王峰教授：各位线上的朋友，大家好！我是中山大学肿瘤防治中心内科的王峰医生。非常高兴在阔别几年之后，又重新来到欧洲肿瘤学会年会的现场，跟大家见面。今年由徐瑞华教授率领的中山大学肿瘤防治中心消化肿瘤内科团队，一共带来了六项口头报告，内容涵盖从食管到胃到肠的最新研究进展。

在ESMO会场，我们也听到了一些胃肠道肿瘤的最新进展，例如化疗联合免疫治疗对比化疗作为胃/胃食管结合部癌围手术期治疗的KEYNOTE-585研究和免疫联合曲妥珠单抗和化疗对比曲妥珠单抗联合化疗治疗HER2阳性转移性胃/胃食管结合部腺癌的KEYNOTE-811研究。这些结果显示，在胃癌围手术期治疗和转移性胃癌一线治疗中，联合免疫治疗取得了更好的疗效。

我们团队在今年六月份召开的美国临床肿瘤学会年会上汇报了一项免疫联合化疗对比化疗围手术期治疗可切除胃癌的研究，结果显示免疫治疗组的病理完全缓解率比化疗组提升了3倍左右。Kohei Shitara教授带来的KEYNOTE-585研究也显示，病理完全缓解率提升了10.9%（免疫组12.9%[95%CI：9.8～16.6]，安慰剂组2%[95%CI：0.9～3.9]；Δ10.9%[95%CI：7.5～14.8]；P<0.00001），中位无事件生存期（event free survival，EFS）也有非常大的提高( 44.4 vs. 25.3个月；HR 0.81，95%CI：0.67～0.99；P=0.0198)。因为预设的P值非常小，虽然没有达到统计学差异，但是EFS的提高非常具有临床意义。

Yelena Y. Janjigian教授汇报的KEYNOTE-811研究显示，在HER2阳性全体胃癌患者中，免疫联合曲妥珠单抗和化疗（免疫组）对比曲妥珠单抗联合化疗（标准治疗组）能非常好地提升患者客观反应率（ORR，72.6% vs. 59.8%）、中位无进展生存期(mPFS，10.0 vs 8.1个月；HR 0.72，95%CI：0.60～0.87；P=0.0002)、24个月PFS率（27% vs. 13%）和中位持续反应时间（mDOR，11.2 vs. 9.0个月）。OS数据尚未成熟。亚组分析显示，在PD-L1 CPS≥1的患者中，免疫组和标准治疗组的ORR分别为73.2%和58.4%，mPFS分别为10.8个月和7.2 个月（HR 0.70，95%CI：0.58～0.85），差异具有显著性 ；但是在PD-L1 CPS＜1的患者中，两组的差异不具有显著性，这提示CPS评分对胃癌免疫治疗获益的预测效能不仅在全人群中有效，在HER2阳性人群中可能也有效。

王峰教授：今年我汇报了我们团队牵头的一项信迪利单抗联合西达本胺和贝伐珠单抗（三药组）对比信迪利单抗联合西达本胺（两药组）三线或以上线治疗MSS/pMMR转移性结直肠癌的多中心、开放标签Ⅱ期研究（摘要号：556MO）。对于微卫星稳定（MSS/pMMR）肠癌而言，免疫单药治疗的有效率小于5%。我们在前期做了大量的探索，包括PD-1抗体联合瑞戈非尼，PD-1抗体联合阿帕替尼，虽然这些结果显示有效率能够提升到10%左右，但是大部分患者还是不能取得非常好的疗效，无进展生存期（PFS）只有1.5～2个月。我们在临床前研究做了一系列的探索，发现HDAC抑制剂西达本胺联合PD-1抗体和抗血管生成药物能产生非常好的协同作用，遂开展了此项Ⅱ期临床研究。

一共入组48例至少接受过二线治疗的化疗失败或不耐受的MSS/pMMR转移性结直肠癌患者，随机分到两组。三药组的ORR为44%，DCR为72.0% ，mPFS为7.3个月；两药组的ORR为13%，DCR为39.1%，mPFS为1.5个月。三药组对比两药组的死亡风险HR值在各个亚组都下降显著。目前OS数据尚未成熟，还不知道OS是否有显著性提高，但是非常期待。不仅在肠癌显示这样的结果，在其他肿瘤的动物模型也看到类似的、非常有前景的结果。希望HDAC抑制剂联合PD-1抑制剂和抗血管生成药能够在多个瘤种取得显著性疗效，研究结果也会很快地呈现给大家，可能为结直肠癌等实体瘤患者带来新的治疗选择。

王峰教授：我还汇报了一项欧司珀利单抗联合替雷利珠单抗二线治疗不可切除局部晚期或复发、转移性PD-L1阳性食管鳞状细胞癌的多中心、随机Ⅱ期AdvanTIG-203研究（摘要号：1020MO）。此项研究在60个中心开展，46家亚洲中心，14家欧洲中心，一共纳入125例患者，一组接受百济神州的PD-1抗体替雷利珠单抗联合安慰剂治疗，即传统的二线标准治疗；另一组接受替雷利珠单抗联合TIGIT抗体欧司珀利单抗治疗。研究结果显示，两组在有效率和安全性上没有显著性差异。当然，在数值上，两组的研究者评估ORR有10%左右的显著差异（欧司珀利单抗组30.6%，安慰剂组20.6%），但是因为样本量问题，两组没有统计学差异。在PFS以及独立评估委员会评估的ORR方面也没有显著性差异。OS数据尚未成熟，已产生的OS数据还小于50%，需要进一步随访。两组的1～4级或3级以上不良事件的发生率相似，安全性没有显著性差异。

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556MO - A phase II clinical trial of sintilimab plus chidamide combined with or without bevacizumab in patients with MSS/pMMR metastatic colorectal cancer

Background

Immune checkpoint inhibitors(ICI) have shown significant clinical benefit for MSI-H/dMMR metastatic colorectal cancer (mCRC) patients. However， the majority of MSS/pMMR mCRC patients show no response to immunotherapy and better combinations are currently lacking. Based on our preclinical research， we designed a study to explore whether an ICI sintilimab combined with an HDAC inhibitor chidamide， with or without bevacizumab would show efficacy in MSS/pMMR mCRC patients.

Methods

This open-label， multicenter trial (NCT04724239) recruited patients with MSS/pMMR mCRC that had failed or were intolerant to at least two lines of systemic therapies. The patients were randomly assigned to two arms， sintilimab plus chidamide (doublet) group， and sintilimab plus chidamide combined with bevacizumab (triplet) group. Patients in the doublet group received sintilimab 200 mg IV q3w plus chidamide 30 mg PO biw. Patients in the triplet group received sintilimab 200 mg IV q3w plus chidamide 30 mg PO biw and bevacizumab 7.5 mg/kg IV q3w. The primary endpoint was progression-free survival rate achieved at 18 weeks (18wPFS). The secondary endpoints included objective response rate (ORR)， progression-free survival (PFS)， overall survival (OS)， disease control rate (DCR)， and safety.

Results

Between March 2021 and April 2022， 23 and 25 patients were randomly allocated to the doublets group and triplets group. 18wPFS was 17.4% in the doublets group and 66.7% in the triplets group (P = 0.0012). ORR was 13.0% and 44.0%， and DCR was 39.1% and 72.0% in the doublets and triplets group. The median PFS was 1.5 months with doublets and 7.3 months with triplets (P = 0.008). The median OS for the triplet arm had not been reached， while the median overall survival for the doublet arm was 18.9 months (P = 0.41). The most common treatment-emergent adverse events (TEAEs) were proteinuria (60.9%)， thrombocytopenia (43.5%)， and animea (39.1%) with doublets and thrombocytopenia (72.0%)， proteinuria (72.0%)， and neutropenia (60.0%) with triplets. Grade 3 and above TEAEs occurred in 7 (30.4%) patients in the doublet arm and 13 (42.0%) patients in the triplet arm.

Conclusions

Sintilimab combined with chidamide and bevacizumab had promising efficacy and tolerable toxicity in MSS mCRC patients.

1020MO - AdvanTIG-203: Phase II randomized， multicenter study of ociperlimab (OCI) + tislelizumab (TIS) in patients (pts) with unresectable， locally advanced， recurrent/metastatic esophageal squamous cell carcinoma (ESCC) and programmed cell death-ligand 1 (PD-L1) positivity

Background

Prognosis of unresectable ESCC is poor， with median overall survival (OS) in 2nd line (2L) of ～10 months. Anti-PD-1 agents， including TIS， have demonstrated an OS increase， albeit still unsatisfactory， in unresectable ESCC pts. In preclinical studies and clinical studies of other tumors， coinhibition of T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) and PD-1 enhances antitumor activity of anti-PD-1. AdvanTIG-203 (NCT04732494) is investigating efficacy/safety of TIS +/- OCI (anti-TIGIT) in advanced ESCC pts， progressing on/after 1st line (1L) systemic therapy.

Methods

Adult ESCC pts with PD-L1 tumor area positivity (TAP) ≥10% and progression on/after 1L systemic therapy were randomized (1:1) to OCI 900 mg + TIS 200 mg (O+T) or placebo + TIS (P+T) every 3 weeks until progression， unacceptable toxicity， or withdrawal. Primary endpoint was investigator (INV)-assessed objective response rate (ORR). Secondary endpoints included progression free survival (PFS).

Results

As of 1 Feb 2023， 125 pts (median age 64 years; 88.8% male) were randomized to O+T (n=62) or P+T (n=63). INV-assessed ORR was 30.6% with O+T vs. 20.6% with P+T; hazard ratio (HR) of INV-assessed PFS was 0.93 (95% CI: 0.61， 1.43) (Table). Incidence of pts with ≥1 any adverse event (AE) was comparable between O+T (93.5%) and P+T (95.2%); most common AE was anemia (O+T: 25.8%; P+T: 28.6%). Respective AE rates for O+T and P+T were 41.9% and 41.3% grade ≥3 AEs， 41.9% and 39.7% serious AEs， 9.7% and 15.9% AEs that led to treatment discontinuation， 45.2% and 30.2% immune-related AEs， and 0% and 3.2% treatment-related fatal AEs. Table: 1020MO

Efficacy

Median follow-up was 7 months. IRC， independent review committee; NE， not estimable aConfirmed per RECIST v1.1bPrimary endpoint cStratified d2-sided; by Cochran-Mantel-Haenszel method eSecondary endpoint fStill immature (event rate 45.6%) g1-sided; by log-rank test

Conclusions

In 2L therapy of advanced ESCC pts with PD-L1 TAP ≥10%， O+T showed tolerable safety profile and trend toward better ORR， but similar PFS vs. P+T.