Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant,
EGFR
–Mutant, Metastatic Nonsquamous Non–Small Cell Lung Cancer
Authors: Yang James Chih-Hsin , Lee Dae Ho , Lee Jong-Seok , Fan Yun , de Marinis Filippo , Iwama Eiji , Inoue Takako , Rodríguez-Cid Jerónimo , Zhang Li , Yang Cheng-Ta , de la Mora Jimenez Emmanuel , Zhou Jianying , Pérol Maurice , Lee Ki Hyeong , Vicente David , Ichihara Eiki , Riely Gregory J. , Luo Yiwen , Chirovsky Diana , Pietanza M. Catherine , Bhagwati Niyati , Lu Shun , Joseph Boyer Michael , Hui Rina , Wong Mark , Mant Andrew , Parente Phillip , John Thomas , Parakh Sagun , Castro Gilberto , Werutsky Gustavo , de Azevedo Sergio Jobim , Andre Franke Fabio , De Almeida Rego Joilda Batista , Martins De Marchi Pedro Rafael , Dix Junqueira Gustavo , Maris Peria Fernanda , Brust Leandro , Cheema Parneet , Doherty Mark , Parmar Ambika , Menjak Ines B. , Leighl Natasha B. , Agulnik Jason , Lu Shun , Han Zhigang , Cui Jiuwei , Zhang Li , Cheng Ying , Chen Gongyan , Zhang Helong , Yao Yu , Hu Chengping , Wang Qiming , Zhang Xin , Zhang Yong , Zhou Jianying , Ying Kejing , Fan Yun , Wang Yan , Wang Ziping , Feng Jifeng , Du YingYing , Wu Lin , Huang Cheng , Zhou Xiangdong , Perol Maurice , Domont Julien , Lamour Corinne , Dutilh Julien , Oulkhouir Youssef , Westeel Virginie , Carmier Delphine , Coudert Bruno , Lagrange Aurelie , Spaeth Dominique , Ropert Stanislas , Christoph Daniel C. , Kern Jens , Kopp Hans-Georg , Griesinger Frank , Wiewrodt Rainer , Wermke Martin , Wesseler Claas , Mueller Annette , Vogel Gunther , Lee Victor , James Ho Chung Man , Oscar Chan Siu Hong , Hung Lo Sing , Jonathan Nyaw Shi Feng , Jacky Li Yu Chung , Bar Jair , Gottfried Maya , Dudnik Julia , Zer Alona , Moskovitz Mor , Wollner Mirjana , Rotem Ofer , Shamai Sivan , Asna Noam , Kamel Mhameed , Novello Silvia , Di Costanzo Francesco , Doni Laura , Mazzoni Francesca , Ferrau Francesco , de Marinis Filippo , Tonini Giuseppe , Galetta Domenico , Piantedosi Francovito , Vitiello Fabiana , Kirita Keisuke , Yoh Kiyotaka , Takahashi Toshiaki , Ohe Yuichiro , Hattori Yoshihiro , Okamoto Isamu , Kurata Takayasu , Yoshioka Hiroshige , Saka Hideo , Oki Masahide , Kato Terufumi , Tanaka Hiroshi , Kumagai Toru , Inoue Takako , Hida Toyoaki , Horio Yoshitsugu , Teraoka Shunsuke , Ichihara Eiki , Kishi Kazuma , Takaya Hisashi , Takai Daiya , Kozuki Toshiyuki , Kasahara Kazuo , Tambo Yuichi , Hosomi Yukio , Kondo Masashi , Ichiki Masao , Takeoka Hiroaki , de la Mora Jimenez Emmanuel , Hernandez Carlos Alberto , Rodriguez Cid Jeronimo Rafael , Rodriguez Oscar Gerardo Arrieta , Han Ji-Youn , Min Young Joo , Kim Dong-Wan , Park Keunchil , Lee Se-Hoon , Lee Ki Hyeong , Lee Jong-Seok , Kang Jin Hyoung , Lee Dae Ho , Cho Eun Kyung , Carcereny Enric , Lopez Pilar Garrido , Tarruella Margarita Majem , Rodriguez Luis Paz-Ares , Vicente Baz David , Font Enriqueta Felip , Cobo-Dols Manuel , Ekman Simon , Bergman Bengt , Ohman Ronny , Vikstrom Anders , Yang Chih-Hsin , Chiu Chao-Hua , Huang Hsu-Ching , Yang Cheng-Ta , Su Jian , Chang Gee-Chen , Yang Tsung-Ying , Hsia Te-Chun , Su Wu-Chou , Wu Shang-Yin , Wang Chin-Chou , Lee Kang-Yun , Lin Sheng-Hao , Lin Chih-Bin , Lee Jih-Hsiang , Huang Chun-Yao , Ahmed Samreen , Newsom-Davis Thomas , Baijal Shobhit , Brock Juliet , Zaki Kam , Shamash Jonathan , Papadatos-Pastos Dionysis , Jain Pooja , Jane Mackean Melanie , Kendall Stephan DiSean , Anderson Ian , Costin Dan , Hall Richard , Campbell Nicholas , Khan Saad , Dowell Jonathan , Mashru Sandeep , Menon Smitha , Raza Ahmad , Ge Li , Riely Gregory J. , Seetharamu Nagashree , Stampleman Laura , Subramanian Janakiraman , Wender Donald B. , Natale Ronald B. , Zhu Viola , Ignatius Ou Sai-Hong , Sanborn Rachel , Evangelist Makenzi C. 
Published: August 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.