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

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 pancre- atic adenocarcinoma had an unconfirmed partial response. Conclusion. The safety profile of MEK and ERK inhibition dem- onstrated 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. The Oncologist 2020;25:833–e1438 DISCUSSION Dysregulation of the MAPK pathway, initiated by mutations in the RAS or BRAF oncogenes or through upstream growth fac- tor signaling, leads to tumorigenesis [1] and has been implicated in $30% of all human cancers [2]. Although targeting RAF and/or MEK has proved clinically effective, single-agent kinase inhibitor regimens have demonstrated limited clinical benefit outside of BRAF-mutant metastatic melanoma [3–6]. Combinations of inhibitors that target mul- tiple nodes within the MAPK pathway, such as MEK and ERK, may therefore be necessary in order to effectively suppress pathway signaling to enhance activity in RAS-and RAF- mutant tumors.