ASCO GI聚光录丨孟祥瑞教授：“VEGF-TIK+PD-1单抗+化疗”模式可能成为PD-L1表达阴性晚期胃癌患者的新治疗选择

郑州大学第一附属医院

对于PD-L1阴性或低表达的晚期GC/GEJC患者，一线治疗的疗效仍有待提高。这项Ib/II期开放标签研究（NCT05024812）评估了呋喹替尼（一种高选择性VEGFR-1、-2、-3抑制剂）联合特瑞普利单抗（抗PD-1单克隆抗体）和SOX作为GC/GEJC一线治疗的疗效，初步结果显示出抗肿瘤活性。本次大会报道更长随访时间的更新结果，特别关注PD-L1 CPS评分和疗效的相关性。

Ib期研究采用3+3剂量递增设计，患者接受呋喹替尼每天一次口服治疗 [3mg/天（DL1）、4mg/天（DL2）或5mg/天（DL3），连续服药两周之后停药一周，每三周为一个治疗周期]以及特瑞普利单抗（240mg，每三周的第一天静脉输注）和奥沙利铂（130mg/m²，每三周的第一天静脉滴注）和S-1（40-60mg，基于体表面积给药，每日两次口服，连续服药两周之后停药一周）治疗。之前已报道Ib期确定的呋喹替尼2期推荐剂量（RP2D）为5mg/天。II期阶段入组的64名患者将接受相同的治疗方案。II期研究的主要终点是PFS。次要终点包括ORR、DCR、OS、DOR和安全性。

截至2024年8月15日，入组的32例患者 (Ib期9例; II期23例) 基线如下：中位年龄 62岁 (38–73); 66%为男性; 88% ECOG PS 1,以及31%为肝转移。31例患者有 PD-L1 CPS评分：40.6% 为CPS＜1，68.8%为CPS＜5的患者。30例疗效可评估患者的ORR为63.5% (95% CI 43.9–80.1) ，其中4例患者达到完全缓解，DCR为96.7% (95% CI 82.8–99.9)。中位随访10.94 个月时，中位PFS达到 了 9.33个月 (95% CI: 5.68–NA)，OS仍未达到。对比CPS ≥5患者， CPS ＜5的患者有更高的缓解率 (65.0 vs 55.6%)和更长的PFS (12.68 个月vs 8.11 个月)，再CPS ＜1 和CPS ≥1 患者中也观察到类似的结果 (ORR: 75.0 vs 52.9%; PFS: 12.68个月vs 8.11 个月). 治疗相关不良事件(TRAEs) 主要为1-2级，最常见的是低白蛋白血症（50%）、中性粒细胞计数下降（34%）、贫血（41%）、血小板计数下降（34%）和白细胞减少（34%）。2名患者出现4级TRAE（肝功能损伤、高甘油三酯血症）。试验中没有与治疗相关的死亡。 

呋喹替尼联合SOX和特瑞普利单抗作为晚期转移性GC/GEJC患者的一线治疗，特别是PD-L1阴性或低表达的患者，具有良好的疗效和可控的毒性。将进一步分析和报告更多数据，包括潜在的预测反应生物标志物等。

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Updated results from the phase Ib/II study of fruquintinib combined with SOX and toripalimab in patients with advanced metastatic gastric/gastroesophageal junction adenocarcinoma (GC/GEJC).

Background:

The efficacy of first-line treatment in advanced GC/GEJC patients (pts) with negative or low PD-L1 expression still needs to be improved. This phase Ib/II, open-label study (NCT05024812) evaluating fruquintinib (a highly selective VEGFR-1, -2, -3 inhibitor) plus toripalimab (anti-PD-1), and SOX has shown preliminary antitumor activity as first-line therapy in GC/GEJC. Here we update the results with longer follow-up duration and a specific focus on PD-L1 CPS features.

Methods:

The study of phase Ib employed a 3+3 dose escalation design, pts were treated with fruquintinib 3mg/d (dose level; DL1), 4mg/d (DL2), or 5mg/d (DL3) po, d1-14, in combination with fixed dose of toripalimab (240mg, iv, d1), oxaliplatin (130 mg/m2, iv, d1) and S-1 (40-60mg based on BSA, po, d1-14) every 3 weeks. It had been reported in phase Ib that fruquintinib 5mg/d was defined as the RP2D. In phase II, a further 64 pts would be treated with the same regimen. Primary endpoint of phase II was PFS per RECIST 1.1. Secondary endpoints included ORR, DCR, OS, DOR and safety.

Results:

As of August 15, 2024, 32 pts (9 in phase Ib; 23 in phase II) had been enrolled. Pts characteristics included: median age 62 (range 38–73); 66% male; 88% with ECOG PS 1, and 31% with liver metastasis. 31 pts had PD-L1 CPS available. 40.6% were CPS < 1 and 68.8% were CPS < 5. Of the 30 pts evaluable for tumor response, the ORR was 63.5% (95% CI 43.9–80.1) with 4 pts achieving complete responses and DCR was 96.7% (95% CI 82.8–99.9). After a median follow-up of 10.94 months, the median PFS was 9.33 (95% CI: 5.68–NA) months and OS result was not reached. Pts with CPS < 5 were more likely to achieve higher response rate (65.0 vs 55.6%) and longer PFS than CPS ≥5 (12.68 vs 8.11 months). Similar trends were observed in pts with CPS < 1 and CPS ≥1 (ORR: 75.0 vs 52.9%; PFS: 12.68 vs 8.11 months). Treatment-related adverse events (TRAEs) were mainly grade 1-2 and the most common ones were hypoalbuminemia (50%), neutrophil count decreased (34%), anemia (41%), platelet count decreased (34%) and white blood cell decreased (34%). Grade 4 TRAEs occurred in 2 pts (impaired liver function, hypertriglyceridemia). There were no treatment related deaths in the trial.

Conclusions:

Fruquintinib combined with SOX and toripalimab provided favorable efficacy and manageable toxicity profile as first-line therapy for pts with advanced metastatic GC/GEJC, especially in pts with negative or low PD-L1 expression. More data including the potential predictive response biomarkers would be further analyzed and reported.