Revolutionizing the Fight: How Immunotherapy is Transforming Esophageal Cancer
Main Article Content
Abstract
The treatment of esophageal cancer has evolved significantly over the past decade with the emergence of immunotherapy, particularly through the use of immune checkpoint inhibitors (ICIs) such as nivolumab and pembrolizumab. Although gastrointestinal cancers initially showed limited response, recent studies have demonstrated efficacy in selected subgroups, particularly in tumors with high PD-L1 expression or microsatellite instability (MSI-H).
Esophageal cancer consists of two main subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (AC), each with distinct molecular, anatomical and epidemiological characteristic requiring tailored therapeutic approaches. Despite advances in multimodal therapy, overall survival remains low, especially in metastatic disease.
In localized disease, studies such as CROSS and CheckMate-577 have established the role of neoadjuvant chemoradiotherapy followed by surgery, with adjuvant nivolumab now considered standard of care for patients with residual disease. In advanced disease, trials such as KEYNOTE-590 and CHECKMATE-648 have shown survival benefits with the addition of immunotherapy to standard chemotherapy as first-line treatment.
PD-L1 remains a key biomarker for patient selection, although its clinical interpretation is influenced by biological and technical challenges. Furthermore, novel immunotherapeutic strategies involving an�bodies targeing TIGIT, LAG-3, and CTLA-4 are currently under investigation.
In conclusion, immunotherapy has redefined the standard of care in esophageal cancer, offering improved outcomes in specific clinical contexts. However, standardization of biomarker evaluation and direct comparison trials are still needed to optimize therapy selection and patient benefit.
Article Details
How to Cite
TAMBURELLI, Mercedes; CASTILLO, Javier.
Revolutionizing the Fight: How Immunotherapy is Transforming Esophageal Cancer.
Medical Research Archives, [S.l.], v. 13, n. 6, june 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6582>. Date accessed: 15 july 2025.
doi: https://doi.org/10.18103/mra.v13i6.6582.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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30. Shah MA, Kojima T, Hochhauser D, et al. Efficacy and Safety of Pembrolizumab for Heavily Pretreated Patients With Advanced, Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus: The Phase 2 KEYNOTE-180 Study. JAMA Oncol. 2019;5(4):546-550. doi:10.1001/jamaoncol.2018.5441
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34. Metges JP, Kato K, Sun JM, et al. First-line pembrolizumab plus chemotherapy versus chemotherapy in advanced esophageal cancer: longer-term efficacy, safety, and quality-of-life results from the phase 3 KEYNOTE-590 study. J Clin Oncol. 2022;40(4_suppl):241. doi:10.1200/jco.2022.40.4_suppl.241
35. Doki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022;386(5):449-462. doi:10.1056/NEJMoa2111380
36. Luo H, Lu J, Bai Y, 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):916-925. doi:10.1001/jama.2021.12836
37. Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study [published correction appears in Lancet Oncol. 2024 Mar;25(3):e102. doi: 10.1016/S1470-2045(24)00018-4.]. Lancet Oncol. 2023;24(5):483-495. doi:10.1016/S1470-2045(23)00108-0
38. Shen L, Lu Z-H, Wang J-Y, et al. LBA52 Sintilimab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced or metastatic esophageal squamous cell cancer: First results of the phase III orient-15 study. Ann Oncol. 2021;32. doi:10.1016/j.annonc.2021.08.2132
39. Wang ZX, Cui C, Yao J, 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):277-288.e3. doi:10.1016/j.ccell.2022.02.
40. Lynch E, Duffy AG, Kelly RJ. Role of Immunotherapy in Gastroesophageal Cancers-Advances, Challenges and Future Strategies. Cancers (Basel). 2023;15(22):5401. Published 2023 Nov 14. doi:10.3390/cancers15225401
41. Klempner SJ, Shitara K, Sison A, et al. Star-221: A randomized, open-label, Multicenter, Phase 3 trial of domvanalimab, zimberelimab, and chemotherapy versus nivolumab and chemotherapy in previously untreated, locally advanced, unresectable or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma. J Clin Oncol. 2023;41(16_suppl). doi:10.1200/jco.2023.41.16_suppl.tps4206
2. Arnold M, Abnet CC, Neale RE, et al. Global burden of 5 major types of gastrointestinal cancer. Gastroenterology. 2020;159(1). doi:10.1053/j.gastro.2020.02.068
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6. Madan A, Uronis HE, Strickler JH. A narrative review of the evolving role of immunotherapy in the management of esophageal and gastric cancer. J Gastrointest Oncol. 2022;13(4):2007-2019. doi:10.21037/jgo-22-55
7. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors. Clin Cancer Res. 2019;25(13):3753-3758. doi:10.1158/1078-0432.CCR-18-4070
8. Mastracci L, Grillo F, Parente P, et al. PD-L1 evaluation in the gastrointestinal tract: from biological rationale to its clinical application. Pathologica. 2022;114(5):352-364. doi:10.32074/1591-951X-803
9. Heskamp S, Hobo W, Molkenboer-Kuenen JD, et al. Noninvasive Imaging of Tumor PD-L1 Expression Using Radiolabeled Anti-PD-L1 Antibodies. Cancer Res. 2015;75(14):2928-2936. doi:10.1158/0008-5472.CAN-14-3477
10. Rebelatto MC, Midha A, Mistry A, et al. Development of a programmed cell death ligand-1 immunohistochemical assay validated for analysis of non-small cell lung cancer and head and neck squamous cell carcinoma. Diagn Pathol. 2016;11(1):95. Published 2016 Oct 8. doi:10.1186/s13000-016-0545-8
11. Munari E, Zamboni G, Lunardi G, et al. PD-L1 Expression Heterogeneity in Non-Small Cell Lung Cancer: Defining Criteria for Harmonization between Biopsy Specimens and Whole Sections [published correction appears in J Thorac Oncol. 2019 Apr;14(4):744. doi: 10.1016/j.jtho.2019.01.018.]. J Thorac Oncol. 2018;13(8):1113-1120. doi:10.1016/j.jtho.2018.04.017
12. Bodor JN, Boumber Y, Borghaei H. Biomarkers for immune checkpoint inhibition in non-small cell lung cancer (NSCLC). Cancer. 2020;126(2):260-270. doi:10.1002/cncr.32468
13. Hendry S, Byrne DJ, Wright GM, et al. Comparison of Four PD-L1 Immunohistochemical Assays in Lung Cancer. J Thorac Oncol. 2018;13(3):367-376. doi:10.1016/j.jtho.2017.11.112
14. Ahn S, Kim KM. PD-L1 expression in gastric cancer: interchangeability of 22C3 and 28-8 pharmDx assays for responses to immunotherapy. Mod Pathol. 2021;34(9):1719-1727. doi:10.1038/s41379-021-00823-9
15. Yeong J, Lum HYJ, Teo CB, et al. Choice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy. Gastric Cancer. 2022;25(4):741-750. doi:10.1007/s10120-022-01301-0
16. Cooper WA, Russell PA, Cherian M, et al. Intra- and Interobserver Reproducibility Assessment of PD-L1 Biomarker in Non-Small Cell Lung Cancer. Clin Cancer Res. 2017;23(16):4569-4577. doi:10.1158/1078-0432.CCR-17-0151
17. Obermannová R, Alsina M, Cervantes A, et al. Oesophageal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(10):992-1004. doi:10.1016/j.annonc.2022.07.003
18. NCCN Clinical Practice Guidelines in Oncology. Esophageal and Esophagogastric Junction Cancer. Version 3.2024 – April 26, 2024. Available online: https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf,accessed 28 DIC 2024
19. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074-2084. doi:10.1056/NEJMoa1112088
20. Eyck BM, van Lanschot JJB, Hulshof MCCM, 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
21. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer [published correction appears in N Engl J Med. 2023 Feb 16;388(7):672. doi: 10.1056/NEJMx220014.]. N Engl J Med. 2021;384(13):1191-1203. doi:10.1056/NEJMoa2032125
22. Mamdani H, Schneider BJ, Abushahin LI, et al. Safety and efficacy of durvalumab following multimodality therapy for locally advanced esophageal and GEJ adenocarcinoma: Results from Big Ten Cancer Research Consortium Study. J Clin Oncol. 2019;37(15_suppl):4058-4058. doi:10.1200/jco.2019.37.15_suppl.4058
23. Valkema MJ, Mostert B, Lagarde SM, Wijnhoven BPL, van Lanschot JJB. The effectivity of targeted therapy and immunotherapy in patients with advanced metastatic and non-metastatic cancer of the esophagus and esophago-gastric junction. Updates Surg. 2023;75(2):313-323. doi:10.1007/s13304-022-01327-0
24. Shah MA, Bennouna J, Doi T, 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):1143-1153. doi:10.2217/fon-2020-0969
25. Wang L, Chen M, Kato K, et al. A phase 3 randomized, double-blind, placebo-controlled, Multicenter, Global Study of durvalumab with and after chemoradiotherapy in patients with locally advanced, unresectable esophageal squamous cell carcinoma: Kunlun. J Clin Oncol. 2022;40(4_suppl). doi:10.1200/jco.2022.40.4_suppl.tps373
26. Eads JR, Weitz M, Catalano PJ, et al. A phase II/III study of perioperative nivolumab and Ipilimumab in patients (PTS) with locoregional esophageal (e) and gastroesophageal junction (GEJ) adenocarcinoma: Results of a safety run-in—a trial of the ECOG-acrin cancer research group (EA2174). J Clin Oncol. 2021;39(15_suppl):4064-4064. doi:10.1200/jco.2021.39.15_suppl.4064
27. Kelly RJ, Landon BV, Zaidi AH, et al. Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/ gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses. Nat Med. 2024;30(4):1023-1034. doi:10.1038/s41591-024-02877-z
28. Goodman KA, Xu R, Chau I, et al. Skyscraper-07: A phase III, randomized, double-blind, placebo-controlled study of atezolizumab with or without tiragolumab in patients with unresectable ESCC who have not progressed following definitive concurrent chemoradiotherapy. J Clin Oncol. 2022;40(4_suppl). doi:10.1200/jco.2022.40.4_suppl.tps374
29. Doi T, Piha-Paul SA, Jalal SI, et al. Safety and antitumor activity of the anti–programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma. J Clin Oncol. 2018;36(1):61-67. doi:10.1200/jco.2017.74.9846
30. Shah MA, Kojima T, Hochhauser D, et al. Efficacy and Safety of Pembrolizumab for Heavily Pretreated Patients With Advanced, Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus: The Phase 2 KEYNOTE-180 Study. JAMA Oncol. 2019;5(4):546-550. doi:10.1001/jamaoncol.2018.5441
31. Kojima T, Shah MA, Muro K, et al. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020;38(35):4138-4148. doi:10.1200/JCO.20.01888
32. Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial [published correction appears in Lancet Oncol. 2019 Nov;20(11):e613. doi: 10.1016/S1470-2045(19)30646-1.]. Lancet Oncol. 2019;20(11):1506-1517. doi:10.1016/S1470-2045(19)30626-6
33. Sun JM, Shen L, Shah MA, 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 [published correction appears in Lancet. 2021 Nov 20;398(10314):1874. doi: 10.1016/S0140-6736(21)02487-9.]. Lancet. 2021;398(10302):759-771. doi:10.1016/S0140-6736(21)01234-4
34. Metges JP, Kato K, Sun JM, et al. First-line pembrolizumab plus chemotherapy versus chemotherapy in advanced esophageal cancer: longer-term efficacy, safety, and quality-of-life results from the phase 3 KEYNOTE-590 study. J Clin Oncol. 2022;40(4_suppl):241. doi:10.1200/jco.2022.40.4_suppl.241
35. Doki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022;386(5):449-462. doi:10.1056/NEJMoa2111380
36. Luo H, Lu J, Bai Y, 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):916-925. doi:10.1001/jama.2021.12836
37. Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study [published correction appears in Lancet Oncol. 2024 Mar;25(3):e102. doi: 10.1016/S1470-2045(24)00018-4.]. Lancet Oncol. 2023;24(5):483-495. doi:10.1016/S1470-2045(23)00108-0
38. Shen L, Lu Z-H, Wang J-Y, et al. LBA52 Sintilimab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced or metastatic esophageal squamous cell cancer: First results of the phase III orient-15 study. Ann Oncol. 2021;32. doi:10.1016/j.annonc.2021.08.2132
39. Wang ZX, Cui C, Yao J, 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):277-288.e3. doi:10.1016/j.ccell.2022.02.
40. Lynch E, Duffy AG, Kelly RJ. Role of Immunotherapy in Gastroesophageal Cancers-Advances, Challenges and Future Strategies. Cancers (Basel). 2023;15(22):5401. Published 2023 Nov 14. doi:10.3390/cancers15225401
41. Klempner SJ, Shitara K, Sison A, et al. Star-221: A randomized, open-label, Multicenter, Phase 3 trial of domvanalimab, zimberelimab, and chemotherapy versus nivolumab and chemotherapy in previously untreated, locally advanced, unresectable or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma. J Clin Oncol. 2023;41(16_suppl). doi:10.1200/jco.2023.41.16_suppl.tps4206