O10.3Rociletinib: an oral, irreversible, highly selective small molecule inhibitor of mutant EGFR including T790M.

BACKGROUND: Rociletinib (CO-1686) is a potent, oral, irreversible inhibitor of mutant EGFR, including the T790M resistance mutation. T790M accounts for 60% of acquired resistance to first and second generation EGFR inhibitors1. We review interim phase 2 data from an ongoing phase 1/2 study (TIGERX; EudraCT 2011-005215-86) in patients with advanced, previously treated, mutant EGFR non small cell lung cancer2.

MATERIALS AND METHODS: Eligible patients have advanced EGFR mutant T790M + /- non small cell lung cancer (NSCLC), previous treatment with at least one EGFR inhibitor, ECOG PS 0-1, and adequate organ function. Stable brain metastases are allowed. Patients all received prior EGFR TKI, with separate phase 2 cohorts receiving EGFR TKI as the only prior treatment and others who had additional prior systemic therapies.

RESULTS: We present efficacy data from T790M positive and negative pts enrolled at therapeutic doses (500mg BID and 625mg BID). Demographic characteristics reflect a Western population with advanced mutant EGFR NSCLC: median age 59 yrs, 70% female, 80% ECOG 1, 55% >1 previous TKI line, median prior therapies 3. The only related ≥ Grade 3 AE occurring in ≥ 5% patients was hyperglycemia (14%) and no pt discontinued for this event. Related AEs (all grades) in ≥ 15% patients were: hyperglycemia (32%), diarrhea (25%), nausea (25%), reduced appetite (20%). In the T790M+ group, the RECIST overall response rate (ORR) is currently 67%, median PFS 10.4 months. In the T790M negative group, the overall response rate is 42%, median PFS 7.5 months. We also present non clinical data that elucidates the mechanism of action of hyperglycemia together with an overview of the current and future development strategy.

CONCLUSION: Rociletinib is associated with durable clinical benefit in patients with advanced EGFR mutant NSCLC. The activity in the T790M negative group may result from assay insensitivity, tumor heterogeneity or from concomitant inhibition by rociletinib of other tyrosine kinases involved in tumor growth.