Repurposed Poziotinib Offers New Hope for Some NSCLC Patients

Clinicians may soon have a new agent to offer patients with non-small cell lung cancer (NSCLC) who have mutations in exon 20. About 80% of NSCLC patients with epidermal growth factor receptor (EGFR) mutations have so-called “classical” mutations that are highly responsive to the approved EGFR inhibitors such as erlotinib, afatinib, and osimertinib. However, about 10% to 15% have mutations in exon 20.

“These tumors are highly resistant to approved EGFR inhibitors, with reported response rates in the 3% to 8% range,” said John Heymach, MD, PhD, chair of Thoracic/Head and Neck Medical Oncology at M.D. Anderson in Houston, Texas. “In a phase II clinical trial, the drug poziotinib has shrunk tumors by at least 30% in 8 (73%) of 11 NSCLC patients whose cancer includes an EGFR mutation called an exon 20 insertion.”

It is estimated that about 2% of NSCLC patients (about 3,500 annually in the United States) have an EGFR exon 20 insertion. The latest results of this ongoing trial were presented at the International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer in Yokohama, Japan.

Dr. Heymach, the lead author of this study, said shrinkage ranged from 30% to 50% among the 8 patients achieving a partial response. One patient has progressed on the clinical trial, which began in March of this year and will enroll up to 50 patients. He said all patients experienced some tumor shrinkage.

Several tyrosine kinase inhibitors against EGFR have been approved by the U.S. Food and Drug Administration, but none have proved effective against the exon 20 insertion. Poziotinib had been tried and abandoned as a general EGFR inhibitor, but now it is getting repurposed. “We found that most inhibitors could not fit into the ATP binding site of exon 20 mutant EGFR or HER2 because the mutations caused the binding site to be ‘squeezed’, but poziotinib was small enough and flexible enough to fit into this constrained binding pocket,” Dr. Heymach told OncoTherapy Network. “We were thrilled to see that the clinical data agrees with what we predicted from the preclinical data. By the time of the first scan, 73% of patients had an objective response.”

He noted the data are preliminary and the duration of response is unknown. Dr. Heymach said the side effects included rash, diarrhea, mucositis, and paronychia. The starting dose was 16 mg.  However, dose reductions were required in 55% of the patients.

Based on these results, an international phase II study has just opened for patients with EGFR and HER2 exon 20 mutations. “There are also discussions about a possible basket study that would cross different tumor types. If the initial results are confirmed, it has the potential to be a new option for a group of patients that do not have any targeted therapy options right now,” said Dr. Heymach.