HER-2 S310Y

These antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro, and in vivo as a xenograft. These results validate HER2 ECD mutations as actionable therapeutic targets and offer promising candidates toward clinical development.

P2, N=102, Active, not recruiting, AstraZeneca | Trial completion date: Jan 2028 --> Jul 2026

Matched tumor samples from six patients identified the same mutations with an 83% concordance rate. In summary, our highly sensitive multiplex digital PCR assays are well suited for plasma-based monitoring of ERBB2 mutational status in patients with MBC.

Lastly, MTAP loss, an emerging biomarker for new synthetic lethality based anti-cancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than non-MPUC (26.9%) (p = 0.018). Characterizing the genomic landscape of MPUC may not only improve our fundamental knowledge about this aggressive morphological variant of UBC, but also has the potential to identify possible prognostic and predictive biomarkers that may drive tumor progression and dictate treatment response to therapeutic approaches.

HER2 status did not influence ADFS for NMIBC; PFS and OS for MIBC regardless of neoadjuvant cisplatin chemotherapy (chemo); OS for 1st line (1L) MetBC treated with gemcitabine plus platinum (GC) chemo or 2nd line (2L) immune checkpoint inhibitor (ICI) therapy post 1L-chemo (table). We present one of the largest and comprehensive study of HER2 mutation in BC. Overall, HER2 amplification was significantly less frequent for NMIBC. HER2 alterations were not a prognostic marker for NMIBC or MIBC independent of neoadjuvant cisplatin-based chemo, MetBC- 1L GC-chemo and 2L ICI post GC-chemo.

Background Given the early promising data with afatinib in advanced UC and the recent approval in NSCLC for anti-HER2 targeted therapy for activating kinase domain exon 20 ERBB2 insertion mutations, there is considerable interest in targeting additional locations in the ERBB2 gene in other tumor types...Conclusions ERBB2 ECD mutation-driven UBC represents a distinct subtype of UBC featuring an enrichment of MPUC histology from 1-2% to 28% incidence in ERBB2 ECD mutated UBC, and unique clinical and molecular characteristics, including differences in mutational signatures and genetic ancestry. Further exploration of anti-HER2 targeted therapy for non-amp sequence mutations in ERBB2 in UBC appears warranted.

In heavily pretreated pts with limited Tx options, T-DXd demonstrated encouraging anticancer activity and long DoR across multiple tumor types with HER2m and a range of HER2 expression levels, with a known safety profile. Translational research will help characterize pts who may derive greatest benefit from T-DXd.

P2, N=25, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Sep 2022

ERBB2 ECD mutation driven UBC is a unique form of UBC featuring enrichment of MPUC histology and a unique clinical and genomic landscape including genomic signatures and ancestry.

Receptor switching to other HER family members in Lapatinib resistance and HER2 receptor tyrosine kinase domain mutations have been elaborated in promoting resistance. BC cells over-expressing HER2-WT or S305C were found sensitive to Trastuzumab (P>0.001) or Neratinib (P>0.001), whereas cells with G309A, S310Y or P523S mutation were non-responder to those drugs as revealed by short-term, long-term viability, anchorage-independent growth and Immunoblot assessments. Conclusion The structural changes ensued after HER2 interaction domain mutations alters the downstream signalling cascades and impacts the therapy response to HER2 targeted medicines.

P2, N=25, Active, not recruiting, City of Hope Medical Center | N=40 --> 25 | Trial completion date: Oct 2021 --> Dec 2022

"HER2 amplification is more frequent in MIBC and metBC than in NMIBC. In NMIBC, HER2 amplification is associated with shorter TTP to MIBC or metBC. HER2 alteration in metBC is associated with a non-significant trend towards improved OS in frontline platinum-treated pts, though this analysis is limited by small sample size."

P2, N=40, Active, not recruiting, City of Hope Medical Center | Trial completion date: Oct 2020 --> Oct 2021 | Trial primary completion date: Oct 2020 --> Oct 2021