{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T15:59:16Z","timestamp":1791993556146,"version":"4.4.0"},"reference-count":35,"publisher":"American Medical Association (AMA)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Oncol"],"published-print":{"date-parts":[[2023,12,1]]},"abstract":"<jats:sec><jats:title>Importance<\/jats:title><jats:p>Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interventions<\/jats:title><jats:p>Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg\/m<jats:sup>2<\/jats:sup>intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg\/m<jats:sup>2<\/jats:sup>intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41];<jats:italic>P<\/jats:italic>\u2009=\u2009.44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96],<jats:italic>P<\/jats:italic>\u2009=\u2009.03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Relevance<\/jats:title><jats:p>In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p>ClinicalTrials.gov Identifier:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT03896503\">NCT03896503<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamaoncol.2023.4025","type":"journal-article","created":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T15:01:18Z","timestamp":1697122878000},"page":"1669","source":"Crossref","is-referenced-by-count":55,"title":["Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer"],"prefix":"10.1001","volume":"9","author":[{"given":"Nobuyuki","family":"Takahashi","sequence":"first","affiliation":[{"name":"National Cancer Institute, Center for Cancer Research, Bethesda, Maryland"},{"name":"National Cancer Center Hospital East, Kashiwa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonglin","family":"Hao","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, University of Kentucky College of Medicine, Lexington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liza C.","family":"Villaruz","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, University of Kansas Medical Center, Kansas City, Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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