Targeting<i>HER2</i>Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Han, Han; Li, Shuai; Chen, Ting; Fitzgerald, Michael; Liu, Shengwu; Peng, Chengwei; Tang, Kwan Ho; Cao, Shougen; Chouitar, Johara; Wu, Jiansheng; Peng, David H.; Deng, Jiehui; Gao, Zhendong; Baker, Theresa E.; Li, Fēi; Zhang, Hua; Pan, Yun; Ding, Hailin; Hu, Hai; Pyon, Val; Thakurdin, Cassandra; Papadopoulos, Eleni; Tang, Sittinon; Gonzalvez, François; Chen, Haiquan; Rivera, Victor M.; Brake, Rachael; Vincent, Sylvie; Wong, Kwok‐Kin

doi:10.1158/0008-5472.can-21-1526

Cited by 32 publications

(24 citation statements)

References 44 publications

(45 reference statements)

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“…It is FDA approved in NSCLC patients with EGFR exon 20 insertions, and has demonstrated anti-tumor activity in HER2 exon 20 insertion mutants in pre-clinical models [ 43 ]. It was particularly effective in HER2 exon 20 G776 > VC tumors, and synergistic with T–DM1 on HER2 exon 20 YVMA tumors for both first–line and second–line settings after acquired resistance [ 44 ]. This agent is being actively investigated in HER2 exon 20 mutated NSCLC, and clinical efficacy data has not yet been reported [ 45 ].…”

Section: Treatment Of Her2-altered Nsclcmentioning

confidence: 99%

HER2 in Non-Small Cell Lung Cancer: A Review of Emerging Therapies

Merkhofer

Baik

2022

Cancers

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Human epidermal growth factor receptor 2 (HER2), a member of the ERBB family of tyrosine kinase receptors, has emerged as a therapeutic target of interest for non-small cell lung cancer (NSCLC) in recent years. Activating HER2 alterations in NSCLC include gene mutations, gene amplifications, and protein overexpression. In particular, the HER2 exon 20 mutation is now a well clinically validated biomarker. Currently, there are limited targeted therapies approved for NSCLC patients with HER2 alterations. This remains an unmet clinical need, as HER2 alterations are present in 7–27% of de novo NSCLC and may serve as a resistance mechanism in up to 10% of EGFR mutated NSCLC. There has been an influx of research on antibody–drug conjugates (ADCs), monoclonal antibodies, and tyrosine kinase inhibitors (TKIs) with mixed results. The most promising therapies are ADCs (trastuzumab-deruxtecan) and novel TKIs targeting exon 20 mutations (poziotinib, mobocertinib and pyrotinib); both have resulted in meaningful anti-tumor efficacy in HER2 mutated NSCLC. Future studies on HER2 targeted therapy will need to define the specific HER2 alteration to better select patients who will benefit, particularly for HER2 amplification and overexpression. Given the variety of HER2 targeted drugs, sequencing of these agents and optimizing combination therapies will depend on more mature efficacy data from clinical trials and toxicity profiles. This review highlights the challenges of diagnosing HER2 alterations, summarizes recent progress in novel HER2-targeted agents, and projects next steps in advancing treatment for the thousands of patients with HER2 altered NSCLC.

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Section: Treatment Of Her2-altered Nsclcmentioning

confidence: 99%

HER2 in Non-Small Cell Lung Cancer: A Review of Emerging Therapies

Merkhofer

Baik

2022

Cancers

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“…Additionally, lung cancers with HER2 G776delinsVC subtypes reported a superior response to mobocertinib than the YVMA subtypes. The combination of ado-trastuzumab emtansine (T-DM1) and mobocertinib had a synergistic function in HER2 YVMA tumors ( 77 ). A phase I/II trial (NCT02716116) showed promising antitumor activities of mobocertinib in advanced NSCLC patients harboring EGFR ex20ins, with a similar safety profile compared to other EGFR-TKIs ( 78 , 79 ).…”

Section: Targeting Her2 In Nsclc: Perplexity and Progressmentioning

confidence: 99%

HER2-Altered Non-Small Cell Lung Cancer: Biology, Clinicopathologic Features, and Emerging Therapies

2022

Front. Oncol.

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Multiple oncogenic molecular alterations have been discovered that serve as potential drug targets in non-small cell lung cancer (NSCLC). While the pathogenic and pharmacological features of common targets in NSCLC have been widely investigated, those of uncommon targets are still needed to be clarified. Human epidermal growth factor receptor 2 (HER2, ERBB2)-altered tumors represent a highly heterogeneous group of diseases, which consists of three distinct situations including mutation, amplification and overexpression. Compared with breast and gastric cancer, previous studies have shown modest and variable results of anti-HER2 treatments in lung cancers with HER2 aberrations, thus effective therapies in these patients represent an unmet medical need. By far, encouraging efforts towards novel treatment strategies have been made to improve the clinical outcomes of these patients. In this review, we describe the biological and clinicopathological characteristics of HER2 alterations and systematically sum up recent studies on emerging therapies for this subset of patients.

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“…Amongst novel HER-TKIs other than poziotinib, pyrotinib and mobocertinib showed preclinical activity in HER2 -mutated lung cancer. 50 , 51 Pyrotinib also showed signs of important antitumour activity in patients with HER2 -mutated advanced NSCLC. 50 , 52 Currently, both drugs are being evaluated in clinical trials (NCT04447118; NCT02716116).…”

Section: Her2 Exon 20 Insertion Mutationsmentioning

confidence: 99%

Advanced non-small-cell lung cancer: how to manage EGFR and HER2 exon 20 insertion mutation-positive disease

Metro¹,

Giglio²,

Ricciuti³

et al. 2022

DIC

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EGFR exon 20 insertion mutations (Ex20ins) and HER 2 mutations characterize an oncogene-addicted subtype of non-small-cell lung cancer (NSCLC) typically associated with a never or light smoking history, female sex, and adenocarcinoma histology. Nevertheless, Ex20ins-mutant and HER 2-mutant advanced NSCLCs are still difficult to treat for various reasons. First, there is a need for sophisticated diagnostic tools (e.g. next-generation sequencing) that could allow the identification of these relatively rare molecular drivers. Second, highly active targeted drugs that might support a significant change in patients’ prognosis when used as first-line therapy are required. In fact, although a few targeted drugs have so far demonstrated antitumour activity for these patients, mainly selective human epidermal receptor-tyrosine kinase inhibitors such as poziotinib and mobocertinib (for both molecular alterations), monoclonal antibodies such as amivantamab (for Ex20ins), and antibody–drug conjugates such as trastuzumab deruxtecan (for HER2 mutants), they are mostly confined for clinical use in pretreated patients. Finally, Ex20ins-targeted or HER2-targeted drugs might be difficult to access in different countries or regions worldwide. In the present review, we provide a concise but comprehensive summary of the challenges that lie ahead as we move towards personalized treatment of Ex20ins-mutant and HER2 -mutant advanced NSCLC, also suggesting a treatment algorithm that could be followed for patients with these genetic aberrations.

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TargetingHER2Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Cited by 32 publications

References 44 publications

HER2 in Non-Small Cell Lung Cancer: A Review of Emerging Therapies

HER2 in Non-Small Cell Lung Cancer: A Review of Emerging Therapies

HER2-Altered Non-Small Cell Lung Cancer: Biology, Clinicopathologic Features, and Emerging Therapies

Advanced non-small-cell lung cancer: how to manage EGFR and HER2 exon 20 insertion mutation-positive disease

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