Cobimetinib/Vemurafenib OS Benefit Sustained at 5 Years in BRAF+ Melanoma

The combination of cobimetinib (Cotellic) and vemurafenib (Zelboraf) maintained an advantage for overall survival and objective response rate in patients with BRAF-positive melanoma versus vemurafenib alone.

Grant A. McArthur, PhD

Combining the MEK inhibitor cobimetinib (Cotellic) with the BRAF inhibitor vemurafenib (Zelboraf) provides long-term clinical benefits for patients with BRAF V600—mutated metastatic melanoma. Data from a final analysis of the phase III coBRIM trial presented at the 16th International Congress of the Society for Melanoma Research showed that the combination maintained an advantage for overall survival (OS) and objective response rate (ORR) compared with vemurafenib alone at 5 years.1

Cobimetinib/vemurafenib improved OS and progression-free survival (PFS) by roughly 5 months compared with vemurafenib alone. The median OS was 22.5 months (95% CI, 20.3-28.8) with the combination compared with 17.4 months (95% CI, 14.5-19.8) for the monotherapy. The 5-years OS rates were 30.8% vs 26.3%, respectively.

“In all subgroup analyses, the OS favored the cobimetinib/vemurafenib arm,” said lead author Grant A. McArthur, PhD, head of the Molecular Oncology Laboratory and of the Cancer Therapeutics Program at the Peter MacCallum Cancer Centre in Melbourne, Australia. “This included the poor prognosis M1c patients, the ECOG performance status 1 patients, patients who had the V600K mutation, and, of course, the LDH patient populations.”

The median PFS at 5 years was 12.6 months (95% CI, 9.5-14.8) with cobimetinib/vemurafenib versus 7.2 months (95% CI, 5.6-7.5) with vemurafenib alone. The 5-year PFS rates were 14% versus 10%, respectively.

The study included 495 treatment-naïve patients with BRAF V600E/K—positive unresectable locally advanced or metastatic melanoma. Patient demographics were well balanced across the 2 arms, including disease stage, ECOG performance status, age, and geographic region. More than half of patients had stage IV, M1c melanoma.

Patients were randomly assigned to continuous vemurafenib at 960 mg twice daily plus either placebo (n = 248) or 60 mg of cobimetinib once daily on days 1-21 of a 28-day cycle (n = 247). The primary endpoint of the study was PFS, with secondary outcome measures including OS, ORR, and duration of response.

The combination induced an ORR of 70% (95% CI, 63-75) with a complete response (CR) rate of 21% and a partial response (PR) rate of 49%. Vemurafenib induced an ORR of 50% (95% CI, 43-56) with a CR of 13% and a PR of 37%.

McArthur added that the proportion of patients in the combination arm achieving CR continues increasing over time.

Patients who responded to the cobimetinib/vemurafenib combination had a superior median OS (32.1 vs 9.7 months) and OS rate (37% vs 13%) at 5 years. Similarly, those patients had superior median PFS (16.6 vs 3.7 months) and PFS rate (18% vs 4%).

Investigators found LDH levels correlated with outcomes in the combination arm. “Among patients treated with the combination, those who had normal LDH had longer PFS and OS compared with patients who had an elevated LDH,” McArthur said.

The median OS for patients with normal LDH was 38.5 months (95% CI, 28.0­—not evaluable). In contrast, the median OS was just 14.8 months (95% CI, 11.3-18.6) in patients with elevated LDH. The combination also produced a better median PFS (15.0 vs 8.6 months) and 5-year PFS rate (18% vs 7%) in patients with normal LDH at baseline compared with those with elevated LDH.

“Among patients who had a normal LDH [at baseline], 43% were still alive at 5 years,” McArthur said. “That is in marked contrast to patients with an elevated LDH, where only 16% of patients were still alive.”

The were no new safety signals observed compared with earlier analyses of the trial, McArthur noted.

Based on previously reported results from the coBRIM trial, the FDA approved the combination of cobimetinib and vemurafenib in 2015 as a treatment for patients with BRAF-positive metastatic or unresectable melanoma.

McArthur GA, Dréno B, Larkin J, et al. 5-year survival update of cobimetinib plus vemurafenib BRAF V600 mutation-positive advanced melanoma: final analysis of the coBRIM study. Presented at: the 16th International Congress of the Society for Melanoma Research; November 20-23, 2019; Salt Lake City, UT.

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