Combination of vemurafenib and cobimetinib in patients with advanced BRAFV600 -mutated melanoma: a phase 1b study

• Published in: The lancet oncology 2014-08, Vol.15 (9), p.954-965
• Main Authors: Ribas, Antoni, Prof, Gonzalez, Rene, Prof, Pavlick, Anna, MD, Hamid, Omid, MD, Gajewski, Thomas F, Prof, Daud, Adil, Prof, Flaherty, Lawrence, MD, Logan, Theodore, MD, Chmielowski, Bartosz, MD, Lewis, Karl, MD, Kee, Damien, FRACP, Boasberg, Peter, MD, Yin, Ming, PhD, Chan, Iris, MD, Musib, Luna, PhD, Choong, Nicholas, MD, Puzanov, Igor, MD, McArthur, Grant A, Prof
• Format: Article
• Language: English
• Subjects: Hematology, Oncology and Palliative Medicine
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(14)70301-8

Summary Background Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance, and abrogates paradoxical activation of the MAPK pathway in preclinical models of BRAF -mutated melanoma. We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF -mutated melanoma. Methods We undertook a phase 1b study in patients with advanced BRAFV600 -mutated melanoma. We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. In the dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), or continuously (28/0). The primary endpoint was safety of the drug combination and to identify dose-limiting toxic effects and the maximum tolerated dose. Efficacy was a key secondary endpoint. All patients treated with vemurafenib and cobimetinib were included in safety and efficacy analyses (intention-to-treat). The study completed accrual and all analyses are final. This study is registered with ClinicalTrials.gov , number NCT01271803. Findings 129 patients were treated at ten dosing regimens combining vemurafenib and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never received a BRAF inhibitor. Dose-limiting toxic effects arose in four patients. One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic effects—one developed grade 3 stomatitis and fatigue and one developed arthralgia and myalgia. The maximum tolerated dose was established as vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. Across all dosing regimens, the most common adverse events were diarrhoea (83 patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events were mild-to-moderate in severity. The most common grade 3 or 4 adv