BBT-176 shows preclinical activity against osimertinib-resistant EGFR C797S lung cancer

Human idea, AI creation10 Jun 2023Oncology

A fourth-generation EGFR inhibitor, BBT-176, was markedly more potent than osimertinib against C797S-mutant EGFR in laboratory models. Two phase I patients showed tumour shrinkage.

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Background

In EGFR-mutant non-small cell lung cancer, the C797S mutation in EGFR partly explains resistance to EGFR inhibitors of the third generation such as osimertinib. These patients currently have no targeted therapy option¹. Researchers have developed BBT-176, a novel tyrosine kinase inhibitor targeting EGFR aimed at C797S¹.

Methods

Inhibitory potency and anticancer activity were tested in vivo as well as in vitro¹. The models were recombinant EGFR proteins, Ba/F3 cell lines, and cells and xenografts derived from patients, all carrying mutant EGFR¹. Case data came from a phase I trial that is still under way (NCT04820023)^1,2.

Potency

IC50 values for BBT-176 against purified proteins were¹:

19Del/C797S: 4.36 nmol/L vs 304.39 nmol/L for osimertinib
19Del/T790M/C797S: 1.79 vs 124.82 nmol/L
L858R/C797S: 5.35 vs 573.72 nmol/L

In Ba/F3 cells, BBT-176 IC50 values were 42, 49, 183 and 202 nmol/L for 19Del/C797S, 19Del/T790M/C797S, L858R/C797S and L858R/T790M/C797S, respectively. The corresponding values for osimertinib were 869, 1,134, 2,799 and 2,685 nmol/L¹.

Resistance and animal findings

N-ethyl-N-nitrosourea mutagenesis indicated that BBT-176 did not induce secondary EGFR mutations but raised EGFR expression¹. When given with cetuximab, an antibody directed against EGFR, BBT-176 suppressed growth of BBT-176-resistant clones¹. In mouse models, it strongly inhibited tumour growth and, under some conditions, caused regression¹.

Early clinical data

Two trial patients with EGFR 19Del/T790M/C797S detected in blood had shrinking tumours and improvement on imaging¹.

The authors describe BBT-176 as a fourth-generation EGFR inhibitor. They report promising preclinical activity in NSCLC that no longer responds to existing EGFR TKIs, together with early signs of clinical efficacy and safety¹.

References

Lim SM, Fujino T, Kim C, Lee G, Lee YH, Kim DW, et al. BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non-Small Cell Lung Cancer. Clin Cancer Res. 2023;29(16):3004-3016. doi:10.1158/1078-0432.CCR-22-3901. PMID: 37249619. PubMed
ClinicalTrials.gov. Accessed November 10, 2026. https://clinicaltrials.gov/study/NCT04820023.

This article is not medical advice. Always check the source and local prescribing information before making treatment decisions. Patients should seek a personal assessment by a licensed physician.

Medically reviewed by Stijn van den Borne, MsC on 10 Nov 2026