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Small‐cell lung cancer (SCLC) occurs infrequently in never/former light smokers. We sought to study this rare clinical subset through next‐generation sequencing (NGS) and by characterizing a representative patient‐derived model. We performed targeted NGS, as well as comprehensive pathological evaluation, in 11 never/former light smokers with clinically diagnosed SCLC. We established a patient‐derived model from one such patient (DFCI168) harboring an NRASQ61K mutation and characterized the sensitivity of this model to MEK and TORC1/2 inhibitors. Despite the clinical diagnosis of SCLC, the majority (8/11) of cases were either of nonpulmonary origin or of mixed histology and included atypical carcinoid (n = 1), mixed non‐small‐cell lung carcinoma and SCLC (n = 4), unspecified poorly differentiated carcinoma (n = 1), or small‐cell carcinoma from different origins (n = 2). RB1 and TP53 mutations were found in four and five cases, respectively. Predicted driver mutations were detected in EGFR (n = 2), NRAS (n = 1), KRAS (n = 1), BRCA1 (n = 1), and ATM (n = 1), and one case harbored a TMPRSS2‐ERG fusion. DFCI168 (NRASQ61K) exhibited marked sensitivity to MEK inhibitors in vitro and in vivo. The combination of MEK and mTORC1/2 inhibitors synergized to prevent compensatory mTOR activation, resulting in prolonged growth inhibition in this model and in three other NRAS mutant lung cancer cell lines. SCLC in never/former light smokers is rare and is potentially a distinct disease entity comprised of oncogenic driver mutation‐harboring carcinomas morphologically and/or clinically mimicking SCLC. Comprehensive pathologic review integrated with genomic profiling is critical in refining the diagnosis and in identifying potential therapeutic options.

Background Tumor response characteristics using immune-related RECIST1.1 (irRECIST1.1) in advanced non-small-cell lung cancer (NSCLC) patients treated with nivolumab monotherapy in the clinical setting have not been previously described with a direct comparison with the assessments according to the conventional RECIST1.1.Methods Fifty-six advanced NSCLC patients treated with nivolumab monotherapy after its Food and Drug Administration (FDA) approval were retrospectively studied. Tumor burden was quantified on serial CT scans during therapy using irRECIST1.1, which uses unidimensional measurements and includes new lesion measurements in total tumor burden. Response assessments by irRECIST1.1 were compared with assessments by RECIST1.1. Responses of individual lesions in different organs were also compared.Results Tumor burden change at best overall response ranged from −66.8 to +278.1% (median: +3.9%). Response rate was 14% (8/56; 8 partial responses, 0 complete responses) by irRECIST1.1 and by RECIST1.1. Time-to-progression (TTP) by irRECIST1.1 was longer than TTP by RECIST1.1 (median TTP: not reached vs. 1.9 months, respectively). No patients experienced pseudoprogression during the study. Among 128 target lesions, the lesion-based size change at best response differed significantly across different organs, with adrenal lesions and lymph nodes having greater size decrease, followed by lung, while liver and other miscellaneous lesions had lesser degree of size decrease (p = 0.002).Conclusions Immune-related response evaluations using irRECIST1.1 in advanced NSCLC patients treated with nivolumab resulted in the identical response rate and longer TTP compared to RECIST1.1. No pseudoprogression cases were observed during the study. Adrenal lesions and lymph nodes were more responsive and liver lesions were less responsive to nivolumab.