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Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. ​

Literature Information ​

DOI10.1038/s41591-018-0101-z
PMID30013197
JournalNature medicine
Impact Factor50.0
JCR QuartileQ1
Publication Year2018
Times Cited946
KeywordsPD-1 inhibition, metastatic gastric cancer, microsatellite instability, Epstein-Barr virus, circulating tumor DNA
Literature TypeClinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't
ISSN1078-8956
Pages1449-1458
Issue24(9)
AuthorsSeung Tae Kim, Razvan Cristescu, Adam J Bass, Kyoung-Mee Kim, Justin I Odegaard, Kyung Kim, Xiao Qiao Liu, Xinwei Sher, Hun Jung, Mijin Lee, Sujin Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Hyuk Lee, Mingew Choi, AmirAli Talasaz, Peter Soonmo Kang, Jonathan Cheng, Andrey Loboda, Jeeyun Lee, Won Ki Kang

TL;DR ​

This study investigates the efficacy of pembrolizumab in metastatic gastric cancer (mGC), revealing that patients with microsatellite instability-high and Epstein-Barr virus-positive tumors exhibit remarkable response rates of 85.7% and 100%, respectively. Additionally, higher response rates were observed in PD-L1 positive tumors, and changes in circulating tumor DNA (ctDNA) levels post-treatment correlated with patient outcomes, highlighting potential biomarkers for identifying candidates likely to benefit from PD-1 targeted therapy.

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PD-1 inhibition · metastatic gastric cancer · microsatellite instability · Epstein-Barr virus · circulating tumor DNA

Abstract ​

Clinical studies support the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic gastric cancer (mGC). With the goal of identifying determinants of response, we performed molecular characterization of tissues and circulating tumor DNA (ctDNA) from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial. In patients with microsatellite instability-high and Epstein-Barr virus-positive tumors, which are mutually exclusive, dramatic responses to pembrolizumab were observed (overall response rate (ORR) 85.7% in microsatellite instability-high mGC and ORR 100% in Epstein-Barr virus-positive mGC). For the 55 patients for whom programmed death-ligand 1 (PD-L1) combined positive score positivity was available (combined positive score cut-off value ≥1%), ORR was significantly higher in PD-L1(+) gastric cancer when compared to PD-L1(-) tumors (50.0% versus 0.0%, P value <0.001). Changes in ctDNA levels at six weeks post-treatment predicted response and progression-free survival, and decreased ctDNA was associated with improved outcomes. Our findings provide insight into the molecular features associated with response to pembrolizumab in patients with mGC and provide biomarkers potentially relevant for the selection of patients who may derive greater benefit from PD-1 inhibition.

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Primary Questions Addressed ​

  1. What specific molecular features are associated with the high response rates in microsatellite instability-high and Epstein-Barr virus-positive metastatic gastric cancer?
  2. How do the clinical outcomes of PD-1 inhibition compare across different molecular subtypes of metastatic gastric cancer beyond just PD-L1 positivity?
  3. What are the potential implications of ctDNA level changes on the long-term management and follow-up strategies for patients undergoing PD-1 targeted therapy?
  4. In what ways could the findings of this study influence future clinical trial designs for therapies targeting PD-1 in gastric cancer?
  5. What other biomarkers could be explored in conjunction with PD-1 inhibition to enhance patient selection and predict treatment outcomes in metastatic gastric cancer?

Key Findings ​

Key Insights ​

  1. Research Background and Objective: The study investigates the clinical responses to PD-1 inhibition in metastatic gastric cancer (mGC), where there is a documented efficacy of PD-1 targeted therapies in a subset of patients. The objective was to identify molecular determinants that predict responses to pembrolizumab treatment, thereby enhancing patient selection for PD-1 inhibition therapy.

  2. Main Methods and Findings: The research involved comprehensive molecular characterization of both tissue samples and circulating tumor DNA (ctDNA) from 61 patients with mGC enrolled in a prospective phase 2 clinical trial. Key findings include:

    • Patients with microsatellite instability-high (MSI-H) tumors exhibited a high overall response rate (ORR) of 85.7%, while those with Epstein-Barr virus (EBV)-positive tumors demonstrated a remarkable ORR of 100%. Notably, these two tumor types are mutually exclusive.
    • Among the 55 patients for whom programmed death-ligand 1 (PD-L1) combined positive score (CPS) data were available, those with PD-L1-positive tumors had a significantly higher ORR of 50.0% compared to 0.0% in PD-L1-negative tumors (P < 0.001).
    • The study also highlighted that changes in ctDNA levels at six weeks post-treatment were predictive of both treatment response and progression-free survival, with decreased ctDNA correlating with improved clinical outcomes.

  3. Core Conclusions: The study concludes that specific molecular characteristics, particularly MSI-H and EBV-positive status, are strong predictors of response to PD-1 inhibition in mGC. Additionally, the PD-L1 CPS serves as a valuable biomarker for identifying patients likely to benefit from pembrolizumab therapy. The ctDNA analysis provides a non-invasive method to monitor treatment efficacy and could facilitate timely clinical decisions.

  4. Research Significance and Impact: This research significantly contributes to the understanding of molecular features that predict the efficacy of PD-1 inhibitors in metastatic gastric cancer, potentially leading to more personalized treatment strategies. The identification of biomarkers such as MSI-H, EBV positivity, and PD-L1 CPS can refine patient selection for immunotherapy, improving outcomes in mGC. Furthermore, the correlation between ctDNA dynamics and clinical response underscores the potential of liquid biopsy techniques in oncology, promoting a shift towards more adaptive treatment approaches in cancer care. This study's findings may influence future clinical protocols and encourage further exploration into the molecular basis of treatment responses in other malignancies.

Literatures Citing This Work ​

  1. What's New in Gastric Cancer: The Therapeutic Implications of Molecular Classifications and Future Perspectives. - Giuseppe Tirino;Luca Pompella;Angelica Petrillo;Maria Maddalena Laterza;Annalisa Pappalardo;Marianna Caterino;Michele Orditura;Fortunato Ciardiello;Gennaro Galizia;Ferdinando De Vita - International journal of molecular sciences (2018)
  2. Computational measurement of tumor immune microenvironment in gastric adenocarcinomas. - Young Hwan Chang;You Jeong Heo;Junhun Cho;Sang Yong Song;Jeeyun Lee;Kyoung-Mee Kim - Scientific reports (2018)
  3. EBV-associated gastric cancer evades T-cell immunity by PD-1/PD-L1 interactions. - Sho Sasaki;Jun Nishikawa;Kohei Sakai;Hisashi Iizasa;Hironori Yoshiyama;Masashi Yanagihara;Takuya Shuto;Kanami Shimokuri;Teru Kanda;Yutaka Suehiro;Takahiro Yamasaki;Isao Sakaida - Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association (2019)
  4. Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8+ T cells in the tumor microenvironment. - Yasuko Tada;Yosuke Togashi;Daisuke Kotani;Takeshi Kuwata;Eichi Sato;Akihito Kawazoe;Toshihiko Doi;Hisashi Wada;Hiroyoshi Nishikawa;Kohei Shitara - Journal for immunotherapy of cancer (2018)
  5. In the literature: October 2018. - Desamparados Roda;Valentina Gambardella;Andrés Cervantes - ESMO open (2018)
  6. PD-L1 expression and the prognostic significance in gastric cancer: a retrospective comparison of three PD-L1 antibody clones (SP142, 28-8 and E1L3N). - Jing Ma;Jianhui Li;Meirui Qian;Weili Han;Miaomiao Tian;Zengshan Li;Zhe Wang;Shuixiang He;Kaichun Wu - Diagnostic pathology (2018)
  7. The role of neoantigen in immune checkpoint blockade therapy. - Ming Yi;Shuang Qin;Weiheng Zhao;Shengnan Yu;Qian Chu;Kongming Wu - Experimental hematology & oncology (2018)
  8. Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine. - Jake R Conway;Eric Kofman;Shirley S Mo;Haitham Elmarakeby;Eliezer Van Allen - Genome medicine (2018)
  9. Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma. - Yoshiyuki Yamamoto;Motohide Uemura;Masashi Fujita;Kazuhiro Maejima;Yoko Koh;Makoto Matsushita;Kosuke Nakano;Yujiro Hayashi;Cong Wang;Yu Ishizuya;Toshiro Kinouchi;Takuji Hayashi;Kyosuke Matsuzaki;Kentaro Jingushi;Taigo Kato;Atsunari Kawashima;Takeshi Ujike;Akira Nagahara;Kazutoshi Fujita;Ryoichi Imamura;Hidewaki Nakagawa;Norio Nonomura - Cancer science (2019)
  10. Clinical efficacy of immune checkpoint inhibitors in the treatment of unresectable advanced or recurrent gastric cancer: an evidence-based review of therapies. - Kazuhiro Togasaki;Yasutaka Sukawa;Takanori Kanai;Hiromasa Takaishi - OncoTargets and therapy (2018)

... (936 more literatures)

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