combination.

The updated analyses were carried out 65 months after the final patients were randomly assigned. Patients were evaluated for the primary end point of PFS, and secondary end points including OS, objective response rate, safety, and tolerability in the overall population. PFS and OS were also assessed in prognostic subgroups.

Results from the 5-years analysis showed that encorafenib/binimetinib has a better ORR compared with the monotherapy arms. The ORR observed with encorafenib plus binimetinib was 64.1% (95% CI, 56.8%-70.8%), which included complete responses (CRs) in 14.1% of patients, partial response (PRs) in 50.0%, stable disease (SD) in 28.1%, and progressive disease (PD) in 7.8%. The disease control rate (DCR) in the encorafenib/binimetinib arm was 92.2% (95% CI, 87.4%-95.6%).

In comparison, the vemurafenib arm had a 40.8% ORR (95% CI, 33.8%-48.2%), consisting of CRs in 8.4%, PRs in 32.5%, SD in 40.3%, and PD in 18.8%. The DCR was 81.2% (95% CI, 74.9%-86.4%).

The encorafenib monotherapy arm also had a lower ORR compared with the combination arm at 51.5% (95% CI, 44.3%-58.8%. Response in the encorafenib-only arm consisted of CRs in 7.7% of patients, PRs in 43.8%, SD in 32.5%, and PD in 16.0%, showing a DCR of 84.0% (95% CI, 78.1%-88.9%).

In the prognostic subgroups, encorafenib appeared to be more successful in patients with normal LDH compared with those who had elevated LDH. The median PFS in the normal LDH population was 22.0 months (95% CI, 17.8-34.9 months) vs 5.6 months (95% CI, 4.8-7.3 months) in the elevated LDH group (unstratified HR, 4.22; 95% CI, (2.83-6.27). In terms of OS, the median in the normal LDH group was 51.7 months (95% CI, 36.8-67.3 months) vs 11.4 months (95% CI, 9.0-17.4 months) in the elevated LDH population (unstratified HR, 3.48; 95% CI, 2.42-5.00).

The study also showed that having a low tumor burden at baseline did not significantly impact survival. The median PFS in the baseline low tumor burden population was 25.9 months (95% CI, 18.5-62.4 months). The median OS in the baseline low tumor burden group was 51.7 months (95% CI, 35.8 to not evaluable).

The safety findings in the overall population after 5 years showed grade 3/4 adverse events (AEs) in approximately 70% of the encorafenib/binimetinib arm vs 66% of the vemurafenib arm, and 70% of the encorafenib arm. AEs led to dose adjustment or interruption in 56% of the combination arm, compared with 62% of the vemurafenib arm, and 72% of the encorafenib arm. The AEs that led to dose adjustment of interruption included gastrointestinal disorders (17%), eye disorders (12%), pyrexia (6%), decreased ejection fraction (5%), and increased gamma-glutamyl transferase (5%).

Treatment discontinuation occurred in 16% to 18% of patients in each treatment arm. In the encorafenib/binimetinib arm, increased alanine aminotransferase in 5 patients led to discontinuation. In the vemurafenib arm, 4 cases of aspartate aminotransferase led to treatment discontinuation, and 8 cases of either blood creatinine, headache, and rash led to discontinuation of encorafenib monotherapy.

In the ongoing part 2 of the COLUMBUS study, encorafenib plus binimetinib twice daily will be compared with encorafenib monotherapy.

“Long-term follow-up of part 2 will provide insight into the outcomes associated with 2 different starting doses of encorafenib in combination with binimetinib. But, given that part 1 incorporated the FDA approved and standard dose administered in clinical practice, these results provide the most relevant evidence of long-term benefit,” Flaherty stated.

_REFERENCE:

_{Dummer R. Flaherty KT, Robert C, et al. COLUMBUS 5-year update: A randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600–mutant melanoma. J Clin Oncol. Published online July 21, 2022. doi: 10.1200/JCO.21.02659}