FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients: a phase II trial by the Gruppo Oncologico Nord Ovest (GONO)
FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients: a phase II trial by the Gruppo Oncologico Nord Ovest (GONO)
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DOI：
10.1093/annonc/mdt165
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发表时间：
2013-08-01
影响因子：
50.5
通讯作者：
Falcone, A.
中科院分区：
文献类型：
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作者：
Fornaro, L.;Lonardi, S.;Falcone, A.
由Gruppo Oncologico诺德Ovest（GONO）开发的FOLFOXIRI方案在转移性结直肠癌（mCRC）中显示出比FOLFIRI更高的活性和疗效。帕尼单抗在某些KRAS密码子12-13野生型mCRC患者中有效。KRAS密码子61、HRAS、NRAS和BRAF V600 E突变可能预示抗表皮生长因子受体抗体的耐药。（第1天6 mg/kg）与略微改良的果诺-FOLFOXIRI（第1天伊立替康150 mg/m2，奥沙利铂85 mg/m2，亚叶酸200 mg/m2，随后氟尿嘧啶3000 mg/m2，从第1天开始连续输注48小时，每2周一次，作为野生型KRAS、HRAS、NRAS的一线治疗（密码子12-13-61）和BRAF不可切除的mCRC患者。在前3名患者中有2名报告3-4级腹泻（1例伴发热性中性粒细胞减少症）后，氟尿嘧啶剂量降至2400 mg/m2。诱导治疗计划最多12个周期，随后进行帕尼单抗+/-氟尿嘧啶/亚叶酸维持治疗直至进展。主要终点为总有效率（ORR），共筛选87例患者，入组37例。33例患者达到客观缓解（ORR：89%; 95%CI 75%至96%）。16例（43%）患者接受了转移瘤的二次手术，13例（35%）患者实现了R 0切除。中位随访时间为17.7个月，中位无进展生存期为11.3个月（95% CI 9.7-12.9个月）。修订后，诱导治疗期间报告的最常见3-4级不良事件为中性粒细胞减少（48%;发热性中性粒细胞减少：5%）、腹泻（35%）、虚弱（27%）、口腔炎（14%）和皮肤毒性反应（14%）。在FOLFOXIRI方案中增加帕尼单抗，减少氟尿嘧啶和伊立替康的剂量以降低腹泻风险是可行的。Ras-BRAF野生型患者中转移瘤的活动性和继发性可切除性是有希望的。
The FOLFOXIRI regimen developed by the Gruppo Oncologico Nord Ovest (GONO) demonstrated higher activity and efficacy compared with FOLFIRI in metastatic colorectal cancer (mCRC). Panitumumab is effective in some patients with KRAS codon 12-13 wild-type mCRC. KRAS codon 61, HRAS, NRAS, and BRAF V600E mutations might predict resistance to anti-epidermal growth factor receptor antibodies.We conducted a phase II study evaluating the combination of panitumumab (6 mg/kg on day 1) with a slightly modified GONO-FOLFOXIRI (irinotecan 150 mg/m(2), oxaliplatin 85 mg/m(2), and folinate 200 mg/m(2) on day 1, followed by fluorouracil 3000 mg/m(2) as a 48-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of wild-type KRAS, HRAS, NRAS (codon 12-13-61), and BRAF unresectable mCRC patients. Fluorouracil dose was reduced to 2400 mg/m(2) after two of the first three patients reported grade 3-4 diarrhoea (in one case with febrile neutropenia). Induction treatment was scheduled for a maximum of 12 cycles, followed by panitumumab +/- fluorouracil/folinate maintenance until progression. Primary end point was overall response rate (ORR).Eighty-seven patients were screened and 37 were enrolled. Thirty-three patients achieved an objective response (ORR: 89%; 95% CI 75% to 96%). Sixteen patients (43%) underwent secondary surgery of metastases, and R0 resection was achieved in 13 cases (35%). At a median follow-up of 17.7 months, median progression-free survival was 11.3 months (95% CI 9.7-12.9 months). After amendment, most common grade 3-4 adverse events reported during induction treatment were neutropenia (48%; febrile neutropenia: 5%), diarrhoea (35%), asthenia (27%), stomatitis (14%), and skin toxic effect (14%). One treatment-related death was registered.Adding panitumumab to FOLFOXIRI is feasible decreasing the dose of fluorouracil and irinotecan to reduce the risk of diarrhoea. Activity and secondary resectability of metastases among Ras-BRAF wild-type patients are promising.