Abstract 374P
Background
NX-019 is a potent, orally bioavailable and CNS penetrant EGFR inhibitor selectively targeting a broad range of EGFR mutations including common mutations (e.g., exon 19 deletions and exon 21 L858R), T790M, exon 20 insertions and other rare mutations. Therefore, NX-019 has the potential to treat patients with mutant EGFR tumors not adequately addressed by current therapies.
Methods
NX-019 was optimized for enhanced CNS penetration and potency against a broad range of EGFR mutations. Preclinical studies in multiple mutant EGFR disease models characterized the properties of NX-019 both in vitro and in vivo. These experiments included assessments of potency, efficacy, pharmacodynamic, pharmacokinetic and toxicity parameters.
Results
Preclinical in vitro and in vivo studies reveal that NX-019 has high potency across a broad range of mutant EGFR models indicating the potential of NX-019 to treat patients not currently covered or resistant to current EGFR TKI therapies. NX-019 is selective for mutant EGFR over wild-type EGFR and exhibits greater potency (7.3-200+ fold) in cell lines in cells with classic, exon20 insertion, and other rare mutations compared to cells expressing wildtype EGFR. This improved mutant selectivity should facilitate improved tolerability at higher dose levels and greater systemic exposures. Studies in preclinical animal models (mouse, rat, dog) did not show classical EGFR dermatological findings, in agreement with the improved selectivity profile of NX-019. Studies to measure the CNS efficacy of NX-019 in xenograft brain models (such as PC9 brain orthotopic model) show tumor regressions and prolonged PD effects (e.g., inhibition of phospho-EGFR). CNS exposure studies in multiple preclinical species shows a Kp,uu of approximately 1 indicating excellent CNS exposure.
Conclusions
Based on the preclinical profile of broad potency and mutant selectivity for EGFR mutations with excellent CNS exposure, NX-019 is entering a Phase I dose escalation and dose expansion trial in mutant EGFR selected patients.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Nalo Therapeutics.
Funding
Nalo Therapeutics.
Disclosure
K. Wilson: Financial Interests, Personal, Full or part-time Employment: Nalo Therapeutics; Financial Interests, Personal, Member of the Board of Directors: Nalo Therapeutics; Financial Interests, Personal, Stocks/Shares: Nalo Therapeutics; Financial Interests, Personal, Leadership Role: Nalo Therapeutics. R. Dusek: Financial Interests, Personal, Full or part-time Employment: Nalo Therapeutics; Financial Interests, Personal, Stocks/Shares: Nalo Therapeutics. G. Gammon: Financial Interests, Personal, Full or part-time Employment: Nalo Therapeutics.
Resources from the same session
373P - Safety and efficacy of aumolertinib treatment in patients with advanced NSCLC harboring uncommon EGFR mutations: Cohort 2
Presenter: WenFeng Fang
Session: Poster viewing 05.
375P - Stereotactic radiotherapy (SRT) in combination with aumolertinib to treat intracranial oligometastatic non-small cell lung cancer (NSCLC): A phase II, prospective study
Presenter: Jiayan Chen
Session: Poster viewing 05.
377P - Aumolertinib as second-line therapy in T790M-positive or-negative patients with EGFR-mutated non-small cell lung cancer (NSCLC): A retrospective study
Presenter: Hongying Lv
Session: Poster viewing 05.
378P - Could the model of EGFR-TKIs plus antiangiogenesis as first-line treatments in patients with EGFR-mutated non-small cell lung cancer take a step further: A updated meta-analysis
Presenter: Yuexiao Qi
Session: Poster viewing 05.
380P - Survival outcome and cost-effectiveness of tyrosine kinase inhibitor in EGFR sensitive mutation advanced-stage NSCLC in Thammasat university hospital
Presenter: Chayanid Rungtivasuwan
Session: Poster viewing 05.
381P - Real-world experience of treatment with afatinib in advanced non-small cell lung cancer (NSCLC) in Vietnam
Presenter: Hiep Dong
Session: Poster viewing 05.
382P - Real-world data on treatment outcome of ALK positive non-small cell lung cancer from an Indian multi-centric cancer registry
Presenter: Soumya Surath Panda
Session: Poster viewing 05.
383P - Treatment outcomes with BRAF inhibitors with or without MEK inhibitors in advanced non-small cell lung cancer with positive BRAF mutation: A systematic review
Presenter: Animesh Saha
Session: Poster viewing 05.
384P - Prevalence of fibroblast growth factor receptor 2b (FGFR2b) protein overexpression in squamous non-small cell lung cancer (sqNSCLC)
Presenter: Hiroaki Akamatsu
Session: Poster viewing 05.