P76.64 Alternating Osimertinib and Gefitinib as Second-Line Treatment for EGFR-Mutated NSCLC Harbouring a T790M Resistance Mutation (OSCILLATE)

Abstract

Osimertinib is standard of care for advanced EGFR-mutated NSCLC following the emergence of T790M resistance mutations, with a median progression-free survival (PFS) of 10 months. Mechanisms of resistance to osimertinib include acquisition of C797S mutations and loss of T790M mutations. We hypothesised that alternating treatment with osimertinib and gefitinib would modulate clonal populations within tumors and delay the emergence of resistance. The aim of this study was to assess the activity, feasibility, and safety of alternating therapy, and to explore plasma ctDNA dynamics and mechanisms of resistance. This open label, single-arm, multi-centre, investigator-initiated, phase 2, cooperative group trial included adults with metastatic, EGFR-mutated NSCLC with an acquired, T790M resistance mutation demonstrated in tissue or plasma. Study treatment was osimertinib 80mg daily for 8 weeks, then alternating 4-week cycles of gefitinib 250mg daily and osimertinib 80mg daily, until disease progression. Blood samples for ctDNA were taken on day 1 of each 28-day cycle, and day 15 of cycles 3 and 4. The primary endpoint was PFS at 1 year. Secondary endpoints included feasibility of alternating treatment, time to treatment failure (TTTF), objective tumour response (OTR), overall survival (OS), and adverse events (AE). We recruited 47 eligible participants from September 2017 to June 2019: 63% female, 55% aged 60 or older; 96% ECOG 0-1; 67% had an exon 19 deletion, 31% had an exon 21 L858R substitution, 4% had an uncommon or compound EFGR mutations; and, 23% had brain/leptomeningeal metastasis. PFS at 1 year was 38% (27% to 55%), median PFS was 9.2 months (7.2 to 13), and median TTTF was 9.4 months (7.6 to 13). The OTRR was 40% (19/47, 95% CI 28 to 55%). Alternating treatment was feasible with only 1 participant discontinuing gefitinib due to treatment side-effects, and only 2 requiring a treatment interruptions within the first 6 months, both for SAEs unrelated to treatment. The most frequent grade 3-4 AE were headache and nausea, each occurring in 2 participants. The one death that occurred during study treatment was due to lung infection and judged unrelated to treatment. Alternating osimertinib and gefitinib was safe, feasible, and PFS was similar to that of single-agent osimertinib, as second-line treatment for EGFR-mutated NSCLC with a T790M resistance mutation. Analyses of ctDNA levels, dynamics, and mechanisms of resistance are ongoing.