Background: Osimertinib (osi) is the preferred 1^st line (1L) therapy for patients (pts) with EGFR+ NSCLC, but acquired resistance is universal. Identification of mechanisms of resistance (MoR) to 1L osi can inform subsequent therapies. We report a retrospective, multi-institutional cohort of pts with tissue biopsy (TBx) and/or liquid biopsy (LBx) upon 1L osi progression (PD). Methods: Pts with advanced EGFR+ NSCLC who had TBx and/or LBx (for ctDNA analysis) obtained at PD on 1L osi at 8 participating institutions were included. Molecular testing was performed using next-generation sequencing (NGS) and, in a subset, FISH per local standards. We retrospectively collected clinical characteristics, tissue histology, NGS/FISH results and subsequent therapies. Results: 193 pts (128 female; median age 64 yrs) had TBx (n = 129) and/or LBx (n = 122) upon PD on 1L osi, 58/193 had both tissue and ctDNA. Primary EGFR mutations included del19 (102), L858R (76), and other (15). Median time from osi start to first bx was 14 mos (range, 1-55). MoRs are summarized in the table. In all, 86/193 (45%) pts had a known MoR identified on TBx and/or LBx. Among 129 pts with TBx, histologic transformation (trans) and MET amplification (amp) were the most common MoR, each seen in 16% pts. Among 122 pts with LBx, secondary EGFR mutations were the most common MoR, seen in 15%. Among the 58 pts with both TBx + LBx, discordance between major MoRs was seen in 21/58 pts (36%), most commonly due to histologic trans detected on TBx only (n = 7) and discordant MET amp status (n = 8; 6 TBx+/LBx-, 2 TBx-/LBx+). No MoR was identified in 53% TBx and 75% LBx (including 14% Lbx where the original EGFR mutation was not detected in ctDNA). Results of TBx led to MoR-directed 2L therapy in 41/129 (32%) pts, while LBx results led to MoR-directed 2L therapy in 16/122 (13%). Conclusions: In this large, multi-institutional cohort, histologic trans (16%) and MET amp (16%) were the most common MoR to 1L osimertinib on tissue bx. In ctDNA, secondary EGFR mutations (15%) were the most frequent MoR. The results of TBx were more likely to impact second-line therapy than LBx. Our results underscore the importance of tissue biopsy (and limitations of liquid biopsy) after osimertinib PD, where tissue testing remains the gold standard. In addition, with more than half of patients having no identifiable MoR despite comprehensive testing, our results highlight the need for MoR-agnostic treatment strategies.