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Randomized Controlled Trial
. 2022 Sep;127(5):836-843.
doi: 10.1038/s41416-022-01854-y. Epub 2022 May 30.

Efficacy of FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in 1st-line treatment of older patients with RAS wild-type metastatic colorectal cancer: an analysis of the randomised trial FIRE-3

Laura E Fischer  1 , Sebastian Stintzing  2 , Ludwig Fischer von Weikersthal  3 , Dominik P Modest  2 , Thomas Decker  4 , Alexander Kiani  5 , Florian Kaiser  6 , Salah-Eddin Al-Batran  7 , Tobias Heintges  8 , Christian Lerchenmüller  9 , Christoph Kahl  10   11 , Gernot Seipelt  12 , Frank Kullmann  13 , Martina Stauch  14 , Werner Scheithauer  15 , Clemens Giessen-Jung  16 , Jens Uhlig  17 , Bettina Peuser  18 , Claudio Denzlinger  19 , Arndt Stahler  2 , Lena Weiss  16 , Kathrin Heinrich  16 , Swantje Held  20 , Andreas Jung  21 , Thomas Kirchner  21 , Volker Heinemann  16   22
Affiliations
Randomized Controlled Trial

Efficacy of FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in 1st-line treatment of older patients with RAS wild-type metastatic colorectal cancer: an analysis of the randomised trial FIRE-3

Laura E Fischer et al. Br J Cancer. 2022 Sep.

Abstract

Background: The evidence on the efficacy of anticancer therapy is limited in older patients with metastatic colorectal cancer (mCRC). This retrospective analysis of phase III FIRE-3 trial assesses the efficacy of FOLFIRI plus either cetuximab or bevacizumab according to the patients' age and sidedness of primary tumour.

Methods: The study endpoints overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between younger (<65 years) and older (≥65 years) patients, followed by stratification according to primary tumour sidedness. ORR was compared using Fisher´s exact test, OS and PFS were estimated by the Kaplan-Meier method and compared using the log-rank test. Univariate Cox regression analyses assessed hazard ratios and 95% confidence intervals for OS and PFS.

Results: Overall, older patients with RAS WT tumours had a significantly shorter OS when compared to younger patients (25.9 months vs 29.3 months, HR 1.29; P = 0.02). Also the proportion of right-sided tumours was significantly greater in older patients (27.1% vs 17.9%; P = 0.029). Secondary resection rates were numerically higher in younger patients (25.4% vs. 17.6%, P = 0.068) than in older patients. This was primarily seen in the Cetuximab arm, where older patients underwent less likely resection (13.1% vs. 26%; P = 0.02). Older patients with left-sided tumours showed only a trend towards greater efficacy of cetuximab (HR 0.86; P = 0.38). In patients with right-sided primary tumours, older patients did not appear to benefit from cetuximab in contrast to younger patients (≥65 years: 16.6 months vs 23.6 months, HR 1.1; P = 0.87; <65 years: 21.9 months vs 16.4 months HR 1.5; P = 0.31).

Conclusions: In FIRE-3, OS was generally shorter in older patients in comparison to younger patients. This could be explained by the overrepresentation of right-sided tumours and a lower secondary resection rate in older patients. The efficacy of targeted therapy was dependent on tumour sidedness in older patients with RAS WT mCRC.

Clinical trial: FIRE-3 (NCT00433927).

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Conflict of interest statement

LEF: No conflicts of interests. SS: Honoraria: AMGEN, Bayer, BMS, ESAI, Lilly, Merck KGaA, MSD, Pierre-Fabre, Roche, Sanofi, Servier, Taiho, Takeda, Financial relationships: Merck KGaA, Pierre-Fabre, Servier, Roche. Advisory role: AMGEN, Bayer, BMS, ESAI, Lilly, Merck KGaA, MSD, Pierre-Fabre, Roche, Sanofi, Servier, Taiho, Takeda. LFvW: Honoraria: Novartis, Lilly, Piere-Fabre and Roche Pharma AG. DPM: Honoraria: Merck Serono, Amgen, Roche, Servier, BMS, MSD, Pierre Fabre, Onkowissen.de, Taiho, Sanofi, Eli Lilly. Consulting or Advisory Role: Merck Serono, Amgen, Bayer, Incyte, Servier, BMS, Onkowissen.de. Research Funding: Amgen (Inst), Servier (Inst). Travel, Accommodations, Expenses: Amgen, Merck Serono, Servier, Bristol-Myers Squibb. TD: Advisory Role: Roche and Novartis. AK: Honoraria: Merck and Roche. FK: Advisory Role: Elsevier, Astellas, MSD, Novartis, Servier, GSK. S-EA-B: No conflicts of interests. TH; No conflicts of interests. CL: No conflicts of interests. CK: No conflicts of interests. GS: No conflicts of interests. FK: No conflicts of interests. MS: No conflicts of interests. WS: No conflicts of interests. CG-J: Honoraria/Travel: Roche. JU: Adboards/Workshops: Roche, Amgen, Servier, MSD, Bristol-Myers Squibb, Sanofi, Merck, Celgene, Novartis, Janssen-Cilag, Boehringer-Ingelheim und Bayer, Biogene. BP: No conflicts of interests. CD: Financial relationships: Janssen, Novartis, Celgene, Incyte, Abbvie, Bayer, Merck. AS: Honoraria: Roche and Servier. Travel: Roche, Merck KGaA, MSD Sharp & Dohme, Pfizer and Amgen. LW: Honoraria: Roche and Servier. KH: No conflicts of interests. SH; No conflicts of interests. AJ: No conflicts of interests. TK: Consulting/Advisory: Amgen, AstraZeneca, BMS, Merck KGaA, MSD, Novartis, Pfizer, Roche. Research Funding: Merck and Roche. Advisory Role: Merck KGaA, Astra Zeneca. VH: Honoraria: Merck, Amgen, Roche, Sanofi, SIRTEX, Servier, Pfizer, Pierre-Fabre, Astra-Zeneca. Consulting: Merck, Amgen, Roche, Sanofi, SIRTEX, BMS; MSD, Novartis, Boehringer Ingelheim, Servier, Pierre-Fabre, Celgene, Terumo. Research funding (for the institution): Merck, Amgen, Roche, Sanofi, Pfizer, Boehringer-Ingelheim, Sirtex, Bayer, Servier. Travel accommodation expenses: Merck, Roche, Amgen, SIRTEX, Bayer, Servier.

Figures

Fig. 1
Fig. 1. Age correlated overall survival according to treatment group in the RAS wild-type population.
For survival times Kaplan–Meier estimation medians and 95% CIs are given. FOLFIRI fluorouracil, leucovorin, and irinotecan, HR hazard ratio, OS median overall survival, wt wild-type.
Fig. 2
Fig. 2. Age correlated overall survival according to secondary resection in the RAS wild-type population.
For survival times Kaplan–Meier estimation medians and 95% CIs are given. OS median overall survival, wt wild-type.
See this image and copyright information in PMC

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