Berzosertib Plus Topotecan for Patients With Relapsed Platinum-Resistant Small-Cell Lung Cancer: DDRiver SCLC 250 Study
Key Clinical Takeaways:
- Key Outcomes: The berzosertib–topotecan combination demonstrated limited activity in platinum-resistant SCLC, with an ORR of 5.5%, median PFS of 2.2 months, and median OS of 6.4 months; a preplanned interim futility analysis led to early study termination.
- Design / Population: This was a phase 2, multicenter, open-label, single-arm study enrolling patients with relapsed, platinum-resistant SCLC treated with berzosertib plus topotecan in 21-day cycles, with efficacy assessed by independent review per RECIST v1.1.
- Clinical Relevance: Despite a strong biologic rationale for ATR inhibition in SCLC, adding berzosertib to topotecan did not provide meaningful clinical benefit over historical outcomes with topotecan alone, underscoring the ongoing unmet need in platinum-resistant disease.
Berzosertib plus topotecan did not yield meaningful clinical benefits for patients with relapsed, platinum-resistant small-cell lung cancer (SCLC) compared with topotecan monotherapy, according to results from the DDRiver SCLC 250 study.
SCLC is marked by pronounced genomic instability, making components of the DNA damage response—such as ataxia telangiectasia and Rad3-related (ATR) kinase and topoisomerase I—attractive therapeutic targets. Berzosertib is a potent, selective ATR inhibitor administered intravenously and has previously shown antitumor activity in platinum-resistant SCLC.
The phase 2, multicenter, open-label, single-arm study (NCT04768296) evaluated berzosertib in combination with topotecan among patients with relapsed, platinum-resistant SCLC. Patients received berzosertib 210 mg/m² on days 2 and 5 and topotecan 1.25 mg/m² on days 1 to 5 of 21-day cycles until disease progression. The primary endpoint was objective response rate (ORR) per RECIST v1.1 as assessed by an independent review committee, with progression-free survival (PFS), overall survival (OS), and safety as key secondary end points.
A preplanned interim futility analysis conducted after 40 patients completed early tumor assessments demonstrated a low likelihood of achieving the prespecified efficacy threshold, resulting in early study termination. At final analysis of 73 treated patients, four confirmed partial responses were observed, yielding an ORR of 5.5%. Median PFS was 2.2 months (95% confidence interval [CI], 1.5 to 2.7), and median OS was 6.4 months (95% CI, 4.2 to 7.6). The combination was generally well-tolerated, with no new safety signals and an adverse event profile consistent with those of berzosertib and topotecan monotherapies.
Overall, the addition of berzosertib to topotecan did not confer a meaningful clinical benefit compared with historical outcomes of topotecan alone in patients with platinum-resistant SCLC.
“In conclusion, while the combination of berzosertib and topotecan failed to yield the desired results in our study, other ATR inhibitors and/or DDR inhibitors that can potentiate the effects of chemotherapy, radiotherapy, and immunotherapy are being actively explored in both preclinical and clinical settings,” study authors concluded.
Source:
Navarro A, Thomas A, Cheng Y, et al. 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). ESMO Open. Published online January 2026. https://www.esmoopen.com/article/S2059-7029(25)01788-0/fulltext
