161P - Biomarkers of neoadjuvant combinational therapy for locally advanced gastric or gastroesophageal junction adenocarcinoma

Background

Gastric or gastroesophageal junction (G/GEJ) cancers is one of the most common lethal malignancies in the world. Nearly half of the G/GEJ cancers are locally advanced at diagnosis and with poor prognosis. Several clinical trials demonstrated that perioperative anti-PD-1 therapy in combination with concurrent chemoradiotherapy (cCRT) for locally advanced G/GEJ cancers could raise the pCR rate over 30%. However, the biomarkers for patients with pCR are nor clear.

Methods

34 patients with locally advanced G/GEJ cancer received neoadjuvant sintilimab in combination with cCRT followed by gastrectomy and adjuvant sintilimab and chemotherapy in our center. Baseline tumor biopsies and post-treatment surgical tissues were collected for multiplex immunofluorescence (mIF), next-generation sequencing (NGS) and mass cytometry (CyTOF).

Results

Our results met the pre-specified primary endpoint, with a pCR rate of 38.2% and median DFS of 17.0 months. Biomarker analysis by mIF showed that patients with positive PD-L1 expression showed a numerically higher pCR rate. Also, higher levels of infiltrating CD3⁺ T cells, CD4⁺ T cells, and CD56⁺ natural killers (NKs) were found in patients achieving pCR than those not achieving pCR (non-pCR). Moreover, the proportion of CD127⁺CD27⁺HLA-DR^-CD38^-CD4 TCM defined by CyTOF was significantly lower in pCR patients. Also, tumor mutation burden (TMB) analyzed by NGS was significantly higher in the pCR group. Clone evolution can explain the therapy efficacy, and could be deployed to overcame therapy resistance. Deletion of cytoband 7q35, where TPK1 locates, was significantly enriched in pCR groups while deletion of 11q14.3, which TRIM family sitting, was significantly enriched in non-pCR groups.

Conclusions

It is consistent with the acknowledged prognostic biomarker of immunotherapy that positive PD-L1 expression, higher T cell infiltration and TMB could be predictive biomarkers of perioperative anti-PD-1 therapy in combination with cCRT for locally advanced G/GEJ. Furthermore, we found a new TCM subtype defined with CD127⁺CD27⁺HLA-DR^-CD38^- and deletion of cytoband 7q35 or 11q14.3 could be novel biomarkers.

Clinical trial identification

The study protocol was published previously. Wei, J. et al. Efficacy and Safety of Sintilimab in Combination with Concurrent Chemoradiotherapy for Locally Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (SHARED): Study Protocol of a Prospective, Multi-Center, Single-Arm Phase 2 Trial. Cancer Manag Res 14, 2007-2015, https://doi.org/10.2147/CMAR.S355687 (2022).

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.