The in vivo antitumor activities of BLU-945 and BLU-701 as single agents suggest both BLU-945 and BLU-701 have the potential to be used as 1L therapy in patients with EGFR L858R-driven NSCLC. The superior in vivo antitumor activity of BLU-945 or BLU-701 in combination with osimertinib in prolonging the DOR or increasing tumor growth inhibition in these models may have clinical application in improving outcomes of patients with EGFR L858R-driven NSCLC in 1L settings.
Consistent with its brain penetration properties, BLU-701 exhibited dose-dependent brain tumour inhibition that surpassed gefitinib and erlotinib in an EGFR ex19del PC9-luc CDX model in which cells were implanted intracranially or inoculated in the carotid artery (followed by migration to the brain). The in vivo activity of BLU-701 supports its potential as a treatment for patients with EGFR-mutated NSCLC, including those with the C797S mutation resistant to covalent 3rd-generation TKIs, such as osimertinib. Its intracranial penetrance and brain tumour response suggest potential benefits in treating and/or preventing brain metastases. Broader EGFR mutational coverage could be achieved with BLU-701 and BLU-945 in combination, which could potentially prolong responses.