Lung cancer rare target therapy has advanced rapidly, and patients are no longer "afraid" because of "rare"

*For medical professionals only

Mainland MET inhibitors open a new era of targeted therapy for MET lung cancer in China!

In recent years, in-depth studies of genotyping have led to rapid changes in the treatment of non-small cell lung cancer (NSCLC). Since the discovery of EGFR mutations in NSCLC in 2004, a series of randomized controlled clinical studies have confirmed the dominant position of tyrosine kinase inhibitors (TKIs) in the treatment of EGFR mutation-positive NSCLC. Other "rare" gene mutation types such as HER2, ROS1, RET, MET, BRAF, NTRK, EGFR20 exon insertion mutations have been discovered, which has made people pay more and more attention to the clinical characteristics and treatment strategies of these patients with "rare" type gene mutations NSCLC, and also makes the targeted therapy of NSCLC more and more accurate [1].

At present, breakthroughs have been made in the research of "rare" mutations, and new drugs with rare targets have been approved for marketing, which has also made the treatment of rare targets for lung cancer gradually usher in the dawn.

Accurate diagnosis and treatment of rare targets has received more and more attention

Although the incidence of rare target mutations is very low, due to the large population base of lung cancer in mainland China, the number of lung cancer patients with rare mutations is actually large. For the diagnosis and treatment of common target mutations in lung cancer, the mainland clinical guidelines have given clear recommended drugs, but for the diagnosis and treatment of rare target mutations, the clinical guidelines have not given many treatment recommendations. In addition, since drugs are already available in some patients with rare mutation types, detection of these rare targets is necessary. At present, the detection of rare target mutations has attracted more and more attention in the clinic.

After lung cancer patients are diagnosed with rare target mutations, follow-up treatment has a greater impact on them, unfortunately, most patients do not understand the relevant concepts. For the treatment of rare cases, most clinicians are also confused.

Moreover, there are differences in the clinicopathological characteristics of rare targets of different classes. For example, BRAF gene mutations occur mostly in lung adenocarcinoma, HER2 gene amplification occurs in male NSCLC patients who smoke, HER2 gene mutations occur more often in NSCLC patients in non-smoking women, and ROS1 gene fusion is more common in young, non-smoking or less smoking lung cancer patients.

Accurate diagnosis and treatment of rare mutations needs to optimize genetic testing methods by combining patient pathological characteristics and corresponding guidelines and consensus, so as to help patients obtain more accurate genetic test results through more detailed means, so that every rare mutation patient who may potentially benefit has the opportunity to obtain corresponding targeted therapy.

At present, a number of hospitals in the mainland have set up rare lung cancer clinics, and the landing of rare clinics is of great significance to both patients and doctors. Rare outpatient clinics not only provide a platform for patients to receive centralized treatment, but also help to improve the professional level and teamwork of doctors, thereby further expanding the influence of rare mutation targeted outpatient clinics for lung cancer and benefiting more lung cancer patients who have no way to seek medical treatment.

Patients with rare mutant lung cancer are ushering in targeted new options

MET gene abnormalities include genetic mutations, amplification, rearrangement, and protein overexpression, with the overall incidence of MET14 exon-jumping mutations in lung cancer being 3 to 4 percent [2]. As a primary oncogene, although the MET14 exon jump mutation is a "niche" gene, based on the large base of lung cancer patients, there are not many people with abnormal genes. In addition, MET amplification is also an important strategy for targeted treatment after EGFR-TKI resistance, which has certain value for clinical practice. Unfortunately, whether it is a META14 exon jump mutation or a MET amplification patient, the previously available treatment options (chemotherapy or immunotherapy) have limited efficacy, so clinicians are more looking forward to the early listing of highly effective new MET inhibitors and their clinical applications to solve this major diagnosis and treatment problem.

A single-arm, multicenter, open-label clinical Phase II study of the highly selective MET inhibitor sivotinib[3] was conducted in 32 hospitals across the country and received widespread attention. A total of 70 patients with locally advanced or metastatic exon jump mutations in META14 were enrolled in the study, with histological type of lung sarcoma-like carcinoma (PSC) or other NSCLC subtypes. The results of the study showed that sivotinib can bring considerable objective response rates (ORR) and disease control rates to patients with MET14 exon jump mutation positive NSCLC, and give patients a longer survival time [3]. In terms of safety that doctors and patients are most concerned about, studies have shown that in all patients treated with sivotinib, treatment-related adverse events are mostly grade 1 to 2, and clinical management is not difficult, reflecting the good safety of sivotinib.

Based on the results of the study, the NSCLC patients with EXON jump mutation of MET14 in China ushered in the first MET inhibitor, sivotinib, which solved the dilemma of "no drug available" in such patients in China. In the 2021 edition of the Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer, sivotinib is also listed as a Class II recommended drug for the treatment of EXON-skipping mutations in MET14 [4].

Fusion of the RET gene is more common in lung adenocarcinomas and occurs in about 1.6% of Chinese [5]. Previously, there were fewer drugs available to patients with RET gene fusion, and in 2021, China's State Drug Administration (NMPA) approved pratinib for the treatment of locally advanced or metastatic NSCLC adult patients who had previously received platinum-containing chemotherapy positive for RET gene fusion. The ARROW study[6] published in the journal Lancet Oncology showed that the ORR was 61% in patients treated with NSCLC, the median progression-free survival (PFS) was 17.1 months, and the median overall survival (OS) was not achieved; in patients who had not previously received systemic therapy, ORR was 70%, the median PFS was 9.1 months, and the median OS was not achieved.

Precise treatment, detection first

At present, the MET14 exon jump mutation detection has been included in the 2021 CSCO NSCLC diagnostic guidelines. Guidelines indicate that insurpassable stage III and IV NSCC patients, exon-skipping mutations in tumor tissue can be detected by single-gene detection techniques or NGS, and if tissue specimens are out of reach, cyclic free DNA (cfDNA)/circulating tumor DNA (ctDNA) may be considered [4]. In addition, the 2021 CSCO NSCLC guidelines also recommend RET fusion testing for non-squamous cell carcinoma tissue specimens in patients with inoperable stage III and stage IV NSCLC [4].

At present, the research of new targets of NSCLC genes is emerging in an endless stream, and with the continuous deepening of rare or rare gene mutation research, NSCLC's precision targeted therapy in internal medicine will surely become more and more exciting. In the future, we hope that more such new drugs and good drugs can appear in front of us to help patients with rare mutations in lung cancer to obtain the possibility of long-term survival. For this field, there are many unknowns and challenges, which need to be continuously explored and look forward to more new achievements in this area.

bibliography:

[1] Yang Guangjian, Wang Yan, Research progress in the treatment of rare gene mutations in non-small cell lung cancer[J].Cancer Progress,2019,17(12):1372-1375

[2] Guo R,Luo J,Chang J,et al. MET-dependent solid tumours-molecular diagnosis and targeted therapy[J]. Nat Rev Clin Oncol.2020;17(9):569-587.

[3] Lu S,Fang J,Li X,et al. Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations:a multicentre,single-arm,open-label,phase 2 study[J]. The Lancet Respiratory Medicine,2021.doi:10.1016/s2213-2600(21)00084-9.

4]2021 Edition of The Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Non-small Cell Lung Cancer.

Luo Jiawei,Wu Fengying,Zhou Caicun. Review of treatment progress of rare driver gene-positive non-small cell lung cancer[J].Electronic Journal of Comprehensive Oncology Treatment,2019,5(2):29-33.

[6] Gainor JF,Curigliano G,Kim DW,et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer(ARROW):a multi-cohort,open-label,phase 1/2 study[published correction appears in Lancet Oncol.2021 Aug;22(8):e347]. Lancet Oncol.2021;22(7):959-969.

Approval number: CN-91825

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*This information is for medical and scientific reference only and does not constitute a recommendation or promotion of any drug or treatment regimen. The information contained in this article should not be a substitute for medical advice provided by healthcare professionals.