Safety, Pharmacokinetics, and Efficacy of Asandeutertinib in Advanced EGFR-mutated NSCLC: A Phase 1 Dose-Escalation and Dose-Expansion Study

Abstract

Introduction

This phase 1 study evaluated the safety, pharmacokinetics, and preliminary efficacy of TY-9591 (asandeutertinib), a deuterated osimertinib derivative.

Methods

Patients with advanced EGFR-mutated (most commonly exon 19 deletions or L858R) NSCLC were enrolled. In the dose-escalation phase, TY-9591 was administered from 20 to 200 mg once daily to assess dose-limiting toxicities and the maximum tolerated dose. In the dose-expansion phase, patients were treated with 80, 120, or 160 mg doses to further evaluate safety, pharmacokinetics, and preliminary efficacy.

Results

A total of 105 patients were enrolled (dose-escalation: n = 19; dose-expansion: n = 86). During the dose escalation phase, no dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) were reported in 100 patients (95.2%). The most common TRAEs were decreased white blood cell count (54.3%), decreased neutrophil count (46.7%), increased blood creatine phosphokinase (39.0%), and anemia (39.0%). Of these patients, 32 (30.5%) experienced grade 3 or higher TRAEs. Pharmacokinetic analysis found that TY-9591 had a favorable profile with reduced levels of active metabolites. During the dose-expansion phase (n = 79), the median progression-free survival for first-line EGFR-mutated (exon 19 deletions or L858R) NSCLC was 21.5 months (95% confidence interval [CI]: 17.3–27.3), whereas the confirmed objective response rate was 85.9% (95% CI: 76.2–92.7). In patients with L858R mutations (n = 36), the median progression-free survival was 19.3 months (95% CI: 13.1–23.5), and the confirmed objective response rate was 86.1% (95% CI: 70.5–95.3).

Conclusion

TY-9591 reported a favorable safety profile and substantial efficacy in treating EGFR-mutated NSCLC, particularly in patients with L858R mutations.