PMID- 32311798 OWN - NLM STAT- MEDLINE DCOM- 20210618 LR - 20221005 IS - 1549-490X (Electronic) IS - 1083-7159 (Print) IS - 1083-7159 (Linking) VI - 25 IP - 10 DP - 2020 Oct TI - 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. PG - 833-e1438 LID - 10.1634/theoncologist.2020-0292 [doi] AB - 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. CI - (c) AlphaMed Press; the data published online to support this summary are the property of the authors. FAU - Weekes, Colin AU - Weekes C AD - Massachusetts General Hospital, Boston, Massachusetts, USA. FAU - Lockhart, Albert AU - Lockhart A AD - Division of Oncology, Washington University Medical School, St. Louis, Missouri, USA. FAU - LoRusso, Patricia AU - LoRusso P AD - Smilow Cancer Center, Yale University, New Haven, Connecticut, USA. FAU - Murray, Elaine AU - Murray E AD - Genentech, Inc., South San Francisco, California, USA. FAU - Park, Erica AU - Park E AD - Genentech, Inc., South San Francisco, California, USA. FAU - Tagen, Mike AU - Tagen M AD - Genentech, Inc., South San Francisco, California, USA. FAU - Singh, Jatinder AU - Singh J AD - Genentech, Inc., South San Francisco, California, USA. FAU - Sarkar, Indrani AU - Sarkar I AD - Genentech, Inc., South San Francisco, California, USA. FAU - Mueller, Lars AU - Mueller L AD - Genentech, Inc., South San Francisco, California, USA. FAU - Dokainish, Hatem AU - Dokainish H AD - Genentech, Inc., South San Francisco, California, USA. FAU - Shapiro, Geoffrey AU - Shapiro G AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. FAU - Burris, Howard AU - Burris H AD - Sarah Cannon Research Institute, Nashville, Tennessee, USA. LA - eng GR - UL1 TR001863/TR/NCATS NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200528 PL - England TA - Oncologist JT - The oncologist JID - 9607837 RN - 0 (Azetidines) RN - 0 (Piperidines) RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - ER29L26N1X (cobimetinib) SB - IM MH - *Adenocarcinoma MH - Azetidines MH - Humans MH - MAP Kinase Signaling System MH - Mitogen-Activated Protein Kinase Kinases MH - *Neoplasms/drug therapy MH - *Pancreatic Neoplasms MH - Piperidines MH - Protein Kinase Inhibitors/adverse effects PMC - PMC7543243 EDAT- 2020/04/21 06:00 MHDA- 2021/06/22 06:00 PMCR- 2020/10/01 CRDT- 2020/04/21 06:00 PHST- 2020/03/24 00:00 [received] PHST- 2020/04/04 00:00 [accepted] PHST- 2020/04/21 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/04/21 06:00 [entrez] PHST- 2020/10/01 00:00 [pmc-release] AID - ONCO13326 [pii] AID - 10.1634/theoncologist.2020-0292 [doi] PST - ppublish SO - Oncologist. 2020 Oct;25(10):833-e1438. doi: 10.1634/theoncologist.2020-0292. Epub 2020 May 28.