IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-33267-z.html
   My bibliography  Save this article

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

Author

Listed:
  • Choong-kun Lee

    (Yonsei University College of Medicine
    Yonsei University College of Medicine)

  • Sun Young Rha

    (Yonsei University College of Medicine
    Yonsei University College of Medicine)

  • Hyo Song Kim

    (Yonsei University College of Medicine
    Yonsei University College of Medicine)

  • Minkyu Jung

    (Yonsei University College of Medicine
    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
    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
    Yonsei University College of Medicine)

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.

Suggested Citation

  • 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 Y, 2022. "A single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33267-z
    DOI: 10.1038/s41467-022-33267-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-33267-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-33267-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Monkol Lek & Konrad J. Karczewski & Eric V. Minikel & Kaitlin E. Samocha & Eric Banks & Timothy Fennell & Anne H. O’Donnell-Luria & James S. Ware & Andrew J. Hill & Beryl B. Cummings & Taru Tukiainen , 2016. "Analysis of protein-coding genetic variation in 60,706 humans," Nature, Nature, vol. 536(7616), pages 285-291, August.
    2. Kwoneel Kim & Hong Sook Kim & Jeong Yeon Kim & Hyunchul Jung & Jong-Mu Sun & Jin Seok Ahn & Myung-Ju Ahn & Keunchil Park & Se-Hoon Lee & Jung Kyoon Choi, 2020. "Predicting clinical benefit of immunotherapy by antigenic or functional mutations affecting tumour immunogenicity," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Kian Hong Kock & Patrick K. Kimes & Stephen S. Gisselbrecht & Sachi Inukai & Sabrina K. Phanor & James T. Anderson & Gayatri Ramakrishnan & Colin H. Lipper & Dongyuan Song & Jesse V. Kurland & Julia M, 2024. "DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Suganth Suppiah & Sheila Mansouri & Yasin Mamatjan & Jeffrey C. Liu & Minu M. Bhunia & Vikas Patil & Prisni Rath & Bharati Mehani & Pardeep Heir & Severa Bunda & German L. Velez-Reyes & Olivia Singh &, 2023. "Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Eun Seop Seo & Ji Won Lee & Jinyeong Lim & Sunghwan Shin & Hee Won Cho & Hee Young Ju & Keon Hee Yoo & Ki Woong Sung & Woong-Yang Park, 2024. "Germline functional variants contribute to somatic mutation and outcomes in neuroblastoma," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    4. Ruoyu Tian & Tian Ge & Hyeokmoon Kweon & Daniel B. Rocha & Max Lam & Jimmy Z. Liu & Kritika Singh & Daniel F. Levey & Joel Gelernter & Murray B. Stein & Ellen A. Tsai & Hailiang Huang & Christopher F., 2024. "Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Pei-Kuan Cong & Wei-Yang Bai & Jin-Chen Li & Meng-Yuan Yang & Saber Khederzadeh & Si-Rui Gai & Nan Li & Yu-Heng Liu & Shi-Hui Yu & Wei-Wei Zhao & Jun-Quan Liu & Yi Sun & Xiao-Wei Zhu & Pian-Pian Zhao , 2022. "Genomic analyses of 10,376 individuals in the Westlake BioBank for Chinese (WBBC) pilot project," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Iker Núñez-Carpintero & Maria Rigau & Mattia Bosio & Emily O’Connor & Sally Spendiff & Yoshiteru Azuma & Ana Topf & Rachel Thompson & Peter A. C. ’t Hoen & Teodora Chamova & Ivailo Tournev & Velina Gu, 2024. "Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Rotem Katzir & Noam Rudberg & Keren Yizhak, 2022. "Estimating tumor mutational burden from RNA-sequencing without a matched-normal sample," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    8. Birgit Burkhardt & Ulf Michgehl & Jonas Rohde & Tabea Erdmann & Philipp Berning & Katrin Reutter & Marius Rohde & Arndt Borkhardt & Thomas Burmeister & Sandeep Dave & Alexandar Tzankov & Martin Dugas , 2022. "Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    9. Farshad Farshidfar & Kahn Rhrissorrakrai & Chaya Levovitz & Cong Peng & James Knight & Antonella Bacchiocchi & Juan Su & Mingzhu Yin & Mario Sznol & Stephan Ariyan & James Clune & Kelly Olino & Laxmi , 2022. "Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Maria Stahl Madsen & Marjoleine F. Broekema & Martin Rønn Madsen & Arjen Koppen & Anouska Borgman & Cathrin Gräwe & Elisabeth G. K. Thomsen & Denise Westland & Mariette E. G. Kranendonk & Marian Groot, 2022. "PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    11. Ricky Lali & Michael Chong & Arghavan Omidi & Pedrum Mohammadi-Shemirani & Ann Le & Edward Cui & Guillaume Paré, 2021. "Calibrated rare variant genetic risk scores for complex disease prediction using large exome sequence repositories," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    12. Mark W. Youngblood & Zeynep Erson-Omay & Chang Li & Hinda Najem & Süleyman Coșkun & Evgeniya Tyrtova & Julio D. Montejo & Danielle F. Miyagishima & Tanyeri Barak & Sayoko Nishimura & Akdes Serin Harma, 2023. "Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    13. Anna Worthmann & Julius Ridder & Sharlaine Y. L. Piel & Ioannis Evangelakos & Melina Musfeldt & Hannah Voß & Marie O’Farrell & Alexander W. Fischer & Sangeeta Adak & Monica Sundd & Hasibullah Siffeti , 2024. "Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    14. Tetsuo Shoda & Kenneth M. Kaufman & Ting Wen & Julie M. Caldwell & Garrett A. Osswald & Pathre Purnima & Nives Zimmermann & Margaret H. Collins & Kira Rehn & Heather Foote & Michael D. Eby & Wenying Z, 2021. "Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    15. James T. Topham & Erica S. Tsang & Joanna M. Karasinska & Andrew Metcalfe & Hassan Ali & Steve E. Kalloger & Veronika Csizmok & Laura M. Williamson & Emma Titmuss & Karina Nielsen & Gian Luca Negri & , 2022. "Integrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    16. Sophie A. Riesmeijer & Zoha Kamali & Michael Ng & Dmitriy Drichel & Bram Piersma & Kerstin Becker & Thomas B. Layton & Jagdeep Nanchahal & Michael Nothnagel & Ahmad Vaez & Hans Christian Hennies & Pau, 2024. "A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren’s disease," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    17. Kellan P. Weston & Xiaoyi Gao & Jinghan Zhao & Kwang-Soo Kim & Susan E. Maloney & Jill Gotoff & Sumit Parikh & Yen-Chen Leu & Kuen-Phon Wu & Marwan Shinawi & Joshua P. Steimel & Joseph S. Harrison & J, 2021. "Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    18. Minhui Chen & Andy Dahl, 2024. "A robust model for cell type-specific interindividual variation in single-cell RNA sequencing data," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    19. Noah Dukler & Mehreen R. Mughal & Ritika Ramani & Yi-Fei Huang & Adam Siepel, 2022. "Extreme purifying selection against point mutations in the human genome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    20. Feng Jiang & Shou-Ye Hu & Wen Tian & Nai-Ning Wang & Ning Yang & Shan-Shan Dong & Hui-Miao Song & Da-Jin Zhang & Hui-Wu Gao & Chen Wang & Hao Wu & Chang-Yi He & Dong-Li Zhu & Xiao-Feng Chen & Yan Guo , 2024. "A landscape of gene expression regulation for synovium in arthritis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33267-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.