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Preliminary results of TATTON, a multi-arm phase Ib trial of AZD9291 combined with MEDI4736, AZD6094 or selumetinib in EGFR-mutant lung cancer.
Background: AZD9291 is an irreversible, mutant-selective EGFR tyrosine kinase inhibitor (TKI) developed to have potency against EGFR mutations, including T790M, while sparing wildtype EGFR. In the previous phase I study of AZD9291, EGFR-mediated toxicity was reduced compared to available EGFR-TKIs. We hypothesized that the safety profile of AZD9291 would permit combinations with other targeted therapies in a tolerable fashion. Methods: TATTON (NCT02143466) is a multi-arm phase Ib trial studying AZD9291 in combination with MEDI4736 (anti-PD-L1 mAb), AZD6094 (MET inhibitor) or selumetinib (MEK1/2 inhibitor; AZD6244, ARRY-142886). Eligibility required advanced EGFR-mutant lung cancer, progression on any prior EGFR-TKI, measurable disease, adequate PS (0-1) and organ function, and tissue for correlatives. In each combination, AZD9291 was dosed at 80 mg daily and the 2nd agent was escalated from a dose below the phase II monotherapy dose. Using a rolling 6 design, patients (pts) were randomly allocated to a combination arm. Data included here are preliminary and will be updated for presentation. Results: As of 8 January 2015, 42 pts have been enrolled on combination therapy (MEDI4736 = 14 pts; AZD6094 = 7 pts, selumetinib = 21 pts). All 3 combination agents were escalated to their phase II monotherapy doses; an additional arm continues to explore intermittent dosing of selumetinib. Adverse event (AE) data is currently available for 20 pts from all arms and cycles and includes mild/moderate AEs in 16 pts (6 skin, 5 laboratory, 2 gastrointestinal, 3 other) and severe AEs in 4 pts (1 skin, 1 laboratory, 1 gastrointestinal and 1 metabolism); 2 DLTs were reported (fatigue – AZD6094 arm; transaminase elevation – selumetinib arm). To date, 3 partial responses (PR) have been seen with AZD9291/MEDI4736, 2 PR with AZD9291/AZD6094, and 2 PR with AZD9291/selumetinib. Combination dose finding is expected to complete by May 2015. Conclusions: The toxicity profile of AZD9291 makes rational combinations with potentially synergistic targeted therapies feasible at biologically active doses. Expansion cohorts are planned for pts with acquired resistance to third-generation EGFR-TKI. Clinical trial information: NCT02143466
Abstracts by Geoffrey R. Oxnard:
A phase II trial of erlotinib for EGFR mutant NSCLC to prospectively assess biopsy feasibility and acquired resistance at disease progression.Meeting: 2015 ASCO Annual Meeting | Abstract No: 8076
A prospective evaluation of cell free DNA (cfDNA) genotyping and circulating tumor cells (CTC) in EGFR mutant NSCLC patients (pts) treated with erlotinib.Meeting: 2015 ASCO Annual Meeting | Abstract No: 11068
A prospective validation of plasma ddPCR for rapid EGFR and KRAS genotyping of advanced NSCLC patients (pts).Meeting: 2015 ASCO Annual Meeting | Abstract No: 11089