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

doi:10.1038/s41467-022-33267-z

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

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	6002
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33267-z
Publication status	Published - 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)

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10.1038/s41467-022-33267-z

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Lee, C. K., Rha, S. Y., Kim, H. S., Jung, M., Kang, B., Che, J., Kwon, W. S., Park, S., Bae, W. K., Koo, D. H., Shin, S. J., Kim, H., Jeung, H. C., Zang, D. Y., Lee, S. K., Nam, C. M., & Chung, H. C. (2022). A single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer. Nature communications, 13(1), [6002]. https://doi.org/10.1038/s41467-022-33267-z

@article{145e484b3080453fbaa8c86106aebcf1,

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

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.",

author = "Lee, {Choong kun} and Rha, {Sun Young} and Kim, {Hyo Song} and Minkyu Jung and Beodeul Kang and Jingmin Che and Kwon, {Woo Sun} and Sejung Park and Bae, {Woo Kyun} and Koo, {Dong Hoe} and Shin, {Su Jin} and Hyunki Kim and Jeung, {Hei Cheul} and Zang, {Dae Young} and Lee, {Sang Kil} and Nam, {Chung Mo} and Chung, {Hyun Cheol}",

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: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-33267-z",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Lee, CK, Rha, SY, Kim, HS, Jung, M, Kang, B, Che, J, Kwon, WS, Park, S, Bae, WK, Koo, DH, Shin, SJ, Kim, H, Jeung, HC, Zang, DY, Lee, SK, Nam, CM & Chung, HC 2022, 'A single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer', Nature communications, vol. 13, no. 1, 6002. https://doi.org/10.1038/s41467-022-33267-z

TY - JOUR

T1 - A single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer

AU - Lee, Choong kun

AU - Rha, Sun Young

AU - Kim, Hyo Song

AU - Jung, Minkyu

AU - Kang, Beodeul

AU - Che, Jingmin

AU - Kwon, Woo Sun

AU - Park, Sejung

AU - Bae, Woo Kyun

AU - Koo, Dong Hoe

AU - Shin, Su Jin

AU - Kim, Hyunki

AU - Jeung, Hei Cheul

AU - Zang, Dae Young

AU - Lee, Sang Kil

AU - Nam, Chung Mo

AU - Chung, Hyun Cheol

N1 - 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).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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JO - Nature Communications

JF - Nature Communications

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ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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