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, Hyun Cheol Chung

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


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.

Original languageEnglish
Article number6002
JournalNature communications
Issue number1
Publication statusPublished - 2022 Dec

Bibliographical note

Funding Information:
We thank the patients, their families, and caregivers for their participation in the study; all primary investigators and site personnel; Hye Jin Choi (Yonsei University College of Medicine) for assistance with the CancerMaster NGS program; and Seulkee Lee (Samsung Medical Center) for performing predictive HLA-corrected neoantigen load modeling. This work was supported by Merck Sharp & Dohme Corp. (USA), who supplied pembrolizumab; Celltrion (South Korea), who supplied trastuzumab; Celemics (South Korea); Daewoong Pharmaceutical (South Korea); and by grants from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea [HA15C0005 to S.Y.R., HA16C0018 to Hye Jin Choi] and National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2020R1C1C1004461 to C.-k.L.). The sponsor (Merck Sharp & Dohme Corp. and Celltrion) only provided drugs and were not involved in study design, data collection, analyses, or manuscript writing.

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)


Dive into the research topics of 'A single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer'. Together they form a unique fingerprint.

Cite this