Pietrantonio Filippo, Morano Federica, Corallo Salvatore, Miceli Rosalba, Lonardi Sara, Raimondi Alessandra, Cremolini Chiara, Rimassa Lorenza, Bergamo Francesca, Sartore-Bianchi Andrea, Tampellini Marco, Racca Patrizia, Clavarezza Matteo, Berenato Rosa, Caporale Marta, Antista Maria, Niger Monica, Smiroldo Valeria, Murialdo Roberto, Zaniboni Alberto, Adamo Vincenzo, Tomasello Gianluca, Giordano Monica, Petrelli Fausto, Longarini Raffaella, Cinieri Saverio, Falcone Alfredo, Zagonel Vittorina, Di Bartolomeo Maria, de Braud Filippo
Oncology and Hemato-oncology Department, University of Milan, Milan, Italy.
Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy.
JAMA Oncol. 2019 Sep 1;5(9):1268-1275. doi: 10.1001/jamaoncol.2019.1467.
Few studies are available on the role of maintenance strategies after induction treatment regimens based on anti-epidermal growth factor receptors, and the optimal regimen for an anti-epidermal growth factor receptors-based maintenance treatment in patients with RAS wild-type metastatic colorectal cancer is still to be defined.
To determine whether maintenance therapy with single-agent panitumumab was noninferior to panitumumab plus fluorouracil and leucovorin after a 4-month induction treatment regimen.
DESIGN, SETTING, AND PARTICIPANTS: This open-label, randomized phase 2 noninferiority trial was conducted from July 7, 2015, through October 27, 2017, at multiple Italian centers. Patients with RAS wild-type, unresectable metastatic colorectal adenocarcinoma who had not received previous treatment for metastatic disease were eligible. Induction therapy consisted of panitumumab plus FOLFOX-4 (panitumumab, 6 mg/kg, oxaliplatin, 85 mg/m2 at day 1, leucovorin calcium, 200 mg/m2, and fluorouracil, 400-mg/m2 bolus, followed by 600-mg/m2 continuous 24-hour infusion at days 1 and 2, every 2 weeks). Cutoff date for analyses was July 30, 2018.
Patients were randomized (1:1) to first-line panitumumab plus FOLFOX-4 for 8 cycles followed by maintenance therapy with panitumumab plus fluorouracil-leucovorin (arm A) or panitumumab (arm B) until progressive disease, unacceptable toxic effects, or consent withdrawal. The minimization method was used to stratify randomization by previous adjuvant treatment and number of metastatic sites.
The prespecified primary end point was 10-month progression-free survival (PFS) analyzed on an intention-to-treat basis with a noninferiority margin of 1.515 for the upper limit of the 1-sided 90% CI of the hazard ratio (HR) of arm B vs A.
Overall, 229 patients (153 male [66.8%]; median age, 64 years [interquartile range (IQR), 56-70 years]) were randomly assigned to arm A (n = 117) or arm B (n = 112). At a median follow-up of 18.0 months (IQR, 13.1-23.3 months]), a total of 169 disease progression or death events occurred. Arm B was inferior (upper limit of 1-sided 90% CI of the HR, 1.857). Ten-month PFS was 59.9% (95% CI, 51.5%-69.8%) in arm A vs 49.0% (95% CI, 40.5%-59.4%) in arm B (HR, 1.51; 95% CI, 1.11-2.07; P = .01). During maintenance, arm A had a higher incidence of grade 3 or greater treatment-related adverse events (36 [42.4%] vs 16 [20.3%]) and panitumumab-related adverse events (27 [31.8%] vs 13 [16.4%]), compared with arm B.
In patients with RAS wild-type metastatic colorectal cancer, maintenance therapy with single-agent panitumumab was inferior in terms of PFS compared with panitumumab plus fluorouracil-leucovorin, which slightly increased the treatment toxic effects.
ClinicalTrials.gov identifier: NCT02476045.
关于基于抗表皮生长因子受体的诱导治疗方案后维持策略的作用，相关研究较少，且RAS野生型转移性结直肠癌患者基于抗表皮生长因子受体的维持治疗的最佳方案仍有待确定。
确定在4个月的诱导治疗方案后，单药帕尼单抗维持治疗是否不劣于帕尼单抗联合氟尿嘧啶和亚叶酸钙。
设计、设置和参与者：这项开放标签、随机2期非劣效性试验于2015年7月7日至2017年10月27日在多个意大利中心进行。符合条件的患者为未接受过转移性疾病先前治疗的RAS野生型、不可切除的转移性结直肠腺癌患者。诱导治疗包括帕尼单抗联合FOLFOX-4（帕尼单抗，6mg/kg，奥沙利铂，第1天85mg/m²，亚叶酸钙，200mg/m²，氟尿嘧啶，400mg/m²推注，随后在第1天和第2天进行600mg/m²持续24小时输注，每2周一次）。分析的截止日期为2018年7月30日。
患者被随机（1:1）分配至一线帕尼单抗联合FOLFOX-4治疗8个周期，随后接受帕尼单抗联合氟尿嘧啶-亚叶酸钙维持治疗（A组）或帕尼单抗维持治疗（B组），直至疾病进展、出现不可接受的毒性作用或患者撤回同意书。采用最小化法按既往辅助治疗和转移部位数量对随机分组进行分层。
预先设定的主要终点是10个月无进展生存期（PFS），基于意向性分析，B组与A组风险比（HR）的单侧90%CI上限的非劣效性界值为1.515。
总体而言，229例患者（153例男性[66.8%]；中位年龄64岁[四分位间距（IQR），56 - 70岁]）被随机分配至A组（n = 117）或B组（n = 112）。在中位随访18.0个月（IQR，13.1 - 23.3个月）时，共发生169例疾病进展或死亡事件。B组较差（HR的单侧90%CI上限，1.857）。A组10个月PFS为59.9%（95%CI，51.5% - 69.8%），B组为49.0%（95%CI，40.5% - 59.4%）（HR，1.51；95%CI，1.11 - 2.07；P = 0.01）。在维持治疗期间，与B组相比，A组3级或更高级别的治疗相关不良事件（36例[42.4%]对16例[20.3%]）和帕尼单抗相关不良事件（27例[31.8%]对
