FOLFOX / Bevacizumab (Beva) +/- Irinotecan in advanced colorectal cancer (CRC): A randomized phase II trial (AIO KRK 0209, CHARTA)

Abstract

Background: TRIBE has shown superiority of adding Oxaliplatin to FOLFIRI / Bev (F. Loupakis, NEJM 2016); STEAM (J. Bendell, ASCO GI 2014) and CHARTA investigate the addition of Irinotecan to FOLFOX + Bev in a randomized Phase II trial. Methods: 7/11 to 12/14 250 patients were randomized to standard FOLFOX / Bev (A) vs. FOLFOXIRI / Bev (B), with dose / schedule as in TRIBE, with exception of 25% dose reductions in cycles 1 and 2 if necessary. Incl.- criteria: ECOG 0-2, ≥ 1 measurable lesion > 1cm. Stratification: ESMO-Group 1,2,3 (Schmoll et. al., Ann Oncol 2012). Treatment-duration: 6 months induction, 12 months maintenance or until progression. Primary Endpoint: Improvement of PFS-rate @ 9 months with p < 0.1 (2-sided, Fisher's-exact test), secondary endpoint: RR- rate, PFS, OS, sec. resection. Results: 241 pts. evaluable (1 not elig., 8 protocol violation); pts. characteristics: m/f: 65%/35%, age 61yrs. (21-82), left/right: left A: 51,5%, B:48,5%; right A: 45%, B: 55%, ECOG 0-1/2: 96% / 4%, ESMO-group 1/2/3: 29%/ 55%/ 16%, Koehne-Score: low/ intermed./high 9% /75%/ 16%; no difference for Avs. B in all subgroups. Primary endpoint was met: PFS-rate @ 9 months of 56% vs. 68% (p= 0,086); median PFS 9,76 vs. 12,0 months, HR 0.77, p = 0.61 (TRIBE-Trial: 9,7 vs. 12,1). Response-rates (A/B): CR 5% vs. 5%, CR + PR 60% vs. 70%, SD 25% vs. 21%, PD 14% vs. 9%. Mets resection: 23% vs. 26%. OS 24.9 vs 27.9 months (prelim.). PFS-Subgroup - analysis did not show significant differences, except left vs. right location: 10.4 vs. 12 months (HR 0.69, p = 0.03). Beyond this, a non-significant improvement was seen in ESMO-Group 3 (HR 0.51), RAS-wt (HR 0.67), Koehne-score High risk (HR 0.58), ECOG 1 (HR 0.69). The QL-Health-Score after induction was slightly reduced in A and improved in B without major changes. Dose-intensity <70%/ 70-90%/ >90% (A vs. B): 39% vs 37%/ 18% vs. 26% / 41% vs. 36%; initial dose-reduction 17% of pts. Toxicity: was low to moderate without major differences between A &B, except grade 3/4 diarrhea 12% vs. 16%, neutrophils 14% vs. 20% & GI 12% vs. 20%. Conclusions: CHARTA reproduces response- & PFS-data of TRIBE and further supports the use of the 4-drug-regimen 1st-line-treatment for most pts.