HER-2 A775

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

Finally, phase II clinical trials involving HER2-altered NSCLC patients demonstrated promising treatment outcomes with trastuzumab deruxtecan, trastuzumab emtansine, pyrotinib, pyrotinib + apatinib and trastuzumab + pertuzumab + docetaxel. In conclusion, the prevalence of HER2 alteration among Malaysian NSCLC patients falls within the global range. A systematic review of clinical trials revealed promising treatment outcomes and Malaysian NSCLC patients with HER2 alterations are anticipated to similarly benefit from HER2-targeted therapies.

Notably, EGFR ex20 insertions exhibited greater insertion diversity. Clinical characteristics of EGFR and ERBB2 ex20 NSCLC were similar, characterized by low tumor mutation burden (TMB), a predominant never-smoker population, and a majority of lung adenocarcinoma cases.

P2; Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

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

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

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.

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.

This study revealed a unique immune landscape at the single-cell level in rare-mutant NSCLC undergoing neoadjuvant chemo-immunotherapy. These findings may have implications for the development of personalized therapeutic strategies for patients with rare mutations in locally advanced NSCLC.

MPLC has a unique genetic mutation characteristic that differs from advanced patients and usually presents with low TMB. Comprehensive NGS helps to diagnose MPLC and guides the MPLC clinical treatment. ARID1A is significantly enriched in IA nodules containing micro-papillary/solid components, suggesting that these MPLC patients may have a poor prognosis.

Long-term survivors with EGFRm mNSCLC treated before the osimertinib era were more likely to be nonsmokers and have no baseline brain metastases. This highlights a subset of EGFRm patients who had excellent outcomes with older treatment strategies and may not benefit as much from intensification approaches. Additional baseline mutational data will be presented at the conference.

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.

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.

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.

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.

Poziotinib demonstrates moderate antitumor activity in previously treated HER2 exon 20 mutant NSCLC patients with a manageable safety profile. In addition, different subgroup mutations show various benefits of poziotinib treatment. Large-scale and multiarm clinical trials are warranted to confirm a suitable population and therapeutic strategies.

All ERBB2 mutated patients were diagnosed with lung adenocarcinoma, were never smokers, and wild-type for EGFR, KRAS, and ALK hotspot alterations. Less than 1% of Brazilian NSCLC patients harbor ERBB2 exon 20 insertions, yet they could benefit in future from the new drugs in development.

In ERBB2-mutant/EGFR-wildtype mNSCLC, while most trastuzumab-based regimens had modest activity in this real-world analysis, trastuzumab deruxtecan had highest response rates and best tumor size reduction. Receipt of any trastuzumab-based regimen was associated with greater OS with A775_G776insYVMA. There remains an unmet need for approved targeted therapies for ERBB2-mutant/EGFR-wildtype NSCLC.

NVL-330 is a wild-type EGFR-sparing, brain-penetrant small-molecule inhibitor of HER2 exon20ins in preclinical models, demonstrating the potential to address a medical need for HER2 exon 20 insertion mutant NSCLC patients.

In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201)... Detection of rare mutations require sensitive and specific diagnostic assays. AmoyDx HER2 Mutation Detection Kit demonstrated robust performance in detecting representa-tive HER2 indel and single nucleotide variant mutations at low frequencies. The AmoyDx Pan Lung Cancer PCR assay showed similarly robust and sensitive detection of the common HER2 A775_G776insYVMA indel in addition to detecting clinically relevant EGFR mutations.

Patients with ERBB2 amplifications or mutations had higher TMB compared with patients with non-ERBB2 alterations. The study provided the landscape of ERBB2 alterations across a variety of solid tumors that may benefit from anti-HER2 agents.

Conclusions This study identified multiple genetic factors associated with afatinib efficacy and resistance. In addition, genomic characteristics such as TMB, tumor heterogeneity and APOBEC signature might serve as biomarkers for afatinib response.

P1/2, N=30, Recruiting, Forward Pharmaceuticals Co., Ltd. | N=130 --> 30

Despite the fact that the study did meet its primary end-point, trastuzumab/pertuzumab was only marginally active in a subset of patients with heavily pre-treated HER2m+ NSCLC.

This study was novel in comprehensively investigating the clinical and molecular characteristics of patients in Chinese and Western populations, and in analyzing the factors affecting the prognosis of Chinese patients. It provided critical data for future therapies against HER2-altered NSCLC.

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)

We report mutational landscape and characteristics of ERBB2 in Chinese NSCLC patients.The prevalence of activating ERBB2 mutations was 3.1% in Chinese NSCLC patients. 80.1% of ERBB2 activating mutations were in TKD and 19.9% were in the non-TKD. The non-TKD mutations might also be used as a therapeutic target in ERBB2-directed target therapy.

This real-world databases identified the helix as the most frequent insertion region of Exon 20 (∼72%). Exon20ins mutations were found less frequently in the loop (∼28%).

Our results demonstrate that tRNA-seq can be implemented in a diagnostic setting as an efficient strategy for simultaneous detection of actionable gene fusions, splice variants, SNVs and indels in NSCLC provided that adequate RNA-seq analysis tools are available, especially for the detection of indels. This approach allows upfront identification of currently recommended targetable molecular alterations in NSCLC samples.

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.