A Phase Ib Study to Evaluate the MEK Inhibitor Cobimetinib in Combination with the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors.

Abstract

LESSONS LEARNED:

Despite strong preclinical rationale, combined cobimetinib-mediated MEK inhibition and GDC-0994-mediated ERK inhibition was not tolerable on two 28-day dosing schedules in which GDC-0994 was given for 21 days continuously and cobimetinib administered over 21 days either continuously or intermittently. Adverse events were as expected for mitogen-activated protein kinase pathway inhibition, but overlapping and cumulative toxicities could not be managed on either dosing schedule. Pharmacokinetic parameters of cobimetinib and GDC-0994 given in combination were similar to those previously observed in monotherapy studies, so that there was no evidence of drug-drug interaction. Cycle 1 metabolic responses were observed by 18F-fluorodeoxyglucose-positron emission tomography but were not predictive of outcome measured by RECIST 1.1.

BACKGROUND:

Simultaneous targeting of multiple nodes in the mitogen-activated protein kinase (MAPK) pathway offers the prospect of enhanced activity in RAS-RAF-mutant tumors. This phase Ib trial evaluated the combination of cobimetinib (MEK inhibitor) and GDC-0994 (ERK inhibitor) in patients with locally advanced or metastatic solid tumors.

METHODS:

Cobimetinib and GDC-0994 were administered orally on two separate dosing schedules. Arm A consisted of concurrent cobimetinib and GDC-0994 once daily for 21 days of a 28-day cycle; Arm B consisted of intermittent dosing of cobimetinib on a 28-day cycle concurrent with GDC-0994 daily for 21 days of a 28-day cycle.

RESULTS:

In total, 24 patients were enrolled. For Arm A, owing to cumulative grade 1-2 toxicity, the dose of cobimetinib was decreased. For Arm B, dose increases of GDC-0994 and cobimetinib were intolerable with grade 3 dose-limiting toxicities of myocardial infarction and rash. Pharmacokinetic data did not show evidence of a drug-drug interaction. Overall, seven patients had a best overall response of stable disease (SD) and one patient with pancreatic adenocarcinoma had an unconfirmed partial response.

CONCLUSION:

The safety profile of MEK and ERK inhibition demonstrated classic MAPK inhibitor-related adverse events (AEs). However, overlapping AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination.

• Authors: Colin Weekes, Albert Lockhart, Patricia LoRusso, Elaine Murray, Erica Park, Mike Tagen, Jatinder Singh, Indrani Sarkar, Lars Mueller, Hatem Dokainish, Geoffrey Shapiro, Howard Burris
• Journal: The oncologist (Oncologist) Vol. 25 Issue 10 Pg. 833-e1438 (10 2020) ISSN: 1549-490X [Electronic] England
• PMID: 32311798 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © AlphaMed Press; the data published online to support this summary are the property of the authors.

Chemical References

• Azetidines
• Piperidines
• Protein Kinase Inhibitors
• Mitogen-Activated Protein Kinase Kinases
• cobimetinib

Topics

• Adenocarcinoma
• Azetidines
• Humans
• MAP Kinase Signaling System
• Mitogen-Activated Protein Kinase Kinases
• Neoplasms (drug therapy)
• Pancreatic Neoplasms
• Piperidines
• Protein Kinase Inhibitors (adverse effects)