177 (PB057) - BLU-945 or BLU-701 as single agents versus their combination with osimertinib in EGFR L858R driven tumor models

Abstract

Background: The most common activating EGFR mutations (EGFRm) in non-small cell lung cancer (NSCLC) are exon 19 deletions (ex19del) and L858R substitutions. EGFR tyrosine kinase inhibitors (TKIs) as first-line (1L) therapy have improved outcomes in EGFR-driven advanced NSCLC; however, treatment resistance eventually occurs. Patients with EFGR L858R-driven advanced NSCLC (39% of all EGFR mutations in NSCLC) have shorter progression-free survival than those with EGFR ex19del, suggesting a significant unmet need. BLU-945 and BLU-701 are investigational, reversible, selective, orally available TKIs optimized for use as singleagent or combination therapy to suppress activating and on-target resistance EGFR mutants while sparing wild-type EGFR. in vivo studies have shown antitumor activity of BLU-945 against EGFR L858R, L858R/C797S, L858R/ T790M and EGFRm/T790M/C797S mutants, and BLU-701 against EGFRm and EGFRm/C797S mutants. Combination of BLU-945 and BLU-701 has also shown in vivo activity in EGFRm/C797S-driven mutant NSCLC. Combining BLU-945 or BLU-701 with osimertinib could potentially enable superior coverage of frequent on-target resistance mechanisms as well additional potency on the primary EGFR activating mutations. Central nervous system (CNS) metastases are an ongoing challenge in NSCLC. BLU-701 has already shown preclinical CNS activity; and both BLU-945 and BLU-701 are currently being investigated for potential treatment or prevention of CNS metastases. Due to poorer outcomes in patients with EGFR L858R-driven advanced NSCLC treated with osimertinib, and the inevitability of treatment resistance, studies were conducted to evaluate the activity of BLU-945 or BLU-701 in combination with osimertinib in prolonging duration of response (DOR) in preclinical NSCLC tumor models driven by the L858R mutation. Material and Methods: The antitumor activity of BLU-945 or BLU-701, as single agents or in combination with osimertinib was evaluated in EGFR L858R-driven tumor models. Results: Administration of single-agent BLU-945 or BLU-701 resulted in tumor growth inhibition in EGFR L858R-driven PDX models. BLU-945 in combination with osimertinib resulted in prolonged DOR and survival when compared with BLU-945 or osimertinib as single agents. BLU-701 in combination with osimertinib resulted in superior tumor growth inhibition compared with BLU-701 or osimertinib as single agents. Conclusions: 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. Conflict of interest: Other Substantive Relationships: Tavera L, Dhande A, Dineen T, Iliou M, Rouskin-Faust T, Rozsahegyi E, Conti C: Employee and/or equity holder of Blueprint Medicines Corporation.