Thymalfasin plus anti-PD-1 immunochemotherapy achieved 30% pCR in locally advanced gastric cancer
Background
Despite advances in neoadjuvant immunochemotherapy for locally advanced gastric and gastroesophageal junction (G/EGJ) adenocarcinoma, a significant proportion of patients still experience limited therapeutic benefit. Current standard-of-care often falls short in achieving deep pathological responses, highlighting a critical need for enhanced strategies. Thymalfasin, an immunomodulatory peptide, presents a promising avenue to amplify antitumor immunity and potentially mitigate treatment-related toxicities, offering a novel approach to improve outcomes in this challenging patient population.
Study Design
This prospective, single-arm phase II clinical trial enrolled 30 patients aged 18-75 with cStage III G/EGJ adenocarcinoma, ECOG 0-1, and adequate organ function. Participants received three 21-day cycles of serplulimab (anti-PD-1) plus SOX (S-1 and oxaliplatin) immunochemotherapy, alongside thymalfasin administered for 9 weeks. Following this neoadjuvant regimen, all patients underwent curative-intent minimally invasive gastrectomy. The primary endpoint was pathological complete response (pCR), with secondary endpoints including major pathological response (MPR), safety, and survival. Peripheral immune remodeling was assessed via flow cytometry, and bulk RNA sequencing of PBMCs investigated thymalfasin-associated transcriptional programs.
Results
All 30 enrolled patients successfully underwent curative-intent minimally invasive gastrectomy. The study reported a pathological complete response (pCR) rate of 30.0% (9/30 patients), with a major pathological response (MPR) achieved in 56.7% (17/30 patients). Furthermore, 63.3% (19/30) of patients achieved ypN0 status, indicating no residual nodal disease, and 80.0% (24/30) experienced N-stage downstaging. At a median follow-up of 14.0 months (range 10.0-17.2), only one retroperitoneal nodal relapse was observed at 14.4 months post-diagnosis, and importantly, no deaths were documented. Any-grade adverse events (AEs) occurred in 93.3% of patients, with grade ≥3 AEs reported in 26.7%, and immune-related AEs in 23.3%. Flow cytometry analysis indicated an expansion of immune cell populations, suggesting thymalfasin's immunomodulatory effects.
Key Findings
- Pathological complete response (pCR) was achieved in 30.0% (9/30) of patients.
- Major pathological response (MPR) was observed in 56.7% (17/30) of patients.
- N-stage downstaging occurred in 80.0% (24/30) of patients, with 63.3% achieving ypN0 status.
- At 14.0 months median follow-up, only one relapse and no deaths were documented.
- The regimen demonstrated manageable safety, with 26.7% grade ≥3 AEs and 23.3% immune-related AEs.
Why It Matters
This study offers compelling early evidence that adding thymalfasin to neoadjuvant anti-PD-1 immunochemotherapy significantly enhances pathological response rates in locally advanced gastric cancer. For clinicians and peptide users, this suggests a potentially more effective protocol for a challenging malignancy, moving beyond current limitations. The combination of thymalfasin with existing immunochemotherapy could become a new standard for improving deep pathological responses and potentially long-term survival. While a phase II trial, the high pCR and MPR rates, coupled with manageable toxicity, indicate a promising clinical translation outlook, warranting further investigation in larger, controlled trials. This approach could redefine neoadjuvant strategies, offering a novel adjunct to boost antitumor immunity.
gastric cancer
thymalfasin
serplulimab
immunochemotherapy
neoadjuvant
phase 2