Continuation of Bevacizumab vs Cetuximab Plus Chemotherapy After First Progression in KRAS Wild-Type Metastatic Colorectal Cancer

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-typeKRASexon 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 ofKRAS(exons 2, 3, and 4),NRAS(exons 2, 3, and 4), andBRAF(V600) was performed for 95 tumor samples. Eighty-one patients had wild-typeKRASand wild-typeNRAStumors.

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-typeRASmetastatic colorectal cancer that progressed with first-line bevacizumab plus chemotherapy.

Trial Registration

ClinicalTrials.gov identifier:NCT01442649and clinicaltrialsregister.eu identifier:EUDRACT 2009-012942-22