Assessing the predictive role of tumor sidedness in <i>RAS</i> and <i>BRAF</i> wild-type metastatic colorectal cancer (mCRC) treated with first-line doublets + anti-EGFRs/bevacizumab (bev) or triplet + bev: An individual patient data pooled analysis

3538 Background: Chemotherapy (chemo) + an anti-EGFR and chemo + bev are currently regarded as preferred upfront options for left- and right-sided pMMR RAS/BRAF wild-type (wt) mCRC patients (pts), respectively. This recommendation is mainly based on trial-level pooled analyses of RAS wt pts’ cohorts, thus including also BRAF mutant cases. Methods: We collected individual patient data from 10 randomized clinical trials (RCT) in first-line mCRC: TRIBE, TRIBE2, TRIPLETE, VALENTINO, ATEZOTRIBE, PANAMA, FIRE-3, FIRE-4, PARADIGM and CALGB/SWOG80405. RAS and BRAF wt mCRC pts treated with doublets + anti-EGFR/bev or triplet + bev were included. Results: 2178 pts were eligible. Left- and right-sided tumors were 1780 (82%) and 398 (18%), respectively. As reported in the table, among 2051 pts treated with doublets/bev or doublets/anti-EGFR, no significant interaction effect between primary sidedness and treatment arm was reported in terms of ORR (p int : 0.27) and PFS (p int : 0.32), with a p-value for interaction for OS of 0.13. Anti-EGFR-based doublets were associated with higher ORR and longer OS among pts with left-sided tumors, while similar outcomes were reported in right-sided ones. Among 339 pts enrolled in trials where triplet was included as a treatment arm, a potential interaction effect between primary sidedness and treatment (triplet/bev or doublet/anti-EGFR) was evident in terms of PFS (p int : 0.14) and OS (p int : 0.08) but not ORR (p int : 0.42). Triplet/bev was associated with longer PFS and OS among pts with right-sided tumors. Conclusions: This is the largest analysis assessing the differential effect of biologic agents and chemo intensification according to primary tumor origin in pts with untreated RAS and BRAF wt mCRC enrolled in RCTs. Doublets/anti-EGFR is superior to doublets/bev in left-sided tumors, with no significant differences in right-sided tumors, where triplet + bev appears as the most efficacious regimen for fit pts. Further analyses assessing the role of molecular hyperselection beyond RAS and BRAF are ongoing. Right Left P int Right Left P int Doublets/antiEGFRN=209 Doublets/bev N=157 Doublets/antiEGFR N=1120 Doublets/bev N=565 Triplet/bev N=95 Doublets/antiEGFR N=189 Triplet/bev N=32 Doublets/antiEGFR N=23 ORR (%) 65 62 74 66 66 83 72 78 OR [95% CI] p 1.13 [0.73-1.73] 0.58 1.48 [1.19-1.84] &lt; 0.001 0.27 0.42 [0.10-1.48] 0.16 0.72 [0.41-1.27] 0.25 0.42 mPFS* 9.6 10.6 12.6 12.6 12.4 10.1 12.2 13.8 HR [95% CI] p 1.12 [0.90-1.40] 0.32 0.99 [0.89-1.10] 0.84 0.32 0.62 [0.35-1.09] 0.09 0.98 [0.75-1.27] 0.88 0.14 mOS* 25.1 29.1 36.4 33.6 37.2 23.8 37.7 35.5 HR [95% CI] p 1.05 [0.83-1.32] 0.69 0.85 [0.76-0.96] 0.007 0.13 0.55 [0.30-1.01] 0.05 0.95 [0.70-1.30] 0