Cardone Claudia, Martinelli Erika, Troiani Teresa, Sforza Vincenzo, Avallone Antonio, Nappi Anna, Montesarchio Vincenzo, Andreozzi Francesca, Biglietto Maria, Calabrese Filomena, Bordonaro Roberto, Cordio Stefano, Bregni Giacomo, Febbraro Antonio, Garcia-Carbonero Rocio, Feliu Jaime, Cervantes Andrés, Ciardiello Fortunato
Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy.
Department of Experimental Medicine, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.
ESMO Open. 2019 Aug 16;4(4):e000519. doi: 10.1136/esmoopen-2019-000519. eCollection 2019.
In patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), the role of maintenance therapy after first-line treatment with chemotherapy plus antiepidermal growth factor receptor (EGFR) monoclonal antibodies (MoAb) is still an object of debate.
We assessed the efficacy and safety of regorafenib as a switch maintenance strategy after upfront 5-fluorouracil-based chemotherapy plus an anti-EGFR MoAb in patients with RAS WT mCRC. RAVELLO was a phase III, international, double-blind, placebo-controlled, academic trial. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and toxicity. Regorafenib or placebo were administered daily for 3 weeks of 4-week cycle until disease progression or unacceptable toxicity, up to 24 months.
The study was stopped prematurely due to slow accrual and lack of funding after the randomisation of 21 patients: 11 in the regorafenib arm and 10 in the placebo arm. The small sample size precludes any statistical analysis. Toxicity was acceptable and consistent with the known regorafenib safety profile. Median PFS was similar in the two arms. However, a subgroup of patients treated with regorafenib experienced a remarkably long PFS. Three patients were progression free at 9 months in the regorafenib arm versus one patient in the placebo arm, whereas at 12 months two regorafenib-treated patients were still progression free versus none in the placebo arm.
RAVELLO trial demonstrated that growing financial and bureaucratic hurdles affect the feasibility of independent academic research. Although stopped prematurely and within the limited sample size, RAVELLO suggests that regorafenib has not a major activity in maintenance setting after upfront chemotherapy and anti-EGFR MoAb. However, a subgroup of patients experienced a remarkable long PFS, indicating that a better refinement of the patient population would help to identify subjects that might benefit from a regorafenib personalised approach in the switch maintenance setting.
在RAS野生型（WT）转移性结直肠癌（mCRC）患者中，化疗联合抗表皮生长因子受体（EGFR）单克隆抗体（MoAb）一线治疗后的维持治疗作用仍存在争议。
我们评估了瑞戈非尼作为RAS WT mCRC患者基于5-氟尿嘧啶的前期化疗联合抗EGFR MoAb后的转换维持策略的疗效和安全性。RAVELLO是一项III期、国际性、双盲、安慰剂对照的学术试验。主要终点是无进展生存期（PFS）。次要终点包括总生存期和毒性。瑞戈非尼或安慰剂每天给药，每4周为一个周期，共3周，直至疾病进展或出现不可接受的毒性，最长24个月。
由于入组缓慢且随机分组21例患者后缺乏资金，研究提前终止：瑞戈非尼组11例，安慰剂组10例。样本量小使得无法进行任何统计分析。毒性是可接受的，且与已知的瑞戈非尼安全性特征一致。两组的中位PFS相似。然而，接受瑞戈非尼治疗的患者亚组经历了显著长的PFS。瑞戈非尼组有3例患者在9个月时无进展，而安慰剂组为1例；在12个月时，瑞戈非尼治疗组有2例患者仍无进展，而安慰剂组无。
RAVELLO试验表明，日益增加的财务和官僚障碍影响了独立学术研究的可行性。尽管提前终止且样本量有限，但RAVELLO表明瑞戈非尼在前期化疗和抗EGFR MoAb后的维持治疗中没有主要活性。然而，一组患者经历了显著长的PFS，这表明对患者群体进行更好的细化将有助于识别可能从转换维持治疗中瑞戈非尼个性化治疗方法中获益的受试者。
