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.)

P1, N=18, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

P1, N=18, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2023 --> Jun 2024 | Trial primary completion date: Aug 2023 --> Jun 2024

P1, N=18, Not yet recruiting, National Cancer Institute (NCI)

Both afatinib and pyrotinib showed favorable activity for NSCLC patients with HER2 exon 20 Gly776 deletion-insertions. Pyrotinib revealed more potent activity to A775_G776insYVMA insertion than afatinib due to the steric binding hindrance induced by YVMA.

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

T-DM1 is a potential treatment option for patients with NSCLC with HER2 exon-20 insertion mutations. Further investigation of biomarkers for T-DM1 is warranted to improve its efficacy for NSCLC with such mutations.

P2; Trial completion date: Mar 2021 --> Mar 2023 | Trial primary completion date: Mar 2021 --> Mar 2022

Patients who were treated with pemetrexed-based chemotherapy, the overall response rate and progression-free survival time were 30.3% and 7.6 months (95% CI: 3.8–11.6), respectively...Conclusion Our study interrogated clinical characteristics of real world HER2-positive NSCLC patients in single ethnicity confirmed by NGS. Given its novel characteristics and distinct clinical responses the treatment strategy for HER2-positive NSCLC remains to be further developed with conventional chemotherapies and targeted therapies.

Pyrotinib combined with apatinib showed potent anti-tumor activity and acceptable safety profile in metastatic NSCLC with HER2 amplification or activating mutations.

NIP142 is a potent EGFR/HER2 exon20 insertions inhibitor and showed excellent activities in preclinical in vitro assays and relevant tumor models. These results together with its preclinical safety data (not shown) support NIP142 to enter the clinical research to explore its potential for treating NSCLC with EGFR/HER2 exon20 insertions.

Experimental data with tarloxotinib validate the novel mechanism of action of a hypoxia-activated prodrug in cancer models by concentrating active drug in the tumor vs. normal tissue and this activity can translate into clinical activity in patients.

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