HER-2 D769H

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.

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.

Herein, we describe a case in which a patient with estrogen receptor-positive/HER2-negative metastatic ILC with 2 activating HER2 mutations (D769H and V777L) exhibited a significant and durable response to anti-HER2 treatment with pyrotinib (an irreversible TKI) in combination with ado-trastuzumab emtansine, which was administered after multiple lines of therapy that had resulted in disease progression. Further, based on the evidence from the present case, TKI plus ADC seems to be a promising combination anti-HER2 regimen for patients with HER2-negative/HER2-mutated advanced BC, although further rigorous studies are warranted to confirm these findings.

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

Prior treatments included platinum-based chemotherapy (100%), bevacizumab (73%), and pembrolizumab (18%). No patients discontinued treatment due to diarrhea. Table: 559P CBR, CR + PR + SD ≥16 weeks; CR, complete response; DoR, duration of response; NE, not estimable; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease Conclusions These encouraging results support the clinical benefit of neratinib in this patient population and warrant further investigation following platinum failure.

ERBB2mts& fusions were observed in all breast cancer subtypes - more commonly in HER2+, metastatic, & lobular histology tumors - & did not influence prognosis. These alterations may reflect response to treatment pressures in HER2+ disease to reactivate HER2-mediated growth pathways following anti-HER2 therapy & may represent a targetable upregulated oncogenic pathway in HER2- disease. Ongoing identification of ERBB2 alterations may augment treatment options for breast cancer pts & clinical outcomes from this approach are under investigation.

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

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

Pembrolizumab 200mg IV D1, Trastuzumab 6mg/kg (after 8mg/kg load) D1, Capecitabine 1000mg/m2 bid D1-14, and Cisplatin 80mg/m2 D1 every 3 weeks was selected as recommended phase II dose. First-line triplet regimen (Pembrolizumab, Trastuzumab, and Chemotherapy) showed promising efficacy based on HER2 amplification by NGS regardless of PD-L1 status in AGC/GEJ cancer. Correlative biomarkers found from NGS study need to be validated through on-going phase III Keynote-811 study (NCT03615326). Response and Survival of PANTHERA Trial (cut-off date: Aug-31-2020).

Pembrolizumab 200mg IV D1, Trastuzumab 6mg/kg (after 8mg/kg load) D1, Capecitabine 1000mg/m2 bid D1-14, and Cisplatin 80mg/m2 D1 every 3 weeks was selected as recommended phase II dose. First-line triplet regimen (Pembrolizumab, Trastuzumab, and Chemotherapy) showed promising efficacy based on HER2 amplification by NGS regardless of PD-L1 status in AGC/GEJ cancer. Correlative biomarkers found from NGS study need to be validated through on-going phase III Keynote-811 study (NCT03615326). Response and Survival of PANTHERA Trial (cut-off date: Aug-31-2020).

Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.

P2, N=150, Recruiting, Spectrum Pharmaceuticals, Inc | Not yet recruiting --> Recruiting