551O Impact of baseline molecular alterations on the efficacy of tucatinib (TUC) plus trastuzumab (Tras) for HER2+, RAS WT metastatic CRC (mCRC) in MOUNTAINEER

HER2 is an actionable biomarker for mCRC, though the impact of concomitant genomic alterations is unknown. On the basis of the MOUNTAINEER study, TUC + Tras was approved by the FDA for use in pts with chemo-refractory HER2+, RAS-WT mCRC. Here we present the impact of concomitant baseline genomic alterations on the clinical activity of TUC + Tras. MOUNTAINEER enrolled pts w/ locally assessed HER2+ mCRC by tissue immunohistochemistry (IHC), in situ hybridization (ISH), and/or next-generation sequencing (NGS). Baseline tissue and blood samples were retrospectively analyzed by IHC/FISH, PGDx tissue NGS and Guardant 360 blood NGS. cORRs (proportion of pts w/ CR or PR per RECIST v1.1 by BICR) and DoR were calculated for selected genomic alterations (SNVs and CNVs) occurring in ≥5 pts treated with TUC + Tras. This analysis was descriptive; no statistical comparisons were made. From 84 pts treated with TUC+Tras, 65 samples were available for FISH testing. cORR was numerically higher w/ greater HER2 amplification as measured by either HER2/CEP17 ratio (>5, n=50: cORR [95%CI] = 44.0% [30.0, 58.7]; ≤5, n=15: cORR [95%CI] = 26.7% [7.8, 55.1]) or HER2 copy number (>9.45, n=57: cORR [95%CI] = 42.1% [29.1, 55.9]; ≤9.45, n=8: cORR [95%CI] = 25.0% [3.2, 65.1]). NGS testing of tissue (n=45) and blood (n=66) samples from pts w/ a central HER2+ test result identified concomitant mutations and/or genomic amplifications in key genes including ERBB2, PIK3CA, APC, and TP53. In these pts, cORR and DOR were generally similar to those observed overall (Table). This exploratory analysis of the MOUNTAINEER trial found generally consistent clinical efficacy of TUC + Tras to the primary analysis across subsets of pts w/ HER2+ RAS-WT mCRC and other clinically relevant genomic alterations.