Combined MEK, BRAF Inhibitors Promising in Melanoma

The combo of cobimetinib and vemurafenib was safe and tolerable in melanoma patients.

Combined treatment of BRAFV600-mutated melanoma with the MEK inhibitor cobimetinib and the BRAF inhibitor vemurafenib was safe and tolerable, according to the results of a phase Ib study.

Based on the promising antitumor activity seen with the combination, researchers led by Antoni Ribas, MD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, and colleagues recommended further clinical development and testing of this combination.

According to background information published with the study in Lancet Oncology, patients with BRAFV600-mutated metastatic melanoma often develop resistance to treatment with a BRAF inhibitor, “which frequently reactivates the MAPK pathway through MEK.” Prior research has shown that sequential treatment with a MEK inhibitor after this progression does not result in meaningful antitumor activity.

In this phase I study, Ribas and colleagues evaluated the concurrent administration of a MEK and a BRAF inhibitor in 129 patients who had either recently progressed on vemurafenib (n = 66) or who had never received treatment with a BRAF inhibitor (n = 53). Patients were enrolled in a dose escalation study, receiving vemurafenib 720 mg or 960 mg twice a day and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off, 21 days on and 7 days off, or continuously.

Of the 129 patients enrolled, dose-limiting toxicities occurred in only four patients: one patient had grade 3 fatigue for more than 7 days, one patient on 960 mg vemurafenib and cobimetinib 60 mg (21 days on and 7 days off) had grade 3 QTc prolongation, and two patients on vemurafenib 960 mg and continuous 60 mg cobimetinib had grade 3 stomatitis and fatigue, and arthralgia and myalgia.

Results of the study established the maximum-tolerated dose as 960 mg vemurafenib and 60 mg cobimetinib on the 21 days on 7 days off schedule.

Most of the reported adverse events were mild or moderate in severity. The most commonly reported events were diarrhea (64%), non-acneiform rash (60%), liver enzyme abnormalities (50%), fatigue (48%), nausea (45%), and photosensitivity (40%). Common grade 3 or 4 events were cutaneous squamous-cell carcinoma (9%), raised alkaline phosphatase (9%), and anemia (7%).

The researchers conducted efficacy analyses of the intention-to-treat patient population. Confirmed objective responses occurred in 15% of patients who had recently progressed on vemurafenib and 87% of patients who had never received a BRAF inhibitor. The median progression-free survival was 2.8 months and 13.7 months, respectively.

In an editorial that accompanied the article, Jeffrey R. Infante, MD, of the Sarah Cannon Research Institute and Tennessee Oncology, and Charles Swanton, MD, PhD, of the Cancer Research UK London Research Institute, called the difference in efficacy between the two groups striking.

“Surprisingly, despite a plethora of scientific literature describing reactivation of MAPK as a major mechanism of acquired resistance, the combination of vemurafenib and cobimetinib only salvages a few patients who have already progressed on a BRAF inhibitor,” Infante and Swanton wrote. “Although numbers of patients are small, the combination of vemurafenib and cobimetinib might partly mitigate the challenge of intrinsically drug-resistant disease, because only two (3%) of 63 patients who had never received a BRAF inhibitor had primary progressive disease, less than the 10%  to 15% reported previously with vemurafenib alone.”