PMID- 28592615 OWN - NLM STAT- MEDLINE DCOM- 20180521 LR - 20191210 IS - 1549-490X (Electronic) IS - 1083-7159 (Print) IS - 1083-7159 (Linking) VI - 22 IP - 9 DP - 2017 Sep TI - A Phase Ib Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Cobimetinib and Duligotuzumab in Patients with Previously Treated Locally Advanced or Metastatic Cancers with Mutant KRAS. PG - 1024-e89 LID - 10.1634/theoncologist.2017-0175 [doi] AB - LESSONS LEARNED: Cobimetinib and duligotuzumab were well tolerated as single agents and in combination with other agents.The cobimetinib and duligotuzumab combination was associated with increased toxicity, most notably gastrointestinal, and limited efficacy in the patient population tested. BACKGROUND: KRAS-mutant tumors possess abnormal mitogen-activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling. The dual-action antibody duligotuzumab (MEHD7945A) inhibits ligand binding to both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). Blockade of EGFR/HER3 and inhibition of mitogen-activated protein kinase (MEK) in KRAS-mutant tumors may provide additive benefit. METHODS: Patients with KRAS-mutant solid tumors were eligible for this phase Ib dose-escalation study with a planned expansion phase. Duligotuzumab was given intravenously (IV) at 1,100 mg every 2 weeks (q2w), while cobimetinib was given orally in a standard 3 + 3 design to identify the recommended phase II dose (RP2D). The primary objective was to evaluate the safety and tolerability of this combination. RESULTS: Twenty-three patients were enrolled. Dose-limiting toxicities (DLTs) included grade 4 hypokalemia and grade 3 mucosal inflammation, asthenia, and dermatitis acneiform. Seventy percent of patients experienced grade 3 or worse adverse events (AEs). Five (22%) and 12 (52%) patients missed at least 1 dose of duligotuzumab and cobimetinib, respectively, and 9 (39%) patients required a cobimetinib dose reduction. Three (13%) patients discontinued due to an AE. Best response was limited to 9 patients with stable disease and 13 patients with progressive disease. CONCLUSION: Given the limited tolerability and efficacy of this combination, the study did not proceed to expansion stage and closed for enrollment. CI - (c) AlphaMedPress; the data published online to support this summary is the property of the authors. FAU - Lieu, Christopher H AU - Lieu CH AD - Division of Medical Oncology, University of Colorado Health Sciences Center, Aurora, Colorado, USA Christopher.lieu@ucdenver.edu. FAU - Hidalgo, Manuel AU - Hidalgo M AD - START Madrid, Centro Integral Oncologico Clara Campal (CIOCC), Madrid, Spain. FAU - Berlin, Jordan D AU - Berlin JD AD - Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA. FAU - Ko, Andrew H AU - Ko AH AD - UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA. FAU - Cervantes, Andres AU - Cervantes A AD - Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain. FAU - LoRusso, Patricia AU - LoRusso P AD - Karmanos Cancer Center, Detroit, Michigan, USA. FAU - Gerber, David E AU - Gerber DE AD - Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA. FAU - Eder, J Paul AU - Eder JP AD - Yale Smilow Cancer Center, New Haven, Connecticut, USA. FAU - Eckhardt, S Gail AU - Eckhardt SG AD - Division of Medical Oncology, University of Colorado Health Sciences Center, Aurora, Colorado, USA. FAU - Kapp, Amy V AU - Kapp AV AD - Genentech, Inc., South San Francisco, California, USA. FAU - Tsuhako, Amy AU - Tsuhako A AD - Genentech, Inc., South San Francisco, California, USA. FAU - McCall, Bruce AU - McCall B AD - Genentech, Inc., South San Francisco, California, USA. FAU - Pirzkall, Andrea AU - Pirzkall A AD - Genentech, Inc., South San Francisco, California, USA. FAU - Uyei, Anne AU - Uyei A AD - Genentech, Inc., South San Francisco, California, USA. FAU - Tabernero, Josep AU - Tabernero J AD - Vall d'Hebron University Hospital and Institute of Oncology, CIBERONC, Universitat Autonoma de Barcelona, Barcelona, Spain. LA - eng SI - ClinicalTrials.gov/NCT01986166 GR - UL1 TR001863/TR/NCATS NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study DEP - 20170607 PL - England TA - Oncologist JT - The oncologist JID - 9607837 RN - 0 (Azetidines) RN - 0 (Immunoglobulin G) RN - 0 (KRAS protein, human) RN - 0 (MEHD7945A) RN - 0 (Piperidines) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ERBB3 protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Receptor, ErbB-3) RN - EC 2.7.12.2 (MAP Kinase Kinase 1) RN - EC 2.7.12.2 (MAP2K1 protein, human) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) RN - ER29L26N1X (cobimetinib) SB - IM MH - Acneiform Eruptions/epidemiology/etiology MH - Administration, Oral MH - Adult MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use MH - Asthenia/epidemiology/etiology MH - Azetidines/pharmacology/*therapeutic use MH - Colorectal Neoplasms/*drug therapy/genetics/pathology MH - Dose-Response Relationship, Drug MH - Drug Eruptions/epidemiology/etiology MH - ErbB Receptors/antagonists & inhibitors/metabolism MH - Female MH - Humans MH - Hypokalemia/epidemiology/etiology MH - Immunoglobulin G/pharmacology/*therapeutic use MH - MAP Kinase Kinase 1/antagonists & inhibitors/metabolism MH - Male MH - Middle Aged MH - Neoplasm Staging MH - Piperidines/pharmacology/*therapeutic use MH - Prospective Studies MH - Proto-Oncogene Proteins p21(ras)/*genetics MH - Receptor, ErbB-3/antagonists & inhibitors/metabolism MH - Signal Transduction/drug effects MH - Treatment Outcome PMC - PMC5599193 EDAT- 2017/06/09 06:00 MHDA- 2018/05/22 06:00 PMCR- 2017/06/07 CRDT- 2017/06/09 06:00 PHST- 2017/03/13 00:00 [received] PHST- 2017/04/13 00:00 [accepted] PHST- 2017/06/09 06:00 [pubmed] PHST- 2018/05/22 06:00 [medline] PHST- 2017/06/09 06:00 [entrez] PHST- 2017/06/07 00:00 [pmc-release] AID - theoncologist.2017-0175 [pii] AID - ONCO12169 [pii] AID - 10.1634/theoncologist.2017-0175 [doi] PST - ppublish SO - Oncologist. 2017 Sep;22(9):1024-e89. doi: 10.1634/theoncologist.2017-0175. Epub 2017 Jun 7.