In a phase II trial reported in JAMA Oncology, Takahashi et al found that the addition of the ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor berzosertib to topotecan did not improve progression-free survival in patients with relapsed small cell lung cancer (SCLC). However, an overall survival benefit was observed with the addition of berzosertib.
Study Details
In the U.S. multicenter study, 60 patients were randomly assigned 2:1 between December 2019 and December 2022 to receive topotecan at 1.25 mg/m2 on days 1 to 5 with (n = 40) or without (n = 20) berzosertib at 210 mg/m2 on days 2 and 5 in 21-day cycles. Prior topotecan treatment was not permitted. The primary endpoint was investigator-assessed progression-free survival.
Progression-Free Survival
After a median follow-up of 21.3 months (interquartile range = 18.1–28.3 months), median progression-free survival was 3.9 months (95% confidence interval [CI] = 2.8–4.6 months) in the berzosertib group vs 3.0 months (95% CI = 1.2–5.1 months) in the control group (hazard ratio [HR] = 0.80, 95% CI = 0.46–1.41, P = .44). Rates at 4 and 6 months were 45.0% vs 42.1% and 27.5% vs 15.8%, respectively.
Median overall survival was 8.9 months (95% CI = 4.8–11.4 months) in the berzosertib group vs 5.4 months (95% CI = 3.2–6.8 months) in the control group (HR = 0.53, 95% CI = 0.29–0.96, P = .03). Rates at 6 and 12 months were 62.5% vs 44.4% and 29.6% vs 11.1%, respectively.
Adverse Events
The frequency of grade 3 or 4 treatment-related adverse events was similar across the berzosertib group and control group, including thrombocytopenia (50% vs 55%), anemia (45% vs 45%), lymphopenia (15% vs 40%), and neutropenia (30% vs 35%). Gastrointestinal adverse events of any grade included nausea (35% vs 45%), vomiting (18% vs 25%), anorexia (20% vs 25%), and diarrhea (18% vs 30%). Adverse events led to discontinuation of treatment in one patient in each group. No treatment-related deaths were observed.
The investigators concluded: “In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve progression-free survival compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved overall survival.”
Anish Thomas, MBBS, MD, of the Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, is the corresponding author of the JAMA Oncology article.
Disclosure: The study was supported by the intramural programs of the Center for Cancer Research, National Institutes of Health, and Merck KGaA. For full disclosures of the study authors, visit jamanetwork.com.
