Background: Osimertinib (Osi) is standard of care in 1^st line (1L) EGFR mut NSCLC and TKI resistant T790M^pos NSCLC but acquired resistance emerges; outcomes are less robust in T790M^neg, C797X^pos and EGFR exon 20 insertion (ex20ins) disease. We examined Osi with the EGFR monoclonal antibody Necitumumab (Neci) in select settings of EGFR TKI resistance. Methods: Pts were accrued to 5 expansion cohorts (ExC) at recommended phase 2 dose (RP2D) of Osi 80 mg daily and Neci 800 mg D1 + D8 of q21d cycle. ExC (18 pts/cohort): A) T790M^neg progressive disease (PD) on 1^st/2^nd gen TKI as last therapy, B) T790M^neg PD on 1^st/2^nd gen TKI and PD on 3^rd gen TKI, C) T790M^pos PD on 1^st/2^nd gen TKI and PD on 3^rd gen TKI, D) EGFR ex20ins PD on chemotherapy, E) PD on 1L osi. In ExC A-C, T790M was confirmed centrally (tissue) by ddPCR. Additional correlative studies include: tissue NGS (> 400 gene panel), EGFR FISH, plasma for PK and serial EGFR ctDNA by ddPCR. Adverse events were graded (Gr) by CTCAEv5; ORR, PFS by RECIST 1.1. Primary pre-specified efficacy endpoint ≥3/18 pts responding per cohort. Results: 101 patients accrued (100 evaluable). Efficacy is summarized in the Table. Drug related Gr 3 AEs were seen in 38% of pts, mainly rash (21%). ORR among all pts was 19% (95% CI 12-28%) that varied across cohorts (Table). In ExC A-C, 69% pts had detectable EGFR activating mutations in ctDNA, with decline in mutant allele frequency (AF) on treatment in 80% and ctDNA clearance in 33%. Conclusions: Osi/Neci is feasible and tolerable at the RP2D. EGFR ctDNA was detectable at baseline in the majority of pts with decrease in AF on treatment. Osi/Neci was active in select settings of EGFR-TKI resistance, meeting its prespecified efficacy endpoint in T790M^neg PD on 1^st/2^nd gen TKI as last therapy (ExC A), EGFR ex20ins post-chemo (ExC D) and PD on 1L osimertinib (ExC E). mPFS in the EGFR ex20ins cohort was within the range of current EGFR Exon 20 ins agents in development. EGFR monoclonal antibodies with osimertinib warrant further study in settings of de novo and acquired EGFR dependent resistance to EGFR-TKI. Clinical trial information: NCT02496663.

*n/a means that the upper limit of the confidence interval was not reached at the time of the analysis; ** cohort met pre-specified efficacy endpoint cPR = confirmed partial response.