A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors

Abstract

Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60-125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAF(V600E) mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAF(V600E) mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.

Keywords: BRAF; Cobimetinib; MEK inhibitor; Melanoma; Phase I.

Fig. 1

Pharmacodynamic response by FDG-PET (a) and corresponding cobimetinib anti-tumor responses (b) in dose-expansion patients with a post-baseline tumor assessment. Dashed lines in (a) indicate a 20 % decrease of SUV_max. Eight patients (4 in Stage II and 4 in Stage IIA) were not evaluable for FDG-PET response. C cycle, D day

Fig. 2

Cobimetinib best anti-tumor responses, as measured by RECIST criteria in patients treated at the MTDs. Dashed lines indicate the RECIST progressive disease (PD) cutoff of 20 % and the RECIST partial response (PR) cutoff of - 30 %, respectively. Individual patient mutation profiles are provided underneath the graph. cPR confirmed partial response, MT mutant, SD stable disease, uCR unconfirmed complete response, WTwild type

Fig. 3

Cobimetinib anti-tumor activity in BRAF^V600E mutant melanoma, imaged using (a) PET, (b) CT-AC, and (c) FDG-PET. (a), (b) Black and yellow scale bars, 1 cm/tick. (b) Red arrow indicates the tumor; red lines indicate the diameter of the tumor. (c) Red line shows the location of the scanned cross-section. C cycle, CT-AC computed tomography-attenuation correction, D day