Immune checkpoint inhibitors in esophageal cancer: Clinical development and perspectives

References

• Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers In 185 countries. CA Cancer J Clin. 2021;71(3):1–12. doi:10.3322/caac.21660.
   Web of Science ®Google Scholar
• Thrift AP. The epidemic of esophageal carcinoma: where are we now? Cancer Epidemiol. 2016;41:88–95. doi:10.1016/j.canep.2016.01.013.
   PubMed Web of Science ®Google Scholar
• Ajani JA, D’Amico TA, Bentrem DJ, Chao J, Corvera C, Das P, Denlinger CS, Enzinger PC, Fanta P, Farjah F, et al. Esophageal and esophagogastric junction cancers, version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Network. 2019;17(7):855–83. doi:10.6004/jnccn.2019.0033.
   PubMed Web of Science ®Google Scholar
• Shah MA. Update on metastatic gastric and esophageal cancer. J Clin Oncol. 2015;33(16):1760–69. doi:10.1200/JCO.2014.60.1799.
   PubMed Web of Science ®Google Scholar
• Ingelfinger JR, Rustgi AK, El-Serag HB, Ingelfinger JR. Esophageal carcinoma. N Engl J Med. 2014;371(26):2499–509. doi:10.1056/NEJMra1314530.
   PubMed Web of Science ®Google Scholar
• American Cancer Society. Esophagus cancer, early detection, diagnosis, and staging; [ accessed 2022 Jun 30]. https://www.cancer.org/cancer/esophagus-cancer/detection-diagnosis-staging/survival-rates.html.
   Google Scholar
• Hiramoto S, Kato K, Shoji H, Okita N, Takashima A, Honma Y, Iwasa S, Hamaguchi T, Yamada Y, Shimada Y, et al. A retrospective analysis of 5-fluorouracil plus cisplatin as first-line chemotherapy in the recent treatment strategy for patients with metastatic or recurrent esophageal squamous cell carcinoma. Int J Clin Oncol. 2018;23(3):466–72. doi:10.1007/s10147-018-1239-x.
   PubMed Web of Science ®Google Scholar
• Moehler M, Maderer A, Thuss -, Brenner B, Meiler J, Ettrich TJ, Hofheinz R-D, Al-Batran SE, Vogel A, Mueller L, et al. Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER). Ann Oncol. 2020;31(2):228–35. doi:10.1016/j.annonc.2019.10.018.
   PubMed Web of Science ®Google Scholar
• Crosby T, Hurt CN, Falk S, Gollins S, Mukherjee S, Staffurth J, Ray R, Bashir N, Bridgewater JA, Geh JI, et al. Chemotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicenter, phase 2/3 randomised trial. Lancet Oncol. 2013;14(7):627–37. doi:10.1016/S1470-2045(13)70136-0.
   PubMed Web of Science ®Google Scholar
• Suntharalingam M, Winter K, Ilson D, Dicker AP, Kachnic L, Konski A, Chakravarthy AB, Anker CJ, Thakrar H, Horiba N, et al. Effect of the addition of cetuximab to paclitaxel, cisplatin, and radiation therapy for patients with esophageal cancer: the NRG oncology RTOG 0436 Phase 3 randomized clinical trial. JAMA Oncol. 2017;3(11):1520–28. doi:10.1001/jamaoncol.2017.1598.
   PubMed Web of Science ®Google Scholar
• Lorenzen S, Schuster T, Porschen R, Al-Batran S-E, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, et al. Cetuximab plus cisplatin–5-fluorouracil versus cisplatin–5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009;20(10):1667–73. doi:10.1093/annonc/mdp069.
   PubMed Web of Science ®Google Scholar
• Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligand in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239–45. doi:10.1038/ni1443.
   PubMed Web of Science ®Google Scholar
• Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19(7):813–24. doi:10.1093/intimm/dxm057.
   PubMed Web of Science ®Google Scholar
• Nurieva RI, Liu X, Dong C. Yin-Yang of costimulation: crucial controls of immune tolerance and function. Immunol Rev. 2009;229(1):88–100. doi:10.1111/j.1600-065X.2009.00769.x.
   PubMedGoogle Scholar
• Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P, Ott PA, Peltola K, Jaeger D, Evans J, et al. CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol. 2018;36(28):2836–44. doi:10.1200/JCO.2017.76.6212.
   PubMed Web of Science ®Google Scholar
• Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018;18(3):153–67. doi:10.1038/nri.2017.108.
   PubMed Web of Science ®Google Scholar
• Brahmer JR, Drake CG, Woller I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, et al. Phase I study of single-agent anti–programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167–75. doi:10.1200/JCO.2009.26.7609.
   PubMed Web of Science ®Google Scholar
• Raufi AG, Klempner SJ. Immunotherapy for advanced gastric and esophageal cancer: preclinical rationale and ongoing clinical investigations. J Gastrointest Oncol. 2015;6(5):561–69. doi:10.3978/j.issn.2078-6891.2015.037.
   PubMed Web of Science ®Google Scholar
• Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu C-H, Doi T, Moriwaki T, Kim S-B, Lee S-H, et al. randomized phase III KEYNOTE-181 Study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncol. 2020;38(35):4138–48. doi:10.1200/JCO.20.01888.
   PubMed Web of Science ®Google Scholar
• Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–55. doi:10.1126/science.aar4060.
   PubMed Web of Science ®Google Scholar
• Kato K, Cho BC, Takahashi M, Okada M, Lin C-Y, Chin K, Kadowaki S, Ahn M-J, Hamamoto Y, Doki Y, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomized, open-label, phase 3 trial. Lancet Oncol. 2019;20(11):1506–17. doi:10.1016/S1470-2045(19)30626-6.
   PubMed Web of Science ®Google Scholar
• Chen L, Sun J, Wu H, Zhou S-M, Tan Y, Tan M, Shan B-E, Lu B-F, Zhang X-G. B7-H4 expression associates with cancer progression and predicts patient’s survival in human esophageal squamous cell carcinoma. Cancer Immunol Immunother. 2011;60(7):1047–55. doi:10.1007/s00262-011-1017-3.
   PubMed Web of Science ®Google Scholar
• Shah MA, Kojima T, Hochhauser D, Enzinger P, Raimbourg J, Hollebecque A, Lordick F, Kim S-B, Tajika M, Kim HT, et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of esophagus. The phase 2 KEYNOTE-180 study. JAMA Oncol. 2019;5(4):546–50. doi:10.1001/jamaoncol.2018.5441.
   PubMed Web of Science ®Google Scholar
• Kudo T, Hamamoto Y, Kato K, Ura T, Kojima T, Tsushima T, Hironaka S, Hara H, Satoh T, Iwasa S, et al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, Phase 2 trial. Lancet Oncol. 2017;18(5):631–39. doi:10.1016/S1470-2045(17)30181-X.
   PubMed Web of Science ®Google Scholar
• Kato K, Doki Y, Ura T, Hamamoto Y, Kojima T, Tsushima T, Hironaka S, Hara H, Kudo T, Iwasa S, et al. Long-term efficacy and predictive correlates of response to nivolumab in Japanese patients with esophageal cancer. Cancer Sci. 2020;111(5):1676–84. doi:10.1111/cas.14380.
   PubMed Web of Science ®Google Scholar
• Shen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, Yu X, Shu Y, Luo Q, Wang J, et al. Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): a randomized phase III study. J Clin Oncol. 2022;40(26):3065–76. JCO2101926. doi:10.1200/JCO.21.01926.
   PubMed Web of Science ®Google Scholar
• Khoja L, Day D, Wei-Wu Chen T, Siu LL, Hansen AR. Tumour- and class-specific patterns of immune-related adverse events of immune check point inhibitors: a systematic review. Ann Oncol. 2017;28(10):2377–85. doi:10.1093/annonc/mdx286.
   PubMed Web of Science ®Google Scholar
• Wang Y, Zhou S, Yang F, Qi X, Wang X, Guan X, Shen C, Duma N, Vera Aguilera J, Chintakuntlawar A, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials a systematic review and meta-analysis. JAMA Oncol. 2019;5(7):1008–19. doi:10.1001/jamaoncol.2019.0393.
   PubMed Web of Science ®Google Scholar
• Gangadher TC, Vonderheide RH. Mitigating the toxic effects of anti-cancer immunotherapy. Nat Rev Clin Oncol. 2014;11(2):91–99. doi:10.1038/nrclinonc.2013.245.
   PubMed Web of Science ®Google Scholar
• Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM, Ginex P, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714–68. doi:10.1200/JCO.2017.77.6385.
   PubMed Web of Science ®Google Scholar
• Gaudhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, et al. Pembrolizumab Plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078–92. doi:10.1056/NEJMoa1801005.
   PubMed Web of Science ®Google Scholar
• Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21(1):15–25. doi:10.1038/cdd.2013.67.
   PubMed Web of Science ®Google Scholar
• Wang Z, Till B, . Chemotherapeutic agent-mediated elimination of myeloid-derived suppressor cells. Oncoimmunology. 2017;6:e1331807. doi:10.1080/2162402X.2017.1331807.
   PubMed Web of Science ®Google Scholar
• Roselli M, Cereda V, di Bari MG, Formica V, Spila A, Jochems C, Farsaci B, Donahue R, Gulley JL, Schlom J, et al. Effects of conventional therapeutic interventions on the number and function of regulatory T cells. Oncoimmunology. 2013;2(10):e27025. doi:10.4161/onci.27025.
   PubMed Web of Science ®Google Scholar
• Lesterhuis WJ, Punt CJ, Hato SV, Eleveld-Trancikova D, Jansen BJH, Nierkens S, Schreibelt G, de Boer A, Van Herpen CML, Kaanders JH, et al. Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J Clin Invest. 2011;121(8):3100–08. doi:10.1172/JCI43656.
   PubMed Web of Science ®Google Scholar
• Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, Kojima T, Metges J-P, Li Z, Kim S-B, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759–71. doi:10.1016/S0140-6736(21)01234-4.
   PubMed Web of Science ®Google Scholar
• Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu C-H, Adenis A, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386(5):449–62. doi:10.1056/NEJMoa2111380.
   PubMed Web of Science ®Google Scholar
• Yoon HH, Kato K, Raymond E, Hubner R, Shu Y, Pan Y, Jiang Y, Zhang J, Park S, Kojima T, et al. RATIONALE-306: randomized, global, placebo-controlled, double-blind Phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma. Esmo Wgi. 2022;33:S375. Abstract LBA-1. doi:10.1016/j.annonc.2022.04.439.
   Web of Science ®Google Scholar
• Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, Zhang Y, Zhao K, Chen Z, Gao S, et al. Effect of camrelizumab vs placebo added to chemotherapy on survival and progression-free survival in patients with advanced or metastatic esophageal squamous cell carcinoma. The ESCORT-1st randomized clinical trial. JAMA. 2021;326(10):916–25. doi:10.1001/jama.2021.12836.
   PubMed Web of Science ®Google Scholar
• Lu Z, Wang J, Shu Y, Liu L, Kong L, Yang L, Wang B, Shun G, Ji Y, Cao G, et al. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ. 2022;377:e068714. doi:10.1136/bmj-2021-068714.
   PubMedGoogle Scholar
• Wang ZX, Cui C, Yao J, Zhang Y, Li M, Feng J, Yang S, Fan Y, Shi J, Zhang X, et al. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): a multi-center phase 3 trial. Cancer Cell. 2022;40(3):277–88.e3. doi:10.1016/j.ccell.2022.02.007.
   PubMed Web of Science ®Google Scholar
• Chau I, Ajani JA, Doki Y, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu C, Adenis A, et al. Nivolumab plus chemotherapy or ipilimumab vs chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma: expanded efficacy and safety analyses from CheckMate 648. Esmo Wgi. 2022;33:S379–80. Abstract O-3. doi:10.1016/j.annonc.2022.04.444.
   Web of Science ®Google Scholar
• Zhou X, Yao Z, Bai H, Duan J, Wang Z, Wang X, Zhang X, Xu J, Fei K, Zhang Z, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitor-based combination therapies in clinical trials: a systematic review and meta-analysis. Lancet Oncol. 2021;22(9):1265–74. doi:10.1016/S1470-2045(21)00333-8.
   PubMed Web of Science ®Google Scholar
• Yang Y, Gin G, Pang Y, Huang Y, Wang W, Zhang H, Tuo G, Wu P, Wang Z, Zhu Z. Comparative efficacy and safety of nivolumab and nivolumab plus ipilimumab in advanced cancer: a systematic review and meta-analysis. Front Pharmacol. 2020;11:40. doi:10.3389/fphar.2020.00040.
   PubMed Web of Science ®Google Scholar
• Da L, Teng Y, Wang N, Zaguirre K, Liu Y, Qi Y, Song F. Organ-specific immune-related adverse events associated with immune checkpoint inhibitor monotherapy versus combination therapy in cancer: a meta-analysis of randomized controlled trials. Front Pharmacol. 2020;10:1671. doi:10.3389/fphar.2019.01671.
   PubMed Web of Science ®Google Scholar
• Park R, Lopes L, Cristancho CR, Riano IM, Saeed A. Treatment -related adverse events of combination immune checkpoint inhibitors: systematic review and meta-analysis. Front Oncol. 2020;10:258. doi:10.3389/fonc.2020.00258.
   PubMed Web of Science ®Google Scholar
• Almutairi AR, McBride A, Slack M, Erstad BL, Abraham I. Potential immune-related adverse events associated with monotherapy and combination therapy of ipilimumab, nivolumab, and pembrolizumab for advanced melanoma: a systematic review and meta-analysis. Front Oncol. 2020;10:91. doi:10.3389/fonc.2020.00091.
   PubMed Web of Science ®Google Scholar
• Gu L, Khadaroo PA, Su H, Kong L, Chen L, Wang X, Li X, Zhu H, Zhong X, Pan J, et al. The safety and tolerability of combined immune checkpoint inhibitors (anti-PD-1/PD-L1 plus anti-CTLA-4): a systematic review and meta-analysis. BMC Cancer. 2019;19(1):559. doi:10.1186/s12885-019-5785-z.
   PubMed Web of Science ®Google Scholar
• Koshkin VS, Sonpavda GP, Hwang C, Mellado B, Tomlinson G, Shimura M, Chisamore MJ, Gil M, Loriot Y. Futibatinib plus pembrolizumab in patients (pts) with advanced or metastatic urothelial carcinoma (mUC): preliminary safety results from a phase 2 study. ASCO Genitourinary Cancer Symposium. 2022;40(6_suppl):501. Abstract #501. doi:10.1200/JCO.2022.40.6_suppl.501.
   Google Scholar
• Doleschel D, Hoff S, Koletnik S, Rix A, Zopf D, Kiessling F, Lederle W. Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth. J Explained Clin Cancer Res. 2021;40(1):288. doi:10.1186/s13046-021-02043-0.
   PubMed Web of Science ®Google Scholar
• Kato Y, Tabata K, Kimura T, Yachie-Kinoshita A, Ozawa Y, Yamada K, Ito J, Tachino S, Hori Y, Matsuki M, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One. 2019;14(2):e0212513. doi:10.1371/journal.pone.0212513.
   PubMed Web of Science ®Google Scholar
• Sharabi AB, Lim M, DeWeese TL, Drake CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 2015;16(13):e498–509. doi:10.1016/S1470-2045(15)00007-8.
   PubMed Web of Science ®Google Scholar
• Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2343–50. doi:10.1056/NEJMoa1809697.
   Web of Science ®Google Scholar
• Shah MA, Bennouna J, Doi T, Shen L, Kato K, Adenis A, Mamon HJ, Moehler M, Fu X, Cho BC, et al. KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma. Future Oncol. 2021;17(10):1143–53. doi:10.2217/fon-2020-0969.
   PubMed Web of Science ®Google Scholar
• Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, Nakamura T, Yabusaki H, Aoyama N, Kurita A, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012;19(1):68–74. doi:10.1245/s10434-011-2049-9.
   PubMed Web of Science ®Google Scholar
• Eyck BM, van Lanschot JJB, Hulshof MCCM, van der Wilk BJ, Shapiro J, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, et al. Ten-Year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: the Randomized controlled CROSS trial. J Clin Oncol. 2021;39(18):1995–2004. doi:10.1200/JCO.20.03614.
   PubMed Web of Science ®Google Scholar
• Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, Kiel K, Willett C, Sugarbaker D, Mayer R. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008;26(7):1086–92. doi:10.1200/JCO.2007.12.9593.
   PubMed Web of Science ®Google Scholar
• Liu J, Li J, Lin W, Shao D, Depypere L, Zhang Z, Li Z, Cui F, Du Z, Zeng Y, et al. Neoadjuvant camrelizumab plus chemotherapy for resectable, locally advanced esophageal squamous cell carcinoma (NIC-ESCC2019): amulticenter, phase 2 study. Int J Cancer. 2022;151(1):128–37. doi:10.1002/ijc.33976.
   PubMed Web of Science ®Google Scholar
• Shang X, Zhao G, Liang F, Zhang C, Zhang W, Liu L, Li R, Duan X, Ma Z, Yue J, et al. Safety and effectiveness of pembrolizumab combined with paclitaxel and cisplatin as neoadjuvant therapy followed by surgery for locally advanced resectable (stage III) esophageal squamous cell carcinoma: a study protocol for a prospective, single-arm, single center, open-label, phase-II trial (Keystone-001). Ann Transl Med. 2022;10:229.
   PubMed Web of Science ®Google Scholar
• Shang X, Zhang W, Zhao G, Liang F, Zhang C, Yue J, Duan X, Ma Z, Chen C, Pang Q, et al. Pembrolizumab combined with neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy followed by surgery for locally advanced oesophageal squamous cell carcinoma: protocol for a multicentre, prospective, randomized-controlled, Phase III clinical study (Keystone-002). Front Oncol. 2022;12:831345.
   PubMedGoogle Scholar
• Li C, Zhao S, Zheng Y, Han Y, Chen X, Cheng Z, Wu Y, Feng X, Qi W, Chen K, et al. Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). Eur J Cancer. 2021;144:232–41. doi:10.1016/j.ejca.2020.11.039.
   PubMed Web of Science ®Google Scholar
• Zheng Y, Li C, Yu B, Zhao S, Li J, Chen X, Li H. Preoperative pembrolizumab combined with chemoradiotherapy for esophageal squamous cell carcinoma: trial design. JTCVS Open. 2021;9:293–99. doi:10.1016/j.xjon.2021.11.003.
   PubMedGoogle Scholar
• Lee S, Ahn BC, Park SY, Kim DJ, Lee CG, Cho J, Kim JH, Kim HR, Kim Y-H, Park SR, et al. A phase II trial of preoperative chemoradiotherapy and pembrolizumab for locally advanced esophageal squamous cell carcinoma (ESCC). 2019. Ann Oncol. 2019;30(v754):v754. doi:10.1093/annonc/mdz266.018.
   Google Scholar
• Kato K, Ito Y, Daiko H, Ozawa S, Ogata T, Hara H, Kojima T, Abe T, Bamba T, Watanabe M, et al. A randomized controlled phase III trial comparing two chemotherapy regimen and chemoradiotherapy regimen as neoadjuvant treatment for locally advanced esophageal cancer, JCOG1109 NExT study. 2022. ASCO Gastrointestinal Cancer Symposium.40(4_suppl): 238. Abstract #238. 10.1200/JCO.2022.40.4_suppl.238
   Google Scholar
• Yamamoto S, Kato K, Daiko H, Kojima T, Hara H, Abe T, Tsubosa Y, Nagashima K, Aoki K, Mizoguchi Y, et al. Feasibility study of nivolumab as neo adjuvant chemotherapy for locally esophageal carcinoma: FRONTiER (JCOG1804E). Future Oncol. 2020;16(19):1351–57. doi:10.2217/fon-2020-0189.
   PubMed Web of Science ®Google Scholar
• Matsuda S, Yamamot S, Kato K, Daiko H, Kojima T, Hara H, Abe T, Tsubosa Y, Kawakubo H, Nagashima K, et al. FRONTiER: a feasibility trial of nivolumab with neoadjuvant CF or DCF, FLOT therapy for locally advanced esophageal carcinoma (Jcog1804e)—short-term results for cohorts C and D. ASCO Gastrointestinal Cancer Symposium. 40(4_suppl): 286. Abstract #286. 10.1200/JCO.2022.40.4_suppl.286
   Google Scholar
• Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, Mendez G, Feliciano J, Motoyama S, Lièvre A, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;384(13):1191–203. doi:10.1056/NEJMoa2032125.
   PubMed Web of Science ®Google Scholar
• Yoon HH, Jin Z, Kour O, Kankeu Fonkoua LA, Shitara K, Gibson MK, Prokop LJ, Moehler M, Kang Y-K, Shi Q, et al. Association of PD-L1 expression and other variables with benefit from immune checkpoint inhibition in advanced gastroesophageal cancer. Systematic review and meta-analysis of 17 Phase 3 randomized clinical trials. JAMA Oncol. 2022;8(10):1456. doi:10.1001/jamaoncol.2022.3707.
   PubMed Web of Science ®Google Scholar
• Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20. doi:10.1056/NEJMoa1500596.
   PubMed Web of Science ®Google Scholar
• Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, Chung HC, Kindler HL, Lopez-Martin JA, Miller WH, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353–65. doi:10.1016/S1470-2045(20)30445-9.
   PubMed Web of Science ®Google Scholar
• Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord J-P, Geva R, Gottfried M, Penel N, Hansen AR, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1–10. doi:10.1200/JCO.19.02105.
   PubMed Web of Science ®Google Scholar
• Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022;603(7903):942–48. doi:10.1038/s41586-022-04508-4.
   PubMed Web of Science ®Google Scholar
• Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomized, open-label, phase 3 trial. Lancet. 2021;398(10294):27–40. doi:10.1016/S0140-6736(21)00797-2.
   PubMed Web of Science ®Google Scholar
• Shitara K, Cutsem EV, Bang YJ, Fuchs C, Wyrwicz L, Lee K-W, Kudaba I, Garrido M, Chung HC, Lee J, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer. The KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6(10):1571–80. doi:10.1001/jamaoncol.2020.3370.
   PubMed Web of Science ®Google Scholar
• Zhao JJ, Yap DWT, Chan YH, Tan BKJ, Teo CB, Syn NL, Smyth EC, Soon YY, Sundar R. Low programmed death-ligand 1–expressing Subgroup outcomes of first-line immune checkpoint inhibitors in gastric or esophageal adenocarcinoma. J Clin Oncol. 2022;40(4):392–402. doi:10.1200/JCO.21.01862.
   PubMed Web of Science ®Google Scholar