Editor’s Note: The clinical use of immune checkpoint inhibitors (ICIs) offers a promising approach for locally advanced gastric and gastroesophageal junction (GEJ) cancers, potentially improving cure rates. Recent clinical trials have demonstrated that ICIs combined with chemotherapy, chemoradiotherapy, anti-HER2, or anti-VEGF agents exhibit synergistic and complementary effects. Compared to chemotherapy alone, these combinations show improved pathologic complete response (pCR) rates, major response rates, ypT0N0 rates, and potentially improve patient outcomes. At the recent 2024 CACA Integrated Gastric Cancer Conference, Prof. Changqing Jing from Shandong Provincial Hospital summarized perioperative ICI trials in gastric cancer, discussing the status of ICIs in neoadjuvant and adjuvant settings and exploring the feasibility of future perioperative immunotherapy combinations.

Development of the “Sandwich” Model for Perioperative Chemotherapy in Gastric Cancer

Before 2006, surgery alone was the standard treatment for gastric cancer, yielding a 5-year survival rate of only 23%.[1] In an effort to improve survival, researchers explored perioperative treatments.

In 2006, the UK’s MAGIC trial[2] showed that preoperative chemotherapy with the ECF regimen (epirubicin, cisplatin, and 5-FU) significantly reduced tumor size and stage compared to surgery alone, increasing the 5-year OS rate to 36% and providing strong evidence for neoadjuvant chemotherapy in European gastric cancer patients.

Following this, the FLOT4 study[3] presented at ASCO 2017 showed that the FLOT regimen (5-FU, leucovorin, oxaliplatin, and docetaxel) was superior to ECF, with a 5-year OS rate of 45%, prompting European guidelines to recommend FLOT as the preferred perioperative regimen.

In Asia, studies such as PRODIGY,[4] RESOLVE,[5] and JCOG0501[6] further explored neoadjuvant approaches. China’s RESOLVE study demonstrated that the SOX regimen (S-1 and oxaliplatin) combined with surgery and postoperative SOX adjuvant therapy significantly improved survival, with a 5-year OS rate of 60% .

These studies established perioperative chemotherapy as an effective strategy, achieving higher survival rates and becoming globally recommended. The model of preoperative chemotherapy, surgery, and postoperative chemotherapy, or the “sandwich” approach, is now widely accepted. However, chemotherapy alone still yields suboptimal outcomes for locally advanced gastric cancer, prompting continued research.

Perioperative Immunotherapy for Gastric Cancer: Mixed Outcomes

Immunotherapy has revolutionized treatment in malignancies such as melanoma. The SWOG S1801 study validated that perioperative pembrolizumab is superior to adjuvant pembrolizumab alone for resectable melanoma, with a 2-year event-free survival (EFS) rate of 72% for the perioperative group vs. 49% for the adjuvant group. Whether this “sandwich” approach can benefit gastric cancer treatment remains a question.

Since introducing ICIs into perioperative gastric cancer therapy, numerous clinical studies have combined ICIs with other treatments, such as chemotherapy, targeted therapy, dual ICIs, and chemoradiotherapy. Non-specific immunotherapies like recombinant red Nocardia, Pseudomonas injection, and thymosin have also shown promise in enhancing immunity. The goal across these combinations is to improve the efficacy of gastric cancer treatment.

1. Neoadjuvant Immunotherapy

Immunotherapy Combined with Chemotherapy

The MATTERHORN study[7] (2023) interim results revealed that perioperative durvalumab combined with FLOT significantly improved the pCR rate in resectable gastric/GEJ cancer by 12% compared to FLOT alone (19% vs. 7%, OR 3.08, P < 0.00001). The durvalumab group also showed better downstaging rates, with comparable adverse events between groups. Although this study showed favorable downstaging, further data is needed to confirm survival benefits.

At the 2023 ASCO GI symposium, the PERSIST study[8] led by Prof. Han Liang and Prof. Xuewei Ding demonstrated promising outcomes for perioperative sintilimab combined with the SOX regimen in locally advanced gastric/GEJ cancers, with a pCR rate of 27.9%, major pathological response (MPR) rate of 65.2%, and downstaging rate of 79.7%. Safety was also acceptable.

However, not all studies yielded positive results. The KEYNOTE-585 trial[9] presented at ESMO 2024 explored neoadjuvant pembrolizumab combined with chemotherapy for gastric cancer but ultimately failed. Although pCR rates were significantly higher in the pembrolizumab group (14.2% vs. 2.8%), the trial did not achieve statistical significance in EFS and OS.

Despite its mixed results, the KEYNOTE-585 trial offers valuable insights for future studies, highlighting factors such as MSI-H status and varying responses based on CPS scores. The study underscores the potential of EFS benefits, raising the question of whether the lack of significance was a statistical or clinical limitation.

Immunotherapy Combined with Anti-angiogenesis and Chemotherapy

The DRAGON IV study[10] (2023) in Journal of Clinical Oncology revealed that camrelizumab combined with chemotherapy and apatinib significantly improved pCR rates in locally advanced resectable gastric/GEJ adenocarcinoma compared to chemotherapy alone. These findings mark the first Phase III trial to evaluate perioperative immunotherapy combined with anti-angiogenesis and chemotherapy for gastric cancer, although EFS data remains immature.

Immunotherapy Combined with Chemoradiotherapy

A study[11] in Nature Communications attempted to combine sintilimab with concurrent chemoradiotherapy for locally advanced gastric/GEJ adenocarcinoma. This approach yielded a pCR rate of 38.2% and an MPR rate of 79.4%, marking a new era for perioperative immunotherapy in gastric cancer.

2. Adjuvant Immunotherapy

The CheckMate 577 study[12] evaluated nivolumab as an adjuvant therapy for resectable esophageal/GEJ cancer, showing improved DFS and establishing nivolumab as the first adjuvant therapy with significant DFS improvement after neoadjuvant chemoradiotherapy and surgery.

Conversely, the Attraction-5 study[13] (ASCO 2023) showed no DFS benefit from adding nivolumab to adjuvant chemotherapy in Stage III gastric/GEJ adenocarcinoma, suggesting that the “sandwich” approach may be more suitable for perioperative immunotherapy in gastric cancer.

Future of Precision Perioperative Therapy for Gastric Cancer

Though perioperative immunotherapy and chemotherapy are still evolving, advances in precision medicine are shaping a more targeted approach. Genetic profiling, tumor microenvironment analysis, liquid biopsy, and machine learning can help identify optimal candidates for tailored therapy. Further studies on microenvironment modulation, gut microbiome adjustment, and overcoming immunotherapy resistance will enhance treatment efficacy.

In summary, perioperative immunotherapy offers new hope for gastric cancer patients, with combined immunotherapy and chemotherapy potentially redefining perioperative treatment strategies. Future research on adjuvant immunotherapy could extend these benefits to even more patients.

Reference

[1] Lavacchi D, Fancelli S, Buttitta E, et al. Perioperative Tailored Treatments for Gastric Cancer: Times Are Changing. Int J Mol Sci. 2023;24(5):4877. Published 2023 Mar 2. doi:10.3390/ijms24054877 [2] Cunningham D, et al. N Engl J Med. 2006;355:11-20. [3] Al-Batran SE, et al. Lancet. 2019;393(10184):1948-1957. [4] KANG Y K, KIM H D, YOOK J H, et al. Neoadjuvant docetaxel, oxaliplatin, and s-1 plus surgery and adjuvant s-1 for resectable advanced gastric cancer: final survival outcomes of the randomized phase 3 PRODIGY trial［J］. J Clin Oncol, 2023, 41(16_suppl): 4067. [5] ZHANG X T, LIANG H, LI Z Y, et al. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial［J］. Lancet Oncol, 2021, 22(8): 1081-1092. [6] IWASAKI Y, TERASHIMA M, MIZUSAWA J, et al. Gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer (JCOG0501): an openlabel, phase 3, randomized controlled trial［J］. Gastric Cancer, 2021, 24(2): 492-502. [7] Y.Y. Janjigian, S-E. Al-Batran, et al. 2023 ESMO. LBA 73. [8] DING X W, WANG X J, LI B, et al. PERSIST: A multicenter, randomized phase Ⅱ trial of perioperative oxaliplatin and S-1 (SOX) with or without sintilimab in resectable locally advanced gastric/gastroesophageal junction cancer (GC/GEJC)［J］. J Clin Oncol, 2023, 41(4_suppl): 364. [9] K. Shitara, S.Y. Rha, et al. 2024 ESMO. LBA 74 [10] C. Li, Y. Zheng, et al. 2023 ESMO. 1512MO [11] Wei J, Lu X, Liu Q, Fu Y, et al. Neoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial. Nat Commun. 2023 Aug 14;14(1):4904. doi: 10.1038/s41467-023-40480-x. PMID: 37580320; PMCID: PMC10425436. [12] Kelly R et al. N Engl J Med 2021 [13] Terashinma M, et al. 2023 ASCO. Abstract 4000.

Prof. Changqing Jing

• Deputy Director, Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated with Shandong First Medical University
• Leading expert in colorectal and gastric cancer
• Vice-Chair, Colorectal Cancer Group, Chinese Society of Clinical Oncology