Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, <i>EGFR</i> –Mutant, Metastatic Nonsquamous Non–Small Cell Lung Cancer
James Chih‐Hsin Yang, Dae Ho Lee, Jong‐Seok Lee, Yun Fan, Filippo de Marinis, Eiji Iwama, Takako Inoue, Jerónimo Rafael Rodríguez‐Cid, Li Zhang, Cheng‐Ta Yang, Emmanuel de la Mora Jimenez, Jianying Zhou, M. Pérol, Ki Hyeong Lee, David Vicente, Eiki Ichihara, Gregory J. Riely, Yiwen Luo, Diana Chirovsky, M. Catherine Pietanza, Niyati Bhagwati, Shun Lü, Michael Boyer, Rina Hui, Mark E. Wong, Andrew Mant, Phillip Parente, Thomas John, Sagun Parakh, Gilberto de Castro, Gustavo Werutsky, Sérgio Jobim Azevedo, Fábio Franke, Joilda Batista De Almeida Rego, Pedro Rafael Martins De Marchi, Gustavo Dix Junqueira, Fernanda Maris Peria, Leandro Brust, Parneet Cheema, Mark Doherty, Ambika Parmar, Ines B. Menjak, Natasha B. Leighl, Jason Agulnik, Shun Lü, Zhigang Han, Jiuwei Cui, Li Zhang, Ying Cheng, Gongyan Chen, Helong Zhang, Yu Yao, Chengping Hu, Qiming Wang, Xin Zhang, Yong Zhang, Jianying Zhou, Kejing Ying, Yun Fan, Yan Wang, Ziping Wang, Ji‐Feng Feng, Yingying Du, Lin Wu, Cheng Zhi Huang, Xiangdong Zhou, M. Pérol, Julien Dômont, Corinne Lamour, Julien Dutilh, Youssef Oulkhouir, Virginie Westeel, D. Carmier, Bruno Coudert, Aurélie Lagrange, Dominique Spaëth, Stanislas Ropert, Daniel C. Christoph, Jens Kern, Hans‐Georg Kopp, Frank Griesinger, Rainer Wiewrodt, Martin Wermke, Claas Wesseler, Annette Mueller, G Vogel, Victor Lee, Chung Man James Ho, Siu Hong Oscar Chan, Sing Hung Lo, Shi Feng Jonathan Nyaw, Yu Chung Jacky Li, Jair Bar, Maya Gottfried, Julia Dudnik, Alona Zer, Mor Moskovitz, Mirjana Wollner, Ofer Rotem, Sivan Shamai
Abstract
PURPOSE Epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR -mutant, metastatic non–small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum–based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR -mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837 ). METHODS Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS. RESULTS Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients. CONCLUSION Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR -mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.