Extrapulmonary small cell carcinoma treated with conventional or tumor-targeted topoisomerase I inhibition plus ATR blockade: Clinical outcomes and molecular correlates.

Abstract

3027 Background: Extrapulmonary Small Cell Carcinoma (EPSCC) is a rare (0.1–0.4% of all cancers), aggressive neuroendocrine cancer with poor outcomes (Median PFS 2-4 months), no established second-line standard, and limited prospective data. We evaluated ATR inhibition with berzosertib combined with topoisomerase I (TOP1) inhibition with topotecan or sacituzumab govitecan (SG) and explored molecular correlates of response. Methods: Given the rare nature of EPSCC, patients were pooled from 3 prospective phase II trials evaluating topotecan or SG with berzosertib (NCT03896503, NCT02487095, NCT04826341) without intent for direct regimen comparison. Eligible patients had platinum-refractory EPSCC and received treatment at recommended phase II doses. Endpoints included efficacy and safety, with exploratory molecular correlates including somatic mutations, copy number alterations, circulating tumor DNA, tumor RNA sequencing, and pharmacogenomic analyses. Results: Of the 41 patients enrolled, 34 were evaluable (topotecan+berzosertib, n=20; SG+berzosertib, n=14). ORR based on RECIST was 10% (95% CI, 2.8–30.1) with topotecan+berzosertib and 21.4% (95% CI, 7.6–47.6) with SG+berzosertib; disease-control rates were 45% and 86%, respectively. Durable clinical benefit was observed in subsets of patients, with PFS ≥6.8 months and OS up to 19.7 months in the SG cohort, and OS >18 months in patients treated with topotecan+berzosertib. Patients with prolonged PFS represented multiple primary sites, including bladder, prostate and laryngeal. Grade 3–4 hematologic adverse events were more frequent with topotecan+berzosertib, whereas gastrointestinal toxicity and alopecia were more common with SG+berzosertib; no unexpected safety signals were observed. In the SG cohort, UGT1A1 intermediate and poor metabolizers experienced higher rates (90%) of grade 3–4 toxicities than normal metabolizers (10%). Early ctDNA declines correlated with radiographic response, while rising ctDNA preceded progression; baseline ctDNA correlated with tumor burden (r = 0.83; P = 0.006). Transcriptomic analyses demonstrated enrichment of E2F-driven and neuroendocrine lineage programs in responders (NES = 1.64–1.67; P < 0.001). Conclusions: In relapsed or refractory EPSCC targeting tumor replication stress through combined ATR and TOP1 pathway inhibition yielded clinically meaningful activity. Tumor-targeted TOP1 delivery with SG plus berzosertib achieved disease-control rate and a manageable safety profile. UGT1A1 phenotype was associated with toxicity in the SG cohort, supporting the relevance of pharmacogenomic-guided risk stratification. Correlative analyses identified E2F-driven transcriptional programs, neuroendocrine lineage signatures and early ctDNA suppression as promising biomarkers for future trials. Clinical trial information: NCT03896503 , NCT02487095 , NCT04826341 .