e-Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2021

First-line (1L) Maintenance Therapy with Niraparib (nira) + Pembrolizumab (pembro) vs Placebo + Pembro in Advanced/Metastatic Non-Small Cell Lung Cancer (NSCLC): Phase 3 ZEAL-1L Study (#403)

Adnan Nagrial 1 , Suresh S Ramalingam 2 , Gilberto de Castro Junior 3 , Marina Chiara Garassino 4 , Julien Mazieres‬ 5 , Rachel Sanborn 6 , Egbert Smit 7 , David R Spigel 8 , Michael Thomas 9 , Vamsidhar Velcheti 10 , Lei Shi 11 , Melissa Whipple Neibauer 11 , Alexander Stojadinovic 11 , Solange Peters 12
  1. University of Sydney, Blacktown Hospital and University of Sydney, Sydney, New South Wales, Australia
  2. Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
  3. Medical School, University of Sao Paulo , Sao Paulo, Brazil
  4. Medical Oncology , IRCCS National Cancer Institute Foundation, Milan, Italy
  5. Service de Pneumologie, Hôpital LARREY, Toulouse, France
  6. Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA
  7. The Netherlands Cancer Institute - Dept of Thoracic Oncology, Antoni van Leeuwenhoek Hospital, Amsterdam , Netherlands
  8. Lung Cancer Research Program, Sarah Cannon Research Institute, Nashville, Tennessee, USA
  9. Internal Oncology of Thoracic Tumors, Thorax Clinic, Heidelberg University Hospital, Heidelberg, Germany
  10. Laura and Isaac Perlmutter Cancer Center, NYU Langone , New York, USA
  11. Oncology, GlaxoSmithKline, Philadelphia, Pennsylvania, USA
  12. Oncology Department, Lausanne University, Lausanne, Switzerland

Background: Pembro (programmed cell death protein-1 [PD-1] inhibitor) ± platinum (Pt)-based induction chemotherapy (ICT), with pembro maintained until disease progression (PD), is a standard 1L treatment for advanced/metastatic NSCLC; long-term benefits are limited to a small subset of patients. Nira, a poly(ADP-ribose) polymerase inhibitor (PARPi), promotes PARP trapping, activates the STING pathway, recruits T cells, and upregulates programmed death-ligand 1 (PD-L1), making it a promising partner for PD-1 inhibitors. Nira crosses the blood-brain barrier in animal models with 34-fold higher brain tissue exposure than other PARPis, suggesting it may reduce risk/progression of brain metastasis (BM). Nira + pembro has shown anti-tumour activity and acceptable safety in triple-negative breast and Pt-resistant ovarian cancer (TOPACIO/KEYNOTE-162), and as 1L therapy in advanced/metastatic NSCLC (JASPER).

Trial design: ZEAL-1L (NCT04475939) is a phase 3, randomised, double-blind trial comparing efficacy/safety of 1L maintenance therapy with oral nira (200/300 mg/day) + intravenous pembro (200 mg on Day 1 of each 21-day cycle; maximum 35 cycles from 1L ICT initiation) versus placebo + pembro in adults with histologically/cytologically confirmed Stage IIIB–IV NSCLC without known driver mutations and stable disease or partial/complete response to 4–6 cycles of 1L Pt-based ICT + pembro. Patients with asymptomatic BM (off corticosteroids and anticonvulsants for ≥7 days) are permitted. Approximately 650 patients will be randomised (1:1), with stratification by histology, PD-L1 status and response to 1L therapy. Treatment will continue until PD, unacceptable toxicity, death, or loss to follow-up. Imaging occurs every 6 weeks (Q6W) for 48 weeks/until PD, and Q12W for patients on treatment thereafter. Primary endpoints are progression-free survival (PFS) and overall survival (OS). Time to central nervous system progression is a key secondary endpoint; others include investigator-assessed PFS, PFS and OS by PD-L1 status, quality of life, safety, and pharmacokinetics. Exploratory analyses are planned. Enrolment began November 2020.