Right place right time: the role of immunotherapy in patients with locally advanced gastric/gastroesophageal junction adenocarcinoma
Editorial Commentary

Right place right time: the role of immunotherapy in patients with locally advanced gastric/gastroesophageal junction adenocarcinoma

Abigail Fong1#, Dani Castillo2#, Pranati Shah3, Sophia Guzman1, Gagandeep Brar2

1Department of Surgical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA; 2Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA; 3Department of Internal Medicine, Loma Linda University, Loma Linda, CA, USA

#These authors contributed equally to this work.

Correspondence to: Gagandeep Brar, MD. Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd, Duarte, CA 91010, USA. Email: gbrar@coh.org.

Comment on: Long B, Zhou H, Yu Z, et al. Neoadjuvant cadonilimab plus FLOT chemotherapy in locally advanced gastric/gastroesophageal junction adenocarcinoma: A multicenter, phase 2 study. Med 2025;6:100531.

Keywords: Gastric cancer; gastroesophageal cancer; immunotherapy

Submitted Oct 15, 2025. Accepted for publication Nov 06, 2025. Published online Dec 23, 2025.

doi: 10.21037/jgo-2025-aw-858

Cancers of the upper gastrointestinal tract (e.g., gastric and gastroesophageal) are a leading cause of cancer related deaths worldwide. In 2025, the estimated new cases and deaths in the United States were approximately 52,370 and 27,030, respectively (1). Although tumor characteristics and causative factors may be different depending on primary tumor location, adenocarcinomas of the gastric and gastroesophageal junction (GEJ) are oftentimes managed similarly (2). In the locally advanced setting, the benefit of perioperative chemotherapy was first demonstrated in the landmark MAGIC trial (3). This study compared epirubicin, cisplatin and fluorouracil (ECF) to surgery alone, and confirmed that perioperative chemotherapy improved progression-free survival and overall survival (OS) in patients with gastric/GEJ adenocarcinoma. More recently, ECF was compared to perioperative 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) in patients with locally advanced, non-metastatic gastric/GEJ adenocarcinoma (4). FLOT was found to be superior in achieving pathologic complete response (pCR), as well as OS. The toxicity profile was manageable and FLOT became the established perioperative chemotherapy regimen recommended for patients with locally advanced gastric or GEJ adenocarcinoma. However, recurrences remain high with a 5-year survival of approximately 35%. Therefore, an unmet need exists to improve patient outcomes, especially in the non-metastatic setting.

With the success of checkpoint inhibitors in advanced stage patients, the MATTERHORN study explored the role of immunotherapy in the perioperative setting, where durvalumab, an anti-programmed cell death protein ligand 1 (PD-L1) inhibitor, was added to FLOT chemotherapy compared to placebo (5). The interim analysis confirmed the primary endpoint of event-free survival (EFS) was met, resulting in a hazard ratio (HR) 0.71 favoring the durvalumab arm. Median OS (mOS) and median disease-free survival (mDFS) were also improved, and there was an equal distribution of patients who were able to complete perioperative therapy without compromising surgical outcomes. Therefore, the MATTERHORN established a new standard of care with chemo-immunotherapy with durvalumab plus FLOT for patients with locally advanced gastric/GEJ adenocarcinoma patients.

In this issue of the Journal of Gastrointestinal Oncology, Long et al. (6) reports the results of the ChiCTR2200066893 study, where the addition of cadonilimab to neoadjuvant chemotherapy was evaluated in patients with non-metastatic gastric/GEJ adenocarcinoma.

This was a phase 2 investigation of neoadjuvant cadonilimab plus FLOT chemotherapy in locally advanced (cT3/4, N+, M0) gastric and GEJ adenocarcinoma, conducted across four hospitals in China. Cadonilimab is a bispecific anti-PD-1 and cytotoxic T lymphocyte-associated protein 4 antibody. Previous studies in advanced stage cancer patients have shown that cadonilimab, when combined with chemotherapy, improved OS and DFS compared to chemotherapy alone. In the COMPASSION-15 trial, cadonilimab plus chemotherapy (capecitabine, oxaliplatin) increased median OS by 3 months and DFS by 1.7 months over chemotherapy alone in patients with unresectable or metastatic gastric/GEJ adenocarcinoma (7).

In the current study, the authors investigated the addition of cadonilimab to FLOT chemotherapy in a neoadjuvant setting. The primary endpoint was pCR, while secondary endpoints included major pathological response (MPR), overall response rate (ORR), disease control rate (DCR), R0 resection rate, downstaging rate, and safety. The study enrolled 38 patients, of whom 32 (84%) completed treatment. The results showed a pCR rate of 21.1% [8/38; 90% confidence interval (CI): 9.7–32.4%], MPR of 44.7% (17/38, 90% CI: 30.9–58.5%), ORR of 60.7% (17/28, 90% CI: 44.7–76.7%), R0 resection rate of 100% (32/32), and DCR of 100% (28/28, 90% CI: 100–100%).

These findings provide a cautiously optimistic basis for future investigations. While promising, they are not conclusive in demonstrating benefit for this patient population. The study is limited by its small sample size, single-arm design, and short duration. In addition, immunotherapy was administered only in the neoadjuvant setting, so it is currently unknown whether neoadjuvant vs perioperative immunotherapy, as used in the MATTERHORN trial, might impact long-term outcomes.

This study also raises an important question that is currently under debate in early-stage trials with interim results: is pCR the appropriate surrogate marker for outcomes in gastroesophageal cancer treatment? Previous studies have examined this issue and found that while pCR may be prognostic at the individual patient level, it does not consistently correlate with OS at the trial level (8-10). Because of this, pCR is not widely accepted as a surrogate marker for OS in larger trials.

From a surgical perspective, the conclusions drawn from the R0 resection rate as a secondary outcome remain uncertain. The small sample size and single-arm design make it difficult to determine whether the 100% R0 resection rate is attributable to the neoadjuvant treatment itself or to factors such as surgical skill, technique, and patient selection. It is also notable that for GEJ tumors in this study, proximal gastrectomies were performed. In many other regions, similar patients would have undergone esophagectomies instead. While this difference is unlikely to affect the reported pCR outcomes, it may influence perioperative outcomes in future studies with longer-term follow-up.

Although exploratory, the subgroup analysis did not show any high-risk feature to be associated with a worse pCR rate, including older age, tumor location, clinical T4 disease and diffuse type or mixed histology. In addition, there was no difference in pCR in patients based on PD-L1 combined positive score (CPS) expression or microsatellite instability-high (MSI-H) status. This is similar to the MATTERHORN and COMPASSION-15 data, although, given the small sample size for each category (e.g., 2/32 MSI-H), it would be difficult to make any sweeping conclusions. In addition, the PD-L1 CPS score was defined as ≥5. However, Western guidelines endorse FLOT plus durvalumab in patients with PD-L1 CPS ≥1 (11). This may skew the magnitude of benefit favoring a higher PD-L1 expression, although most patients in this study were defined as PD-L1 negative (65.8% PD-L1 CPS ≤5). For example, patients with a PD-L1 CPS ≥5 achieved a higher pCR of 30.8% compared to 16.0%, suggesting better response, however, this did not translate to statistical significance. These results highlight the challenges of understanding the mechanisms of tumor biology with limited and inferior predictive biomarkers.

Efforts to integrate biomarker-guided strategies into the perioperative management of gastric/GEJ cancers have been limited so far. Several trials, including KEYNOTE-585 (12), DANTE (13), and ATTRACTION-5 (14), listed in Table 1, explored the addition of immune checkpoint inhibitors in unselected patient populations. However, none demonstrated a clear survival advantage across all subgroups. MATTERHORN is the first phase 3 trial to show a statistically significant improvement in EFS and a favorable trend in OS with perioperative durvalumab plus FLOT. This establishes a new benchmark and is likely to become practice-changing in this setting. Among phase 3 perioperative chemo-immunotherapy trials, MATTERHORN is the first to clearly meet its primary endpoint of EFS, with a sizeable HR and improved pCR, while maintaining similar rates of grade 3 or higher toxicity (5). KEYNOTE-585 improved pCR and showed a nominal EFS benefit but did not meet its overall prespecified efficacy targets. OS was not statistically significant, and the EFS signal was borderline under multiplicity, leading to a generally disappointing interpretation. Signal enrichment has been consistent across studies for MSI-H and higher CPS scores, particularly CPS ≥10 and MSI-H subpopulations. For example, in the DANTE study (13), CPS ≥10 was observed in 33% of one cohort and 12% in another, while MSI was present in 63% and 27%, respectively. PANDA’s impressive pCR and MPR rates come from a small, non-randomized total-neoadjuvant design. An MPR, defined as 10% or less residual viable tumor, was observed in 14 of 20 patients (70%; 95% CI: 46–88%), including nine patients (45%; 95% CI: 23–68%) who achieved pCR (15). In the pure adjuvant setting, ATTRACTION-5, which evaluated nivolumab plus chemotherapy after D2 surgery, was negative. In contrast, CheckMate 577 (16) was positive following neoadjuvant chemoradiation and resection, although the populations, treatment modalities, and tumor biology were different. Updated data show a numerical improvement in OS with adjuvant nivolumab compared to placebo, with median OS of 51.7 versus 35.3 months. However, this OS difference has not yet reached statistical significance according to the latest published report. The DFS benefit remains sustained, and no new safety signals have been reported with longer follow-up.

Table 1

Summary of major clinical trials evaluating immune checkpoint inhibitors in gastroesophageal adenocarcinoma, perioperative and adjuvant treatment strategies

Trial name Patient population Phase/sample size Treatment regimen vs. control Biomarker selection Primary endpoint(s) Key results Clinical notes
KEYNOTE-585 Perioperative GC/GEJ adenocarcinoma Phase III, n=~804 (FLOT cohort, n=~203) Neoadjuvant + adjuvant pembrolizumab + chemotherapy (CAPOX/FOLFOX or FLOT) vs. placebo + chemotherapy All-comers (exploratory analyses: MSI-H, PD-L1 CPS) pathCR, EFS, OS OS HR 0.86; EFS HR 0.81; higher pathCR rates; safety profile similar to control Did not meet prespecified efficacy thresholds for primary endpoints. Demonstrated benefit in MSI-H and CPS ≥10 subgroups, supporting biomarker-directed approaches
MATTERHORN Perioperative resectable GC/GEJ adenocarcinoma Phase III, n=948 Perioperative durvalumab + FLOT → durvalumab maintenance vs. placebo + FLOT → placebo maintenance All-comers (unselected population) EFS as primary endpoint; OS and pCR as secondary endpoints EFS HR 0.71 (P<0.001); pCR rate 19.2% vs. 7.2%; OS data not yet statistically significant First phase III perioperative ICI + FLOT regimen to demonstrate statistically significant EFS benefit. Represents potential new standard of care
DANTE (IKF-s633) Perioperative EGA (GC/GEJ) Phase II → III, n=295 (phase II) Atezolizumab + FLOT (4 cycles neoadjuvant + 4 cycles adjuvant) → atezolizumab maintenance vs. FLOT alone All-comers in phase II; exploratory biomarker analyses (MSI-H/PD-L1 CPS) Phase II: downstaging, pCR. Phase III: survival outcomes pCR rate: 24% vs. 15%; MSI-H subgroup: 63% vs. 27%; CPS ≥10 subgroup: 33% vs. 12%; phase III ongoing German AIO/SAKK collaborative study. Demonstrates promising biological activity, particularly in MSI-H and CPS-high populations. Phase III results awaited
PANDA Neoadjuvant EGA (GC/GEJ) Phase II, n=21 1 cycle atezolizumab monotherapy → 4 cycles atezolizumab + DOC (docetaxel/oxaliplatin/capecitabine) → surgery All-comers; extensive translational correlative studies Safety, MPR, pCR Regimen feasible; MPR rate 70%, pCR rate 45%; 3-year recurrence rate ~27% Small, non-randomized trial with total neoadjuvant design. Strong immune correlates identified. Exploratory study demonstrating proof-of-concept for immunotherapy priming strategy
ATTRACTION-5 Adjuvant post-D2 gastrectomy, stage III gastric/GEJ cancer (Asian population) Phase III, n=755 Nivolumab + adjuvant chemotherapy (S-1 or CapeOx) vs. placebo + adjuvant chemotherapy All-comers (PD-L1 expression exploratory) RFS 3-year RFS: 68.4% vs. 65.3%; HR 0.90; P=0.44 (not significant) Negative trial. No statistically significant RFS benefit with addition of adjuvant PD-1 inhibitor following D2 resection and adjuvant chemotherapy
CheckMate 577 Adjuvant therapy post-neoadjuvant CRT in resected esophageal/GEJ cancer (adenocarcinoma and squamous cell carcinoma) Phase III, n=794 Nivolumab monotherapy for 1 year vs. placebo (no adjuvant chemotherapy in either arm) All-comers (PD-L1 expression exploratory) DFS Median DFS: 22.4 vs. 11.0 months; HR 0.69 (P<0.001) Practice-changing positive trial for patients with residual disease following CROSS-like neoadjuvant CRT regimen. Now standard of care in this setting

Summary of pivotal clinical trials investigating ICIs in the perioperative and adjuvant treatment settings for gastroesophageal malignancies. Results reflect most recent published or presented data as of the knowledge cutoff date. AIO, german working group for medical oncology; CAPOX, capecitabine/oxaliplatin; CapeOx, capecitabine/oxaliplatin; CPS, combined positive score; CRT, chemoradiotherapy; D2, D2 lymphadenectomy; DFS, disease-free survival; DOC, docetaxel/oxaliplatin/capecitabine; EFS, event-free survival; EGA, esophagogastric adenocarcinoma; FLOT,5-fluorouracil, leucovorin, oxaliplatin, and docetaxel; FOLFOX, 5-fluorouracil, leucovorin, and oxaliplatin; GC, gastric cancer; GEJ, gastroesophageal junction; HR, hazard ratio; ICI, immune checkpoint inhibitor; MPR, major pathologic response; MSI-H, microsatellite instability-high; OS, overall survival; pathCR, pathologic complete response; PD-L1, programmed death-ligand 1; pCR, pathologic complete response; RFS, relapse-free survival; SAKK, swiss group for clinical cancer research; SCC, squamous cell carcinoma; S-1, tegafur/gimeracil/oteracil.

The phase 2 multicenter study of cadonilimab plus FLOT demonstrated promising neoadjuvant activity in locally advanced gastric and GEJ. The study achieved an R0 resection rate of 100% and a pCR rate of 21%. The regimen showed manageable toxicity and encouraged MPR, suggesting enhanced tumor regression compared with historical FLOT data. However, the trial’s single-arm design, small sample size, and limited follow-up preclude definitive conclusions about survival benefit. Ongoing randomized studies are needed to validate efficacy and to define biomarker-based patient selection strategies for perioperative dual-checkpoint blockade.

Acknowledgments

None.

Footnote

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

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-858/coif). G.B. reports being a member of data safety monitoring committee at City of Hope. The other authors have 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.

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References

  1. Siegel RL, Kratzer TB, Giaquinto AN, et al. Cancer statistics, 2025. CA Cancer J Clin 2025;75:10-45. [Crossref] [PubMed]
  2. van Laarhoven H. Management of locally advanced gastric cancer. Lancet Oncol 2025;26:267-9. [Crossref] [PubMed]
  3. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20. [Crossref] [PubMed]
  4. Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 2019;393:1948-57. [Crossref] [PubMed]
  5. Janjigian YY, Al-Batran SE, Wainberg ZA, et al. Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer. N Engl J Med 2025;393:217-30. [Crossref] [PubMed]
  6. Long B, Zhou H, Yu Z, et al. Neoadjuvant cadonilimab plus FLOT chemotherapy in locally advanced gastric/gastroesophageal junction adenocarcinoma: A multicenter, phase 2 study. Med 2025;6:100531. [Crossref] [PubMed]
  7. Shen L, Zhang Y, Li Z, et al. First-line cadonilimab plus chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: a randomized, double-blind, phase 3 trial. Nat Med 2025;31:1163-70. [Crossref] [PubMed]
  8. Lin C, Ma J, Zhu C, et al. Is Pathologic Complete Response a Good Predictor for the Long-Term, Clinical Outcome in Patients with Gastric Cancer After Neoadjuvant Chemotherapy? A Retrospective, Multi-institution Study in China. Ann Surg Oncol 2023;30:5534-42. [Crossref] [PubMed]
  9. Okui J, Nagashima K, Matsuda S, et al. Evaluation of pathological complete response as a surrogate endpoint for overall survival in resectable oesophageal cancer: integrated analysis of individual patient data from phase III trials. Br J Surg 2025;112:znaf131. [Crossref] [PubMed]
  10. Wei C, Sun H, Hu J, et al. Association of pathological response with long-term survival outcomes after neoadjuvant immunotherapy: A meta-analysis. Int Immunopharmacol 2024;133:112078. [Crossref] [PubMed]
  11. Oncology RwpftNCPGi, Cancer NGfGCVNC, Network IArrA--Tvt, most recent and complete version of the guideline gotNo. Available online: https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
  12. 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]
  13. 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]
  14. Kang YK, Terashima M, Kim YW, et al. Adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy for stage III gastric or gastro-oesophageal junction cancer after gastrectomy with D2 or more extensive lymph-node dissection (ATTRACTION-5): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 2024;9:705-17. [Crossref] [PubMed]
  15. Verschoor YL, van de Haar J, van den Berg JG, et al. Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial. Nat Med 2024;30:519-30. [Crossref] [PubMed]
  16. 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]
Cite this article as: Fong A, Castillo D, Shah P, Guzman S, Brar G. Right place right time: the role of immunotherapy in patients with locally advanced gastric/gastroesophageal junction adenocarcinoma. J Gastrointest Oncol 2025;16(6):2895-2899. doi: 10.21037/jgo-2025-aw-858

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