Negative Hyperselection of Patients With <i>RAS</i> and <i>BRAF</i> Wild-Type Metastatic Colorectal Cancer Who Received Panitumumab-Based Maintenance Therapy.

Abstract

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 <i>RAS</i> and <i>BRAF</i> wild-type metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies [PRESSING] panel) in patients with <i>RAS</i>/<i>BRAF</i> 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). This prespecified retrospective analysis included 199 evaluable patients with <i>RAS</i>/<i>BRAF</i> wt. The PRESSING panel included the following: immunohistochemistry (IHC) and in situ hybridization for <i>HER2/MET</i> amplification, IHC with or without RNA sequencing for <i>ALK/ROS1/NTRKs/RET</i> fusions, next-generation sequencing for <i>HER2</i>/<i>PIK3CAex.20/PTEN</i>/<i>AKT1</i> and <i>RAS</i> mutations with low mutant allele fraction, and multiplex polymerase chain reaction for microsatellite instability. PRESSING status (any positive biomarker <i>v</i> 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. 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% <i>v</i> 74.1%; <i>P</i> = .037), PFS (8.4 <i>v</i> 11.5 months; <i>P</i> = .026), and OS (2-year rate: 50.2% <i>v</i> 65.1%; <i>P</i> = .062). Similar results were observed in the PRESSING-positive versus PRESSING-negative subgroup for ORR (59.2% <i>v</i> 75.3%; <i>P</i> = .030), PFS (7.7 <i>v</i> 12.1 months; <i>P</i> < .001), and OS (2-year rate: 48.1% <i>v</i> 68.1%; <i>P</i> = .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 <i>P</i> = .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%). The combined assessment of sidedness and molecular alterations of anti-EGFR primary resistance identified a consistent proportion of patients with <i>RAS</i>/<i>BRAF</i>-wt mCRC who had inferior benefit from initial anti-EGFR-based regimens, particularly after maintenance with single-agent anti-EGFRs.