Abstract 3328: Antitumor activity of BLU-945 and BLU-701 as single agents and in combination in EGFR L858R-driven models of NSCLC
Authors: Tavera Luz , Schalm Stefanie , Campbell John , Guo Jian , Medendorp Clare , Chen Maxine , Albayya Faris , Dineen Tom , Zhang Zhuo , Iliou Maria , Job Ebby , Perez Nisha , Timsit Yoav , Wardwell Scott , McGinn Katie , Woessner Richard , Conti Chiara 
Published: June 2022

Abstract
BACKGROUND: Lung cancer is the leading cause of cancer death globally. EGFR mutations are the most common genomic drivers of non-small cell lung cancer (NSCLC), occurring in ~17% and up to 50% of Caucasian and Asian patients, respectively, with exon 19 deletions (ex19del) and L858R substitutions being the most prevalent activating EGFR mutations (EGFRm). Outcomes have improved in patients with EGFR-driven NSCLC since the introduction of EGFR tyrosine kinase inhibitors (TKIs); however, treatment resistance almost inevitably occurs. It has been reported that patients harboring the EGFR L858R mutation, who represent 3.4% of lung adenocarcinoma cases in North America and 23% in Asia, have poorer outcomes than those with EGFR ex19del, suggesting a significant unmet need in this population. BLU-945 and BLU-701 are investigational, reversible, selective, and orally available TKIs optimized for use as single-agent or combination therapy to effectively suppress activating and on-target resistance EGFR mutants while sparing WT EGFR, and have the potential to treat or prevent central nervous system metastases. In vivo studies previously demonstrated the antitumor activity of BLU-945 against EGFR L858R/T790M and EGFRm/T790M/C797S mutants, and BLU-701 against EGFR ex19del and EGFRm/C797S mutants. Because EGFR L858R-driven NSCLC constitutes a large population of patients who may not be receiving the same benefit from third-generation (3G) TKIs as those with EGFR ex19del, studies were conducted to evaluate the antitumor activity of BLU-945 and BLU-701, as single agents and in combination, in preclinical NSCLC tumor models driven by L858R in the absence of the T790M mutation.
METHODS: The in vivo antitumor activities of BLU-945 and BLU-701, as single-agents or in combination, were evaluated in 2 EGFR L858R-driven patient-derived xenograft (PDX) subcutaneous tumor models and in an engineered EGFR L858R/C797S-driven Ba/F3 cell line-derived xenograft (CDX) subcutaneous tumor model.
RESULTS: Oral daily administration of single-agent BLU-945 and single-agent BLU-701 resulted in sustained tumor regression in 2 PDX models of EGFR L858R NSCLC. Compared with single agents in an EGFR L858R/C797S Ba/F3 CDX tumor model, combination of BLU-945 with BLU-701 resulted in marked antitumor activity and prolonged tumor regression.
CONCLUSION: The in vivo antitumor activities of BLU-945 and BLU-701 in preclinical tumor models suggest that both BLU-945 and BLU-701 have the potential to be used in patients with EGFR L858R-driven NSCLC, including those who are treatment naïve or previously treated with 3G TKI. Combining BLU-945 and BLU-701 may enable coverage of frequent on-target resistance mechanisms, including the EGFR C797S mutation, in addition to the common L858R activating mutation.
Citation Format: Luz Tavera, Stefanie Schalm, John Campbell, Jian Guo, Clare Medendorp, Maxine Chen, Faris Albayya, Tom Dineen, Zhuo Zhang, Maria Iliou, Ebby Job, Nisha Perez, Yoav Timsit, Scott Wardwell, Katie McGinn, Richard Woessner, Chiara Conti. Antitumor activity of BLU-945 and BLU-701 as single agents and in combination in EGFR L858R-driven models of NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3328.