Abstract

Oncogenic EGFR ex20ins mutations are the third most common type of activating EGFR activating mutation in non-small cell lung cancer (NSCLC) and are not potently targeted by many inhibitors of common activating mutations such as L858R and exon 19 mutations. Like other types of EGFR-mutated NSCLC, CNS metastases are a challenge to treat. Approximately 25% of patients with EGFR ex20ins NSCLC have brain metastases at the time of initial presentation, and progression can be associated with development of CNS metastases. The presence of CNS metastases (brain and leptomeninges) complicates disease management, can cause significant morbidity, and has been associated with poorer outcomes for patients with EGFR ex20ins NSCLC. The standard of care (SOC) for patients with NSCLC with activating EGFR mutations is treatment with a tyrosine kinase inhibitor (TKI) or platinum-based chemotherapy. The US Food and Drug Administration has recently approved two agents, amivantamab and mobocertinib, for patients who progress after a platinum-based chemotherapy, but neither have established CNS activity. BLU-451 is a CNS penetrant, wild type-sparing, covalent small molecule inhibitor of EGFR ex20ins as well as of atypical (G719C, G719S, L861Q) and common EGFR mutants. Preclinical data have shown BLU-451 to have potent antitumor activity, including in an intracranial xenograft model, which has led to its clinical development in EGFR-mutant NSCLC. BLU-451 is a phase 1/2, global, open-label study designed to evaluate single agent BLU-451 in patients with NSCLC harboring EGFR ex20ins that has progressed following prior treatment for incurable recurrent or metastatic disease. Phase 1 consists of two parts: a 3+3 dose escalation and a dose expansion. Phase 2 will evaluate the antitumor activity of BLU-451 administered at the RP2D in patients with or without brain metastases in three cohorts (n=18 each). PK will be assessed by evaluating plasma levels of BLU-451 in Cycle 1 and periodically in subsequent cycles. Biomarker assessments may include circulating tumor DNA (ctDNA) or tumor biopsy to identify the presence of EGFR mutations including EGFR ex20ins. All patients will receive BLU-451 as a single agent administered once daily, or twice daily on a 21-day treatment cycle. Primary endpoints for Phase 1 will include: maximum tolerated dose, recommended phase 2 dose on DLT, safety and tolerability while secondary endpoints will include antitumor activity, CNS antitumor activity using RECIST v1.1, and Pharmacokinetics. The primary endpoints for Phase 2 will be objective response rate at RP2D using RECIST v1.1, while secondary endpoints included additional measures of anti-tumor activity, CNS antitumor activity using RECIST v1.1, pharmacokinetics, safety and tolerability.