PO.CT01.05 · 临床试验
瑞戈非尼联合avelumab治疗巨噬细胞低浸润的微卫星稳定型结直肠癌：一项前瞻性研究
Regorafenib plus avelumab in macrophage-low microsatellite-stable colorectal cancer: A prospective study
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摘要 Abstract
中文摘要
背景：微卫星稳定（MSS）型结直肠癌（CRC）在很大程度上对免疫检查点阻断无效。瑞戈非尼可重塑肿瘤微环境，可能与PD-L1阻断产生协同作用。在II期REGOMUNE试验（队列A，NCT03475953）中，瑞戈非尼联合avelumab在未经选择的化疗难治性MSS CRC中显示出中等活性，但一项探索性生物标志物分析提示，低基线肿瘤相关巨噬细胞（TAM）浸润与临床获益相关（Cousin等，Clin Cancer Research 2021）。我们在一个新的专门队列（A′）中前瞻性地评估了基于TAM的富集。
方法：REGOMUNE A′是一项多中心、单臂、II期研究，入组通过集中式多重免疫荧光在基线肿瘤组织上筛选出低巨噬细胞浸润的化疗难治性MSS CRC患者。患者接受瑞戈非尼80 mg每日一次（服药3周/停药1周）加avelumab 10 mg/kg每2周一次。主要终点是经中心影像学评审的4个月无进展率（PFR）。一项探索性汇总分析在有巨噬细胞定量数据的患者中，比较了巨噬细胞低浸润肿瘤（队列A+A′）与巨噬细胞高浸润肿瘤（队列A）的结果。
结果：从2021年至2024年，共筛选851例患者以入组32例巨噬细胞低浸润的MSS CRC患者；28例符合条件并可评估疗效。4个月PFR为32.1%（90% CI 17.9-49.4），超过预设的20%活性阈值。最佳总体应答为2例经确认的部分缓解（7.1%）；疾病控制率为46.4%（90% CI 30.4-63.0）。中位PFS为1.8个月（95% CI 1.7-4.6；局部评估），中位OS为14.1个月（95% CI 9.9-21.8），中位随访15.7个月。治疗相关3-4级不良事件发生于11/32例患者（34.4%）；最常见的≥3级事件为手足红肿疼痛综合征（4/32，12.5%）和高血压（2/32，6.3%）。报告了2起5级治疗相关事件（6.3%）。在汇总巨噬细胞分析中（n=50例入组队列A和A′且有巨噬细胞数据的患者），巨噬细胞低浸润肿瘤比巨噬细胞高浸润肿瘤有更高的4个月PFR（31.8% vs 0.0%）、更长的中位PFS（3.5 vs 1.9个月；局部评估）和更长的中位OS（14.1 vs 4.6个月）。在有肝转移的患者中（n=34），巨噬细胞低浸润仍与改善的OS（10.9 vs 4.6个月）和4个月PFR（21.4% vs 0.0%）相关。
结论：前瞻性筛选低TAM浸润是可行的，并可富集出从瑞戈非尼联合avelumab治疗MSS CRC中获益的患者。这些汇总数据强化了TAM密度作为TKI+PD-L1联合方案预测性生物标志物的价值，并支持在MSS CRC中开展带有随机验证的生物标志物驱动试验。
试验注册：NCT03475953
查看英文原文 English abstract
Background: Microsatellite-stable (MSS) colorectal cancer (CRC) is largely refractory to immune checkpoint blockade. Regorafenib can remodel the tumor microenvironment and may synergize with PD‑L1 blockade. In the phase II REGOMUNE trial (cohort A, NCT03475953), regorafenib plus avelumab showed modest activity in unselected chemorefractory MSS CRC , but an exploratory biomarker analysis suggested that low baseline tumor-associated macrophage (TAM) infiltration was associated with clinical benefit (Cousin et al Clin Cancer Research 2021). We prospectively evaluated TAM-based enrichment in a new dedicated cohort (A′).
Methods: REGOMUNE A′ is a multicenter, single‑arm, phase II study enrolling patients with chemorefractory MSS CRC selected for low macrophage infiltration on baseline tumor tissue by centralized multiplex immunofluorescence. Patients received regorafenib 80 mg once daily (3 weeks on/1 week off) plus avelumab 10 mg/kg every 2 weeks. The primary endpoint was the 4‑month progression‑free rate (PFR) by central radiology review. An exploratory pooled analysis compared outcomes in macrophage‑low tumors (cohorts A + A′) versus macrophage‑high tumors (cohort A) among patients with available macrophage quantification.
Results: From 2021 to 2024, 851 patients were screened to enroll 32 patients with macrophage‑low MSS CRC; 28 were eligible and assessable for efficacy. The 4‑month PFR was 32.1% (90% CI 17.9-49.4), exceeding the prespecified 20% activity threshold. Best overall response was 2 confirmed partial responses (7.1%); disease control rate was 46.4% (90% CI 30.4-63.0). Median PFS was 1.8 months (95% CI 1.7-4.6; local assessment) and median OS was 14.1 months (95% CI 9.9-21.8) with a median follow‑up of 15.7 months. Treatment‑related grade 3-4 adverse events occurred in 11/32 patients (34.4%); the most common grade ≥3 events were palmar‑plantar erythrodysesthesia (4/32, 12.5%) and hypertension (2/32, 6.3%). Two grade 5 treatment‑related events were reported (6.3%). In the pooled macrophage analysis (n=50 patients enrolled in cohorts A and A' with macrophage data), macrophage‑low tumors had higher 4‑month PFR (31.8% vs 0.0%), longer median PFS (3.5 vs 1.9 months; local assessment), and longer median OS (14.1 vs 4.6 months) than macrophage‑high tumors. Among patients with liver metastases (n=34), macrophage‑low remained associated with improved OS (10.9 vs 4.6 months) and 4‑month PFR (21.4% vs 0.0%).
Conclusions: Prospective selection for low TAM infiltration is feasible and enriches for patients deriving benefit from regorafenib plus avelumab in MSS CRC. These pooled data strengthen TAM density as a predictive biomarker for TKI + PD‑L1 combinations and support biomarker‑driven trials with randomized validation in MSS CRC.
Trial registration: NCT03475953
利益披露 Disclosure
K. Iphigenie, None..
S. Cousin, None..
N. Huchet, None..
J. Metges, None..
P. Cassier, None..
M. hilmi, None..
A. Adenis, None..
A. Hollebecque, None..
C. Bellera, None.
J. Guegan,
Explicyte Employment.
A. Bessede,
Explicyte Employment.
A. Italiano,
BMS ).
ASTRAZENECA ).
MERCK ).
AMGEN ).
ROCHE ).