Primary tumor sidedness and negative hyperselection to modulate anti-EGFR-based maintenance strategies in patients with RAS wild-type metastatic colorectal cancer: individual patient data pooled analysis of two randomized clinical trials

Background: Patients with RAS wild-type (WT), left-sided metastatic colorectal cancer (mCRC), negatively hyperselected for anti-EGFR resistance alterations, benefit most from anti-EGFR-based first-line treatment. The predictive impact of these stratification parameters on maintenance strategy efficacy is unclear. Methods: This pooled analysis included individual patient data from the PanaMa (NCT01991873) and Valentino (NCT02476045) phase 2 trials. Patients with RAS WT mCRC received FOLFOX plus Panitumumab induction therapy followed by maintenance with 5-fluorouracil/leucovorin (5-FU/LV) plus Panitumumab vs. 5-FU/LV monotherapy (PanaMa) or Panitumumab monotherapy (Valentino). Outcomes included progression-free survival (PFS) and overall survival (OS). Subgroup analyses examined primary tumor sidedness (left vs. right) and hyperselection status (negative vs. altered). Results: Among 607 patients receiving induction, sidedness and hyperselection status were available for 589 and 511 patients, respectively. Left-sided and negative hyperselected tumors were observed in 80.2% and 63.9% of patients, respectively. Panitumumab-based maintenance improved PFS in left-sided, negative hyperselected patients compared to 5-FU/LV alone, with no OS differences. PFS and OS were comparable for Panitumumab alone vs. Panitumumab plus 5-FU/LV. Conclusion: Tumor sidedness and hyperselection status significantly influence maintenance strategy efficacy in mCRC. For left-sided, negative hyperselected patients, Panitumumab monotherapy may optimize efficacy while minimizing toxicity. Further investigation into the relative contribution of individual hyperselection parameters in this setting is warranted.