Medical Oncology, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), CITOHL, Centre Hospitalier Lyon-Sud, 165 Chemin du Grand Revoyet, Pierre-Benite, 69495, Lyon, France.
Faculté de Médecine Lyon Sud, EA 3738 CICLY, Université Claude Bernard Lyon 1, Lyon, France.
Cancer Chemother Pharmacol. 2023 May;91(5):361-373. doi: 10.1007/s00280-023-04508-9. Epub 2023 Feb 25.
Everolimus (EVE) and sorafenib (SOR) combination was associated with synergistic activity in preclinical models. However, previous clinical studies were hampered by cumulative toxicities when both were given continuously. The academic EVESOR trial (NCT01932177) was designed to assess alternative doses and intermittent dosing schedules of EVE and SOR combination therapy to improve the benefit-risk ratio for patients with solid tumors.
EVESOR is a multiparameter dose-escalation phase I trial investigating different doses and dosing schedules, with the final objective of generating data for modeling and simulation. Patients were allocated into continuous (A and B) or intermittent (C and D) schedules to determine the recommended phase II dose (RP2D). The clinical outcomes are presented here.
Forty-three patients were included from 2013 to 2019. Most of them had gynecological (25.6%), cholangiocarcinomas (23.2%), colorectal (14.0%), and breast cancers (11.6%). Dose-escalation up to EVE 10 mg QD and SOR 400 mg BID was possible on intermittent schedules. Five dose-limiting toxicities were observed, and dose reductions were required in 39.5% patients, stabilizing at EVE 5 mg and SOR 200 mg BID for 58.1% of them. The overall response rate was 6.3%, and disease control rate was 75.0%. The median progression-free survival (PFS) was 3.6 months. The longest median PFS were observed in cholangiocarcinomas (9.9 months), and gynecological adenocarcinomas (9.2 months).
Intermittent arms were associated with improved efficacy/toxicity profiles; and EVE 5 mg QD and SOR 200 mg BID was defined a clinically feasible dose. Strong signs of efficacy were found in cholangiocarcinomas and gynecologic carcinomas.
ClinicalTrials.gov Identifier: NCT01932177.
依维莫司（EVE）和索拉非尼（SOR）联合应用在临床前模型中具有协同作用。然而，以前的临床研究由于两种药物连续给药时累积毒性而受阻。学术性 EVESOR 试验（NCT01932177）旨在评估 EVE 和 SOR 联合治疗的替代剂量和间歇性给药方案，以提高实体瘤患者的获益风险比。
EVESOR 是一项多参数剂量递增的 I 期试验，研究不同剂量和给药方案，最终目标是为建模和模拟生成数据。患者被分配到连续（A 和 B）或间歇性（C 和 D）方案，以确定推荐的 II 期剂量（RP2D）。这里呈现的是临床结果。
2013 年至 2019 年期间，共纳入 43 例患者，其中大多数患有妇科（25.6%）、胆管癌（23.2%）、结直肠癌（14.0%）和乳腺癌（11.6%）。在间歇性方案中，可以增加到 EVE 10 mg QD 和 SOR 400 mg BID 的剂量。观察到 5 例剂量限制毒性，39.5%的患者需要减少剂量，其中 58.1%的患者稳定在 EVE 5 mg 和 SOR 200 mg BID。总缓解率为 6.3%，疾病控制率为 75.0%。中位无进展生存期（PFS）为 3.6 个月。最长的中位 PFS 见于胆管癌（9.9 个月）和妇科腺癌（9.2 个月）。
间歇性方案与改善的疗效/毒性特征相关；EVE 5 mg QD 和 SOR 200 mg BID 被定义为临床可行的剂量。在胆管癌和妇科癌中发现了明显的疗效迹象。
ClinicalTrials.gov 标识符：NCT01932177。
