HER-2 YVMA

The derivatives with the pyrido[2,3,4-de]quinazoline core displayed superior efficacy of antiproliferation in BaF3 cells harboring HER2insYVMA mutation compared with afatinib and neratinib. Oral administration of 4a and 10e (30 mg/kg, QD) displayed significant antitumor efficacy in an in vivo xenograft model. We proposed promising strategies for the development of HER2insYVMA mutant inhibitors in this study.

P2, N=45, Completed, IFCT

Introduction: HER2 (ERBB2) is a target for various anti-cancer therapies, including large (Trastuzumab deruxtecan) or small molecules (Neratinib). An AI-powered pan-cancer image analysis of HER2 IHC of tumor cells in conjunction with genomic data reveals a positive correlation between ex20ins and S310x ERBB2 mutation and protein expression. This correlation is also seen at the RNA level, but the lesser levels relative to ERBB2 amplified cases suggests the effect may be mediated at the protein level.

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

P2, N=46, Completed, Intergroupe Francophone de Cancerologie Thoracique | Active, not recruiting --> Completed

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

P2, N=46, Active, not recruiting, Intergroupe Francophone de Cancerologie Thoracique | Trial completion date: Jul 2023 --> Feb 2024

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.

Additionally, ELVN-002 in combination with ado-trastuzumab emtansine (T-DM1) or trastuzumab deruxtecan (T-DXd) exhibited increased anti-tumor activity in vivo compared to either drug alone.Non-clinical data suggests ELVN-002 has a favorable pharmacokinetic (PK) profile and low risk of QTc prolongation. The trial opened for enrollment in February 2023.Study sponsor: Enliven Therapeutics. NCT0565087

Additionally, ELVN-002 in combination with ado-trastuzumab emtansine (T-DM1) or trastuzumab deruxtecan (T-DXd) exhibited increased anti-tumor activity in vivo compared to either drug alone.Non-clinical data suggests ELVN-002 has a favorable pharmacokinetic (PK) profile and low risk of QTc prolongation. Sponsor: Enliven Therapeutics. NCT0565087

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

In two large independent cohorts, Chinese and Western, ERBB2 mutation and co-mutation patterns were similar. ERBB2 exon 20 insertions/mutations were dominant at over 80% with Y772_A775dupYVMA being the most common driver mutation; TP53 and EGFR were the most frequently co-occurred genes. ERBB2 mutation lung cancers had low TMB and PDL1, as expected in female dominant lung adenocarcinomas, similar to EGFR exon 20 NSCLC.

With the recent approval of fam-trastuzumab deruxtecan-nxki, the first targeted treatment option became available for HER2 mutant NSCLC patients. In addition, the compound was active in a subset of endogenously HER2 mutant cancer cell lines. The in vitro activity of BAY 2927088 was validated in vivo in a patient-derived xenograft model carrying the HER2 exon20 insertion mutation A775insYVMA.The strong preclinical activity of BAY 2927088 in HER2 mutant NSCLC supports clinical evaluation in this indication and might offer a novel targeted therapy option for NSCLC patients that carry HER2 mutations.

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.

Enhertu (T-DXd), a HER2-specific antibody-drug conjugate was recently approved as an important therapy for this patient population...Currently, tucatinib is the only HER2-selective small molecule inhibitor approved for metastatic breast cancer in combination with trastuzumab and capecitabine...Additionally, ELVN-002 could provide a meaningful therapeutic option for patients with CNS metastases. ELVN-002 has been selected for clinical development.

In a patient-derived xenograft model of HER2YVMA mutant lung cancer, we observed that HER2 CAR-NK cells showed enhanced antitumor activity in mice treated with the HER2 inhibitor, poziotinib, for two weeks, compared to CAR-NK cells only, poziotinib only, or mice treated upfront with HER2 CAR-NK cells plus poziotinib. Furthermore, we determined that CD70-targeting CAR-T and CAR-NK cells showed promising in vitro activity against the DTPCs of osimertinib-treated EGFR mutant NSCLC. These results demonstrate CAR-based cellular therapy as an effective approach to target DTPCs and identify CD70 as a novel therapeutic target for combatting DTPCs in NSCLC.

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