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

This phase II, multicenter, open-label, single-arm study (NCT04768296) included patients with relapsed platinum-resistant SCLC who received berzosertib (210 mg/m2 on days 2, 5) and topotecan (1.25 mg/m2 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.