KEYLYNK-012: A Phase 3 Study of Pembrolizumab With Concurrent Chemoradiation Therapy (CCRT) Followed by Pembrolizumab With or Without Olaparib vs. CCRT Followed by Durvalumab in Unresectable, Locally Advanced, Stage III Non‒Small-Cell Lung Cancer

Abstract

Pembrolizumab, an anti‒PD-1 antibody is standard of care therapy for metastatic non‒small-cell lung cancer (NSCLC) as monotherapy and in combination with chemotherapy. Durvalumab, an anti-PD-L1 antibody, is approved for unresectable, stage III NSCLC without disease progression following CCRT. Early trials of pembrolizumab in combination with chemoradiotherapy, either concurrently or as consolidation, showed acceptable tolerability and promising PFS in patients with unresectable stage III NSCLC. Early data suggest the combination of poly(ADP-ribose) polymerase (PARP) plus anti-PD-(L)1 inhibition can enhance treatment effects. KEYLYNK-012 (NCT04380636) is evaluating pembrolizumab plus CCRT followed by pembrolizumab with/without the PARP inhibitor olaparib vs CCRT followed by durvalumab in patients with unresectable, locally advanced, stage III NSCLC.This global phase 3, randomized, placebo- and active-controlled, double-blind study is enrolling patients aged ≥18 y with previously untreated, pathologically confirmed, stage IIIA-C NSCLC, an ECOG PS of 0 or 1, and a tumor sample available for PD-L1 evaluation. Patients are randomized 1:1:1 to CCRT (platinum-doublet chemotherapy [cisplatin plus pemetrexed or etoposide; or carboplatin plus paclitaxel] plus radiotherapy 60 Gy over 6 wks [cycles 2-3]) with pembrolizumab 200 mg Q3W (groups A and B) or CCRT alone (group C) for 3 cycles. This is followed by pembrolizumab 200 mg Q3W for 17 cycles plus placebo (group A) or olaparib 300 mg BID (group B); or durvalumab 10 mg/kg Q2W for 26 cycles (group C). Randomization is stratified by disease stage (IIIA vs IIIB/IIIC), tumor histology (squamous vs nonsquamous), PD-L1 tumor proportion score (≥50% vs < 50%) and region (East Asia vs North America/Western Europe/UK vs other). PFS (RECIST v1.1 by blinded independent central review [BICR]) and OS are dual primary endpoints. Secondary endpoints include ORR, duration of response, safety and tolerability, and quality of life (QoL). Tumor response will be evaluated per RECIST v1.1 by BICR at baseline, week 12, Q9W until year 2, Q12W until year 3, Q26W until year 5, and Q52W thereafter until disease progression, new cancer therapy, study withdrawal, or death. AEs will be graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 and monitored during the study and for 30 days after the final dose (90 days for serious AEs). QoL outcomes will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Lung Cancer Module (EORTC QLQ-LC13). Enrollment began July 6, 2020 and as of Feb 26, 2021, is ongoing at 204 sites in 24 countries.forthcoming CONCLUSION: forthcoming.