Promising Phase Ib Findings With Combined BRAF and MEK Inhibition With Vemurafenib and Cobimetinib in Advanced BRAF V600–Mutant Melanoma
In a phase Ib study reported in The Lancet Oncology, Ribas et al found that the combination of the BRAF inhibitor vemurafenib (Zelboraf) and the MEK inhibitor cobimetinib was safe and active in the treatment of advanced BRAF V600–mutant melanoma. Preclinical studies have shown that the combined approach improves antitumor effect, delays development of resistance, and prevents “paradoxical” activation of the MAPK pathway observed with BRAF inhibition alone.
Study Details
In the study, 129 patients who had recently shown disease progression on vemurafenib (n = 66) or never received a BRAF inhibitor (n = 63) received vemurafenib at 720 mg or 960 mg twice a day continuously and cobimetinib at 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.
Maximum Tolerated Dose
Dose-limiting toxicities occurred in four patients: one receiving vemurafenib at 960 mg and cobimetinib at 80 mg on the 14/14 day schedule had grade 3 fatigue for > 7 days; one receiving vemurafenib at 960 mg and cobimetinib at 60 mg on the 21/7 day schedule had grade 3 prolongation of QTc; and two patients receiving vemurafenib at 960 mg and cobimetinib at 60 mg on the continuous schedule had grade 3 stomatitis and fatigue and arthralgia and myalgia, respectively. The maximum tolerated dose was established as vemurafenib at 960 mg twice a day in combination with cobimetinib at 60 mg once a day on the 21/7 day schedule.
Among all patients, the most common adverse events of any grade were diarrhea (64%), nonacneiform rash (60%), liver enzyme abnormalities (50%), fatigue (48%), nausea (45%), and photosensitivity (40%). The most common grade 3 or 4 adverse events were cutaneous squamous-cell carcinoma (9%, all grade 3), increased ALT (9%), and anemia (7%).
Response Rates
Confirmed objective response was observed in 15% of patients who had recently had disease progression on vemurafenib and in 87% who had never received a BRAF inhibitor, including complete response in 10% of the latter. Median progression-free survival was 2.8 months (95% confidence interval [CI] = 2.6–3.4) and 13.7 months (95% CI = 10.1–17.5) in the two subgroups.
The investigators concluded, “The combination of vemurafenib and cobimetinib was safe and tolerable when administered at the respective maximum tolerated doses. The combination has promising antitumour activity and further clinical development is warranted in patients with advanced BRAFV600-mutated melanoma, particularly in those who have never received a BRAF inhibitor; confirmatory clinical testing is ongoing.”
Grant McArthur, MBBS, PhD, of Peter MacCallum Cancer Centre, East Melbourne, is the corresponding author for The Lancet Oncology article.
The study was funded by F. Hoffmann-La Roche/Genentech. For full disclosures of the study authors, visit www.thelancet.com.
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