Abstract CT218: A phase II trial of niraparib plus dostarlimab in relapsed small cell lung cancer and other high-grade neuroendocrine carcinomas
Authors: Gay Carl M. , Stewart C. Allison , Frumovitz Michael , Fujimoto Junya , xi Yuann , Wang Qi , Wang Runsheng , Novegil Veronica , Altan Mehmet , Cascone Tina , Dasari Arvind , Elamin Yasir Y. , Fossella Frank V. , Glisson Bonnie S. , Lu Charles S. , Negrao Marcelo V. , Skoulidis Ferdinandos , Vokes Natalie , Cardnell Robert J. , Wistuba Ignacio I. , Wang Jing , Heymach John V. , Byers Lauren A. 
Published: April 2023

Abstract
Objectives: Small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas (NECs) share many clinical features, including limited response to immune checkpoint inhibitors (ICIs). However, preclinical data suggest synergistic response with combined ICI and poly (ADP-ribose) polymerase inhibitors (PARPi) in SCLC models. This single-institution, phase II trial (NCT04701307) assessed the efficacy of a combination of the anti-PD-1 monoclonal antibody, dostarlimab, with the selective PARPi, niraparib, in patients with relapsed SCLC or NECs.
Methods: Eligible patients with SCLC (Cohort 1) or NECs (Cohort 2) had received at least one prior line of therapy and were treated with niraparib 300 mg (or 200 mg if &lt;77kg or platelets &lt; 150,000/µL) PO daily, and dostarlimab 500 mg IV q21d (1000mg IV q42d starting with Cycle 5). Co-primary endpoints were objective response rate (ORR) by RECISTv1.1 and 6-month progression free-survival (PFS6). Using a Bayesian Optimal Phase 2 (BOP2) design, interim futility analyses were planned after enrolling up to 15 SCLC and 9 NEC patients (NEC), respectively. Adverse events (AE) were monitored continuously. Patients underwent biopsies, if feasible, at Cycle 1 and Cycle 3, as well as longitudinal plasma collection for translational studies.
Results: From Feb 2021 to Aug 2021, 14 and 9 patients enrolled with SCLC and NEC, respectively. NECs included tumors from gynecological, head/neck, and gastrointestinal sites. In Cohort 1 (SCLC), 12 of 14 patients were evaluable by RECISTv1.1, including 1 complete response (CR), while 4 patients not achieving partial response (PR) had minor responses (-2%, -14%, -19%, and -24% from baseline). Only 1 patient in this cohort achieved PFS6, though 2 additional patients progressed between 5 and 6 months. In Cohort 2 (NEC), 6 of 9 patients were evaluable by RECISTv1.1 and no CR/PRs were observed. One patient did experience durable minor response (-21%), but no patients achieved PFS6. Dose-limiting, niraparib-related hematological AEs, typically thrombocytopenia, occurred in 12 of 23 patients. Non-hematological, treatment-related serious AEs occurred in only 1 patient (Grade 3 inflammatory arthritis), while 1 additional patient experienced brief dose-interruption due to Grade 2 pneumonitis. Preliminary translational data, including bulk and single-cell RNAseq, indicate molecular features, such as transcriptional subtype, are shared across SCLC and NECs and may predict response to this combination.
Conclusions: In heavily pre-treated patients across SCLC and NEC cohorts, combined niraparib and dostarlimab failed to exceed interim futility criteria. However, multiple SCLC patients experienced durable disease control, including one patient with sustained CR and associated translational studies point to potential biomarker-driven approaches in the future.
Trial supported by GlaxoSmithKline.
Citation Format: Carl M. Gay, C. Allison Stewart, Michael Frumovitz, Junya Fujimoto, Yuann xi, Qi Wang, Runsheng Wang, Veronica Novegil, Mehmet Altan, Tina Cascone, Arvind Dasari, Yasir Y. Elamin, Frank V. Fossella, Bonnie S. Glisson, Charles S. Lu, Marcelo V. Negrao, Ferdinandos Skoulidis, Natalie Vokes, Robert J. Cardnell, Ignacio I. Wistuba, Jing Wang, John V. Heymach, Lauren A. Byers. A phase II trial of niraparib plus dostarlimab in relapsed small cell lung cancer and other high-grade neuroendocrine carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT218.