Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) with insertions in exon 20 (1–2% of all patients with NSCLC) generally do not respond to approved EGFR tyrosine kinase inhibitors (TKIs). A similar situation occurs for HER2 exon 20 mutations, which are detected in another ~2% of patients with NSCLC. In a study with results now published, John Heymach and colleagues searched for inhibitors that could benefit these patients.

“Using structural modelling, we observed that exon 20 insertions created a ‘bulge’ in the drug-binding pocket that prevented the interaction with approved EGFR TKIs. We hypothesized that smaller and more-halogenated TKIs would have greater activity,” explains Heymach, adding “We tested the candidate poziotinib against a panel of cells with insertions in exon 20 of EGFR or HER2, observing potent activity.”

The investigators then conducted a phase II trial of poziotinib in patients with NSCLC harbouring insertions in exon 20 of EGFR. At 6.6 months, the first 11 patients had an objective response rate (ORR) of 64%, and the median progression-free survival (PFS) duration had not been reached. These results contrast with ORRs of <10% and PFS durations of <2 months observed when such patients have received approved EGFR TKIs.

“Our improved understanding of the structure of different exon 20 insertions should enable us to find or design even more specific drugs that work for some of the tougher-to-treat mutations,” comments Heymach. Other avenues that are being further explored include two large studies with poziotinib in patients with NSCLC harbouring insertions in exon 20 of EGFR or HER2, as well as the response of patients with other cancer types harbouring these alterations (such as breast cancer, glioblastoma, or anal cancer) to poziotinib. Finally, an aspect that Heymach wants to highlight is that many of the patients involved in the study have been in touch with each other to share their experiences.