Anti-tumor activity of BH-30643, a novel macrocyclic kinase inhibitor, in <i>EGFR</i> -mutant lung cancer models.

Abstract

3110 Background: Outcomes on tyrosine kinase inhibitor (TKI) treatment in EGFR -mutant non-small cell lung cancer (NSCLC) fall short of the durable benefit observed with next-generation targeted therapies in ALK and ROS1 -driven NSCLC. Novel targeted therapies are needed to address treatment resistance and offer prolonged patient benefit with reduced toxicity. We recently described (AACR 2025) the design and discovery of BH-30643, a first-in-class macrocyclic reversible TKI targeting the active conformation of mutant EGFR and offering potent, mutant-selective EGFR inhibition across classical and non-classical EGFR mutations. Here we study diverse preclinical models to assess the breadth of activity from this novel approach. Methods: Anti-tumor activity of BH-30643 was evaluated in cell-derived xenograft (CDX) or patient-derived xenograft (PDX) tumor models carrying classical or atypical EGFR mutations. CNS activity of BH-30643 was investigated in an intracranial xenograft model. BH-30643 was administered twice daily via oral gavage; osimertinib when used as a comparator was dosed daily. Studies were done with n ≥ 5. The activity of BH-30643 against diverse EGFR exon 20 insertions (ex20ins) was evaluated in 34 engineered Ba/F3 cell lines in cell proliferation assays in vitro. Results: In the PC-9 (exon 19 del) CDX model, BH-30643 led to deep tumor regressions, similar to what was observed with osimertinib at the 25 mg/kg dose level. Similarly deep responses with BH-30643 were observed in double mutant CDX models including those derived from H1975 cells (cis L858R / T790M) and Ba/F3 cells engineered with exon 19 del / T790M. In a triple-mutant PDX model (cis exon 19 del / T790M / C797S) and a Ba/F3 triple-mutant CDX model (cis L858R / T790M / C797S), deep responses were observed with BH-30643 while osimertinib demonstrated no anti-tumor effect. BH-30643 activity was also evident in the HCC827-luc (exon 19 del) intracranial xenograft model with 90% tumor reduction. In two Ba/F3 CDX models carrying atypical mutations (cis G719A / S768I and cis G719A /L861Q), BH-30643 maintained strong anti-tumor activity. Finally, we explored the activities of BH-30643 against 34 different EGFR ex20ins in engineered Ba/F3 cell lines and BH-30643 showed anti-cell proliferation activity with a median IC 50 value of 6.06 nM. Conclusions: These preclinical studies demonstrate broad activity of BH-30643 against classical and atypical EGFR activating mutations, EGFR ex20ins, as well as acquired resistance EGFR mutations. Such an "OMNI-EGFR" inhibitor may be able to overcome some of the limitations of earlier agents. Supported by favorable ADME and preclinical safety profiles, BH-30643 is now being assessed in a first-in-human study in locally advanced or metastatic NSCLC harboring EGFR and/or HER2 mutations (NCT06706076, SOLARA).