First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M)
|Date||27 March 2014|
|Session||Proffered Papers 1 - Advanced disease with tageted agents|
|Topics|| Drug Development
Non-Small-Cell Lung Cancer, Metastatic
|Citation||Journal of Thoracic Oncology (2014) 9 (Supplement 9): S7-S52. 10.1097/JTO.0000000000000131|
H. Wakelee1, J. Soria2, R. Camidge3, S. Gadgeel4, J. Goldman5, A. Varga2, B. Solomon6, V. Papadimitrakopoulou7, P. Kaur8, L.V. Sequist9
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.
This is an ongoing first-in-human dose finding study in patients with EGFR mutated recurrent, advanced NSCLC. All patients are previously treated with an EGFR TKI and must undergo tumor tissue biopsy within 28 days before study drug dosing for central EGFR genotyping. Oral CO-1686 is administered continuously in 21-day cycles. Endpoints include safety, pharmacokinetics (PK), and efficacy.
As of 15th November 2013, 66 patients were treated with CO-1686; initially, 57 with CO-1686 free base, up to 900mg BID (N=19 dose expansion at 900 mg BID); then, following formulation optimization, 9 with CO-1686 HBr up to 750 mg BID). Dose escalation continues. 70% of patients are T790M+,14% are T790M unknown/pending, median age is 60 years, 80% are female, 80% are white, and 75% are ECOG 1. The median number of previous therapies was 3 (range: 1- 6); 45% had received > one line of EGFR TKI. Treatment-related AEs (all grades) occurring in ≥20% patients were: nausea (21%) and fatigue (20%). The majority of all events were mild or moderate. Events typical of EGFR WT inhibition, in particular rash combined with diarrhea, have not been observed. Nine T790M+ patients treated with 900 mg BID (free base) were evaluable for response; 6 (67%) achieved PRs, 2 (22%) achieved SD. One patient at a lower dose also achieved a PR. Eight of the 9 patients had progressed on an EGFR TKI immediately before initiating CO-1686. Data for the cohorts receiving the optimized formulation are maturing and current data will be presented at the meeting.
CO-1686 has demonstrated good tolerability and promising efficacy against proven T790M+ EGFR mutant NSCLC. Dose-related WT-driven diarrhea and rash has not been seen. Dose escalation is continuing with CO-1686 HBr which has improved exposure and reduced PK variability.
H. Wakelee: Research funding from Clovis Oncology to Stanford University. R. Camidge: Advisory board member for Clovis Oncology. S. Gadgeel: Research funding from Clovis to Karmanos. J. Goldman: Advisory board member and research funding from Clovis Oncology. B. Solomon: Advisory board member for Clovis Oncology. P. Kaur: Employee and stock owner of Clovis Oncology Ltd L.V. Sequist: Advisory board member for Clovis Oncology. Research funding from Clovis Oncology to Mass General. All other authors have declared no conflicts of interest.