Continuation of Bevacizumab vs Cetuximab Plus Chemotherapy After First Progression in KRAS Wild-Type Metastatic Colorectal Cancer: The UNICANCER PRODIGE18 Randomized Clinical Trial

Abstract

Importance: Second-line treatment with chemotherapy plus bevacizumab or cetuximab is a valid option for metastatic colorectal cancer.

Objective: To evaluate the progression-free survival (PFS) rate at 4 months with chemotherapy plus bevacizumab vs cetuximab for patients with progression of metastatic colorectal cancer after bevacizumab plus chemotherapy.

Design, setting, and participants: A prospective, open-label, multicenter, randomized phase 2 trial was conducted from December 14, 2010, to May 5, 2015. The main eligibility criterion was disease progression after bevacizumab plus fluorouracil with irinotecan or oxaliplatin in patients with wild-type KRAS exon 2 metastatic colorectal cancer. All analyses were performed on the modified intent-to-treat population.

Interventions: Patients were randomized to arm A (FOLFIRI [fluorouracil and folinic acid combined with irinotecan] or modified FOLFOX6 [fluorouracil and folinic acid combined with oxaliplatin] plus bevacizumab) or arm B (FOLFIRI or modified FOLFOX6 plus cetuximab); the second-line chemotherapy regimen was chosen according to first-line treatment (crossover).

Main outcomes and measures: The primary end point was the 4-month PFS rate. Secondary end points included safety, objective response rate, overall survival, and PFS.

Results: A total of 132 patients (47 women and 85 men; median age, 63.0 years [range, 33.0-84.0 years]; 74 patients with an Eastern Cooperative Oncology Group performance status of 0, 54 patients with a performance status of 1, and 4 patients with unknown performance status) were included at 25 sites. The 4-month PFS rate was 80.3% (95% CI, 68.0%-88.3%) in arm A and 66.7% (95% CI, 53.6%-76.8%) in arm B. The median PFS was 7.1 months (95% CI, 5.7-8.2 months) in arm A and 5.6 months (95% CI, 4.2-6.5 months) in arm B (hazard ratio, 0.71; 95% CI, 0.50-1.02; P = .06), and the median overall survival was 15.8 months (95% CI, 9.5-22.3 months) in arm A and 10.4 months (95% CI, 7.0-16.2 months) in arm B (hazard ratio, 0.69; 95% CI, 0.46-1.04; P = .08). A central analysis of KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), and BRAF (V600) was performed for 95 tumor samples. Eighty-one patients had wild-type KRAS and wild-type NRAS tumors.

Conclusions and relevance: The results of the PRODIGE18 (Partenariat de Recherche en Oncologie DIGEstive) study showed a nonsignificant difference but favored continuation of bevacizumab with chemotherapy crossover for patients with wild-type RAS metastatic colorectal cancer that progressed with first-line bevacizumab plus chemotherapy.

Trial registration: ClinicalTrials.gov identifier: NCT01442649 and clinicaltrialsregister.eu identifier: EUDRACT 2009-012942-22.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Bennouna reported receiving honoraria from Roche, Amgen, Boehringer-Ingelheim, AstraZeneca, Bristol-Myers Squibb, and Bayer. Dr Hiret reported serving as a consultant for AstraZeneca. Dr Bouché reported serving as a consultant for Roche, Amgen, Merck Sereno, and Bayer and participating in speakers bureaus for Pierre Fabre and Servier. Dr François reported receiving honoraria from Merck Serono, Roche, Amgen, Lilly, Servier, and Sanofi. Dr Seitz reported receiving honoraria from Merck Serono, Roche, and Sanofi. Dr Artru reported receiving honoraria from Roche, Merck Serono, Amgen, Servier, Bayer, Sanofi, Lilly, and Celgene. Dr Denis reported receiving honoraria from AstraZeneca, Pfizer, Bristol-Myers Squibb, and Boehringer Ingelheim and receiving grants from Roche Diagnostics and Merck. Dr Adenis reported receiving honoraria from Roche, Sanofi, Bayer, and Amgen and receiving grants from Sanofi and Bayer. Dr Borg reported receiving honoraria from Roche and Servier and receiving grants from Roche.

Figures

Figure 1.. Patient Enrollment

mCRC Indicates metastatic colorectal cancer, wt, wild-type.

Figure 2.. Kaplan-Meier Estimates of Progression-Free Survival

A, Progression-free survival among patients with wild-type (wt) KRAS exon 2 (log-rank P = .06). B, Progression-free survival among patients with wtKRAS and wtNRAS exons 2, 3, and 4 (log-rank P = .08). C, Progression-free survival among patients with wtKRAS and wtNRAS exons 2, 3, and 4 and wtBRAF (log-rank P = .10). Plus signs indicate censored patients.

Figure 3.. Kaplan-Meier Estimates of Overall Survival

A, Overall survival among patients with wild-type (wt) KRAS exon 2 (log-rank P = .07). B, Overall survival among patients with wtKRAS and wtNRAS exons 2, 3, and 4 (log-rank P = .32). C, Overall survival among patients with wtKRAS and wtNRAS exons 2, 3, and 4 and wtBRAF (log-rank P = .37). Plus signs indicate censored patients.