Randomised trial of cetuximab every 2 weeks with FOLFIRI or cetuximab with alternating FOLFIRI/FOLFOX in patients with RAS and BRAF wild type metastatic colorectal cancer: Nordic 8 results

Abstract

Introduction: Adding cetuximab to first‐line FOLFIRI improves outcome in RAS and BRAF wild‐type metastatic colorectal cancer (mCRC). Triplet chemotherapy improves efficacy further but at the cost of increased toxicity. We hypothesized that alternating FOLFIRI/FOLFOX maintains efficacy of triplet therapy but with lower toxicity. Here we report the primary results from Nordic 8, a multi‐center, open‐label, randomised trial comparing cetuximab with FOLFIRI (arm A) or cetuximab with FOLFIRI alternating with FOLFOX (arm B). Methods: In this investigator‐initiated randomised trial, 173 chemo‐naïve mCRC patients received cetuximab (500 mg/m2 day 1 every two weeks) with FOLFIRI (irinotecan 180 mg/m2 day 1, d,l‐leucovorin 400 mg/m2 day 1, 5‐FU 400 mg/m2 bolus day 1 followed by 5‐FU 2400 mg/m2 as 46 hours infusion every 2 weeks) or cetuximab with FOLFIRI (2 cycles) alternating with FOLFOX (oxaliplatin 85 mg/m2 day 1, 2 cycles) until PD. Main inclusion criteria were PS 0 or 1, RAS wildtype and ESMO group 1‐3 (prior to April 2014 only ESMO group 1 (potentially resectable), when 36 patients had been included). The primary aim was to increase response rate (RR) from 60% to 75% (RECIST 1.1); PFS, OS, and safety were secondary endpoints. All endpoints were evaluated by the local investigator. Results: Between May 2012 and May 2018, 86 patients were randomised to FOLFIRI + cetuximab (arm A) and 87 patients to alternating FOLFIRI/FOLFOX + cetuximab (arm B). Median age was 64 years, female 34%, PS 0 61%, ESMO group 1/2/3 64%/ 23%/13%, liver only disease 43%, and 25% had resection of the primary tumour. Patient and disease characteristics at baseline were generally well‐balanced between the two groups. Median duration of therapy was 6.2 months in both arms and patients received a median of 11 and 12 cycles, respectively, without any difference in doseintensity. Overall RR was not significantly increased (arm A, 69%; arm B 78%, p=0.17). Median PFS was 11.9 (arm A) and 11.8 months (arm B) (HR 1.10; p=0.60) and median OS was 40.7 and 39.2 months (HR 1.05; p=0.82), respectively. Most important grade ≥ 3 adverse events were neutropenia (15% vs 17%), rash (9% vs 15%), diarrhoea (7% vs 11%), fatigue (7% vs 7%), and febrile neutropenia (3% vs 1%); 20% in arm B experienced neuropathy grade 2 (no grade 3). Conclusion: Cetuximab every two weeks with FOLFIRI or alternating FOLFIRI/ FOLFOX were well tolerated with high RRs and long PFS and OS, however, Nordic 8 did not meet its primary endpoint and we recommend FOLFIRI + cetuximab every 2 weeks in patients with RAS and BRAF wild type mCRC.