A phase II study of asandeutertinib (TY-9591) in advanced NSCLC patients with EGFR-positive mutations and brain metastases.

2004 Background: Asandeutertinib (TY-9591), a deuterated osimertinib derivative, is a new central nervous system-active 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), that can potently and selectively inhibit EGFR - sensitizing mutations (EGFRm+) and T790M resistance mutation. The phase I study for asandeutertinib (NCT04204473) showed had a very superior clinical efficacy on the NSCLC with EGFR mutations. This phase II study (NCT05146219) aimed to further evaluate the efficacy and safety of asandeutertinib in patients with locally advanced or metastatic EGFRm+ NSCLC with brain metastases (BM). Methods: 29 patients were enrolled and received asandeutertinib treatment at a dose of 160 mg once daily. The 27 patients with EGFR -sensitizing mutations (19 Del or L858R) did not take any EGFR-TKI previously, while the 2 patients with EGFR T790M resistance mutation previously received 1st or 2nd-generation EGFR-TKIs therapy. The primary endpoints were the intracranial objective response rate (iORR) assessed by investigator (INV) per RANO-BM and the extracranial objective response rate (eORR) assessed by INV per the RECIST v1.1. Results: At the time of data cutoff at March 21,2024, the median follow-up time was 16.4 months. The confirmed INV-iORR was 93.1% (95% CI: 77.2%-99.2%) (n = 29). The confirmed INV-iORR for those who were treated with asandeutertinib as first line was 92.6% (95% CI：75.7%-99.1%) (n = 27). The 2 patients with previous EGFR-TKI therapy were intracranial partial response (iPR). The median intracranial duration of response (iDoR) and intracranial progression-free survival (iPFS) were not reached. The 12-month iDoR was 82.8%, and the 12-month iPFS was 96.6%. The median PFS was 13.5 months (95% CI: 12.5-NA) (n = 29) and 15.1 months (95%CI：12.5 - NA) (n = 27) for those without previous EGFR-TKI therapy. Any intracranial or extracranial progression was evaluated as systemic progression, which may lead to underestimation of the systemic PFS. The mean treatment was 402.9 days (n = 29). 27 (93.1%) patients experienced treatment-related adverse events (TRAEs). The most common TRAEs (≥10%) included decreased white blood cell count, decreased absolute neutrophil count, decreased platelet count, elevated serum creatine phosphokinase, diarrhea, etc (majority grade 1/2). Grade 3 TRAEs occurred in 27.6% patients while no grade 4/5 adverse event. Six serious adverse events were reported by five patients (17.2%), of which two patients (6.9%) were study drug-related. The interstitial lung disease, cardiomyopathy and keratitis were not reported. Conclusions: Asandeutertinib is highly effective and well-tolerated in locally advanced or metastatic EGFRm+ NSCLC patients with BM. Pivotal phase II study (NCT05948813) and phase II trials (NCT05382728) are onging. Keywords: TY-9591; Deuterated osimertinib derivative; Brain metastases. Clinical trial information: NCT05146219 .