JASPER: Phase 2 trial of first-line niraparib plus pembrolizumab in patients with advanced non-small cell lung cancer

Abstract

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors may synergize with programmed cell death receptor-1 (PD-1) inhibitors to enhance adaptive and innate antitumor immune responses. In the phase 2 JASPER study (NCT04475939), the PARP inhibitor niraparib was evaluated in combination with the PD-1 inhibitor pembrolizumab in patients with metastatic and/or locally advanced non-small cell lung cancer (NSCLC).

Methods: Patients whose tumors had programmed cell death ligand 1 (PD-L1) tumor proportion scores (TPS) ≥50% (cohort 1) or 1%-49% (cohort 2) received first-line niraparib (200 mg once daily) plus pembrolizumab (200 mg every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics.

Results: Thirty-eight patients were enrolled in cohorts 1 and 2. In cohort 1, ORR (95% confidence interval [CI]) was 56.3% (9 of 16 patients; 29.9%-80.2%); 2 of 16 patients had complete responses and 7 of 16 had partial responses (PRs). In cohort 2, ORR was 20.0% (5.7%-43.7%) with 4 of 20 PRs. In cohorts 1 and 2, the median DoR was 19.7 months (95% CI, 4.2 months to not estimable [NE]) and 9.4 months (95% CI, 4.2 months to NE), the median PFS was 8.4 months (95% CI, 3.9-22.1 months) and 4.2 months (95% CI, 2.0-6.2 months), and the median OS was NE (95% CI, 6.0 months to NE) and 7.7 months (95% CI, 4.0-12.5 months), respectively. Grade ≥3 treatment-emergent adverse events occurred in 88.2% and 85.7% of patients in cohorts 1 and 2, respectively. Safety was consistent with known profiles of single-agent niraparib and pembrolizumab.

Conclusions: Niraparib plus pembrolizumab showed clinical activity in patients with advanced and/or metastatic NSCLC.

Lay summary: The JASPER clinical trial studied a new combination treatment for advanced or metastatic non-small cell lung cancer (NSCLC). Pembrolizumab, a drug approved for NSCLC, was given with niraparib. Previous research showed that these 2 drugs together might work better than either drug alone. This study found that more than half of patients with high levels of a tumor marker responded to the combination, and one-fifth of patients with lower levels of the marker responded. The types of side effects from the combination were similar to side effects from both drugs alone. These results support more research on this combination.

Keywords: clinical study; combination drug therapy; lung neoplasms; niraparib; non-small cell lung carcinoma; pembrolizumab; poly(ADP-ribose) polymerase inhibitors.

Conflict of interest statement

Suresh S. Ramalingam received grant funding and/or other support (for consultancy) from Amgen, AstraZeneca, Bristol‐Myers Squibb, Merck, Takeda, Tesaro, Advaxis, AbbVie, and Genentech/Roche. Mark M. Awad received grant funding and/or personal fees from AstraZeneca, Bristol‐Myers Squibb, Genentech, Ariad, Blueprint Medicine, Gritstone, Maverick, Merck, Nektar, Syndax, and Lilly. Afshin Dowlati received grant funding (to the institution) and/or personal fees (for consultancy) from Bayer, Bristol‐Myers Squibb, Eli Lilly, EMD Serono, Incuron, Ipsen, Mirati, Regeneron, Roche, Takeda, Tesaro, United Therapeutics, Vertex, AbbVie, AstraZeneca, Millenium, Seattle Genetics, and Ariad. Thomas E. Stinchcombe received personal fees (for advisory boards) from AstraZeneca, EMD Serono, Foundation Medicine, G1 Therapeutics, Genentech/Roche, Lilly Oncology, Novartis, and Takeda and grant funding (to the institution) from Advaxis, AstraZeneca, Blueprint Medicines, Genentech/Roche, Merck, Regeneron, and Takeda. Grace K. Dy received personal fees (for consultancy) from GlaxoSmithKline. David R. Spigel received research grant funding from, and had a consulting and/or advisory role (with or without funds to the institution) with, AstraZeneca, Bristol‐Myers Squibb, Celgene, EMD Serono, Genentech/Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Nektar, Takeda, AbbVie, Amgen, Aptitude Health, Bayer, Boehringer Ingelheim, Dracen Pharmaceuticals, Evelo Therapeutics, Foundation Medicine, Iksuda Therapeutics, Illumina, Intellisphere, Moderna Therapeutics, Molecular Templates, PharmaMar, Precision Oncology, Seattle Genetics, TRIPTYCH Health Partners, TRM Oncology, Aeglea Biotherapeutics, Astellas Pharma, BIND Therapeutics, Celldex, Clovis Oncology, Daiichi Sankyo, Eisai, G1 Therapeutics, GRAIL, ImClone Systems, Ipsen, Janssen, MedImmune, Neon Therapeutics, Tesaro, Transgene, and University of Texas Southwestern Medical Center‐Simmons Cancer Center. Nithya Iyer Singh is an employee of GlaxoSmithKline. Yongqiang Tang is an employee of GlaxoSmithKline. Sharon Lu is an employee of GlaxoSmithKline. Iryna Teslenko was an employee of GlaxoSmithKline at the time of this work and holds stocks and/or shares in GlaxoSmithKline. The other authors made no disclosures.

© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.

Figures

Figure 1

Consolidated Standards of Reporting Trials diagram. *A total of 53 patients were enrolled across all cohorts in the study; 38 patients were enrolled and assigned to cohorts 1 and 2. †In cohort 1, 15 of 17 patients discontinued niraparib treatment (10 adverse event, 3 disease progression, 1 physician decision, 1 protocol noncompliance) and 17 of 17 patients discontinued pembrolizumab treatment (5 disease progression, 4 adverse event, 4 other reason, 1 physician decision, 1 protocol noncompliance, 1 patient withdrawal of consent, 1 died). In cohort 2, 21 of 21 patients discontinued niraparib treatment (7 adverse event, 6 disease progression, 4 died, 2 physician decision, 1 protocol noncompliance, 1 patient withdrawal of consent), and 21 of 21 discontinued pembrolizumab treatment (9 disease progression, 4 adverse event, 3 died, 2 physician decision, 2 patient withdrawal of consent, 1 other reason). ‡mITT (efficacy‐evaluable) population included all patients who received any study drug and did not withdraw consent before having ≥1 post‐baseline tumor assessment. §Response‐evaluable patients were those who received any study drug, did not withdraw consent, and had ≥1 post‐baseline tumor assessment. ¶PK population included patients who received niraparib and had sufficient evaluable samples to determine PK parameters. mITT, indicates modified intent‐to‐treat; NSCLC, non–small cell lung cancer; PD‐L1, programmed cell death receptor ligand 1; PK, pharmacokinetics; TPS, tumor proportion score.

Figure 2

Tumor response in patients treated with niraparib plus pembrolizumab with (A) PD‐L1 TPS ≥50% (cohort 1) and (B) PD‐L1 TPS 1% to 49% (cohort 2). Cohort 1 enrolled 17 patients; 1 patient withdrew consent before the first dose (mITT n = 16). Cohort 2 enrolled 21 patients; 1 patient withdrew consent before the first dose (mITT n = 20). Orange arrows indicate patients with squamous cell carcinoma. mITT, indicates modified intent‐to‐treat; PD‐L1, programmed cell death receptor ligand 1.

Figure 3

Best percent change in target tumor lesion in patients treated with niraparib plus pembrolizumab with (A) PD‐L1 TPS ≥50% (cohort 1) and (B) PD‐L1 TPS 1% to 49% (cohort 2). Patients who withdrew consent or died before having at least 1 post‐baseline assessment were not included. Confirmed best overall response was determined based on change in sum of target lesion dimensions and the appearance of new lesions based on RECIST v1.1. 2 patients died in cohort 1 and 2 patients in cohort 2 before post‐baseline tumor assessment scan. PD‐L1 indicates programmed cell death receptor ligand 1.