1256TiP Phase III study of pembrolizumab (Pembro) with concurrent chemoradiation therapy (CCRT) followed by pembro with or without olaparib (Ola) vs CCRT followed by durvalumab (Durva) in unresectable, locally advanced, stage III non-small cell lung cancer (NSCLC): KEYLYNK-012

Abstract

Pembro, an anti‒PD-1 antibody is standard of care therapy for metastatic NSCLC as monotherapy and in combination with chemotherapy. Durva, an anti–PD-L1 antibody, is approved for unresectable, stage III NSCLC without disease progression (PD) following CCRT. Early trials of pembro in combination with CRT, either concurrent or as consolidation, showed acceptable tolerability and promising PFS in patients (pts) with unresectable stage III NSCLC. Early data suggest the combination of poly(ADP-ribose) polymerase (PARP) + anti–PD-(L)1 inhibition can enhance treatment effects. KEYLYNK-012 (NCT04380636) evaluates pembro + CCRT followed by pembro with/without the PARP inhibitor ola vs CCRT followed by durva in pts with unresectable, locally advanced, stage III NSCLC. This global phase 3, randomized, placebo- and active-controlled, double-blind study will enroll pts aged ≥18 y with previously untreated, pathologically confirmed, stage IIIA–C NSCLC, ECOG PS 0/1, and tumor sample available for PD-L1 evaluation. Pts will be randomized 1:1:1 to CCRT (platinum-doublet chemotherapy [cisplatin + pemetrexed or etoposide; or carboplatin + paclitaxel] + radiotherapy 60 Gy over 6 wk [cycles 2–3]) with pembro 200 mg Q3W (groups A and B) or CCRT alone (group C) for 3 cycles. This will be followed by pembro 200 mg Q3W for 17 cycles + placebo (group A) or ola 300 mg BID (group B); or durva 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, DOR, safety and tolerability, and QOL outcomes. After CCRT, tumor response will be evaluated per RECIST v1.1 by BICR and at regular intervals throughout the study until PD, new cancer therapy, study withdrawal, or death. AEs will be graded by NCI CTCAE v5.0. Enrollment will begin Jun 8, 2020 at 220 sites. NCT04380636; EudraCT, 2019-003237-41. Writing support was provided by Christabel Wilson, MSc, of ICON plc (North Wales, PA, USA). Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.