FOLFOXIRI/bevacizumab in microsatellite stable (pMMR/MSS) <i>RAS</i> and <i>BRAF</i> wild-type “gene-altered” metastatic colorectal cancer (mCRC): The HYPERTRIBE study.

3560 Background: Negative hyperselection may allow patient refinement for the use of anti-EGFRs in chemo-naïve pMMR/MSS, RAS and BRAF wild-type (wt) mCRC patients. However, outcomes are poor with both doublets/anti-EGFRs and doublets/bevacizumab (bev) among patients with gene-altered tumors. We investigated the efficacy of chemotherapy intensification with FOLFOXIRI/bev in this subgroup. Methods: We prospectively selected mCRC patients with pMMR/MSS, RAS and BRAF wt tumors harbouring at least one genomic alteration potentially implied with anti-EGFR resistance in published studies ( ERBB2 / PIK3CAexon20 / PTEN / AKT1 / NTRKs / ERBB3 / NF1 / MAP2K1-2-4 / AKT2 / EGFR / subclonal RAS mutations; ERBB2 / MET / ERBB3 / FGFR2 / IGF1R / KRAS / ARAF / AKT1-2 amplification; ALK / ROS1 / NTRKs / RET fusions; EGFR rearrangements; PTEN / NF1 loss), treated with upfront FOLFOXIRI/bev in 11 Italian centres. Assuming that the use of FOLFOXIRI/bev could lead to an increase in median PFS (mPFS) from 9 (as observed with doublets/anti-EGFRs) to 16 months (mos), with one-sided α and β errors of 0.10 and 0.20, respectively, 33 patients were needed. Secondary endpoints were overall survival (OS) and objective response rate (ORR). Outcomes were paired with a propensity score-matched external cohort of pMMR RAS and BRAF wt gene-altered patients treated with doublets/anti-EGFRs in clinical trials. Results: 35 patients were included. Main patients' characteristics were: median age 54 years, ECOG PS 0 83%, left-sided tumours 54%. Amplification in ERBB2 and MET genes accounted for 26% and 6% of cases, respectively. The most frequent mutant gene was ERBB2 (17%), followed by MAP2K1 (9%) , PTEN (9%), NF1 (6%), PIK3CAexon20 (3%), EGFR (3%). Subclonal RAS mutations were found in 14% of tumors. Fusions, detected in ALK and RET genes, accounted for 6% of cases. FOLFOXIRI/bev resulted into a mPFS of 12.3 mos (80% CI: 9.2 – 14.3 mos, Brookmeyer-Crowley test p = 0.023), an ORR of 74% and a mOS of 35.9 mos. PFS and OS with FOLFOXIRI/bev were longer than those achieved in the propensity score-matched cohort of patients treated with doublets/anti-EGFRs (mPFS: 12.3 vs 10.3 mos, HR: 0.74, 95% CI: 0.45 – 1.21, p=0.226; mOS: 35.9 vs 27.2 mos, HR: 0.57, 95% CI: 0.32 – 1.03, p=0.058). Similarly, a numerical advantage in ORR was reported (74% vs 63%, OR: 1.69 95% CI 0.61 – 4.88, p=0.303). No interaction (int) between the effect of treatment and primary tumor location was evident (p intPFS =0.267; p intOS =0.459; p intORR =0.866). Conclusions: Waiting for efficacy results about the upfront use of targeted treatments directed against specific molecular subgroups, FOLFOXIRI/bev may be the preferred first-line option for clinically fit pMMR/MSS RAS and BRAF wt mCRC patients harbouring at least one genomic alteration of potential resistance to anti-EGFRs, regardless of primary tumor sidedness.