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Original Investigation
January 2019

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

Author Affiliations
  • 1Department of Hepatogastroenterology, Digestive Oncology, Centre Hospitalier Universitaire de Nantes, Nantes, France
  • 2Department of Medical Oncology, Institut de Cancérologie de l’Ouest, Saint-Herblain, France
  • 3Department of Medical Oncology, Georges-François Leclerc Cancer Center, Dijon, France
  • 4Department of Hepatogastroenterology, Centre Hospitalier Universitaire Robert Debré, Reims, France
  • 5Department of Medical Oncology, Hôpital Saint-Joseph, Paris, France
  • 6Department of Medical Oncology, Centre Paul Strauss, Strasbourg, France
  • 7Department of Medical Oncology, Centre Antoine-Lacassagne, Nice, France
  • 8Institut de Cancérologie de Lorraine, et Vandoeuvre-Lès Nancy, Université de Lorraine, Vandoeuvre-Lès Nancy, France
  • 9Department of Medical Oncology, Assistance Publique–Hôpitaux de Paris, Paris, France
  • 10Department of Hepatogastroenterology, Digestive Oncology, Assistance Publique–Hôpitaux de Marseille La Timone, Marseille, France
  • 11Hôpital Privé Jean Mermoz, Lyon, France
  • 12Department of Medical Oncology, University Hospital, Lille, France
  • 13UNICANCER, Paris, France
  • 14Centre Hospitalier Universitaire de Nantes, Nantes, France
  • 15Department of Medical Oncology, Centre Oscar Lambret, Lille, France
  • 16Department of Medical Oncology, Centre Hospitalier Universitaire de Besançon, Besançon, France
JAMA Oncol. 2019;5(1):83-90. doi:10.1001/jamaoncol.2018.4465
Key Points

Question  Which is the most appropriate treatment for patients with wild-type RAS metastatic colorectal cancer progressing after bevacizumab plus chemotherapy: chemotherapy with bevacizumab or cetuximab?

Findings  In this randomized phase 2 study, the 4-month progression-free survival rate was numerically higher with bevacizumab plus chemotherapy than with cetuximab plus chemotherapy, though the difference was not statistically significant.

Meaning  The present PRODIGE18 (Partenariat de Recherche en Oncologie DIGEstive) study highlights that, after a first progression of metastatic colorectal cancer with bevacizumab plus chemotherapy, continuation of bevacizumab plus a switch of chemotherapy may be the most appropriate option.


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