Neoadjuvant immunotherapy for esophageal cancer: have we been in the era?

The ESCORT-NEO/NCCES01 trial was an important study that took place across multiple centers in China, focusing on patients with resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) (1). This phase 3 study investigated how effective and safe it is to add the programmed cell death 1 (PD-1) inhibitor camrelizumab to standard neoadjuvant chemotherapy. A total of 391 participants were enrolled and divided into three groups: one group received camrelizumab with nab-paclitaxel and cisplatin, another received camrelizumab with paclitaxel and cisplatin, while the third group was treated with paclitaxel and cisplatin alone. The main goals of the trial in terms of dual primary endpoints were to evaluate the rates of pathological complete response (pCR) and event-free survival (EFS). The results demonstrated that adding camrelizumab significantly increased pCR rates, with the group receiving camrelizumab plus nab-paclitaxel achieving a pCR rate of 28.0%, cisplatin and paclitaxel plus camrelizumab 15.4%, compared to just 4.7% in the chemotherapy-only group. Although these promising results highlight the potential benefits of combining immunotherapy with chemotherapy, EFS data are as yet immature.

Strengths and limitations of the study

The ESCORT-NEO/NCCES01 trial (1) has several strengths, primarily its solid design as a multicenter, randomized controlled trial, which provides preliminary evidence for the effectiveness of camrelizumab as a neoadjuvant treatment for LA-ESCC. By including two different chemotherapy regimens, the trial allows for an insightful comparison of how different taxanes work when paired with immunotherapy, potentially guiding better treatment strategies. It’s possible that nab-paclitaxel proved more effective as steroids were not required pre-treatment, which may impact the efficacy of immune checkpoint inhibitors (ICIs).

Like in perioperative immunotherapies trials of LA non-small cell lung cancer, improved pCR and EFS were both significantly improved in the neoadjuvant chemoimmunotherapy group compared with chemotherapy-only in CheckMate 816 (2), AEGEAN (3), KEYNOTE 671 (4), NeoTorch (5). Moreover, the CTNeoBC pooled analysis confirmed that breast patients who achieved pCR after neoadjuvant therapy improved EFS and overall survival (OS), and had prognostic value in patients with highly proliferative tumors, though the surrogation of the marker is still in debate (6). With confirmed improved pCR translating into improved OS in breast cancer, the significant increase in pCR rates observed with camrelizumab suggests that LA-ESCC patients could have improved survival outcomes potentially.

However, the study does come with notable limitations. For instance, its non-blinded design may lead to bias in determining the results, even though pCR assessment is objective. Also, the absence of a comparison with neoadjuvant chemoradiotherapy—a common treatment strategy outside Asia—means the findings might not apply broadly to patients in other parts of the world. Conducted entirely in China, the study’s results may not be as applicable to non-Asian populations, given potential differences in genetic backgrounds, environmental factors, and healthcare systems. Lastly, since the EFS data are still emerging, longer follow-up is required to confirm if the short-term pCR benefits translate into long-term survival gains.

Global standards of treatment for LA-ESCC

Treatment guidelines for ESCC can vary significantly between Asia and other regions, largely influenced by different disease prevalence rates, healthcare resources, and clinical practices. In East Asia, especially in China and Japan, neoadjuvant chemotherapy or chemoradiotherapy is widely recognized as the standard care for patients with resectable LA-ESCC. This approach often relies on regional studies, like the JCOG9907 trial (7), which demonstrated improved survival with neoadjuvant chemotherapy compared to adjuvant strategies.

Conversely, in the West, neoadjuvant chemoradiotherapy is more commonly used, supported by significant trials, such as the CROSS study (8), which highlighted the survival advantages of this method over surgery alone and 49% of patients with ESCC achieved a pCR. The difference in treatment approaches may also stem from varying responses to treatments seen in different populations.

The Dutch CROSS study (8) and Chinese NEOCRTEC5010 study (9) have demonstrated that neoadjuvant chemoradiotherapy prolongs OS in patients with locally advanced esophageal cancer (LA-EC) compared to surgery alone. However, there remains more controversy when the Japanese JCOG1109 study (10) and Chinese CMISG1701 study (11) indicated that neoadjuvant chemoradiotherapy did not further improve OS in patients with LA-ESCC compared to neoadjuvant chemotherapy. Therefore, the optimal neoadjuvant therapy strategy remains uncertain. These findings may in part stem from different operative strategies in Asia vs. non-Asian countries.

Neoadjuvant immunotherapy from theory into practice

Immunotherapy has been established as standard of care in first- or second- line treatment in esophageal cancer in Asia and Western world. The current ESCORT-NEO/NCCES01 study added new evidence for camrelizumab in neoadjuvant therapy in operable ESCC patients, as well as the previously published CheckMate 577 study (12) which confirmed the disease-free survival (DFS) benefit of nivolumab as adjuvant therapy in patients with resected esophageal or gastroesophageal junction (GEJ) cancer who had received neoadjuvant chemoradiotherapy. It appears that immunotherapy could have a role in operable LA-ESCC. Meanwhile, camrelizumab has also been investigated for non-operable LA-ESCC patients (13), as well as other large global trials of ICI plus definitive chemoradiation in EC, including durvalumab (KUNLUN) (14), pembrolizumab (KEYNOTE 975) (15), tislelizumab (RATIONALE 311) (16). These ongoing phase III trials will add new evidence for the management for localized or LA disease.

Adding ICI to neoadjuvant therapy has drawn interest to investigators in many clinical scenarios, including in combination with radiation. Promising pCR was reported by adding ICI in neoadjuvant chemoradiation for twenty selected resectable ESCC patients from a single arm phase II trial conducted in a China center (17). In contrast to squamous cell carcinoma (SCC), several phase III studies have explored the role of neoadjuvant immunotherapy in gastric cancer and GEJ adenocarcinoma with mixed outcomes, including KEYNOTE-585 (18), MATTERHORN28 (19) and DANTE/FLOT8 (20) trials of neoadjuvant immunotherapy for gastric and GEJ adenocarcinoma showed higher pCR rates. Meanwhile, the phase 2/3 ECOG-ACRIN EA2174 trial (21) showed that adding ICI did not improve the outcome of pCR in these patients unfortunately. These diverse explorations will further deepen our understanding of perioperative immunotherapy in esophagogastric cancers. However, ESCC is notably more sensitive to ICI compared to adenocarcinoma, and better results can be hoped for in this disease.

Personalized neoadjuvant therapeutic approaches in EC

Programmed death-ligand 1 (PD-L1) expression is a key biomarker for ESCC immunotherapy and plays an important role in guiding treatment decisions. For esophagogastric adenocarcinoma, subgroup analysis of KEYNOTE-859 (22) and Checkmate-649 (23) showed that patients with high PD-L1 expression had a better trend of benefit. In SCC, the ESCORT study (24) shows clinical benefits at all PD-L1 levels for camrelizumab as 2^nd line treatment in metastatic disease, with greater advantages for individuals with higher expression. However, it is more complicated when immunotherapy is combined with chemo(radio)therapy. The ESCORT-1st study (25) showed that patients with PD-L1 expression ≥1% had enhanced OS, although not statistically significant. In the current study, approximately half of the patients (51.4%) showed PD-L1 positivity [tumor proportion score (TPS) ≥1%], consistent with the findings of ESCORT (42.6%) and ESCORT-1st studies (55.2%). Subgroup analysis of CheckMate 577 showed that patients with PD-L1 CPS score ≥5 in postoperative tumor tissue benefited more significantly. The current study emphasized the significant pCR advantage of patients with high PD-L1 expression who received combination therapy. Further studies will be needed to validate biomarkers like PD-L1 for decision making in the neoadjuvant setting, leading a personalized therapeutic approach selection.

Avenues for future research

Given the encouraging pCR rates observed with camrelizumab in the ESCORT-NEO/NCCES01 trial, there are several important research avenues to explore. First, it’s crucial to monitor the maturation of EFS and OS data to see if the short-term pCR benefits translate into longer-term survival improvements. Additionally, further studies comparing neoadjuvant chemoradiotherapy with neoadjuvant immunochemotherapy will help determine the best treatment approach for LA-ESCC, especially across diverse populations. Exploring biomarkers, such as PD-L1 expression, could also be key in predicting how well patients will respond to immunotherapy, paving the way for more personalized treatment strategies and better outcomes.

Furthermore, understanding how different chemotherapy regimens work with immunotherapy—especially comparing nab-paclitaxel to traditional paclitaxel—will be essential for maximizing treatment efficacy while reducing side effects.

Summary

In summary, while the ESCORT-NEO/NCCES01 trial offers compelling evidence supporting the use of camrelizumab in neoadjuvant therapy for LA-ESCC, ongoing research and long-term follow-up will be vital to fully harness the potential of this approach and refine treatment strategies to benefit patients around the world.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Esophagus. The article has undergone external peer review.

Peer Review File: Available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-29/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-29/coif). E.C.S. reports grants and personal fees from BMS, AstraZeneca, Amgen, Daiichi Sankyo, non-financial support from Mirati, personal fees from Merck, Viracta, Astellas, Novartis, Pfizer, Zymeworks, and BeiGene, outside the submitted work; and EORTC Gastric Cancer Taskforce Chair 2021–2024, UK & Ireland Oesophagogastric Cancer Group Trustee since 2022. E.C.S. is supported by the NIHR Biomedical Research Centre at Oxford. The views expressed in this Article are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health. 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. Qin J, Xue L, Hao A, et al. Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial. Nat Med 2024;30:2549-57. [Crossref] [PubMed]
2. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-85. [Crossref] [PubMed]
3. Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:491-503. [Crossref] [PubMed]
4. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:1672-84. [Crossref] [PubMed]
5. Lu S, Zhang W, Wu L, et al. Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial. JAMA 2024;331:201-11. [Crossref] [PubMed]
6. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164-72. [Crossref] [PubMed]
7. Ando N, Kato H, Igaki H, 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;19:68-74. [Crossref] [PubMed]
8. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:2074-84. [Crossref] [PubMed]
9. Yang H, Liu H, Chen Y, et al. Neoadjuvant Chemoradiotherapy Followed by Surgery Versus Surgery Alone for Locally Advanced Squamous Cell Carcinoma of the Esophagus (NEOCRTEC5010): A Phase III Multicenter, Randomized, Open-Label Clinical Trial. J Clin Oncol 2018;36:2796-803. [Crossref] [PubMed]
10. Kato K, Machida R, Ito Y, et al. Doublet chemotherapy, triplet chemotherapy, or doublet chemotherapy combined with radiotherapy as neoadjuvant treatment for locally advanced oesophageal cancer (JCOG1109 NExT): a randomised, controlled, open-label, phase 3 trial. Lancet 2024;404:55-66. [Crossref] [PubMed]
11. Tang H, Wang H, Fang Y, et al. Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy followed by minimally invasive esophagectomy for locally advanced esophageal squamous cell carcinoma: a prospective multicenter randomized clinical trial. Ann Oncol 2023;34:163-72. [Crossref] [PubMed]
12. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med 2021;384:1191-203. [Crossref] [PubMed]
13. Study of Camrelizumab (SHR-1210) in Combination With Concurrent Chemoradiotherapy in Locally Advanced Esophageal Cancer. Available online: https://clinicaltrials.gov/ct2/show/NCT04426955
14. 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:TPS373. [Crossref]
15. 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;17:1143-53. [Crossref] [PubMed]
16. Yu R, Wang W, Li T, et al. RATIONALE 311: tislelizumab plus concurrent chemoradiotherapy for localized esophageal squamous cell carcinoma. Future Oncol 2021;17:4081-9. [Crossref] [PubMed]
17. Li C, Zhao S, Zheng Y, et al. Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). Eur J Cancer 2021;144:232-41. [Crossref] [PubMed]
18. Shitara K, Rha SY, Wyrwicz LS, et al. Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study. Lancet Oncol 2024;25:212-24. [Crossref] [PubMed]
19. Janjigian YY, Al-Batran SE, Wainberg ZA, et al. LBA73 Pathological complete response (pCR) to durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric and gastroesophageal junction cancer (GC/GEJC): Interim results of the global, phase III MATTERHORN study. Ann Oncol. 2023;34:S1315-S1316. [Crossref]
20. Lorenzen S, Götze TO, Thuss-Patience P, et al. Perioperative Atezolizumab Plus Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel for Resectable Esophagogastric Cancer: Interim Results From the Randomized, Multicenter, Phase II/III DANTE/IKF-s633 Trial. J Clin Oncol 2024;42:410-20. [Crossref] [PubMed]
21. Eads JR, Graham N, Gibson MK, et al. A phase II/III study of peri-operative nivolumab (nivo) and ipilimumab (ipi) in patients (pts) with locoregional esophageal (E) and gastroesophageal junction (GEJ) adenocarcinoma: results of the neoadjuvant pathologic complete response (pCR) rate (ECOG-ACRIN EA2174). Presented at: ASCO 2024; May 31-June 4, 2024; Chicago, IL. Abstract 4000.
22. Rha SY, Oh DY, Yañez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2023;24:1181-95. [Crossref] [PubMed]
23. Janjigian YY, Ajani JA, Moehler M, et al. First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial. J Clin Oncol 2024;42:2012-20. [Crossref] [PubMed]
24. 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]
25. 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;326:916-25. [Crossref] [PubMed]