HER-2 A775_G776insYVMA

P1, N=30, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

MSI-high was observed in 15 samples. Conclusions Comprehensive ctDNA NGS can identify ERBB2m including complex insertions and co-alterations that may inform therapeutic decisions for patients with AC in AME.

P1, N=30, Recruiting, National Cancer Institute (NCI) | N=18 --> 30

42.8% of pts received antibody-drug conjugates targeting ERBB2 in further lines of therapy, trastuzumab emtansine (37.1%) and Trastuzumab Deruxtecan (5.7%). ERBB2 mts in NSCLC are rare. In this comprehensive retrospective real-world multicenter cohort of Latin American NSCLC pts, the frequency of ERBB2 mutations was identified in 2,8% of patients. The most common ERBB2 mutation identified was A775_G776insYVMA, similar to what is reported in the literature.

P2; Trial completion date: Mar 2024 --> Sep 2024 | Trial primary completion date: Mar 2024 --> Sep 2024

It was superior to Mobocertinib (IC50 = 27.1 nM for YVMA and IC50 = 3.3 nM for GSP) and comparable with Poziotinib (IC50 = 3.4 nM for YVMA and IC50 = 0.4 nM for GSP). JIN-A04 is highly potent against HER2 exon 20 insertion mutations including YVMA and GSP, while largely sparing HER2 WT activity. Also, JIN-A04 demonstrated effective HER2 pathway inhibition. Based on these robust activities for HER2 exon 20 insertion, JIN-A04 is expected to provide a potent therapeutic opportunity for NSCLC patients with HER2 exon20 insertion mutations.

P2; Trial completion date: Mar 2023 --> Mar 2024 | Trial primary completion date: Mar 2023 --> Mar 2024

P2; Recruiting --> Active, not recruiting | N=80 --> 116

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

Patients treated with pemetrexed-based chemotherapy (75%) had an overall response rate (ORR) and progression-free survival (PFS) of 30% and 8.3 months (95% CI: 3.9-12.7), respectively. The ORR and PFS of HER2-targeted agent treated patients (14%) were 0.0% and 1.9 months (95% CI: 0.1-2.8), respectively. Given its distinct characteristics and treatment responses, novel treatment strategies for HER2-mutant NSCLC should be developed promptly to improve survival outcomes of patients.

P2; Trial primary completion date: Mar 2022 --> Mar 2023

In 7 patients who received HER2-directed therapies, limited responses to afatinib (n=5), trastuzumab emtansine (n=3) and tucatinib (n=1) were observed and no responses were seen with immunotherapy monotherapy (n=2). The incidence of HER2-M+ is 3.1% in East Asian non-squamous NSCLC, with only 1/26 HER2ex20 overlapping with activating EGFR mutations. The clinical phenotype and genomic features of HER2ex20 tumours appear distinct from HER2other, the latter demonstrating higher TMB, co-occurring drivers and predominant non-ageing signature. The therapeutic implications of the genomic and clinical features of HER2-M+ warrant further investigation.)