Safety, Pharmacokinetics, and Efficacy of TY-9591 (Deuterated Osimertinib Derivative) in Advanced EGFR-mutated Non-Small Cell Lung Cancer: A Phase 1 Dose-Escalation and Dose-Expansion Study.

Background: 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) non-small cell lung cancer (NSCLC) were enrolled. In the dose-escalation phase, TY-9591 was administered from 20 mg to 200 mg once daily to assess dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). In the dose-expansion phase, patients were treated with 80 mg, 120 mg, 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 DLTs were observed, and MTD was not reached. Treatment-related adverse events (TRAEs) were reported in 100 patients (95.2%), with 32 (30.5%) experiencing grade ≥3 TRAEs. The most common TRAEs were white blood cell count decreased (54.3%), neutrophil count decreased (46.7%), blood creatine phosphokinase increased (39.0%), and anaemia (39.0%). Pharmacokinetic analysis showed 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 (mPFS) for first-line EGFR-mutated (exon 19 deletions or L858R) NSCLC was 21.5 months (95% CI: 17.3, 27.3), while confirmed objective response rate (ORR) was 85.9% (95% CI: 76.2, 92.7). In patients with L858R mutations (n=36), mPFS was 19.3 months (95% CI: 13.1, 23.5), and confirmed ORR was 86.1% (95% CI: 70.5, 95.3).

Conclusion: TY-9591 demonstrated a favorable safety profile and substantial efficacy in treating EGFR-mutated NSCLC, especially in patients with L858R mutations.