JTO Published Phase I Study Results of Asandeutertinib Mesylate Tablets
Time：2025/04/16
Recently, the innovative drug Asandeutertinib Mesylate Tablets (TY-9591), independently developed by TYK medicines (Stock code: 02410.HK), has officially published its phase I study results in the Journal of Thoracic Oncology (IF 21, Q1). The study was led by Professor Baohui Han from Shanghai Chest Hospital, with Professor Wu Lin from Hunan Cancer Hospital and Professor Zhao Yanqiu from Henan Cancer Hospital as co-investigators. It involved 18 research centers across China and included 105 patients. The study results indicate that Asandeutertinib
Mesylate Tablets have good safety and significant efficacy in treating patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC), especially those with the exon 21 L858R mutation and brain metastases.
Study Design
The published phase I study (NCT04204473) is a single-arm, open-label, dose-escalation and dose-expansion clinical trial evaluating the safety, pharmacokinetics, and efficacy of Asandeutertinib Mesylate Tablets in patients with advanced EGFR-mutant NSCLC. The study included patients with advanced EGFR-mutant NSCLC and involved a dose-escalation phase (6 dose levels: 20-200 mg) and a dose-expansion phase (80, 120, and 160 mg).
Results
Baseline Characteristics
A total of 105 patients were enrolled (19 in the dose-escalation phase; 86 in the dose-expansion phase), and all received the study medication. In the dose-escalation phase, 42.1% of the 19 patients had brain metastases, 63.2% had the 19del mutation, and 36.8% had the L858R mutation. In the dose-expansion phase, 86 patients included 5 with rare mutations, 2 had previously received EGFR TKIs, and 79 patients with EGFR-sensitive mutations had not received prior EGFR TKI treatment (FAS). Among the 79 patients, 46.8% had brain metastases, with the highest percentage in the 160 mg dose group (83.3%, 10/12), 54.4% had the 19del mutation, and 45.6% had the L858R mutation. One patient lacked post-baseline tumor assessment data, and 78 patients were included in the evaluable response set (ERS).
Safety
During the dose-escalation phase, no dose-limiting toxicity (DLT) was observed, and the maximum tolerated dose (MTD) was not reached. Among the 105 patients, 95.2% reported treatment-related adverse events (TRAEs). The most common TRAEs were decreased white blood cell count, decreased neutrophil count, elevated serum creatine phosphokinase, and anemia. Non-hematological toxicities, including diarrhea and skin reactions, were less common, occurring in 30.5% and 17.1% of patients, respectively. Most adverse events were grade 1-2 and resolved spontaneously without intervention. AEs of special interest were observed in 15.2% patients, all of which involved electrocardiogram QT prolonged, with no occurrences of interstitial lung disease, cardiomyopathy, or keratitis.
PK
According to AUC0-t calculations, the exposure of the active metabolite D1 was 5.16%~7.09% of the parent drug across all dosage groups, while the exposure of the active metabolite D2 was 4.75%~13.2% of the parent drug. At 160 mg, the steady-state exposure level of the D1 metabolite was approximately 5.87% of the parent drug, and the steady-state exposure level of the D2 metabolite was about 10.21% of the parent drug.
Efficacy
Based on FAS efficacy analysis, the median progression-free survival (PFS) was 21.5 months (95% CI: 17.3-27.3), and the OS data were not mature. Seven patients (8.9%) experienced disease progression due to brain metastases, with the lowest incidence of 8.3% observed in the 160 mg dose group (only one case, in a patient with pre-existing brain metastasis at baseline).
Based on ERS efficacy analysis, the confirmed objective response rate (ORR) was 85.9% (95% CI: 76.2-92.7), the disease control rate (DCR) was 96.2% (95% CI: 89.2-99.2), and the clinical benefit rate (CBR) was 93.6% (95% CI: 85.7-97.9), with a median tumor response depth of 50.46% (95% CI: 9.8-84.3). The highest ORR was observed in the 160 mg dose group (n=12) at 91.7% (95% CI: 61.5-99.8).
Genetic subgroup analysis shows that for 19del patients (n=43), the median PFS is 25.7 months (95% CI: 17.5-NE), with a confirmed ORR of 85.7% (95% CI: 71.5-94.6). For patients with the L858R mutation (n=36), the median PFS is 19.3 months (95% CI: 13.1-23.5), with a confirmed ORR of 86.1% (95% CI: 70.5-95.3).
Brain metastasis subgroup analysis indicates that for patients with brain metastasis (n=37), the median PFS is 17.5 months (95% CI: 15.2-25.7), and the confirmed ORR is 88.9% (95% CI: 73.9-96.9). For patients without brain metastasis (n=42), the median PFS is 24.6 months (95% CI: 19.3-NE), with a confirmed ORR of 83.3% (95% CI: 68.8-93.0).
Additionally, in a further subgroup analysis of 19 patients (24.1%) with the L858R mutation and baseline brain metastases, the median PFS was 17.2 months (95% CI: 11.0-27.3), and the confirmed ORR was 94.7% (95% CI: 74.0-99.9).
Summary
This Phase I study is the first to report the safety and favorable efficacy of Asandeutertinib Mesylate Tablets in patients with EGFR-mutant advanced NSCLC, especially in those with the exon 21 L858R mutation and brain metastases, showing a significant trend of prolonged PFS.
Reference
Han B, Liu J, Wu L, et al. Safety, Pharmacokinetics, and Efficacy of Asandeutertinib in Advanced EGFR-mutated NSCLC: A Phase 1 Dose-Escalation and Dose-Expansion Study. J Thorac Oncol. Published online February 8, 2025. doi:10.1016/j.jtho.2025.02.003
