Samalin E, Evesque L, Turpin A, De La Fouchardiere C, Khemissa-Akouz F, Bouché O, Muller M, Dermeche S, Botsen D, Tougeron D, Zaanan A, Ben Abdelghani M, Guardiola E, Dubreuil O, Le Brun Ly V, Hennequin A, Watson S, Sefrioui D, Lecomte T, De Sousa Carvalho N, Hulin A, Crapez E, Castan F, Senellart H
ICM, Department of Medical Oncology, Université de Montpellier, Montpellier, France.
Centre Antoine Lacassagne, Nice, France.
ESMO Open. 2025 May;10(5):105096. doi: 10.1016/j.esmoop.2025.105096. Epub 2025 May 12.
Several options have been evaluated in metastatic gastro-oesophageal adenocarcinomas (mGA) after failure of first-line fluoropyrimidine and platinum-based chemotherapy. Regorafenib (REGO), a receptor tyrosine kinase inhibitor, has shown promising activity as second- and third-line treatment of mGA.
PRODIGE58-UCGI35-REGIRI was a comparative, prospective, phase II, open-label study evaluating the safety and efficacy of REGO [160 mg/day on day 2 (D2)-D8/D16-D22] plus irinotecan (IRI: 180 mg/m intravenously on D1/D15 every 28 days) versus IRI alone in patients with mGA (gastric or gastro-oesophageal junction/tumour Siewert II and III) after failure of first-line fluoropyrimidine and platinum-based chemotherapy. Primary endpoint was overall survival (OS).
Forty-four patients were included in the REGIRI arm and 45 in the IRI arm, primary tumours (67.4%) were mainly localised in the gastro-oesophageal junction, and 60.7% patients had synchronous metastases. With a median follow-up of 19.4 months [95% confidence interval (CI) 16.8-29.9 months], median OS was 6.3 months (95% CI 5.2-7.1 months) versus 8.2 months (95% CI 5.2-9.7 months) in the REGIRI versus IRI arms (hazard ratio 1.11, 95% CI 0.70-1.74, P = 0.66). Median progression-free survival was 2.2 months versus 1.9 months, objective response rate 15.9% versus 13.3%, and disease control rate 45.5% versus 33.3%. Grade 3 treatment-related adverse events (AEs) were reported for 52.3% of patients in the REGIRI arm versus 23.3% in the IRI arm with four toxic deaths (two homozygous UGT1A1∗28 patients died from sepsis and thrombotic microangiopathy, and two heterozygous UGT1A1∗1/∗28 patients from diarrhoea and pulmonary embolism), versus one (UGT1A1∗1 wild-type patient died from primary tumour perforation). Main grade ≥3 AEs were diarrhoea (18.2% versus 7.0%), hypertension (9.1% versus 0.0%), asthenia (6.8% versus 0.0%), febrile neutropenia (6.8% versus 0.0%), neutropenia (6.8% versus 11.6%), and weight decrease (6.8% versus 0.0%).
The study was stopped early because of limited efficacy and increased toxicities in the REGIRI arm, possibly due to drug interactions. No optimal sub-population that could benefit from a REGIRI regimen exposure was identified.
在一线氟嘧啶和铂类化疗失败后的转移性胃食管腺癌（mGA）中，已评估了多种治疗方案。瑞戈非尼（REGO）是一种受体酪氨酸激酶抑制剂，作为mGA的二线和三线治疗已显示出有前景的活性。
PRODIGE58-UCGI35-REGIRI是一项比较性、前瞻性、II期、开放标签研究，评估瑞戈非尼[第2天（D2）-D8/D16-D22每日160mg]联合伊立替康（IRI：每28天第1天/第15天静脉注射180mg/m²）与单独使用IRI相比，在一线氟嘧啶和铂类化疗失败的mGA（胃或胃食管交界/肿瘤Siewert II和III型）患者中的安全性和疗效。主要终点为总生存期（OS）。
REGIRI组纳入44例患者，IRI组纳入45例患者，原发肿瘤（67.4%）主要位于胃食管交界，60.7%的患者有同步转移。中位随访19.4个月[95%置信区间（CI）16.8 - 29.9个月]，REGIRI组与IRI组的中位OS分别为6.3个月（95%CI 5.2 - 7.1个月）和8.2个月（95%CI 5.2 - 9.7个月）（风险比1.11，95%CI 0.70 - 1.74，P = 0.66）。中位无进展生存期分别为2.2个月和1.9个月，客观缓解率分别为15.9%和13.3%，疾病控制率分别为45.5%和33.3%。REGIRI组52.3%的患者报告有3级治疗相关不良事件（AE），IRI组为23.3%，有4例毒性死亡（2例纯合UGT1A1∗28患者死于败血症和血栓性微血管病，2例杂合UGT1A1∗1/∗28患者死于腹泻和肺栓塞），而IRI组有1例（UGT1A1∗1野生型患者死于原发性肿瘤穿孔）。主要的≥3级AE为腹泻（18.2%对7.0%）、高血压（9.1%对0.0%）、乏力（6.8%对0.0%）、发热性中性粒细胞减少（6.8%对0.0%）、中性粒细胞减少（6.8%对11.6%）和体重减轻（6.8%对0.0%）。
由于REGIRI组疗效有限且毒性增加，该研究提前终止，可能是由于药物相互作用。未发现能从REGIRI方案治疗中获益的最佳亚组人群。
