CO-1686 has demonstrated a good tolerability and promising efficacy against T790M+ epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC). It spares wild-type (wt) EGFR signalling in an early study, according to presentation of Dr Heather Wakelee of Thoracic Oncology Unit, Stanford University, USA. The findings were reported in a proffered papers session at 4th European Lung Cancer Conference (26-29 March 2014, Geneva, Switzerland).
Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 60% of patients. In addition, skin rash and diarrhoea are significant problems caused by wt-EGFR inhibition. CO-1686 is a novel, oral, selective, covalent TKI that targets common activating EGFR mutations and T790M, while sparing wt-EGFR.
Phase I Study with CO-1686
Dr Wakelee reported that the phase I part of phase I/II study in EGFR-mutated advanced NSCLC patients has been recently completed. The study initiated with free-base formulation and early data were presented at the 2013 World Conference on Lung Cancer. However, superior hydrobromide (HBr) salt tablet form of CO-1686 was adopted in August 2013. All free-base recipients are still on study and converted to HBr in the fall of 2013. Expansion cohorts are now comparing 500mg, 750mg and 1000mg HBr twice daily. The study is designed to support potential accelerated approval in USA.
Patients with EGFR mutated recurrent, advanced NSCLC previously treated with an EGFR TKI were enrolled. Tumour tissue biopsy was mandatory within 28 days before study drug dosing. EGFR genotyping was centrally performed. CO-1686 is administered orally, in continuous 21-day cycles.
Phase I patient characteristics indicate that approximately 75% come directly off of TKI with progressive TKI resistance. Median number of previous TKI lines is two. In total, 62 patients are included with a mean age of 59 years. Females comprise 77% of study population and Asian patients, 16%. ECOG performance status 0 was recorded in 27% of patients.
Tolerability and Efficacy
CO-1686 is very well tolerated with hyperglycaemia (grade 3 in 19%) which is typically asymptomatic and managed with a single oral agent. Etiology of hyperglycaemia is currently unknown. Other toxicities observed: nausea, diarrhoea, decreased appetite, vomiting, fatigue and myalgia were mild in most cases. Percentage of diarrhoea and rash indicate no wild-type EGFR inhibition and the compound represents truly third-generation of EGFR TKIs. QTC prolongation grade 3 was observed in 5% of patients and resolved in most cases upon dose reduction. However, only one patient has discontinued drug due to adverse events.
In terms of efficacy, it is indicative that responses deepen over time. HBr shows consistent clinical benefit; the data with HBr are evolving with >80% of patients being still on drug. Efficacy is clear across dose levels in centrally-confirmed T790M+ patients with overall response rate of 64%. Response rate remains above 50% even when patients with currently T790M-unknown status are included. Median progression-free survival exceeds six months in T790M+ patients.
Dr Wakelee reported the phase II/III registration trials are planned to enrol the patients this year. TIGER1 is a phase II/III study in newly diagnosed EGFR-mutated NSCLC, that foreseen 1:1 randomisation for CO-1686 and erlotinib; primary endpoint is progression-free survival. TIGER2 is a phase II study planned for patients progressing upon first and only TKI treatment and biopsy-proven T790M+ disease; primary endpoint is overall response rate. TIGER3 is a phase III study in patients who progress upon doublet chemotherapy or TKI in T790M+ and T790M- setting. Randomisation is foreseen to CO-1686 versus chemotherapy. TIGER4 is a phase II study in plasma T790M+ setting and patient population like in the TIGER2 trial.
Dr Wakelle concluded that CO-1686 is a novel, oral, selective, covalent inhibitor of EGFR mutant NSCLC that inhibits key activating and T790M resistance mutations. It spares wild-type EGFR signalling and is generally well-tolerated. Promising activity is seen across all dose levels with durable benefit.
Dr Tony Mok, who discussed the study results, compared CO1686 characteristics as a third generation TKI inhibitor with characteristics of first generation TKIs (gefitinib and erlotinib) and second generation TKIs (afatinib, dacomitinib). He characterised the response rate observed with CO1686 as impressive, and emphasised the need to develop T790M as a companion biomarker. As unanswered questions, he wonders if CO1686 works in T790M negative tumours and if yes, why. He also asked if a T790M EGFR TKI should be used as first line treatment for patients with only sensitising EFGR mutation.
Abstract 93O: First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M).
Dr Wakelee reports receiving research funding from Clovis Oncology to Stanford University. Dr Camidge serves as advisory board member for Clovis Oncology. Dr Gadgeel receives research funding from Clovis to Karmanos institute. Dr Goldman serves as an advisory board member and receives research funding from Clovis Oncology. Dr Solomon serves as an advisory board member for Clovis Oncology. Dr Kaur is an employee and stock owner of Clovis Oncology Ltd. Dr Sequist serves as an advisory board member for Clovis Oncology and receives research funding from Clovis Oncology to Massachusetts General Hospital. All other authors have declared no conflicts of interest.
The European Lung Cancer Conference (ELCC) is organised by the European Society for Medical Oncology (ESMO) and the International Association for the Study of Lung Cancer (IASLC). During the four-day programme, attendees benefit from educational and scientific updates provided by thoracic oncology specialists on different multidisciplinary topics important for research and clinical practice in the field of lung cancer.