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

Author(s): James Chih-Hsin Yang, MD, PhD1; Dae Ho Lee, MD, PhD2; Jong-Seok Lee, MD, PhD3; Yun Fan, MD4; Filippo de Marinis, MD, PhD5; Eiji Iwama, MD, PhD6; Takako Inoue, MD7; Jerónimo Rodríguez-Cid, MD8; Li Zhang, MD9; Cheng-Ta Yang, MD10; Emmanuel de la Mora Jimenez, MD11; Jianying Zhou, MD12; Maurice Pérol, MD13; Ki Hyeong Lee, MD, PhD14; David Vicente, MD15; Eiki Ichihara, MD, PhD16; Gregory J. Riely, MD, PhD17; Yiwen Luo, PhD18; Diana Chirovsky, PhD18; M. Catherine Pietanza, MD18; Niyati Bhagwati, MD18; Shun Lu, MD, PhD19
Source: https://doi.org/10.1200/JCO.23.0274

Dr. Maen Hussein's Thoughts

Pembrolizumab in addition to chemotherapy DID NOT help, recall now we have new approval for those patients (datopotamab).

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.

Author Affiliations

1National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan; 2Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; 3Seoul National University Bundang Hospital, Seoul, South Korea; 4Zhejiang Cancer Hospital, Hangzhou, China; 5Istituto Europeo di Oncologia, IRCCS, Milan, Italy; 6Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 7Osaka International Cancer Institute, Osaka, Japan; 8Oncology Center, Medica Sur Hospital, Mexico City, Mexico; 9Peking Union Medical College Hospital, Beijing, China; 10Chang Gung Memorial Hospital, Taoyuan, Taiwan; 11Instituto Jalisciense de Cancerología, Guadalajara, Mexico; 12The First Affiliated Hospital, Zhejiang University, Zhejiang, China; 13Centre Léon Bérard, Lyon, France; 14Chungbuk National University Hospital, Cheongju-si, South Korea; 15Hospital Universitario Virgen Macarena, Sevilla, Spain; 16Okayama University Hospital, Okayama, Japan; 17Memorial Sloan Kettering Cancer Center, New York, NY; 18Merck & Co, Inc, Rahway, NJ; 19Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China;

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