Spectrum Pharmaceutecals Inc (SPPI)

[antihama]

AACR pozi abstract now available on AACR website

4772/1-Poziotinib overcomes de novo resistance of HER2 exon 20 mutations in NSCLC and other cancers: Preclinical studies and initial clinical testing

Abstract
HER2 is mutated in ~3% of NSCLC cases, with most of these mutations occurring within exon 20. HER2 TKIs including afatinib and dacomitinib have objective response rates <30% in NSCLC. We have shown that EGFR exon 20 insertions stabilize the active confirmation, and restrict the size of the ATP pocket; and the small, flexible TKI, poziotinib, potently inhibits EGFR exon 20 insertions. Therefore, we hypothesized that HER2 exon 20 insertions induce similar changes, resulting in limited activity of EGFR/HER2 TKIs; and exon 20 HER2 mutations can be targeted with small, flexible covalent TKIs. To this end, Ba/F3 cells expressing 8 different HER2 exon 20 mutations were generated and screened against TKIs including erlotinib, lapatinib, afatinib, dacomitinib, neratinib, poziotinib, osimertinib and others. In Ba/F3 cells with HER2 exon 20 mutations, 1st and 3rd generation TKIs failed to inhibit cell (IC50 values >115nM). While 2nd generation TKIs had some activity (average IC50 =11nM), poziotinib significantly inhibited the growth of all HER2 exon 20 mutations tested with an average IC50 value of 1.9nM. 3D modeling revealed that HER2 exon 20 insertions induce conformational changes which cause constitutive activation and steric hindrance of C805 reducing the ability of larger TKIs to covalently bind. Therefore the smaller flexible terminal group of poziotinib can overcome the structural changes induced by exon 20 insertions. To test this in vivo HER2 A775insYVMA GEMMs were treated daily with poziotinib. Treatment reduced tumor burden by 60% at 4 weeks and had a durable response of 322 days. Based on preclinical data, a heavily pre-treated patient with HER2 driven NSCLC (HER2 A771insAYVM) was placed on a compassionate use protocol and received 16mg poziotinib daily. After 4 weeks, the patient experienced a significant radiological response with reduction in FDG avidity in the left 7th rib, right sacrum and a right lower lobe nodule among others. Moreover, HER2 A771insAYVM circulating free DNA dropped from 2.4% to <0.3%. Finally the frequency and sensitivity of HER2 exon 20 mutations in other cancers has not been fully characterized. To this end we have examined HER2 mutations across patients treated at MD Anderson Cancer Center. HER2 exon 20 mutations were found to occur in breast, endometrial, esophageal, small intestine, colorectal, melanoma and other cancers. In vitro testing of many of these mutations confirms their sensitivity to poziotinib. Collectively, these preclinical and clinical data indicate that poziotinib is a potent, clinically active inhibitor of HER2 exon 20 mutant-driven cancers. Based on these findings and the preclinical and clinical activity of poziotinib in EGFR exon 20 mutants, two phase II clinical studies of poziotinib in EGFR and HER2 exon 20 mutant NSCLC are currently ongoing and a basket trial for other HER2 and EGFR exon 20 mutant cancers is in development.

Bodes well for a basket trial to start this year.