Abstract C151: BLU-451 is a CNS-penetrant, wild-type-sparing EGFR inhibitor with broad coverage of uncommon EGFR mutations across structure-based subsets
Authors: Le Xiuning , Millet Yves , Nilsson Monique , Dhande Aditya , Keats Jeffrey , Ponichtera Holly , Kim Joseph , He Junqin , Elamin Yasir Y. , Heymach John V. , Conti Chiara , Lee Stephanie 
Published: December 2023

Introduction: Uncommon EGFR mutations in non-small cell lung cancer (NSCLC), including exon 20 insertion and atypical mutations, are generally associated with poorer clinical outcomes than common EGFR mutations. Patients (pts) with these mutations have limited effective therapeutic options. Afatinib is the only approved agent for uncommon mutations but is associated with high rates of toxicity and limited central nervous system (CNS) penetration. Amivantamab and mobocertinib are approved for patients with relapsed EGFR exon 20 insertion NSCLC but are associated with limitations in efficacy and CNS activity. BLU-451 is an investigational, CNS-penetrant, EGFR-wild-type (WT)–sparing, selective inhibitor against exon 20 insertion and uncommon EGFR mutations that is currently being evaluated in the phase 1/2 CONCERTO study (NCT05241873). Here, we report on the prevalence of uncommon EGFR mutations from a single center, real-world data set (MD Anderson Cancer Center [MDACC]), and report preclinical activity of BLU-451 on a broad spectrum of uncommon EGFR mutations by structure classification. 

Methods: BLU-451 cellular activity was evaluated in engineered BaF3 cell lines expressing 62 EGFR kinase domain mutations as well as in cell lines dependent on WT EGFR, using the CellTiter-Glo® Luminescent Cell Viability Assay and a phosphorylation-specific EGFR AlphaLISA® assay. The MDACC Moon Shot™ Genomic Marker-Guided Therapy Initiative (GEMINI) database was searched for pts with NSCLC whose tumors harbored EGFR kinase domain mutations.

Results: In the MDACC GEMINI database, a total of 1495 unique patients with NSCLC harboring EGFR mutations were identified, including 1025 with classical mutations (exon 19 deletion and L858R) with or without T790M, 223 with exon 20 insertion mutations, and 247 with only atypical mutations. In BaF3 cells, BLU-451 demonstrated nanomolar potency in multiple atypical and exon 20 insertion mutation cell lines with selectivity against WT EGFR.

Conclusion: Atypical EGFR mutations represent a sizable NSCLC pt population, of similar magnitude to that of EGFR exon 20 insertion mutations. BLU-451 preclinical data in EGFR atypical and exon 20 insertion mutations showed broad, potent, and selective activity, supporting continued evaluation of BLU-451 in the phase 1/2 CONCERTO study in pts with advanced or metastatic NSCLC harboring uncommon EGFR mutations.

Citation Format: Xiuning Le, Yves Millet, Monique Nilsson, Aditya Dhande, Jeffrey Keats, Holly Ponichtera, Joseph Kim, Junqin He, Yasir Y. Elamin, John V. Heymach, Chiara Conti, Stephanie Lee. BLU-451 is a CNS-penetrant, wild-type-sparing EGFR inhibitor with broad coverage of uncommon EGFR mutations across structure-based subsets [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C151.