FOLFOX/bevacizumab +/- irinotecan in advanced colorectal cancer (CHARTA): Long term outcome

Introduction: FOLFOXIRI/bevacizumab (Bev) was superior to FOLFIRI/Bev in the TRIBE trial. However the comparison with FOLFOX/Bev as the alternative standard was not proven. The CHARTA trial was developed in parallel to TRIBE, but with FOLFOX/Bev as control arm; for comparison reasons TRIBE and CHARTA used the same dose and schedule. Methods: From 7/11 to 12/14 250 patients were randomized, including ECOG 0-2, ≥ 1 measurable lesion > 1cm, stratified by ESMO-Group 1,2,3. Induction: 6 months, maintenance capecitabine+Bev until progression or max. 12 months, at P reinduction by investigators decision. 25% dose reduction was allowed in cycle 1 + 2 on the investigator's discretion. Primary EP: significant improvement of PFS-rate @ 9 months (p < 0.1, 2-sided Fisher's-exact test); secondary EP: RR, PFS, OS, toxicity. Results: 241 pts (1 not elig., 8 prot. violation) are evaluable and have been previously presented after a follow up of 31.4 (0.1-51) months (Schmoll et al, World GI 2017). The Primary Endpoint was met: PFS @ 9 months 56% vs. 68%, p = 0.086. PFS was improved: 9.8 vs. 12.0 months, HR 0.7 (ns.), identical to TRIBE with 9.7 vs. 12.1 months. Response rate (A/B): CR: 5%/5%, CR/PR 60%/70%, SD 25%/21%, PD 14%/9%. OS was not significant different (24 vs 28). Toxicity was low to moderate without major differences except grade ¾ diarrhea (12%/16%) and neutrophils (14%/20%). Clinical/molecular prognostic or predictive factors are equally distributed (stratified by ESMO groups). PFS was significantly improved (p = 0.027) in the subgroup of pts. with synchronous metastases (91% of pts); the strongest improvement by the 4-drug combination was shown in those pts. with synchronous mets., who never had resection of the primary (52% of the pts.): 17 vs. 26.5 mos. (p < 0.01). In the subgroup of "liver/lung only" there was no difference, however with a long OS in both arms (45.3 / 44.2 mos.). In univariate analysis there are major, but mostly not significant differences in RR/ PFS in most subgroups (borderline significant: risk score high HR 0.66; ESMO group 3 HR 0.62; BRAF HR 0.72; right location HR 0.73), however, not strong enough to safely identify patients with high potential to benefit from the 4-drug combination. Conclusion: After 12 further months of follow-up with a median of 38 with a maximum of 7 years. All data for PFS and OS are mature and ready for final evaluation, including clinical and molecular subgroup and multivariate analyses as well data on reinduction and salvage treatments. Translational research is ongoing. The final clinical data will be available at the meeting.