Targeting HER2 alterations in non-small cell lung cancer: Therapeutic breakthrough and challenges. (March 2023)

• Record Type: Journal Article
• Authors: Yu, Ying; Yang, Yehao; Li, Hui; Fan, Yun
• Is Part Of: Cancer treatment reviews. Volume 114(2023)
• Publication Date: 2023-03
• Subjects: Non-small cell lung cancer -- HER2 alterations -- selective HER2 tyrosine kinase inhibitors -- Antibody-drug conjugates -- HER2-targeted monoclonal antibodies -- Immune checkpoint inhibitors; ADC antibody-drug conjugate -- CNS central nervous system -- DAR drug-to-antibody ratio -- DCR disease control rate -- ex20ins insertions in exon 20 -- FDA Food and Drug Administration -- FISH fluorescence in situ hybridization -- HER2 human epidermal growth factor receptor 2 -- ICIs immune checkpoint inhibitors -- IHC immunohistochemistry -- ILD interstitial lung disease -- iORR intracranial ORR -- iPFS intracranial PFS -- mDoR median duration of response -- mOS median overall survival -- mPFS median progression-free survival -- NSCLC non-small cell lung cancer -- ODAC Oncologic Drugs Advisory Committee -- ORR objective response rate -- T-DXd trastuzumab deruxtecan -- TKI tyrosine kinase inhibitor -- TMB tumour mutational burden -- TRAEs treatment-related adverse events -- WT EGFR wild type EGFR -- YVMAins A775_G776insYVMA mutation; Cancer -- Periodicals; Cancer -- Treatment -- Periodicals; Neoplasms -- therapy -- Periodicals; Cancer -- Périodiques; Cancer -- Traitement -- Périodiques; Cancer -- Treatment; Electronic journals; Periodicals; 616.99406
• DOI: 10.1016/j.ctrv.2023.102520
• Languages: English
• ISSNs: 0305-7372

Abstract

Highlights: T -DXd has achieved a significant breakthrough and has been approved by the FDA for pretreated advanced HER2-mutant NSCLC. Although poziotinib has shown promising antitumour activity, the significant toxicity hinders its subsequent development. An explicit definition of the cut-off values for HER2 amplification or overexpression is imperative. Future studies should focus on T -DXd-based therapy and the intracranial activity of anti-HER2 agents. Abstract: In non-small cell lung cancer (NSCLC) with human epidermal growth factor receptor 2 (HER2) alterations, chemotherapy remains the standard treatment over a decade, due to the minor efficacy of traditional pan-HER tyrosine kinase inhibitors (TKIs) and HER2-targeted monoclonal antibodies. In recent years, novel selective HER2 TKIs have been developed for pretreated HER2-mutant patients. In particular, pyrotinib has shown moderate efficacy as well as a manageable safety profile, and it is now being further evaluated as monotherapy or combined with other existing therapies; by contrast, while poziotinib has demonstrated promising preliminary results, the high rates of toxicity has hampered subsequent studies. Most notably, trastuzumab deruxtecan ( T -DXd, DS-8201) has led to a significant breakthrough, with the most encouraging efficacy data (response rate of 55 %, median progression-free survival of 8.2 months and median overall survival of 17.8 months) among all the anti-HER2 agents. This is certainly remarkable progress, and T -DXd is undoubtedly the key drug for the treatment of this disease. Future developments regarding T -DXd are favourable, including shifting from monotherapy to combination strategies, improving structural design to optimise antitumour activity and minimise toxicity, identifying the potential resistance mechanisms and developing therapeutic strategies to overcome them. Several other challenges need to be addressed, such as the intracranial activity of anti-HER2 agents and the optimal sequencing of therapies. Here, we summarise recent therapeutic advances in targeting HER2 alterations in NSCLC and highlight the future perspectives of these patient populations.