背景:目前治疗局部进展期胃癌(GC)的标准包括新辅助化疗和根治性手术。最近,这种情况的新辅助治疗涉及探索免疫治疗加化疗作为一种潜在方法.然而,疗效仍不确定。
方法:单臂,本研究进行了2期研究,目的是评估卡莫瑞珠单抗联合mFOLFOX6新辅助治疗的疗效和耐受性,并通过多组学分析,确定可切除的局部晚期GC患者的潜在应答生物标志物.主要终点是病理完全缓解(pCR)率。次要终点包括R0率,接近pCR率,无进展生存期(PFS),无病生存率(DFS),总生存率(OS)。通过全外显子组测序评估多组学分析,转录组测序,以及新辅助治疗前后使用活检的多重免疫荧光(mIF)。
结果:这项研究涉及60名患者,其中55人接受了胃切除术。其中,5人(9.1%)达到病理完全缓解(pCR),11(20.0%)达到接近pCR。未观察到因治疗引起的意外不良事件或围手术期死亡。并且该方案提供了可管理的安全性。通过多组学分析确定的分子变化与治疗反应相关,强调HER2阳性和CTNNB1突变与治疗敏感性和良好预后之间的关联。免疫细胞浸润分析和mIF进一步支持了这一发现。表达数据揭示了一个具有四个基因的风险模型(RALYL,SCGN,CCKBR,NTS)与反应不佳有关。此外,治疗后CD8+T淋巴细胞浸润与病理反应呈正相关。
结论:研究结果表明,PD-1抑制剂和mFOLFOX6的组合对局部晚期GC具有疗效和可接受的毒性。需要延长随访以确定响应的持续时间。这项研究为制定精确的新辅助治疗方案奠定了必要的基础。
BACKGROUND: The current standard of care for locally advanced gastric cancer (GC) involves neoadjuvant chemotherapy followed by radical surgery. Recently, neoadjuvant treatment for this condition has involved the exploration of immunotherapy plus chemotherapy as a potential approach. However, the efficacy remains uncertain.
METHODS: A single-arm, phase 2 study was conducted to evaluate the efficacy and tolerability of neoadjuvant camrelizumab combined with mFOLFOX6 and identify potential biomarkers of response through multi-omics analysis in patients with resectable locally advanced GC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the R0 rate, near pCR rate, progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). Multi-omics analysis was assessed by whole-exome sequencing, transcriptome sequencing, and multiplex immunofluorescence (mIF) using biopsies pre- and post-neoadjuvant therapy.
RESULTS: This study involved 60 patients, of which 55 underwent gastrectomy. Among these, five (9.1%) attained a pathological complete response (pCR), and 11 (20.0%) reached near pCR. No unexpected treatment-emergent adverse events or perioperative mortality were observed, and the regimen presented a manageable safety profile. Molecular changes identified through multi-omics analysis correlated with treatment response, highlighting associations between HER2-positive and CTNNB1 mutations with treatment sensitivity and a favourable prognosis. This finding was further supported by immune cell infiltration analysis and mIF. Expression data uncovered a risk model with four genes (RALYL, SCGN, CCKBR, NTS) linked to poor response. Additionally, post-treatment infiltration of CD8+ T lymphocytes positively correlates with pathological response.
CONCLUSIONS: The findings suggest the combination of PD-1-inhibitor and mFOLFOX6 showed efficacy and acceptable toxicity for locally advanced GC. Extended follow-up is required to determine the duration of the response. This study lays essential groundwork for developing precise neoadjuvant regimens.