Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial

Importance: Patients with relapsed small cell lung cancer (SCLC), a tumor characterized by high replication stress, have poor prognoses and limited treatment options. A phase 2 study previously demonstrated antitumor activity when the ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor berzosertib was added to topotecan.

Objective: To determine whether the addition of berzosertib to topotecan improves clinical outcomes in patients with relapsed SCLC.

Design, Setting, and Participants: This open-label, phase 2, randomized clinical trial enrolled 60 patients with relapsed SCLC from 16 US cancer centers between December 1, 2019, and December 31, 2022. Eligible patients had relapsed after 1 or more prior therapies and had not received prior topotecan treatment.

Interventions: Patients were randomly assigned to receive either topotecan alone (group 1), 1.25 mg/m² intravenously on days 1 through 5, or topotecan combined with berzosertib (group 2), 210 mg/m² intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified based on tumor sensitivity to first-line platinum-based chemotherapy.

Main Outcomes and Measures: The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Secondary endpoints included overall survival (OS) for the overall population and for those with platinum-sensitive or platinum-resistant tumors. PFS and OS were estimated using the Kaplan-Meier method, with comparisons between groups made using the log-rank test. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Of the 60 patients (median age, 59 years; range, 34-79 years; 55% male), 20 were assigned to topotecan alone and 40 to the combination of topotecan and berzosertib. After a median follow-up of 21.3 months, no significant difference in PFS was observed between the two groups (median PFS: 3.0 months [95% CI, 1.2-5.1] for group 1 vs 3.9 months [95% CI, 2.8-4.6] for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). However, OS was significantly longer in the combination therapy group (5.4 months [95% CI, 3.2-6.8] vs 8.9 months [95% CI, 4.8-11.4]; HR, 0.53 [95% CI, 0.29-0.96]; P = .03). The adverse event profiles were similar between the two groups, with grade 3 or 4 thrombocytopenia occurring in 55% of the topotecan-only group and 50% of the combination group, and any-grade nausea in 45% vs 35%, respectively.

Conclusions and Relevance: In this randomized clinical trial, adding berzosertib to topotecan did not improve progression-free survival compared to topotecan alone in patients with relapsed SCLC. However, the combination therapy significantly improved overall survival, suggesting a potential benefit in extending patient survival despite similar PFS outcomes.