Negative selection of patients (pts) with HER2-positive and RAS wild-type (wt) metastatic colorectal cancer (mCRC) receiving dual HER2 blockade.
Authors: Randon Giovanni , Nakamura Yoshiaki , Yaeger Rona , Lonardi Sara , Cremolini Chiara , Elez Elena , Nichetti Federico , Ghelardi Filippo , Nasca Vincenzo , Bergamo Francesca , Conca Veronica , Ros Montañá Javier , Maddalena Giulia , Prisciandaro Michele , Bando Hideaki , Schrock Alexa Betzig , Walch Henry S. , Yoshino Takayuki , Pietrantonio Filippo 
Published: June 2023

e15164 Background: Refining the selection of pts with HER2-positive mCRC for dual HER2 blockade is a challenge for precision oncology. Alterations in receptor tyrosin-kinase (RTK)/MAPK pathway and HER2 gene copy number (GCN) are promising predictive biomarkers for primary resistance or sensitivity, respectively. Methods: We conducted a multicentric case-control study to evaluate the negative predictive impact of a panel of candidate genomic alterations of primary resistance (PRESSING-HER panel) in pts with HER2-positive, RAS wt mCRC treated with trastuzumab-based dual HER2 blockade. Comprehensive genomic profiling was performed on archival pre-treatment tumor samples and screening sources were: the TRIUMPH trial (Oncomine Comprehensive Assay), the Italian-Spanish observational cohort (Foundation One CDx) and the MSKCC cohort (MSK-IMPACT). The panel grouped resistance alterations with a solid biological rationale as on-target, i.e. HER2 pathogenic mutations or rearrangements or off-target, i.e. mutations/amplifications in RTK/MAPK genes. Primary resistance was defined by PFS < 4 months (mos), sensitivity was defined by PFS ≥4 mos. Hypothesizing a prevalence of PRESSING-HER alterations equal to 5% and 30% among controls and cases, respectively, 35 cases and 35 controls were needed to reject the null hypothesis of equally prevalent alterations, with α and β errors of 0.05 and 0.20. HER2 GCN was derived from NGS and the cut-off was calculated by ROC curve analyses using 4-month PFS rate as endpoint. Results: Sixty-eight pts were evaluable (33 resistant and 35 sensitive). In the overall population, PRESSING-HER alterations were found in 14 (20.6%) pts and included HER2 mutations in 7 (50%), HER2 rearrangements in 4 (29%), BRAF class 1 mutations in 2 (14%) and EGFR amplification in 1 (7%). PRESSING-HER alterations were significantly more frequent in pts with primary resistant (12/21, 57%) versus (vs) sensitive tumors (2/35, 6%; P= 0.004). HER2 GCN had a median value of 34.5 (IQR: 18.7-78.5) and an optimal cut-off of 33. In multivariable analyses including the main baseline clinical prognostic features, PRESSING-HER alterations were independently associated with inferior PFS (median PFS 2.0 vs 5.4 mos; adjusted HR 3.5, 95%CI 1.7-7.0; P< 0.001) and OS (median OS 3.7 vs 14.8 mos; adjusted HR 3.9, 95%CI 1.8-8.3; P< 0.001). HER2 GCN < 33 was associated with significantly inferior median PFS (2.6 vs 5.4 mos; adjusted HR 1.8, 95%CI 1.0-3.1; P= 0.038) and numerically inferior OS (median OS 9.1 vs 15.4 mos; adjusted HR 1.3, 95%CI 0.7-2.5; P= 0.356). The predictive accuracy of PRESSING-HER was 66% and it was increased to 77% when combined with HER2 GCN. Conclusions: The combined assessment of HER2 on/off-target alterations and HER2 GCN stratifies patient outcomes to HER2 dual blockade.