Abstract 68P
Background
Despite benefits of HER2 therapy in HER2-amplified colorectal cancer (CRC), eventual universal resistance arises. We aim to describe the utility of blood ctDNA assays for the potential detection of mechanisms of resistance to HER2 therapy.
Methods
After retrieving patients (pts) with microsatellite stable, RAS/RAF wild-type, advanced HER2-amplified CRC who received HER2-targeted therapy between February 2017 and February 2024, we described only those with pre- and post-HER2 therapy ctDNA assessments by Guardant360 assay. We then cross-checked the newly detected gene alterations against published literature on HER2 resistance.
Results
Out of 131 CRC pts with ctDNA testings, 10 pts met inclusion criteria, median age was 50.5 years (range 21-67), and 2 were females. Trastuzumab plus a tyrosine kinase inhibitor (4 tucatinib, 1 neratinib) were the most used first choice for HER2 therapy. The median progression-free survival (PFS) with first exposure to HER2 therapy was 8 months (range 3.5-31). Newly acquired genetic alterations putatively associated with HER2 therapy resistance were detected in 7 pts, 6 of them had ≥2 alterations. In 3 pts, multiple new activating mutations (mut) in the HER2 tyrosine kinase domain were detected, including in D769Y, L755S, V777L, D769Y, G727A; other HER2 alterations included c.1899-19_1905del, P643S, T862S, and Q429H. Additional HER2 resistant alterations were EGFR amplification (N=2), KRAS-Q61H (N=1), BRAF-S614P (N=1), MET amplification (N=2), CCNE1amplification (N=1), RB1-Q444H (N=1). Alterations of unclear significance included CDK12 deletion, MET-R793C, AR-E898D. Upon progression, 6 pts received trastuzumab deruxtecan (T-DXd). Of these, 2 pts lost HER2 amplification on ctDNA prior to T-DXd, and 1 of them had a concomitant ERBB2-D769Y mut. Their PFS on T-DXd were respectively 4.6 and 2.5 months.
Conclusions
In HER2-amplified CRC, post-treatment blood ctDNA analysis can detect genetic alterations associated with HER2 therapy failure. Additional research is warranted to examine the clinical utility of serial ctDNA monitoring to predict HER2 treatment response and failure.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
M.B. Sonbol: Financial Interests, Institutional, Funding: Eli Lilly, Taiho; Financial Interests, Personal, Advisory Role: Novartis. C. Wu: Financial Interests, Institutional, Research Grant: Boston Biomedical, Bristol Myers Squibb, Lycera, RAPT Therapeutics, Seagen, Symphogan, Vaccinex, INHBRX, Pfizer; Financial Interests, Personal, Advisory Board: Array Biopharma, Signatera, Daiichi Sankyo, Pfizer, Exelixis, Seagen; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Hutchmed, Xilis; Non-Financial Interests, Advisory Role, Safety monitoring committee: Seagen. D. Ahn: Financial Interests, Personal, Advisory Board: Exelixis, Advanced Accelerator Applications, Incyte; Financial Interests, Personal, Advisory Role: Genentech, Eisai, Daiichi Sankyo, Ipsen Biopharmaceuticals, Inc; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal, Other, Advisor: Novartis; Financial Interests, Personal, Stocks/Shares: Natera. M. Borad: Financial Interests, Personal, Advisory Role: ADC Therapeutics, Exelixis, Inspyr, G1 Therapeutics, Immunovative, OncBioMune, Western Oncolytics, Lynx; Financial Interests, Personal, Research Grant: AstraZeneca, Senhwa Pharmaceuticals, Adaptimmune, Halozyme, Celgene, Five Prime, EMD Merck Serono, Taiho, Sun Biopharmaceuticals, Boston Biomed, Basilea, Toray, Dicerna, Isis Pharmaceuticals, Incyte, Mirna, MedImmune, Bioline, Sillhajen, Ariad, Puma, Novartis, QED, Pieris; Financial Interests, Personal and Institutional, Proprietary Information: Mayo Clinic. T. Bekaii-Saab: Financial Interests, Institutional, Advisory Board: Bayer, Pfizer, Incyte, Ipsen, Seattle Genetics, Genentech, Merck KGA, Merus, Eisai, Servier; Financial Interests, Institutional, Other, DSMB: Merck; Financial Interests, Personal, Advisory Board: AbbVie, Boehringer Ingelheim, Janssen, AstraZeneca, Daiichi Sankyo, Natera, Celularity, Exact Science, Sobi, BeiGene, Xilis, Foundation Medicine, Stemline, Blueprint, Celularity, Caladrius, Glaxo SmithKline, Deciphera, Zai Labs, Illumina, Sanofi, Immuneering, Replimune Artiva; Financial Interests, Personal, Other, DSMB: AstraZeneca, Exelixis, The Valley Hospital, FibroGen; Financial Interests, Personal, Other, DSMC: PanCAN; Financial Interests, Personal, Royalties, WO/2018/183488: human PD1 peptide vaccines and uses thereof: Imugen; Financial Interests, Personal, Royalties, WO/2019/055687: methods and compositions for the treatment of cancer cachexia: Recursion; Financial Interests, Institutional, Research Grant: Agios, Arys, Bayer, Amgen, Ipsen, Clovis, Pfizer, Celgene, Novartis, Arcus, Atreca, Mirati, Merus, Abgenomics, BMS; Financial Interests, Institutional, Invited Speaker: Boston Biomedical, Incyte, Seattle Genetics; Non-Financial Interests, Advisory Role: Imugene, Sun BioPharma; Financial Interests, Institutional, Funding: Lilly, Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: TreosBio, Kanaph, MJH Life Sciences, Aptitude Health; Financial Interests, Personal, Other, Independent data monitoring committees or data safety monitoring boards: Suzhou Kintor, 1Globe; Financial Interests, Personal, Royalties: UptoDate. All other authors have declared no conflicts of interest.