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

Federica Morano, Salvatore Corallo, Sara Lonardi, Alessandra Raimondi, Chiara Cremolini, Lorenza Rimassa, Roberto Murialdo, Alberto Zaniboni, Andrea Sartore-Bianchi, Gianluca Tomasello, Patrizia Racca, Matteo Clavarezza, Vincenzo Adamo, Federica Perrone, Annunziata Gloghini, Elena Tamborini, Adele Busico, Antonia Martinetti, Federica Palermo, Fotios Loupakis, Massimo Milione, Giovanni Fucà, Maria Di Bartolomeo, Filippo de Braud, Filippo Pietrantonio, Federica Morano, Salvatore Corallo, Sara Lonardi, Alessandra Raimondi, Chiara Cremolini, Lorenza Rimassa, Roberto Murialdo, Alberto Zaniboni, Andrea Sartore-Bianchi, Gianluca Tomasello, Patrizia Racca, Matteo Clavarezza, Vincenzo Adamo, Federica Perrone, Annunziata Gloghini, Elena Tamborini, Adele Busico, Antonia Martinetti, Federica Palermo, Fotios Loupakis, Massimo Milione, Giovanni Fucà, Maria Di Bartolomeo, Filippo de Braud, Filippo Pietrantonio

Abstract

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

Figures

FIG 1.
FIG 1.
Heatmap detailing the incidence of the genomic alterations included in the primary resistance in RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies (PRESSING) panel study population. Green indicates amplifications, violet, gene fusions, and red, mutations. Blue indicates patients with high microsatellite instability (MSI) status; gray indicates patients with right-sided tumors. (*) Targeted screening for ALK, ROS1, NTRKs, RET fusions; (†) mutant allele fraction < 5%.
FIG 2.
FIG 2.
Prognostic analysis according to tumor sidedness and primary resistance in RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies (PRESSING) panel status: Kaplan-Meier curves for (A) progression-free survival (PFS) and (B) overall survival (OS) in patients stratified according to tumor sidedness; (C) PFS and (D) OS according to PRESSING panel status; and (E) PFS and (F) OS according to the combined analysis. HR, hazard ratio; NA, not assessable; ref, reference.
FIG 3.
FIG 3.
Predictive analysis according to tumor sidedness and primary resistance in RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies (PRESSING) panel status: Kaplan-Meier curves for (A) progression-free survival (PFS) and (B) overall survival (OS) in patients stratified according to the two different maintenance treatment arms and sidedness (right- v left-sided tumors) and for (C) PFS and (D) OS according to treatment arm and PRESSING panel status (positive [pos] v negative [neg]).
FIG A1.
FIG A1.
CONSORT diagram of the study.
FIG A2.
FIG A2.
Survival analysis in the overall study population: (A) progression-free survival (PFS) and (B) overall survival (OS). NA, not assessable.
FIG A3.
FIG A3.
Activity analysis according to tumor sidedness and primary resistance in RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies (PRESSING) panel status: overall response (OR) rate in patients stratified according to (A) sidedness, (B) PRESSING panel status, and (C) combined analysis. Neg, negative; Pos, positive.
FIG A4.
FIG A4.
Duration of response analysis according to (A) sidedness: right sided and left sided in red and blue, respectively; (B) primary resistance in RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies (PRESSING) panel status and (C) combined analysis. IQR, interquartile range; PRESSING, primary resistance in RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-EGFRmonoclonal antibodies.
FIG A5.
FIG A5.
Prognostic analysis according to microsatellite instability (MSI) status: Kaplan-Meier curves for (A) progression-free survival (PFS) and (B) overall survival (OS) in patients stratified according to MSI status. HR, hazard ratio; MSS, microsatellite stable; NA, not assessable; ref, reference.
FIG A6.
FIG A6.
Predictive analysis according to combined tumor sidedness and primary resistance in RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies (PRESSING) panel status in left-sided tumors. Kaplan-Meier curves for (A) progression-free survival (PFS) and (B) overall survival (OS) in the patient subgroup with left-sided/PRESSING-negative tumors stratified according to the two different maintenance treatment arms or the patient subgroup with left-sided/PRESSING-positive tumors stratified according to the two different maintenance treatment arms. FU + LV, fluorouracil plus leucovorin; neg, negative; pan, panitumumab; pos, positive.

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