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

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.

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.

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.

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.

CONSORT diagram of the study.

FIG A2.

Survival analysis in the overall study population: (A) progression-free survival (PFS) and (B) overall survival (OS). NA, not assessable.

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.

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.

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.

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.