A single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer

Choong-kun Lee, Sun Young Rha, Hyo Song Kim, Minkyu Jung, Beodeul Kang, Jingmin Che, Woo Sun Kwon, Sejung Park, Woo Kyun Bae, Dong-Hoe Koo, Su-Jin Shin, Hyunki Kim, Hei-Cheul Jeung, Dae Young Zang, Sang Kil Lee, Chung Mo Nam and Hyun Cheol Chung ()
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Choong-kun Lee: Yonsei University College of Medicine
Sun Young Rha: Yonsei University College of Medicine
Hyo Song Kim: Yonsei University College of Medicine
Minkyu Jung: Yonsei University College of Medicine
Beodeul Kang: CHA University
Jingmin Che: Yonsei University College of Medicine
Woo Sun Kwon: Yonsei University College of Medicine
Sejung Park: Yonsei University College of Medicine
Woo Kyun Bae: Chonnam National University Medical School and Hwasun Hospital
Dong-Hoe Koo: Sungkyunkwan University School of Medicine
Su-Jin Shin: Yonsei University College of Medicine
Hyunki Kim: Yonsei University College of Medicine
Hei-Cheul Jeung: Yonsei University College of Medicine
Dae Young Zang: Hallym University Medical Center, Hallym University College of Medicine
Sang Kil Lee: Yonsei University College of Medicine
Chung Mo Nam: Yonsei University College of Medicine
Hyun Cheol Chung: Yonsei University College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract In this multi-center phase II trial, we evaluated the efficacy and safety of a quadruplet regimen (pembrolizumab, trastuzumab, and doublet chemotherapy) as first-line therapy for unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) (NCT02901301). The primary endpoints were recommended phase 2 dose (RP2D) for phase Ib and objective response rate (ORR) for phase II. The secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to response and safety. Without dose-limiting or unexpected toxicities, the starting dose in the phase Ib trial was selected as RP2D. In 43 patients, the primary endpoint was achieved: the objective response rate was 76.7% (95% confidence interval [CI]: 61.4–88.2), with complete and partial responses in 14% and 62.8% of patients, respectively. The median progression-free survival, overall survival, and duration of response were 8.6 months, 19.3 months, and 10.8 months, respectively. No patients discontinued pembrolizumab because of immune-related adverse events. Programmed death ligand-1 status was not related to survival. Post hoc analyses of pretreatment tumor specimens via targeted sequencing indicated that ERBB2 amplification, RTK/RAS pathway alterations, and high neoantigen load corrected by HLA-B were positively related to survival. The current quadruplet regimen shows durable efficacy and safety for patients with HER2-positive AGC.

Date: 2022
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DOI: 10.1038/s41467-022-33267-z

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