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
Authors: James Chih-Hsin Yang, Dae Ho Lee, Jong-Seok Lee, Yun Fan, Filippo de Marinis, Eiji Iwama, Takako Inoue, Jerónimo Rodríguez-Cid, Li Zhang, Cheng-Ta Yang, Emmanuel de la Mora Jimenez, Jianying Zhou, Maurice Pérol, Ki Hyeong Lee, David Vicente, Eiki Ichihara, Gregory J. Riely, Yiwen Luo, Diana Chirovsky, M. Catherine Pietanza, Niyati Bhagwati, Shun Lu, Michael Joseph Boyer, Rina Hui, Mark Wong, Andrew Mant, Phillip Parente, Thomas John, Sagun Parakh, Gilberto Castro, Gustavo Werutsky, Sergio Jobim de Azevedo, Fabio Andre 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 Lu, 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, Jifeng Feng, YingYing Du, Lin Wu, Cheng Huang, Xiangdong Zhou, Maurice Perol, Julien Domont, Corinne Lamour, Julien Dutilh, Youssef Oulkhouir, Virginie Westeel, Delphine Carmier, Bruno Coudert, Aurelie Lagrange, Dominique Spaeth, Stanislas Ropert, Daniel C. Christoph, Jens Kern, Hans-Georg Kopp, Frank Griesinger, Rainer Wiewrodt, Martin Wermke, Claas Wesseler, Annette Mueller, Gunther 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, Noam Asna, Mhameed Kamel, Silvia Novello, Francesco Di Costanzo, Laura Doni, Francesca Mazzoni, Francesco Ferrau, Filippo de Marinis, Giuseppe Tonini, Domenico Galetta, Francovito Piantedosi, Fabiana Vitiello, Keisuke Kirita, Kiyotaka Yoh, Toshiaki Takahashi, Yuichiro Ohe, Yoshihiro Hattori, Isamu Okamoto, Takayasu Kurata, Hiroshige Yoshioka, Hideo Saka, Masahide Oki, Terufumi Kato, Hiroshi Tanaka, Toru Kumagai, Takako Inoue, Toyoaki Hida, Yoshitsugu Horio, Shunsuke Teraoka, Eiki Ichihara, Kazuma Kishi, Hisashi Takaya, Daiya Takai, Toshiyuki Kozuki, Kazuo Kasahara, Yuichi Tambo, Yukio Hosomi, Masashi Kondo, Masao Ichiki, Hiroaki Takeoka, Emmanuel de la Mora Jimenez, Carlos Alberto Hernandez, Jeronimo Rafael Rodriguez Cid, Oscar Gerardo Arrieta Rodriguez, Ji-Youn Han, Young Joo Min, Dong-Wan Kim, Keunchil Park, Se-Hoon Lee, Ki Hyeong Lee, Jong-Seok Lee, Jin Hyoung Kang, Dae Ho Lee, Eun Kyung Cho, Enric Carcereny, Pilar Garrido Lopez, Margarita Majem Tarruella, Luis Paz-Ares Rodriguez, David Vicente Baz, Enriqueta Felip Font, Manuel Cobo-Dols, Simon Ekman, Bengt Bergman, Ronny Ohman, Anders Vikstrom, Chih-Hsin Yang, Chao-Hua Chiu, Hsu-Ching Huang, Cheng-Ta Yang, Jian Su, Gee-Chen Chang, Tsung-Ying Yang, Te-Chun Hsia, Wu-Chou Su, Shang-Yin Wu, Chin-Chou Wang, Kang-Yun Lee, Sheng-Hao Lin, Chih-Bin Lin, Jih-Hsiang Lee, Chun-Yao Huang, Samreen Ahmed, Thomas Newsom-Davis, Shobhit Baijal, Juliet Brock, Kam Zaki, Jonathan Shamash, Dionysis Papadatos-Pastos, Pooja Jain, Melanie Jane Mackean, Stephan DiSean Kendall, Ian Anderson, Dan Costin, Richard Hall, Nicholas Campbell, Saad Khan, Jonathan Dowell, Sandeep Mashru, Smitha Menon, Ahmad Raza, Li Ge, Gregory J. Riely, Nagashree Seetharamu, Laura Stampleman, Janakiraman Subramanian, Donald B. Wender, Ronald B. Natale, Viola Zhu, Sai-Hong Ignatius Ou, Rachel Sanborn, Makenzi C. Evangelist
Journal: Journal of Clinical Oncology (2024)

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.