Cremolini Chiara, Antoniotti Carlotta, Stein Alexander, Bendell Johanna, Gruenberger Thomas, Rossini Daniele, Masi Gianluca, Ongaro Elena, Hurwitz Herbert, Falcone Alfredo, Schmoll Hans-Joachim, Di Maio Massimo
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, University Hospital of Pisa, Pisa, Italy.
Hematology-Oncology Practice Hamburg (HOPE), University Cancer Center Hamburg, Hamburg, Germany.
J Clin Oncol. 2020 Aug 20:JCO2001225. doi: 10.1200/JCO.20.01225.
A proper estimation of the magnitude of the overall survival (OS) benefit from infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab versus doublets + bevacizumab is lacking because all trials that have investigated this regimen had primary end points other than OS. To test OS with higher power and to explore the interaction of treatment effect with main patient and disease characteristics, we performed an individual patient data (IPD) meta-analysis.
IPD from 5 eligible trials were collected: CHARTA (ClinicalTrials.gov identifier: NCT01321957), OLIVIA (ClinicalTrials.gov identifier: NCT00778102), STEAM (ClinicalTrials.gov identifier: NCT01765582), TRIBE (ClinicalTrials.gov identifier: NCT00719797), and TRIBE2 (ClinicalTrials.gov identifier: NCT02339116). The primary end point was OS. Secondary end points were progression-free survival (PFS), objective response rate (ORR), R0 resection rate, grade 3/4 adverse events, and subgroup analyses according to clinical and molecular characteristics.
A total of 1,697 patients were randomly assigned to FOLFOXIRI + bevacizumab (n = 846) or doublets + bevacizumab (n = 851). Most (78%) had an Eastern Cooperative Oncology Group performance status of 0, and the median age was 61 years. After a median follow-up of 39.9 months, patients assigned to FOLFOXIRI + bevacizumab had significantly longer OS than those assigned to doublets + bevacizumab (median, 28.9 24.5 months; hazard ratio [HR], 0.81; 95% CI, 0.72 to 0.91; < .001), with no significant heterogeneity among trials ( = .39; I = 2%). No significant interaction effect between treatment arm and investigated characteristics was demonstrated. Patients assigned to FOLFOXIRI + bevacizumab had longer PFS (median, 12.2 9.9 months; HR, 0.74; 95% CI, 0.67 to 0.82; < .001), higher ORR (64.5% 53.6%; < .001), higher R0 resection rate (16.4% 11.8%; = .007), and higher rates of grade 3/4 neutropenia (45.8% 21.5%; < .001), febrile neutropenia (6.3% 3.7%; = .019), and diarrhea (17.8% 8.4%; < .001).
FOLFOXIRI + bevacizumab significantly and meaningfully improves survival of patients with metastatic colorectal cancer compared with doublets + bevacizumab and provides advantage in PFS, ORR, and R0 resection rate at the price of a moderate increase in toxicity. No increased benefit is observed among patients with -mutant tumors.
由于所有研究该方案的试验的主要终点均非总生存期（OS），因此目前缺乏对持续输注氟尿嘧啶、亚叶酸钙、奥沙利铂和伊立替康（FOLFOXIRI）联合贝伐单抗相对于双联方案联合贝伐单抗所带来的OS获益程度的恰当评估。为了更有力地检验OS，并探索治疗效果与主要患者和疾病特征之间的相互作用，我们进行了一项个体患者数据（IPD）荟萃分析。
收集了5项符合条件的试验的IPD：CHARTA（ClinicalTrials.gov标识符：NCT01321957）、OLIVIA（ClinicalTrials.gov标识符：NCT00778102）、STEAM（ClinicalTrials.gov标识符：NCT01765582）、TRIBE（ClinicalTrials.gov标识符：NCT00719797）和TRIBE2（ClinicalTrials.gov标识符：NCT02339116）。主要终点为OS。次要终点为无进展生存期（PFS）、客观缓解率（ORR）、R0切除率、3/4级不良事件，以及根据临床和分子特征进行的亚组分析。
共有1697例患者被随机分配至FOLFOXIRI联合贝伐单抗组（n = 846）或双联方案联合贝伐单抗组（n = 851）。大多数患者（78%）的东部肿瘤协作组体能状态为0，中位年龄为61岁。中位随访39.9个月后，分配至FOLFOXIRI联合贝伐单抗组的患者的OS显著长于分配至双联方案联合贝伐单抗组的患者（中位值分别为28.9个月对24.5个月；风险比[HR]为0.81；95%置信区间[CI]为0.72至0.91；P <.001），各试验间无显著异质性（P = 0.39；I² = 2%）。未证实治疗组与所研究特征之间存在显著的交互作用。分配至FOLFOXIRI联合贝伐单抗组的患者的PFS更长（中位值分别为12.2个月对9.9个月；HR为0.74；95%CI为0.67至0.82；P <.001），ORR更高（64.5%对53.6%；P <.001），R0切除率更高（16.4%对11.8%；P = 0.007），3/4级中性粒细胞减少症、发热性中性粒细胞减少症和腹泻的发生率也更高（分别为45.8%对21.5%；P <.001、6.3%对3.7%；P = 0.019、17.8%对8.4%；P <.001）。
与双联方案联合贝伐单抗相比，FOLFOXIRI联合贝伐单抗显著且有意义地提高了转移性结直肠癌患者的生存率，并在PFS、ORR和R0切除率方面具有优势，但代价是毒性适度增加。在携带KRAS突变肿瘤的患者中未观察到额外的获益。
