Abstract LB_A10: Efficacy of ATR inhibitor berzosertib plus topotecan or topotecan alone in patients with relapsed small cell lung cancer: A randomized clinical trial
Authors: Takahashi Nobuyuki , Hao Zhonglin , Villaruz Liza C , Zhang Jun , Ruiz Jimmy , Petty W. Jeffrey , Mamdani Hirva , Riess Jonathan W , Nieva Jorge , Pachecho Jose M , Fuld Alexander D , Shum Elaine , Chauhan Aman , Nichols Samantha , Shimellis Hirity , McGlone Jessie , Sciuto Linda , Pinkiert Danielle , Graham Chante , Shelat Meenakshi , Kattappuram Robbie , Abel Melissa , Schroeder Brett , Upadhyay Deep , Krishnamurthy Manan , Sharma Ajit Kumar , Kumar Rajesh , Malin Justin , Schultz Christopher W , Goyal Shubhank , Redon Christophe E , Pommier Yves , Aladjem Mirit I , Gore Steven D , Steinberg Seth M , Vilimas Rasa , Desai Parth , Thomas Anish 
Published: December 2023

Abstract
Background: Patients with relapsed small cell lung cancer (SCLC) have a poor prognosis and few therapeutic options, especially after standard treatment of platinum doublet chemotherapy +/- immunotherapy. SCLC is characterized with high replication stress. A previous single-arm phase 2 study showed anti-tumor activity with the addition of ataxia-telangiectasia–mutated and rad3-related (ATR) kinase inhibitor berzosertib to topotecan. This study aimed to investigate whether the addition of berzosertib to topotecan improves clinical outcomes in patients with relapsed SCLC.
Patients and methods: The randomized, open-labeled phase 2 study recruited patients with SCLC and relapse after one or more prior therapies from 16 US cancer centers as members of the National Cancer Institute Cancer Therapy Evaluation Program. Patients previously treated with topotecan were not eligible. Eligible patients were randomly assigned to receive topotecan (arm 1: 1.25 mg/m2 intravenously on days 1 through 5) alone or with berzosertib (arm 2: 210 mg/m2 intravenously on days 2 and 5), in 21-day cycles. Randomization was stratified by sensitivity to first-line platinum-based chemotherapy. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Secondary endpoints included overall survival (OS), objective response rate (ORR), and duration of response (DOR) in the overall population and in platinum-sensitive or -resistant patients.
Results: Between December 2019 and December 2022, sixty patients were randomly assigned to receive topotecan alone (n=20) or in combination of with berzosertib (n=40). After a median potential follow-up of 21.3 months, there was no difference in PFS between the two arms [median: 3.0 months in arm 1 versus 3.9 months in arm 2, hazard ratio (HR) (95% CI): 0.80 (0.46 to 1.41), P = 0.44]. OS was significantly longer with the combination [5.4 months in arm 1 versus 8.9 months in arm 2, HR (95% CI): 0.53 (0.29 to 0.96), P = 0.033]. Of 57 evaluable patients, a numerically higher ORR was observed in patients receiving the combination: 5.6% (1/18, 95% CI: 0.1% to 27.3%) in arm 1 versus 25.6% (10/39, 13.0% to 42.1%) in arm 2. In an unplanned post hoc analysis, the depth of target lesion responses was significantly associated with better OS in patients on the combination arm (adjusted P = 0.022 by landmark analysis), suggesting that the deeper tumor regressions by the combination of berzosertib and topotecan may have eventually contributed to OS improvement. Adverse event profiles were similar between the two arms.
Conclusions: In this randomized clinical trial, berzosertib plus topotecan did not improve PFS compared with topotecan alone in patients with relapsed SCLC. However, the combination significantly improved OS, suggesting potential efficacy of replication-stress targeted therapies in SCLC.
Citation Format: Nobuyuki Takahashi, Zhonglin Hao, Liza C Villaruz, Jun Zhang, Jimmy Ruiz, W. Jeffrey Petty, Hirva Mamdani, Jonathan W Riess, Jorge Nieva, Jose M Pachecho, Alexander D Fuld, Elaine Shum, Aman Chauhan, Samantha Nichols, Hirity Shimellis, Jessie McGlone, Linda Sciuto, Danielle Pinkiert, Chante Graham, Meenakshi Shelat, Robbie Kattappuram, Melissa Abel, Brett Schroeder, Deep Upadhyay, Manan Krishnamurthy, Ajit Kumar Sharma, Rajesh Kumar, Justin Malin, Christopher W Schultz, Shubhank Goyal, Christophe E Redon, Yves Pommier, Mirit I Aladjem, Steven D Gore, Seth M Steinberg, Rasa Vilimas, Parth Desai, Anish Thomas. Efficacy of ATR inhibitor berzosertib plus topotecan or topotecan alone in patients with relapsed small cell lung cancer: A randomized clinical trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A10.