Glumetinib

Gumarontinib has previously shown activity in patients with non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutation (METex14). We hereby report the updated results from the phase II stage of GLORY study after additional 18-month follow-up.

The single-arm, multicenter, open-label, phase II of the GLORY study was conducted at 42 centers across China and Japan. Patients with locally advanced or metastatic METex14-positive NSCLC received gumarontinib 300 mg orally once daily until disease progression or intolerable toxicity. Eligible patients had failed one or two prior lines of therapy (not including a MET inhibitor) and had no genetic alterations targetable with standard therapies. The primary endpoint was the objective response rate (ORR) by the blinded independent review committee (BIRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The study was registered at ClinicalTrials.gov (NCT04270591).

The phase II stage of GLORY study included 84 patients. As of the data cutoff date on October 28, 2023, the ORR assessed by BIRC was 65.8% [95% confidence interval (CI): 54.3% to 76.1%], with 70.5% (95% CI: 54.8% to 83.2%) in treatment-naïve and 60.0% (95% CI: 42.1% to 76.1%) in pre-treated populations. The median duration of response (DOR) assessed by BIRC was 8.3 (95% CI: 6.2 to 18.3) months, the median progression-free survival (PFS) was 7.7 (95% CI: 7.6 to 9.7) months, and the median overall survival (OS) was 19.4 (95% CI: 12.1 to 30.1) months, with a median OS of 25.4 [95% CI: 11.7 to not evaluable (NE)] months in treatment-naïve population and 16.3 (95% CI: 8.7 to NE) months in the pre-treated population. The most common treatment-related adverse events (any grade) were oedema (67/84, 79.8%) and hypoalbuminemia (32/84, 38.1%). Grade ≥3 treatment-related adverse events occurred in 53.6% (45/84) patients. Treatment-related adverse events leading to permanent discontinuation occurred in 8.3% (7/84) of patients.

Gumarontinib showed promising efficacy and acceptable toxicities in East Asian population, with a rapid onset of action, substantial and durable response, which can be converted into a long-term survival benefit.

With the rapid development of epidermal growth factor receptor (EGFR) gene testing of lung adenocarcinoma patients has been routinely carried out, EGFR mutations are also possible for some small samples of non-smoking female lung squamous cell carcinoma patients. This increases the opportunity for targeted therapy for this group of patients. However, drug resistance in patients with lung squamous cell carcinoma during targeted therapy is an important factor affecting subsequent treatment. There are multiple mechanisms of acquired drug resistance in targeted therapy, and the alteration of mesenchymal-epithelial transition factor (MET) signaling pathway is one of the common mechanisms of drug resistance. At present, some selective tyrosine kinase inhibitors (TKIs) of MET has been approved for non-small cell lung cancer with MET gene 14 exon skipping mutation, such as Glumetinib, Savolitinib, Tepotinib, Capmatinib, etc. Drugs that target secondary MET amplification are still in clinical trials. This paper retrospectively analyzed the clinical data of a female patient with EGFR-TKIs resistant secondary MET amplified squamous cell lung cancer, and reviewed relevant literature to explore how to optimize the treatment of lung squamous cell carcinoma patients with EGFR mutation, so as to provide clinical reference for the diagnosis and treatment of such patients.
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