Background: 5-10% of EGFR-mutant ACs undergo SCLC/neuroendocrine transformation (SCLC-T) but the clinical course of such pts is poorly characterized. Methods: We identified 50 pts with EGFR-mutant SCLC-T seen at our institutions. Medical records were reviewed retrospectively after IRB approval. Demographics, disease features and outcomes were analyzed. Results: Among 50 pts (27F/23M), median (med) age was 55. At diagnosis, 44 had AC histology; 5 had de novo SCLC or mixed AC/SCLC. All but the 5 cases with baseline SCLC received ≥1 EGFR TKI prior to SCLC-T; 93% were on a TKI at the time of SCLC-T (24 erlotinib/gefitinib, 5 afatinib, 9 osimertinib, 4 other). Med time from original diagnosis to SCLC-T was 17.8 mo (95% CI 13.0-25.9). 44/50 cases had tissue genotyping at first evidence of SCLC (albeit with varied assays); all maintained their founder EGFR mutation; among 16 with prior T790M-positivity, 13 lost T790M at SCLC-T, 3 were T790M-pos at SCLC-T. Other recurrent mutations included TP53 (24/33, 73%), Rb1 (13/21, 62%) and PIK3CA (10/36, 28%). The most common therapy given upon SCLC-T was platinum-etoposide (n = 35); this regimen had a clinical response rate (cRR) of 51% and med PFS of 2.8 mo (95% CI 2.1-4.8). 20 pts received taxane-based therapy at some point after SCLC-T: cRR = 50%, med PFS = 3.1 mo (95% CI 0.9-3.2). None of 15 pts receiving immunotherapy (including 6 ipi/nivo) for SCLC-T responded. Med OS from stage IV cancer diagnosis was 36.8 mo (95% CI 25.0-41.5) and med OS from time of SCLC diagnosis was 10.9 mo (95% CI 7.3-13.8). Conclusions: EGFR-mutant AC with SCLC-T is a rare but recurrent phenomenon, often characterized by Rb1, TP53 and PIK3CA mutations. The SCLC-T subclone is typically distinct from the T790M subclone in pts with serial biopsies. The med OS of 10.9 mo after SCLC-T is similar to newly diagnosed, EGFR wild-type advanced SCLC. Responses to platinum-etoposide and taxanes were frequent but transient, while no responses were seen with immunotherapy. Interestingly, med OS from initial diagnosis was similar to that of pts that never transform to SCLC at 36.8 mo. Further investigation is needed to better elucidate optimal strategies for this group.