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Randomized Controlled Trial
. 2021 Feb;124(3):587-594.
doi: 10.1038/s41416-020-01140-9. Epub 2020 Nov 6.

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

Volker Heinemann  1 , Ludwig Fischer von Weikersthal  2 , Thomas Decker  3 , Alexander Kiani  4 , Florian Kaiser  5 , Salah-Edin Al-Batran  6 , Tobias Heintges  7 , Christoph Lerchenmüller  8 , Christoph Kahl  9 , Gernot Seipelt  10 , Frank Kullmann  11 , Markus Moehler  12 , Werner Scheithauer  13 , Swantje Held  14 , Lisa Miller-Phillips  15 , Dominik Paul Modest  15 , Andreas Jung  16 , Thomas Kirchner  16 , Sebastian Stintzing  17
Affiliations
Randomized Controlled Trial

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

Volker Heinemann et al. Br J Cancer. 2021 Feb.

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.

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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
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
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
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.
See this image and copyright information in PMC

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