Second-line treatment with chemotherapy plus Bev or Cet is now established as a valid option in mCRC. The main objective of this French multicenter, randomized open phase II trial, was to evaluate the Progression Free Survival (PFS) rate at 4 months with chemotherapy plus Bev or Cet in patients with disease progression after Bev plus chemotherapy.
The main eligibility criterion was disease progression after bevacizumab + 5-FU with irinotecan or oxaliplatin in patients with WT KRAS exon 2 mCRC. Patients were randomized in Arm A (FOLFIRI or mFOLFOX6 plus Bev) or in Arm B (FOLFIRI or mFOLFOX6 plus Cet); the chemotherapy doublet was chosen according to the first line (cross over). Analyses were performed in ITT population. They were repeated on the KRAS + NRAS WT population and in the triple negative population (KRAS, NRAS, and BRAF negative).
From October 2010 to May 2015, 133 patients were included in 25 sites (1 patient ineligible): 85 males (64%), PS 0 (74, 56%), 1 (54, 41%), unknown (4, 3%). 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. Median PFS was 7.1 months in Arm A vs 5.6 months in Arm B (p = 0.060). Median OS reached 15.8 months in Arm A vs 10.4 months in Arm B (p = 0.073). Tumors samples were collected by a central laboratory and 95 were analysed using the KRAS/BRAF mutation analysis panel kit (KRAS exon 2,3,4 and BRAF V600E) and NRAS mutation detection kit (exons 2,3,4; Entrogen). On the whole, 81 patients were KRAS and NRAS WT (41 in Arm A and 40 in Arm B). Median PFS was respectively 7.8 months and 5.6 months in Arm A and Arm B (p = 0.076); median OS was 21.0 months in Arm A vs 10.7 months in arm B (p = 0.324). 73 were negative for the 3 genes (n = 36 and 37). Their median PFS were 8.2 months in Arm A) vs 5.7 months in arm B (p = 0.100). Median OS was 21.1 months vs 12.6 months (p = 0.365).
PRODIGE18 study is in favour of bevacizumab continuation beyond progression with chemotherapy cross over in WT RAS mCRC initially treated with first-line Bev plus chemotherapy.
Clinical trial identification
Clinical trial information:
Legal entity responsible for the study
J. Bennouna: Advisory Board for Roche, Boehringer Ingelheim, AstraZeneca, Servier, BMS. S. Hiret: Roche, Boehringer Ingelheim, AstraZeneca. C. Borg: Roche, Sanofi, Servier. O. Bouche: Roche, Merck, Amgen, Lilly, Pierre Fabre, Boehringer Ingelheim, Novartis. E. Francois: Advisory Board: Roche, Merck. F. Ghiringhelli: Roche, Sanofi, Amgen, BMS. J-F. Seitz: Roche, Merck, Sanofi. P. Artru: Roche, Merck, Amgen. A. Adenis: Roche. All other authors have declared no conflicts of interest.