Dostarlimab or pembrolizumab plus chemotherapy in previously untreated metastatic non-squamous non-small cell lung cancer: the randomized PERLA phase II trial

Abstract

PERLA is a global, double-blind, parallel phase II trial (NCT04581824) comparing efficacy and safety of anti-PD-1 antibodies dostarlimab and pembrolizumab, plus chemotherapy (DCT and PCT, respectively) as first-line treatment in patients with metastatic non-squamous NSCLC without known targetable genomic aberrations. Patients stratified by PD-L1 tumor proportion score and smoking status were randomized 1:1, receiving ≤35 cycles 500 mg dostarlimab or 200 mg pembrolizumab, ≤35 cycles 500 mg/m² pemetrexed and ≤4 cycles cisplatin (75 mg/m²) or carboplatin (AUC 5 mg/ml/min) Q3W. Primary endpoint was overall response rate (ORR) (blinded independent central review). Secondary endpoints include progression-free survival (PFS) based on investigator assessment, overall survival (OS) and safety. Exploratory endpoints include ORR by PD-L1 subgroup and duration of response. PERLA met its pre-specified endpoint. ORR (n/N; 95% CI) is 45% (55/121; 36.4-54.8) for DCT and 39% (48/122; 30.6-48.6) for PCT (data cut-off: 07 July 23), numerically favoring dostarlimab in PD-L1-positive subgroups. Median PFS (months [95% CI]) is 8.8 (6.7-10.4) for DCT and 6.7 (4.9-7.1) for PCT (HR 0.70 [95% CI: 0.50-0.98]; data cut-off: 04 August 22). Median OS (months [95% CI]) is 19.4 (14.5-NR) for DCT and 15.9 (11.6-19.3) for PCT (HR 0.75 [95% CI: 0.53-1.05]) (data cut-off: 07 July 23). Safety profiles are similar between groups. In this study, DCT shows similar efficacy to PCT and demonstrates clinical efficacy as first-line treatment for patients with metastatic non-squamous NSCLC.

Fig. 1. Study design.

*Or more frequently, if clinically indicated. ^†Imaging will continue to be performed until discontinuation of study treatment due to disease progression with clinical instability, start of subsequent anticancer treatment, withdrawal of informed consent, or death, whichever comes first. ^‡Up to 35 cycles pemetrexed with either cisplatin or carboplatin for the first four cycles. BICR blinded independent central review, CT chemotherapy, DOR duration of response, ECOG PS Eastern Cooperative Oncology Group performance status, INV investigator assessment, IV intravenous, NSCLC non-small cell lung cancer, ORR overall response rate, PD-L1 programmed death ligand 1, PFS progression-free survival, QxW every x weeks, RECIST v1.1 Response Evaluation Criteria in Solid Tumors version 1.1, TPS tumor proportion score.

Fig. 2. CONSORT flow diagram.

*Most common reasons were patients not meeting the inclusion criteria for confirmed metastatic non-squamous NSCLC with documented absence of genomic aberration with available approved target therapy (n = 24) and for documented PD-L1 status by the 22C3 pharmDx assay (n = 22). ^†Other reasons included death (n = 4) and lost to follow-up (n = 1). ^‡Pemetrexed plus platinum-based therapy (either cisplatin or carboplatin). CONSORT Consolidated Standards of Reporting Trials, NSCLC non-small cell lung cancer, PD-L1 programmed death ligand 1.

Fig. 3. Kaplan–Meier PFS and OS curves of dostarlimab plus chemotherapy and pembrolizumab plus chemotherapy.

a PFS (data cut-off: August 4, 2022) and b OS (data cut-off: July 7, 2023) Note: + symbols represent individual censoring events. CI confidence interval, HR hazard ratio, NR not reached, OS overall survival, PFS progression-free survival.

Fig. 4. Tornado plot showing types of AEs in patients receiving dostarlimab + chemotherapy and pembrolizumab + chemotherapy (safety population as of July 7, 2023).

*Subjects who had a fatal AE recorded and died were not recorded as due unequivocally to disease under study. ^†Pneumonitis; immune-related pneumonitis, urosepsis. ^‡Myelosuppression, respiratory failure. ^§No new immune-related deaths were observed. AE adverse event, CT chemotherapy, IO immuno-oncology agent, ir immune-related, SAE serious adverse event.