Abstract CT107: 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 (2017)

Abstract Background: Dysregulation of the MAPK pathway, initiated by mutations in the RAS or BRAF oncogenes or through upstream growth factor signaling, has been implicated in ~30% of all human cancers. While targeting RAF and/or MEK has proven clinically effective, resistance frequently develops. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced activity in RAS-/RAF-mutant tumors and a reduced potential for acquired resistance. An open-label, dose-escalation Phase Ib study combining cobimetinib (MEK inhibitor) and GDC-0994 (ERK inhibitor) to evaluate safety and tolerability, pharmacokinetics (PK), and preliminary signs of efficacy was conducted in patients with locally advanced or metastatic solid tumors. Methods: Cobimetinib and GDC-0994 were administered orally on two separate dosing schedules. Schedule A consisted of concurrent cobimetinib and GDC-0994 once daily on a 21-day on/7-day off schedule, while Schedule B consisted of intermittent dosing of cobimetinib on Days 1, 4, 8, 11, 15, and 18 of a 28-day cycle concurrent with GDC-0994 QD for 21 consecutive days of a 28-day cycle. Results: In total, 23 patients were enrolled (Schedule A, n=8; Schedule B, n=15). The majority of adverse events (AE) were Grade 1 or Grade 2 and those occurring in ≥ 2 patients in each schedule included diarrhea, nausea, fatigue, decreased appetite, vomiting, blurred vision, dermatitis acneiform, peripheral edema, asthenia, rash, and increased blood creatinine. For Schedule A, a single dose-limiting toxicity (DLT) of Grade 3 diarrhea occurred in cohort A1 (at 40 mg of cobimetinib + 200 mg of GDC-0994). Due to cumulative Grade 1-2 toxicity, the dose of cobimetinib was decreased to 20 mg in cohort A0. For Schedule B, cohort B1 enrolled patients at a dose of 80 mg of cobimetinib + 200 mg of GDC-0994. Dose escalation to cohort B2 (GDC-0994 increased to 400 mg) and cohort B3 (cobimetinib dose increased to 100 mg) resulted in intolerability in both cohorts. As a result, 3 additional patients were enrolled in cohort B1. Two of these patients experienced a DLT of Grade 3 myocardial infarction and Grade 3 rash, respectively. PK data did not show evidence of a drug-drug interaction for either schedule. Overall, 6 patients had a best overall response of SD and 1 patient with pancreatic adenocarcinoma had an unconfirmed partial response. Conclusion: The safety profile of this combination of a MEK and ERK inhibition demonstrated classic MAPK-inhibitor related AEs. No new safety signals were identified. However, overlapping Grade 1-2 AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination. Citation Format: Colin D. Weekes, Albert Lockhard, Patricia LoRusso, Elaine Murray, Erica Park, Michael Tagen, Lars Mueller, Hatem Dokainish, Geoffrey Shapiro, Howard Burris. 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]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT107. doi:10.1158/1538-7445.AM2017-CT107