1360TiP First-line (1L) maintenance therapy with niraparib (nira) + pembrolizumab (pembro) vs placebo + pembro in advanced/metastatic non-small cell lung cancer (NSCLC): Phase III ZEAL-1L study
Annals of Oncology
chiles; portland; oregon
Pembro (programmed death protein 1 [PD-1] inhibitor) ± platinum (Pt)-based chemotherapy (CT), with pembro maintained until progression, is a standard 1L treatment for advanced/metastatic NSCLC. However, durable long-term benefit is 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 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 PARPi, suggesting it may reduce risk/progression of brain metastasis (BM). Nira + pembro has shown antitumour activity and acceptable safety in triple-negative breast cancer and Pt-resistant ovarian cancer (TOPACIO/KEYNOTE-162), and as 1L therapy in advanced/metastatic NSCLC (JASPER).
ZEAL-1L (NCT04475939) is a phase III, randomised, double-blind trial comparing efficacy and 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 start of 1L induction CT) versus placebo + pembro in adults with histologically/cytologically confirmed Stage IIIB–IV NSCLC without known driver mutations and with stable disease or partial/complete response to 4–6 cycles of 1L Pt-based induction CT + pembro. Patients with asymptomatic BM (i.e. 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 induction CT + pembro. Treatment will continue until disease progression (PD), unacceptable toxicity, death, or loss to follow-up. Imaging occurs every 6 weeks (Q6W) for 48 weeks/until PD, and Q12W for patients still on treatment thereafter. Primary endpoints are PFS and 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 also planned. Enrolment began November 2020.
Clinical trial identification
Medical writing support was provided by Nadia Hashash, PhD, of Core Medica, London, UK, funded by GlaxoSmithKline.
Legal entity responsible for the study
GlaxoSmithKline (ID: 213400).
Earle A. Chiles Research Institute
Ramalingam, SS; de Castro Jr, G; Garassino, MCC; Mazieres, J; Sanborn, Rachel E; Smit, EFF; Spigel, DR; Thomas, M; Velcheti, V; Zhi, E; Whipple Neibauer, M; Stojadinovic, A; and Peters, S, "1360TiP First-line (1L) maintenance therapy with niraparib (nira) + pembrolizumab (pembro) vs placebo + pembro in advanced/metastatic non-small cell lung cancer (NSCLC): Phase III ZEAL-1L study" (2021). Articles, Abstracts, and Reports. 5791.