FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial

Abstract

Background: Cetuximab plus FOLFIRI improved overall survival compared with bevacizumab plus FOLFIRI in KRAS wild-type metastatic colorectal cancer (mCRC) in FIRE-3, but no corresponding benefit was found for progression-free survival. This analysis aimed to determine whether cetuximab improves response and survival versus bevacizumab among response-evaluable patients receiving first-line FOLFIRI for RAS wild-type mCRC and the effect of primary tumour side on outcomes.

Methods: The intent-to-treat population included 593 patients with KRAS exon 2 wild-type mCRC. Further testing identified 400 patients with extended RAS wild-type disease; of these, 352 (88%) who received ≥3 cycles of therapy and had ≥1 post-baseline scan were evaluable for response and constituted the per-protocol population (169 cetuximab and 183 bevacizumab). Patients received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) with either weekly cetuximab or biweekly bevacizumab given on day 1 of each 14-day cycle until response, progression or toxicity occurred. The primary endpoint was the objective response rate (ORR) in the per-protocol population. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). The effect of primary tumour location was evaluated.

Results: Median OS in the RAS wild-type population was 31 vs 26 months in the cetuximab and bevacizumab groups, respectively (HR 0.76, P = 0.012). In the per-protocol population, outcomes favoured cetuximab for ORR (77% vs 65%, P = 0.014) and median OS (33 vs 26 months, HR 0.75, P = 0.011), while PFS was comparable between groups. The advantage of cetuximab over bevacizumab occurred only in patients with left-sided primary tumours.

Conclusions: FOLFIRI plus cetuximab resulted in a significantly higher ORR and longer OS compared to FOLFIRI plus bevacizumab among patients with left-sided tumours. The superior response associated with cetuximab may particularly benefit patients with symptomatic tumours or borderline-resectable metastases. CLINICALTRIALS.

Gov identifier: NCT00433927.

Conflict of interest statement

Dr. Heinemann reported financial relationships with Merck-Serono, Roche, Servier, Sirtex, Bristol-Myers Squibb, Merck Sharp & Dohme, Bayer, Boehringer-Ingelheim and Eli Lilly and Company. Dr. Jung reported financial relationships with Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Roche, Novartis and Merck-Serono. Dr. Kiani reported receiving honoraria from Merck & Co, Roche and Amgen. Dr. Kirchner reported financial relationships with Merck-Serono, AstraZeneca, Amgen, Merck Sharp & Dohme, Novartis, Pfizer and Roche. Dr. Kullmann reported financial relationships with Roche and Celgene. Dr. Modest reported financial relationships with Merck-Serono, Roche, Servier, Sirtex, Bristol-Myers Squibb, Merck Sharp & Dohme, Bayer, Boehringer-Ingelheim and Eli Lilly and Company. Dr. Moehler reported financial relationships with Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck-Serono, Eli Lilly and Company, Dr. Falk Pharma GmbH, Pfizer and Roche. Dr. Stintzing reported receiving honoraria from Amgen, Merck-Serono, Pierre-Fabre, Servier, Roche, Sanofi, Bayer, Takeda and Eli Lilly and Company. Dr. von Weikersthal reported receiving honoraria from Roche, Novartis and Genzyme. No other disclosures were reported.

Figures

Fig. 1. Survival times in the RASwt population (n = 400).

Progression-free (a) and overall (b) survival in the RAS wild-type population (N = 400). Bev bevacizumab, Cet cetuximab.

Fig. 2. Survival times in the RASwt population that were per protocol accessible for tumour response (n = 352).

Progression-free (a) and overall (b) survival in the RAS wild-type per-protocol population (N = 352). Bev bevacizumab, Cet cetuximab.

Fig. 3. Primary tumour location and survival in the RAS wild-type per-protocol population.

Left-sided tumours (N = 273): a progression-free survival, b overall survival; right-sided tumours (N = 75): c progression-free survival, d overall survival. Bev bevacizumab, Cet cetuximab.