Background: The role of immune checkpoint inhibitors (ICIs) in the treatment of extrapulmonary neuroendocrine carcinoma (EP-NEC) has yet to be established. While objective responses have been observed, it is still unknown which patients are likely to derive benefit. We investigated the genomic profiles of patients who did and did not benefit from ICIs. Methods: Previously we reported the objective responses to ICI in a retrospective series of patients with EP-NEC. RECIST 1.1 criteria were used to categorize patients as achieving disease control (DC = CR, PR, or SD) vs progressive disease (PD). The EMR was reviewed to identify patients who had genomic panels performed, and results were extracted for analysis. Results: Of 31 patients eligible for RECIST assessment, 19 had genomic panels available (9 with DC: 4 SD, 5 PR vs 10 with PD). Of those with NEC histology specified, 9 were small cell, 1 combined large and small cell, 3 were large cell. All tumors were microsatellite-stable. All but one (with TMB = 25) of 16 tumors with TMB status available were < 10 m/MB. Of those with disease control, 67% had both TP53 and RB1 alterations, compared with only 10% in those with progressive disease; this was statistically significant (p = 0.0198, Fisher exact). Of 7 tumors with TP53 + RB1 alterations, 4 were specified as small cell carcinoma. Half of those with PD showed alterations in β-catenin pathway genes CTNNB1 or APC, compared to only one of the DC group, but this did not reach significance (p = 0.1409, Fisher exact). In an analysis of all Mayo patients (not just those treated with ICI) with NGS data available (Tempus and FoundationOne), concurrent TP53 + RB1 alteration was significantly more common in SCLC than in EP-NEC (Table). Conclusions: In this small series of patients with EP-NEC treated with ICIs, the SCLC-like genomic signature of concurrent TP53 + RB1 alterations was significantly more common in those with disease control than in those with progressive disease. An analysis of all patients with NGS data (not just on ICI) showed that the dual alteration was more common in SCLC, and SCLC also had more TMB-high tumors. This may explain why ICIs are more effective in SCLC than in EP-NEC. Further study is warranted to determine whether TP53 + RB1 mutations predict response to ICI in NEC.