Background: FOLFIRI (5-FU + leucovorin + irinotecan) plus ramucirumab is one of the standards in second-line metastatic colorectal cancer (CRC) patients progressing after treatment with oxaliplatin/fluoropyrimidine with bevacizumab, but there is no evidence on its efficacy without prior bevacizumab. Moreover, VEGF-D has not been confirmed as a predictive biomarker for ramucirumab’s efficacy, either. Methods: The RAINCLOUD study was a multicenter, single-arm, phase II trial conducted in Japan. Patients with recurrent CRC pretreated with fluoropyrimidine and oxaliplatin without bevacizumab were analyzed. The primary endpoint was progression-free survival (PFS). The secondary endpoints measured were overall survival (OS), overall response rate (ORR), and safety. Results: A total of 48 patients were enrolled from 15 sites between September 2017 and September 2020. Their median age was 63.5 years (25~77), 20.1% had a right-sided tumor, and 68.8% hadRAS-mutant cancer. The median PFS was 8.9 months (90% CI: 6.3–11.8), so the primary endpoint was met. Their median OS and ORR were 22.3 months (95% CI: 17.4-NA) and 41.7% (95% CI: 4.9–7.6), respectively. An incidence of grade 3/4 adverse events that reached over 5% applied to neutropenia (44%), leucopenia (10%), and hypertension (8%). In the biomarker analysis, the serum VEGF-D levels post-treatment were higher than those pre-treatment, but the PFS in those with high VEGF-D levels trended towards being worse than that in those with low VEGF-D (7.6M/5.6M (p= 0.095; HR: 0.56)). Instead, those with low TSP-2 had a better PFS than those with high TSP-2 (7.5M/4.3M (p= 0.022; HR: 0.45)). Conclusions: Our data suggested that FOLFIRI plus ramucirumab was effective and tolerable for CRC refractory to fluoropyrimidine and oxaliplatin without anti-angiogenesis. Serum VEGF-D levels may not be predictive but TSP-2 may be a potential prognostic biomarker for ramucirumab’s efficacy.
背景：FOLFIRI（5-氟尿嘧啶+亚叶酸钙+伊立替康）联合雷莫西尤单抗是奥沙利铂/氟嘧啶联合贝伐珠单抗治疗后进展的转移性结直肠癌（CRC）患者的二线标准治疗方案之一，但尚无证据表明其在未接受过贝伐珠单抗治疗的患者中的疗效。此外，VEGF-D作为雷莫西尤单抗疗效的预测性生物标志物也尚未得到证实。方法：RAINCLOUD研究是一项在日本开展的多中心、单臂、II期临床试验。研究对象为既往接受过氟嘧啶和奥沙利铂治疗但未使用贝伐珠单抗的复发性结直肠癌患者。主要终点为无进展生存期（PFS）。次要终点包括总生存期（OS）、总缓解率（ORR）和安全性。结果：2017年9月至2020年9月期间，从15个研究中心共入组48例患者。中位年龄为63.5岁（范围25~77岁），20.1%为右侧肿瘤，68.8%为RAS突变型癌症。中位PFS为8.9个月（90% CI：6.3–11.8），达到了主要终点。中位OS和ORR分别为22.3个月（95% CI：17.4-NA）和41.7%（95% CI：4.9–7.6）。发生率超过5%的3/4级不良事件包括中性粒细胞减少症（44%）、白细胞减少症（10%）和高血压（8%）。在生物标志物分析中，治疗后血清VEGF-D水平高于治疗前，但高VEGF-D水平患者的PFS有劣于低VEGF-D水平患者的趋势（7.6个月/5.6个月，p=0.095；HR：0.56）。相反，低TSP-2水平患者的PFS优于高TSP-2水平患者（7.5个月/4.3个月，p=0.022；HR：0.45）。结论：我们的数据表明，对于未接受抗血管生成治疗且对氟嘧啶和奥沙利铂耐药的结直肠癌患者，FOLFIRI联合雷莫西尤单抗方案有效且耐受性良好。血清VEGF-D水平可能不具有预测价值，但TSP-2可能是雷莫西尤单抗疗效的潜在预后生物标志物。
肿瘤(癌症)患者之家