Abstract 1269: Negative ultra-selection of patients with RAS/BRAF wild-type (wt), microsatellite stable (MSS) metastatic colorectal cancer (mCRC) receiving anti-EGFR-based therapy: The PRESSING2 study
Authors: Randon Giovanni , Maddalena Giulia , Germani Marco Maria , Pagani Filippo , Bergamo Francesca , Giordano Mirella , Pircher Chiara , Sposetti Caterina , Zambelli Luca , Corti Francesca , Bini Marta , Rametta Alessandro , Spagnoletti Andrea , Montagna Aldo , Fassan Matteo , Boccaccino Alessandra , Vetere Guglielmo , Damian Silvia , Milione Massimo , de Braud Filippo , Cremolini Chiara , Lonardi Sara , Pietrantonio Filippo 
Published: June 2022

Background: Several genomic alterations beyond RAS and BRAFV600E mutations have been preclinically validated as primary resistance drivers to EGFR inhibition in mCRC. We showed that our PRESSING panel (including PIK3CA exon 20/AKT1/PTEN mutations, ERBB2/MET amplification and ALK/ROS1/RET/NTRKs fusions) is useful to promote a new paradigm of negative hyper-selection, since patients with RAS/BRAF wt MSS mCRC and PRESSING alterations achieve significantly worse survival upon anti-EGFRs. With the aim of further refining molecular selection (negative ultra-selection), we investigated the clinical impact of candidate resistance alterations with even lower frequency (PRESSING2 panel) in a cohort of hyper-selected patients.

Methods: A prospective dataset was developed at 3 Italian Academic Hospitals and included 650 mCRC patients with comprehensive genomic profiling of FFPE tumor tissue by means of FoundationOne CDx. We selected those with RAS/BRAF wt, MSS and PRESSING negative treated with anti-EGFRs. Alterations of the PRESSING2 panel were selected based on their actionability and biological value, as follows: ALK, ROS1, NTRKs, ERBB2/3/4, NF1, ARAF, MAP2K1 pathogenic mutations, PTEN loss, KRAS and AKT1-2 amplification, FGFR2 amplification/fusions, EGFR fusions. PRESSING2 status was correlated with progression-free survival (PFS) and overall survival (OS).

Results: 163 molecularly hyper-selected patients with PRESSING negative status were identified; 30 (18%) had PRESSING2 alterations, which were mutually exclusive in 26 (87%) samples. No significant differences in baseline clinical and pathological characteristics - including sidedness - were found in PRESSING2 positive vs negative patients. The median follow-up was 34.6 months (IQR 23.5-49.3). Patients with PRESSING2 positive status had significantly worse PFS and OS vs those with PRESSING2 negative disease (median PFS 7.0 and 13.0 months; HR 3.54, 95%CI 2.26-5.52, P&lt;0.001; median OS 24.5 and 51.2 months; HR 2.91, 95%CI 1.64-5.18, P&lt;0.001). In the multivariable model, the adjusted HRs were 3.40 for PFS and 2.71 for OS, respectively. 121 (74%) patients received an anti-EGFR agent upfront. In this first-line cohort, median PFS were 8.1 vs 13.2 months for PRESSING2 positive and negative subgroups (HR 3.24, 95%CI 1.89-5.57; P&lt;0.001; adjusted HR 2.96), whereas median OS were 26.2 vs 49.9 months, respectively (HR 2.28, 95%CI 1.15-4.54, P=0.018; adjusted HR 2.34).

Conclusions: In the era of comprehensive genomic profiling, several resistance alterations with extremely low prevalence may be detected, especially in CRCs that do not bear other genomic drivers. Negative ultra-selection may represent a relevant step forward in precision medicine in patients with RAS/BRAF wt MSS mCRC potentially eligible for EGFR blockade.

Citation Format: Giovanni Randon, Giulia Maddalena, Marco Maria Germani, Filippo Pagani, Francesca Bergamo, Mirella Giordano, Chiara Pircher, Caterina Sposetti, Luca Zambelli, Francesca Corti, Marta Bini, Alessandro Rametta, Andrea Spagnoletti, Aldo Montagna, Matteo Fassan, Alessandra Boccaccino, Guglielmo Vetere, Silvia Damian, Massimo Milione, Filippo de Braud, Chiara Cremolini, Sara Lonardi, Filippo Pietrantonio. Negative ultra-selection of patients with RAS/BRAF wild-type (wt), microsatellite stable (MSS) metastatic colorectal cancer (mCRC) receiving anti-EGFR-based therapy: The PRESSING2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1269.