Time：2023-03-26 00:21:17 source：psychiatricethics.com author：Relax Read：804次

New use of old targets for the treatment of HER2-mutant non-small cell lung cancer, a new heavy weapon

The overexpression of human epidermal growth factor receptor 2 (HER2, ERBB2) is closely related to the malignancy of cancer. Among them, breast cancer is the most common HER2-mutated tumor, and the targeted drug trastuzumab for HER2 mutation has been used in It is approved worldwide for the treatment of patients with metastatic HER2-positive breast and gastric cancer. Just this year, the HER2-mutated population in non-small cell lung cancer (NSCLC) patients also received the first HER2-targeted drug for lung cancer, Trastuzumab Deruxtecan (DS-8201), which was approved by the United States. FDA-approved for the treatment of HER2-mutated metastatic or unresectable NSCLC [1]. The related clinical research (DESTINY-lung01) results "Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer" were first published in the famous medical journal "The New England journal of medicine" [2]. Source: Reference [2]

Precise targeting of rare mutations, none of which can be missing

Lung cancer is the most common malignant tumor , According to traditional histological classification, NSCLC accounts for about 85% of all lung cancer types. NSCLC is further classified into EGFR-mutant, ALK-mutant, HER2-mutant, etc. according to the presence or absence of driver gene mutations [3]. Different from the common HER2 gene amplification and HER2 protein overexpression in breast cancer and gastric cancer, the main changes of HER2 in NSCLC are frameshift insertion mutations in exon 20 of the tyrosine kinase region (exon 20 insertion, ex20ins). ) as the main [4]. This leads to the fact that routine clinical immunohistochemical methods cannot detect HER2 gene mutations in NSCLC patients [5], and more special methods are required; at the same time, traditional HER2-targeted drugs are also helpless for HER2-mutant NSCLC: HER2 gene mutation in NSCLC After mutation, the drug-binding pocket of the tyrosine kinase region produces obvious steric hindrance, which makes it difficult for traditional HER2-targeting drugs to bind to the drug-binding pocket and to inhibit HER2 [6]. ⬇️ Source of frequency map of abnormal oncogenic driver molecular targets in NSCLC: Reference [3] Although the population base of HER2-mutant NSCLC is small, accounting for about 1% to 5% of NSCLC, this type of tumor shows strong metastatic ability and invasive capacity, up to 47% of patients with HER2-mutant NSCLC develop central nervous system (CNS) involvement. Moreover, HER2-mutant patients are less sensitive to conventional chemotherapy, are prone to relapse, and have a shorter survival time than general patients. At present, there is no effective standard treatment recommendation for HER2-mutant NSCLC in the world. Therefore, actively exploring precise targeted therapy for HER2-mutant lung cancer without giving up any patient has become one of the goals of current NSCLC treatment.

Desi trastuzumab, providing continuous benefit to subjects

HER2-targeting drug development in lung cancer is mainly It is organized around three types of structures: tyrosine kinase inhibitors (TKIs), monoclonal antibodies combined with cytotoxic drugs, and antibody conjugated drugs (ADCs). The approved Trastuzumab Deruxtecan (DS-8201) is an ADC-type drug of HER2 antibody + chemotherapeutic drugs. It targets and binds to abnormally expressed HER2 outside the cell to guide the chemotherapeutic drugs at the other end of the antibody. It can precisely act on tumor cells, thereby efficiently inducing DNA damage and apoptosis in tumor cells, and the bystander killing effect will also act on adjacent cancer cells, further improving the anti-tumor efficiency [8]. ⬇️ Schematic diagram of the internal effect of Dexi Trastuzumab Source: Xiaohe Medical Code To prove the efficacy and safety of DS-8201 in patients with HER2-mutant NSCLC, the research team carried out research in 21 regions in North America, Japan and Europe A multicenter, open-label, two-cohort phase II study - DESTINY-Lung01 [2]. The study included 91 patients with HER2-mutant NSCLC from Asian, European, and North American ethnicities of different skin tones who received DS-8201 intravenously every 3 weeks. Ninety-five percent of the patients had received platinum-based chemotherapy, and 66% had received anti-PD-1/PD-L1 immunotherapy. The median follow-up time was 13.1 months (0.7-29.1 months). The efficacy evaluation results showed that among 91 patients, 84 patients (92%) had their disease under effective control, 50 patients (55%) confirmed objective response, of which 1 patient (1%) was confirmed as complete response, and 49 patients were confirmed as complete response. A partial response was confirmed in patients (54%). The median duration of response was 9.3 months, the median progression-free survival was 8.2 months, and the median overall survival was 17.8 months. In terms of safety, the results of adverse event analysis showed that all patients had at least one adverse event during treatment, of which 88 patients (97%) had at least one drug-related adverse event, most of which were grade 1 or 2. , common adverse events included gastrointestinal and hematologic reactions, decreased appetite, and hair loss. Drug-related adverse events of grade 3 or higher occurred in 42 (46%) patients, most commonly neutropenia (19%) and anemia (10%). Drug-related interstitial lung disease occurred in 26% of patients and resulted in 2 deaths. In view of the sustained efficacy and safety concerns of DS8201 in the DESTINY-Lung01 study, the research team also conducted a lower-dose study of the same type of cancer, DESTINY-Lung02 [9]. In this study, 52 patients with HER2-mutant unresectable and/or metastatic NSCLC were also included and received DS-8201 after disease progression. Preliminary study results showed that 58% of patients achieved an objective response, of which 29 patients (55.8%) had a partial response and 1 patient (1.9%) had a complete response, with a median duration of response of 8.7 months. Safety was consistent with previous studies and no new safety issues were identified. Both studies demonstrate that DS8201 has the ability to deliver tumor shrinkage efficacy and longer survival benefits in patients with HER2-mutant NSCLC. Although the DESTINY-Lung02 research paper has not yet been published, its exact and effective research results bring new treatment hope for patients with HER2-mutant NSCLC!

The dawn has come, how should domestic patients choose?

Of course, these two studies have obvious shortcomings. For example, they lack a control group or a placebo group, so it is difficult to judge the difference in efficacy between traditional trastuzumab and traditional trastuzumab; the research data is also relatively one-sided, and there is evidence of efficacy in Chinese patients Not sure yet. "An open-label, randomized, multicenter evaluation of the efficacy and safety of Trastuzumab Deruxtecan (T-DXd, DS-8201) as first-line therapy in patients with unresectable, locally advanced, or metastatic NSCLC harboring HER2 mutations," conducted by the research team. , Phase 3 study (DESTINY-Lung04)” has officially started recruitment in China, looking forward to the release of more research data, bringing new treatment options to domestic HER2-mutant NSCLC patients. Therefore, for domestic HER2-positive NSCLC patients, in addition to relying on more accurate gene sequencing to detect individual rare gene mutations as early as possible, fully understanding the development of large-scale randomized controlled clinical trials of anti-HER2 drugs at home and abroad may also provide Illness brings more hope. With the concerted efforts of doctors and patients, increasingly detailed and transparent research evidence will clear the fog of precise individual cancer treatment, and lead patients with rare mutant tumors into a new era of targeted therapy! Disclaimer: This article is only the content of medical science and cannot replace the diagnosis and treatment opinions of clinicians. For specific circumstances, please refer to the diagnosis and treatment opinions of the attending physician. References: [1] FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer, FDA Approved Drugs, 2022 Aug 12. https://www.fda.gov/drugs/resources- information-approved-drugs/[2] Bob T. Li et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell LungCancer [J]. NewEngland journal of medicine 2022; 386:241-251.[3] Tan AC, Tan DSW. Targeted Therapies for Lung Cancer Patients With Oncogenic Driver Molecular Alterations. J Clin Oncol. 2022 Feb 20;40(6):611-625.[4] LiBT, RossDS, AisnerDL, et al. HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers[J]. J Thorac Oncol, 2016, 11(3): 414-419.[5] StephensP, HunterC, BignellG, et al. Lung cancer: intragenic ERBB2 kinase mutations in tumors[J]. Nature, 2004, 431(7008): 525-526.[6] RobichauxJP, ElaminYY, TanZ, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer[J] . Nat Med, 2018, 24(5): 638-646. [7] Xu Fei, Wang Yan. Current status and prospects for the treatment of human epidermal growth factor receptor 2-mutated non-small cell lung cancer[J]. Chinese Journal of Oncology, 2020, 42(10) : 829-837.[8] ENHERTU® (fam-trastuzumab deruxtecan -nxki) | Patient Site, https://www.enhertu.com/en/nsclc[9] Daiichi Sankyo, Inc. Trastuzumab Deruxtecan in Participants With HER2-mutated Metastatic Non-small Cell Lung Cancer (NSCLC) (DESTINY-LUNG02 ), https://clinicaltrials.gov/ct2/show/record/NCT04644237?term=NCT04644237&draw=2&rank=1[10] E.F.F. Smit, B.T. Li, J. Mazieres, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-mutated (HER2m) metastatic non-small cell lung cancer (NSCLC): A phase (ph) II study (DESTINY-Lung02)[Z]. ANN ONCO, 2021,32(s5):S1032-1033 .

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