The triplet combination of irinotecan, oxaliplatin and 5FU/LV (FOLFOXIRI) vs the doublet of irinotecan and 5FU/LV (FOLFIRI) as first-line treatment of metastatic colorectal cancer (MCRC): Results of a randomized phase III trial by the Gruppo Oncologico Nord Ovest (G.O.N.O.)

Abstract

3513 Background: We demonstrated interesting activity and manageable toxicities for the FOLFOXIRI regimen in phase I-II studies. Methods: The G.O.N.O. conduced a phase III study comparing FOLFIRI (CPT11 180 mg/sqm d1, l-LV 100 mg/sqm d1+d2, 5FU 400 mg/sqm bolus d1+d2, 5FU 600 mg/sqm 22-h inf. on d1+d2, arm A), to FOLFOXIRI (CPT11 165 mg/sqm d1, LOHP 85 mg/sqm d1, l-LV 200 mg/sqm d1, 5FU 3200 mg/sqm 48-h inf. starting on d1, arm B). Both treatments were repeated every 2 weeks and at progression to FOLFIRI a FOLFOX combination was recommended. Selection criteria included measurable and not resectable MCRC, age 18–75 years, no prior chemotherapy for advanced disease. Primary endpoint was response rate (RR) and planned accrual was 240 pts. Secondary endpoints were PFS, OS, post-CT R0 surgical resections, safety and QoL. Results: A total of 244 pts were randomized. Main toxicities were (arm A/arm B): grade 3–4 diarrhea 12%/20%, grade 3–4 vomiting 2%/7%, grade 3–4 stomatitis 3%/5%, grade 2–3 peripheral neurotoxicity 0%/20%, grade 4 neutropenia 11%/17%, febrile neutropenia 3%/5%. Two pts in each arm died within 60 days, but no toxic deaths occurred. Responses, assessed by investigators, were (arm A/arm B): complete 6%/8%, partial 35%/58%, stable 33%/21%, progression 24%/11%, for an overall RR of 41% vs 66%, p=0.0002. RR confirmed by an external panel was 34%/60%, p<0.0001. This increased activity allowed a radical secondary resection of mts in a greater percentage of patients in the FOLFOXIRI arm (6% vs 14%, p=0.05, among all 244 pts and 12% vs 36%, p=0.02, among 81 patients with liver mts only). At a median follow-up of 15.2 months 112 vs 104 pts have progressed and 81 vs 65 have died with a significant improvement in progression-free and overall survival in favor of the triplet (median PFS 6.9 vs 9.8 mos, HR: 0.63, p=0.0006; median S 16.7 vs 22.6, HR:0.70, p=0.032). Conclusions: The FOLFOXIRI regimen is feasible with manageable toxicities and significantly increases RR, R0 resection of mts, PFS and overall S compared to FOLFIRI. (Partially supported by Fondazione ARCO). [Table: see text]