Reference Detail

Ref Type

Journal Article

PMID

(27424159)

Authors

Rosen LS, LoRusso P, Ma WW, Goldman JW, Weise A, Colevas AD, Adjei A, Yazji S, Shen A, Johnston S, Hsieh HJ, Chan IT, Sikic BI

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs	34	5	2016 Oct	604-13	Invest New Drugs

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	melanoma	predicted - sensitive	Cobimetinib	Case Reports/Case Series	Actionable	In a Phase I trial, Cotellic (cobimetinib) treatment resulted in a confirmed partial response in six melanoma patients harboring BRAF V600E (PMID: 27424159).	27424159