Detection Discrepancies in HER2 Amplification: Implications for Therapeutic Strategies - Insights from the MOUNTAINEER Study Presented at the 2023 ASCO and ESMO Annual Meetings

The MOUNTAINEER study, as presented at the 2023 ASCO and ESMO annual meetings, provides an update on the detection of HER2 amplification in mCRC patients using blood NGS and tissue assays. Patients in whom HER2 amplification is not initially detected by blood NGS may be identified through tissue-based assays, suggesting a potential benefit from HER2-directed therapy. In the study, HER2 amplification detected by tissue assays demonstrated a high percentage agreement and showed a clinical benefit trend in patients with RAS wild-type HER2+ unresectable or metastatic colorectal cancer (mCRC) treated with tucatinib in combination with trastuzumab. Exploratory biomarker analyses revealed that many patients exhibited multiple heterogeneous resistance alterations, including PIK3CA, EGFR, and MET alterations in disease progression.

Tucatinib, in combination with trastuzumab, received FDA approval for the treatment of patients with RAS wild-type HER2+ unresectable or mCRC that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. The 2023 ASCO annual meeting poster reported on the correlation between tissue- and blood-based assays in HER2 amplification detection and the impact of different HER2 testing methodologies on clinical benefit. The highest level of percentage agreement was observed between IHC/FISH and tissue NGS (92.6%). The percentage agreement in IHC/FISH vs. blood NGS and tissue NGS vs. blood NGS was 79.5% and 81%, respectively.

Response assessment data revealed that in different testing platforms, progression-free survival (PFS) for HER2+ (IHC3+ and IHC2+/ISH+) and HER2- in the IHC/FISH group were 10.1 months and 2.8 months, respectively. In tissue NGS, HER2 amp+ and HER2 amp- had PFS values of 10.9 months and 2.1 months, while in blood NGS, HER2 amp+ and HER2 amp- had PFS values of 8.1 months and 10.9 months, respectively. These findings suggest that tissue-based assays have the potential to uncover HER2 amplification that may be overlooked in ctDNA NGS. Patients with such findings could potentially benefit from HER2-directed therapy.

Additionally, exploratory analysis presented at the 2023 ESMO Annual Meeting demonstrated that most patients acquired multiple heterogeneous resistance alterations, with common genomic alterations including PIK3CA, EGFR, FGFR, MET, and KRAS/NRAS. Understanding the genomic drivers of acquired resistance may provide valuable insights for future therapeutic opportunities.

Ref:
Strickler et al. presented in 2023 ESMO annual meeting. #5510

John H Strickler et al. posted in 2023 ASCO annual meeting. #3528

‍