Negative Hyperselection of Patients With and Wild-Type Metastatic Colorectal Cancer Who Received Panitumumab-Based Maintenance Therapy.

Purpose: We assessed the prognostic/predictive role of primary tumor sidedness and uncommon alterations of anti-epidermal growth factor receptor (EGFR) primary resistance (primary resistance in and wild-type metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies [PRESSING] panel) in patients with / wild-type (wt) metastatic colorectal cancer (mCRC) who were randomly assigned to panitumumab plus fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) induction followed by maintenance with panitumumab with or without fluorouracil (FU) plus leucovorin (LV); Valentino trial (ClinicalTrials.gov identifier: NCT02476045).

Patients And Methods: This prespecified retrospective analysis included 199 evaluable patients with / wt. The PRESSING panel included the following: immunohistochemistry (IHC) and in situ hybridization for amplification, IHC with or without RNA sequencing for fusions, next-generation sequencing for // and mutations with low mutant allele fraction, and multiplex polymerase chain reaction for microsatellite instability. PRESSING status (any positive biomarker all negative) and sidedness were correlated with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in the study population and by treatment arm.

Results: Overall, left- and right-sided tumors were 85.4% and 14.6%, respectively, and PRESSING-negative and -positive tumors were 75.4% and 24.6%, respectively. At a median follow-up of 26 months, inferior outcomes were consistently observed in right- versus left-sided tumors for ORR (55.2% 74.1%; = .037), PFS (8.4 11.5 months; = .026), and OS (2-year rate: 50.2% 65.1%; = .062). Similar results were observed in the PRESSING-positive versus PRESSING-negative subgroup for ORR (59.2% 75.3%; = .030), PFS (7.7 12.1 months; < .001), and OS (2-year rate: 48.1% 68.1%; = .021). The PFS benefit of FU plus LV added to panitumumab maintenance, reported in the study, was independent from sidedness and PRESSING status (interaction for PFS = .293 and .127, respectively). However, outcomes were extremely poor in patients who received single-agent panitumumab and had right-sided tumors (median PFS, 7.7 months; 2-year OS, 38.5%) or PRESSING-positive tumors (median PFS, 7.4 months; 2-year OS, 47.0%).

Conclusion: The combined assessment of sidedness and molecular alterations of anti-EGFR primary resistance identified a consistent proportion of patients with /-wt mCRC who had inferior benefit from initial anti-EGFR-based regimens, particularly after maintenance with single-agent anti-EGFRs.