HER2 exon 20 insertions in Non–Small Cell Lung Cancer are Sensitive to the Irreversible Pan-HER Receptor Tyrosine Kinase Inhibitor Pyrotinib

Abstract

Background

Effective targeted therapy for NSCLC patients with HER2 mutations remains an unmet need. This study investigated the anti-tumor effect of an irreversible pan-HER receptor tyrosine kinase inhibitor, pyrotinib.

Patients and methods

Using patient-derived organoids and xenografts established from a HER2-A775_G776YVMA-inserted advanced lung adenocarcinoma patient sample, we investigated the anti-tumor activity of pyrotinib. Preliminary safety and efficacy of pyrotinib in 15 HER2-mutant NSCLC patients in a phase 2 clinical trial are also presented.

Results

Pyrotinib showed significant growth inhibition of organoids relative to afatinib in vitro (P=0.0038). In the PDX model, pyrotinib showed a superior anti-tumor effect than afatinib(P=0.0471) and T-DM1(P=0.0138). Mice treated with pyrotinib displayed significant tumor burden reduction (mean tumor volume, -52.2%). In contrast, afatinib (25.4%) and T-DM1 (10.9%) showed no obvious reduction. Moreover, pyrotinib showed a robust ability to inhibit pHER2, pERK and pAkt. In the phase 2 cohort of 15 patients with HER2-mutant NSCLC, pyrotinib 400mg resulted in an ORR of 53.3% and a median PFS of 6.4 months.

Conclusion

Pyrotinib showed activity against NSCLC with HER2 exon 20 mutations in both patient-derived organoids and a PDX model. In the clinical trial, pyrotinib showed promising efficacy.

Clinical trial registration

NCT02535507

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