Negative hyperselection as a predictive biomarker of benefit from first-line doublets + anti-EGFRs/bevacizumab (bev) in microsatellite stable (pMMR/MSS) RAS and BRAF wild-type (wt) and HER2− metastatic colorectal cancer (mCRC): An individual patient data pooled analysis of seven clinical trials (CTs).

3550 Background: Primary tumor sidedness is nowadays a major driver for the choice of biologics in the first line of pMMR/MSS RAS and BRAF wt mCRC patients (pts). It has been suggested that it might be replaced by a broader molecular profiling, but the evidence provided by individual trials is uncertain for the adoption of different panels and underrepresentation of gene-altered cases. We recently showed that HER2+ status does not predict resistance to first-line doublets + anti-EGFRs. Methods: We collected individual patient data from 7 CTs in first-line mCRC: TRIBE2, TRIPLETE, VALENTINO, CAPRI-2, FIRE-3, PARADIGM and CALGB/SWOG80405. pMMR/MSS RAS and BRAF wt and HER2− cases treated with doublets + anti-EGFRs/bev with available NGS data were included. Hyperselected tumors were those without MET+ status, ALK/ROS1/NTRKs/RET fusions, and HER2/PIK3CAexon20/PTEN/AKT1 mutations. Propensity score adjustment was used to assess clinical outcomes (aHR and aOR) according to first-line doublets + anti-EGFRs/bev. Results: Out of 1198 included pts, 990 (83%) had left-sided and 208 (17%) right-sided tumors. Anti-EGFR based regimens were associated with numerically longer OS (aHR: 0.86) in left-sided tumors, but not in right-sided ones (aHR: 0.98), with an insignificant p for interaction int = 0.60). Hyperselected and gene-altered cases were 1077 (91%) and 121 (9%), respectively. The anti-EGFR benefit in OS was magnified in hyperselected pts (aHR: 0.83), with an aHR of 1.16 in gene-altered ones (p int =0.11, adjusted also for tumor sidedness). As reported in the table, there was no interaction between the effect of biologics and primary tumor location either in the hyperselected (p int =0.86) or in the gene-altered group (p int =0.41). Conclusions: Hyperselection outperforms tumor sidedness as a predictive marker of benefit from doublets + anti-EGFR/bev in pMMR/MSS RAS/BRAF wt and HER2− mCRC. The OS benefit from anti-EGFR-based regimens is restricted to pts with hyperselected tumors, independently of primary tumor location. Therefore, in hyperselected mCRC, doublets + anti-EGFRs remain the standard for left-sided pts and may deserve consideration in right-sided ones. Hyperselected Gene-altered Left Right P int Left Right P int Anti-EGFRs N=537 Bev N=365 Anti-EGFRs N=87 Bev N=88 Anti-EGFRs N=57 Bev N=31 Anti-EGFRs N=19 Bev N=14 ORR (%) 81 67 72 65 74 52 58 57 aOR 95% CI 2.29 1.67 – 3.14 1.44 0.75 – 2.77 0.24 3.48 1.29 – 9.97 1.02 0.25 – 4.20 0.23 mPFS* 13.2 12.9 11.1 10.2