First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M).

Lung Cancer - Non-Small Cell Metastatic
Session Type and Session Title: 
Clinical Science Symposium, Targeting EGFR: The Next 10 Years
Abstract Number: 
J Clin Oncol 32:5s, 2014 (suppl; abstr 8010^)
Lecia V. Sequist, Jean-Charles Soria, Shirish M. Gadgeel, Heather A. Wakelee, D. Ross Camidge, Andrea Varga, Benjamin J. Solomon, Vassiliki Papadimitrakopoulou, Sarah S. Jaw-Tsai, Lisa Caunt, Paramjit Kaur, Lindsey Rolfe, Andrew R. Allen, Jonathan Wade Goldman; Massachusetts General Hospital, Boston, MA; Gustave Roussy Institute, Villejuif, France; Karmanos Cancer Institute, Wayne State University, Detroit, MI; Stanford Cancer Institute, Stanford, CA; University of Colorado Cancer Center, Aurora, CO; Gustave Roussy, Villejuif, France; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The University of Texas MD Anderson Cancer Center, Houston, TX; Clovis Oncology, Inc., Boulder, CO; UCLA Santa Monica Hematology-Oncology, Santa Monica, CA

Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures


Background: Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 60% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition. CO-1686 is an oral, covalent TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR. Methods: This is a completed dose finding study in patients with EGFR mutated advanced NSCLC. Patients were previously treated with EGFR TKI and had a tumor biopsy in screening for central EGFR genotyping. CO-1686 was administered twice daily. Endpoints included safety, pharmacokinetics (PK), and efficacy. Results: As of 17thJanuary 2014, 88 patients were treated: 57 with CO-1686 free base (up to 900 mg BID); 31 with CO-1686 HBr (500 to1000 mg BID). 10 transitioned from free base to HBr. 63% were T790M+, median age 61 years, 77% female, 76% white, and 72% ECOG 1. Median number of previous therapies was 3 (1- 7); 40% had >1 prior line of EGFR TKI. PK of the CO-1686 HBr formulation was dose proportional with three times greater exposure than the equivalent free base dose. The dose limiting toxicity (DLT) rate at all doses was <33%. Related AEs (all grades) in ≥ 20% patients were: nausea (25%), fatigue (21%), impaired glucose tolerance/hyperglycemia (21%). Hyperglycemia was well managed with oral hypoglycemics and/or dose reduction. A recommended phase 2 dose of 750 mg BID has been selected. Nine T790M+ patients treated with 900 mg BID (free base) were evaluable for response; 6 (67%) achieved PRs, 2 (22%) achieved SD, one of whom subsequently achieved a PR after transition to CO-1686 HBr. Eight of nine progressed on EGFR TKI immediately before CO-1686. PRs have occurred among patients treated with CO-1686 HBr, however the majority of patients have not reached the first restaging. Efficacy data for at least 41 patients on CO-1686 HBr will be presented at the meeting. Conclusions: CO-1686 has demonstrated promising efficacy against T790M+ EGFR mutant NSCLC. CO-1686 HBr delivered higher exposures than free base and was equally well tolerated. Dose-related WT-driven diarrhea and rash has not been seen. The phase 2/3 program will open in 2014. Clinical trial information: NCT01526928.