Immune checkpoint inhibition in advanced esophageal squamous cell carcinoma: how can we personalise management?

Esophageal cancer comprises two main histological subtypes, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). ESCC is the most common subtype worldwide, and has a dismal prognosis—5-year overall survival (OS) is ~15% (1). The majority of cases are diagnosed when curative treatment is not an option. For those who are eligible for and undergo curative treatment, relapse rate is high, either loco-regional tumour persistence or recurrence. When this occurs, first-line palliative systemic therapy comprises platinum-based chemotherapy with or without an immune checkpoint inhibitor (ICI) (2,3). On progression, options for second-line systemic therapy include chemotherapy or an ICI (4-7).

In this issue of Journal of Thoracic Disease, Zhu et al. (8) report findings from a meta-analysis of five randomised controlled trials investigating the role of ICIs as second-line therapies in advanced ESCC. Their meta-analysis of five phase 2 and 3 trials demonstrates, convincingly, that second-line therapy based on ICIs is more effective than chemotherapy for patients with advanced ESCC, with a lower side-effect burden. This finding was consistent across objective response rate [odds ratio (OR) =2.07; 95% CI: 1.22–3.52] and OS [hazard ratio (HR) =0.73; 95% CI: 0.66–0.81], although not progression-free survival (HR =0.93; 95% CI: 0.77–1.12).

ICI therapy has become a powerful tool to treat many solid-organ malignancies (9,10). For the proportion of patients whose disease shows response to ICI therapy, these drugs can offer durable tumour control, prolonged survival and are relatively well tolerated (10). In advanced ESCC, Zhu and colleagues’ meta-analysis demonstrates the benefit of ICI over chemotherapy in the second-line setting. Given the superiority of ICI to chemotherapy in the second-line setting, attention has already turned to the use of ICIs as a first-line treatment. Both the CheckMate 648 and KEYNOTE-590 trials (3,11) showed that a combination of ICI and chemotherapy was superior to chemotherapy alone as a first-line treatment for advanced ESCC; the investigators of CheckMate 648 further showed that a combination of two different ICIs, without chemotherapy, was superior to chemotherapy alone (3).

Despite this, only approximately 10–20% of all patients respond to single-agent ICI therapy (primary resistance) (8). For those that do respond, the majority subsequently progress (acquired resistance). Understanding the reasons underlying this differential response and identifying biomarkers is essential to improving patient outcomes (12).

Individualised treatment approaches must be based on patients’ specific tumour biology, but unfortunately the main biomarker studied in these trials [programmed death ligand-1 (PD-L1) expression] seems to muddy rather than clarify the waters. Zhu and colleagues (8) stratified their meta-analysis on the basis of two established measures of PD-L1 expression: the tumour proportion score (TPS), which measures the proportion of tumour cells that stain positive for PD-L1; and the combined positivity score (CPS), which counts not only PD-L1-positive tumour cells but also PD-L1-positive tumour-associated immune cells.

Their findings suggest a potentially greater impact on OS among patients with TPS ≥1% (versus TPS <1%) and among those with TPS ≥10% (versus TPS <10%). By contrast, in a pooled analysis of ICIs in the first-line setting, Yap et al. similarly found a greater OS benefit for ICI for patients with TPS ≥1% but no survival advantage at all for patients with TPS <1% (13).

In addition, while Zhu and colleagues showed greater benefit for patients with CPS ≥10 (versus CPS <10) and no benefit for patients with CPS <10, Yap et al. found survival benefits both for CPS ≥10 and (albeit smaller) with CPS <10 (13). Standardisation of CPS and TPS between studies is almost impossible to establish, and where these findings leave researchers, clinicians, and patients is unclear.

Zhu and colleagues’ analyses, and the more recent studies of ICIs as first-line palliative therapies and in patients with residual disease after radical therapy, support the role of ICI as a therapeutic option in patients with advanced ESCC. However, they do not answer the important questions of what to do after ICI treatment has failed and how do we improve patient selection and response to ICI therapy? To answer these questions, we need a precision approach both with targeted therapies and better biomarkers.

Most research so far has understandably focused on the role of PD-L1/PD-1. However, other biomarkers within the tumour microenvironment warrant investigation (Figure 1) (12,15). For example, epidermal growth factor receptor (EGFR) is overexpressed in 30–70% of ESCC tumours (14,16). EGFR activation is associated with depleted tumour-infiltrating lymphocytes and resistance to ICIs (14). This suggests that further investigation of the role of and precision targeting of EGFR-driven ESCC in combination with ICI could be a therapeutic strategy to overcome ICI resistance.

Figure 1 Emerging approaches to improve immune checkpoint inhibitor responses in ESCC. Figure adapted from Baxter et al. (14) under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0). ICI, immune checkpoint inhibitor; RTK, receptor tyrosine kinase; DDRD, DNA Damage Response Deficient; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; CNG, copy number gain; CNL, copy number loss; mut, mutation; CTx, chemotherapy.

Overall, the authors should be congratulated on completing a study which adds to the literature and confirms the safety and efficacy of ICI therapy after failure of first-line chemotherapy in patients with advanced ESCC. Considering the unmet clinical need and lack of targets for precision medicine in ESCC, research attention must now turn to better understanding the mechanisms underlying ICI resistance (12). This will enable individualised treatment strategies for the majority of patients who progress despite ICI treatment.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-598/coif). MAB reports consultancy fees from Servier, Honoraria from Ipsen and BMS and support for attending meetings from Servier. RDP reports personal fees from Eli Lilly, Bristol Myers Squib, and Servier, and grants from AstraZeneca, Roche, Sanofi, Merck Sharp & Dohme, Five Prime Therapeutics, and Jansen outside the submitted work. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Smyth EC, Lagergren J, Fitzgerald RC, et al. Oesophageal cancer. Nat Rev Dis Primers 2017;3:17048. [Crossref] [PubMed]
2. Kato K, Sun JM, Shah MA, et al. LBA8_PR Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: The phase 3 KEYNOTE-590 study. Ann Oncol 2020;31:abstr S1142-215.
3. Doki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med 2022;386:449-62. [Crossref] [PubMed]
4. Shen L, Kato K, Kim SB, 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;40:3065-76. [Crossref] [PubMed]
5. Huang J, Xu J, Chen Y, et al. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study. Lancet Oncol 2020;21:832-42. [Crossref] [PubMed]
6. 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;38:4138-48. [Crossref] [PubMed]
7. Xu J, Li Y, Fan Q, et al. Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 study (ORIENT-2). Nat Commun 2022;13:857. [Crossref] [PubMed]
8. Zhu K, Chen H, Xu C, et al. Efficacy and safety of immune checkpoint inhibitors versus chemotherapy in the second-line treatment of advanced esophageal squamous cell carcinoma: a meta-analysis and systematic review. J Thorac Dis 2023;15:1186-95. [Crossref] [PubMed]
9. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 2020;20:651-68. [Crossref] [PubMed]
10. Esfahani K, Roudaia L, Buhlaiga N, et al. A review of cancer immunotherapy: from the past, to the present, to the future. Curr Oncol 2020;27:S87-97. [Crossref] [PubMed]
11. 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. Lancet 2021;398:759-71. Erratum in: Lancet 2021;398:1874. [Crossref] [PubMed]
12. Baxter MA, Middleton F, Cagney HP, et al. Resistance to immune checkpoint inhibitors in advanced gastro-oesophageal cancers. Br J Cancer 2021;125:1068-79. [Crossref] [PubMed]
13. Yap DWT, Leone AG, Wong NZH, et al. Effectiveness of Immune Checkpoint Inhibitors in Patients With Advanced Esophageal Squamous Cell Carcinoma: A Meta-analysis Including Low PD-L1 Subgroups. JAMA Oncol 2023;9:215-24. [Crossref] [PubMed]
14. Wang KL, Wu TT, Choi IS, et al. Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas: association with poor outcome. Cancer 2007;109:658-67. [Crossref] [PubMed]
15. Baxter MA, Spender LC, Petty RD. Combining precision medicine and prophylaxis in oesophageal squamous cell carcinoma. Br J Cancer 2020;123:1585-7. [Crossref] [PubMed]
16. Hanawa M, Suzuki S, Dobashi Y, et al. EGFR protein overexpression and gene amplification in squamous cell carcinomas of the esophagus. Int J Cancer 2006;118:1173-80. [Crossref] [PubMed]