A phase II, multicenter, open-label, single-arm study of berzosertib plus topotecan in patients with relapsed platinum-resistant small-cell lung cancer (DDRiver SCLC 250)

BACKGROUND: Small-cell lung cancer (SCLC) is characterized by high genomic instability. Proteins involved in maintaining genomic stability, such as ataxia telangiectasia and Rad3-related (ATR) and topoisomerase 1, are promising therapeutic targets in SCLC. Berzosertib, a highly potent, selective, intravenously administered ATR inhibitor, has demonstrated promising antitumor activity in patients with platinum-resistant SCLC. MATERIALS AND METHODS: on days 1-5) intravenously in 21-day cycles until disease progression. Primary endpoints were objective response rate (ORR per RECIST v1.1), assessed by an Independent Review Committee. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A preplanned interim analysis for futility after the first 40 patients had completed their second on-treatment tumor assessment (or dropped out/died prematurely) revealed a low probability of reaching the predefined efficacy threshold, leading to premature study termination. At the final analysis (n = 73), four patients achieved confirmed partial response, resulting in an ORR of 5.5%. The median PFS was 2.2 months [95% confidence interval (CI) 1.5-2.7 months], and the median OS was 6.4 months (95% CI 4.2-7.6 months). No new safety concerns were observed, with the safety profile of berzosertib and topotecan combination therapy being consistent with the known risk profile of the respective monotherapies. CONCLUSIONS: No added clinical benefit of berzosertib and topotecan combination was observed over topotecan monotherapy in patients with platinum-resistant SCLC.