Poziotinib maintains high response rate against harmful lung cancer mutation

MD Anderson clinical trial tests drug against exon 20 EGFR- and HER2-positive cancer

A drug revived by researchers at The University of Texas MD Anderson Cancer Center continues to provide unprecedented response rates among stage 4 non-small cell lung cancer patients with genetic mutations that have previously defied treatment.

Early results from a phase 2 clinical trial, reported today at the IASLC 19th World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer, show 24 of 44 patients (55 percent) with exon 20 mutations in the epidermal growth factor receptor (EGFR) and six of 12 patients (50 percent) with exon 20 mutations in the human epidermal growth factor receptor (HER2) had their tumors shrink at eight weeks after treatment with poziotinib.

“These findings confirm earlier observations that poziotinib is highly active against this previously untargetable mutation and durable responses are observed, with some patients on treatment now for more than a year,” said principal investigator John Heymach, M.D., Ph.D., professor and chair of Thoracic/Head and Neck Medical Oncology.

Nineteen patients remain on treatment, six for more than a year. All responses so far are partial responses.

Previous early results had been reported for 11 EGFR patients. Heymach’s presentation is the first to include HER2 patients. Researchers estimate exon 20 EGFR mutations occur in about 1-2 percent of non-small cell lung cancer patients and HER2 exon 20 variations occur in about 3 percent.

The MD Anderson investigator-initiated clinical trial provides the largest data set among exon 20 lung cancer patients worldwide. Spectrum Pharmaceuticals, which makes poziotinib, has opened a multi-center phase II trial.

Response rates of exon 20 patients to other targeted therapies aimed at EGFR and HER2 have been 12 percent or less, the researchers note. There are no approved therapies for these patients.

  • Median progression free survival on the EGFR arm of the poziotinib trial was 5.5 months. It has not been reached in the HER2 arm.
  • In the EGFR cohort, 56 percent of patients had a side effect of grade 3 or higher, most commonly skin rash (34.9 percent), diarrhea (17.5 percent) and inflammation around the fingernails and toenails called paronychia (9.5 percent); one patient stopped treatment due to grade 3 skin rash and 60 percent had dose reductions. Side effects in HER2 cohort were similar. One death from pneumonitis in the HER2 cohort was considered to be possibly drug-related.

MD Anderson Lung Cancer Moon Shot resurrects poziotinib

Heymach’s team decided to focus on exon 20 patients while selecting projects for MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into life-saving advances.  Review of a patient database found exon 20 patients had a median progression-free survival of just two months.

In a series of cell line and mouse model experiments, combined with structural modeling of both EGFR and HER2 mutations and available drugs to target them, the researchers found that poziotinib’s structure made it a good fit for exon 20-mutated disease, even though it had largely failed against other mutations. The tighter target pocket on EGFR and HER2 tumors with exon 20 mutations also explained why other targeted therapies had been unable to bind with and inhibit the proteins.

Heymach and colleagues contacted Spectrum Pharmaceuticals and collaborated to launch the first phase II trial at MD Anderson in 2017.

Heymach, Jacqulyne Robichaux, Ph.D., postdoctoral fellow, Shuxing Zhang, PHARMD, Ph.D., associate professor of Experimental Therapeutics, and colleagues published their results this year in Nature Medicine.

The MD Anderson team continues to study resistance mechanisms to poziotinib and work with colleagues to study exon 20 insertions in other types of cancer. They have identified about 20 other cancer types that include exon 20 EGFR or HER2 mutations and plan a basket clinical trial of poziotinib against other cancers.

Spectrum and MD Anderson signed a licensing agreement covering MD Anderson discoveries about poziotinib earlier this year.