New BRAF/MEK Combo Highly Effective in Phase III Melanoma Study

BRAF-mutant unresectable melanoma, according to findings from cohort 1 of the phase III COLUMBUS trial presented at the 2016 Society for Melanoma Research Congress.

The PFS by independent review was 14.9 months with encorafenib plus binimetinib versus 7.3 months for vemurafenib (HR, 0.54; 95% CI, 0.41-0.71;P<.001). In the single-agent encorafenib arm, the median PFS was 9.6 months.

&ldquo;This regimen does represent, potentially, a new treatment option for these patients,&rdquo; said lead investigator Keith T. Flaherty, MD, director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital and professor of Medicine, Harvard Medical School. "At the time this trial was launched, vemurafenib was the treatment standard and combination therapy was still in phase II trials. The median of 7.3 months with vemurafenib is what we would have expected based on historical data.&rdquo;

In part 1 of the COLUMBUS study, 577 patients were randomized in a 1:1:1 ratio to receive encorafenib plus binimetinib (n = 192), encorafenib alone (n = 194), or vemurafenib alone (n = 191). Those with untreated CNS lesions, leptomeningeal metastases, uveal melanoma, and mucosal melanoma were excluded from the trial. Baseline characteristics were well balanced across arms, for number of organs with metastasis and LDH levels. The median age of patients in the combination arm was 57 years and 71% had an ECOG performance status of 0.

In the combination arm, encorafenib was administered at 450 mg daily (QD) and binimetinib was administered at 45 mg twice daily (BID). Single-agent encorafenib was given at 300 QD. Vemurafenib was administered at 960 BID. The primary endpoint for part 1 of the study was a comparison of PFS for the combination versus vemurafenib by independent review. Secondary endpoints included an analysis of PFS for the combination versus single-agent encorafenib and overall survival (OS) for the combination versus vemurafenib.

When single-agent encorafenib was compared with the combination arm the difference between the groups did not reach statistical significance (HR, 0.75; 95% CI, 0.56-1.00;P= .051). However, median PFS with encorafenib was statistically superior to vemurafenib (HR, 0.68; 95% CI, 0.52-0.90;&nbsp;P= .007). Findings for OS were not yet available.

The objective response rate (ORR) with the combination was 63% versus 40% with vemurafenib. With single-agent encorafenib, the ORR was 51%. The complete response rate was 8% with the combination versus 5% and 6% with encorafenib and vemurafenib, respectively. The median duration of response was 16.6 months with the combination versus 14.9 months with encorafenib and 12.5 months with vemurafenib.

By local review, median PFS with the combination was 14.8 versus 7.3 months with vemurafenib (HR, 0.49; 95% CI, 0.37-0.64;P<.001). The ORRs by local review were 75% for the combination versus 49% and 58% for vemurafenib and encorafenib monotherapy, respectively.

In this assessment, the combination was superior to single-agent encorafenib (HR, 0.68; 95% CI, 0.52-0.90;P= .006). The median PFS with encorafenib was 9.2 months, which was also superior to single-agent vemurafenib (HR, 0.70; 95% CI, 0.54-0.91;&nbsp;P= .008).

"We've never generated head-to-head data with vemurafenib, so that's another point of comparison that one can make," said Flaherty. "Interestingly, encorafenib itself was superior to vemurafenib in terms to PFS."

All-grade AEs with the most variability between the two arms for the combination, single-agent encorafenib, and vemurafenib, respectively, were arthralgia (26%, 44%, 45%), pyrexia (18%, 15%, 28%), alopecia (14%, 56%, 37%), hyperkeratosis (14%, 38%, 29%), dry skin (14%, 30%, 23%), rash (14%, 21%, 29%), palmoplantar keratoderma (9%, 26%, 16%), and palmar-plantar erythrodysesthesia syndrome (7%, 51%, 14%). All-grade AEs of special interest with the combination included rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%) and photosensitivity (5%).

Grade 3/4 adverse events (AEs) were experienced by 58% of patients treated with the combination versus 66% and 63% with encorafenib and vemurafenib, respectively. The most common grade 3/4 AEs with the combination were gamma-glutamyltransferase, increased blood creatine phosphokinase, and hypertension. Time to first grade 3/4 AE was long with the combination, at 2.5 months versus 0.4 months for encorafenib and 1.3 months for vemurafenib.

&ldquo;This time dependent analysis makes a fairly compelling case that this is a very well-tolerated regimen. It has in several ways a unique profile in terms of tolerability,&rdquo; said Flaherty. &ldquo;Quality of life was also superior with the combination.&rdquo;

Part 2 of the COLUMBUS study was designed to provide additional data, with statistical analysis only planned if the primary and secondary PFS endpoints were reached. Findings from this portion of the study are anticipated in mid-2017 and could help illuminate the comparison of the combination and encorafenib monotherapy. In this portion of the study, 344 patients were randomized in a 3:1 ratio to receive encorafenib plus binimetinib at 45 mg BID or encorafenib alone. In this portion of the study, encorafenib was given at 300 mg QD in both arms.

A new drug application is currently pending with the FDA for binimetinib as a treatment for patients withNRAS-mutant melanoma. This application was given a standard review by the FDA, along with notice that the agency plans to hold an Oncologic Drugs Advisory Committee (ODAC) meeting as part of the review process. Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the NDA by June 30, 2017.

In addition to melanoma, binimetinib and encorafenib are also under exploration as a treatment for patients withBRAFV600E-mutant colorectal cancer in the phase III BEACON CRC trial. This trial, which is not yet open, will look at encorafenib plus cetuximab with or without binimetinib.