Tarloxotinib, a hypoxia-activated pan HER-2 tyrosine kinase inhibitor, showed promising antitumor activity and a tolerable safety profile in patients with non–small cell lung cancer (NSCLC) harboring HER-2 activating mutations, according to data from the RAIN-701 trial presented at the ESMO Virtual Congress 2020.
“Tarloxotinib is a prodrug that embeds in, but cannot permeate, the cell membrane,” said Stephen V. Liu, MD, associate professor of medicine, director of thoracic oncology and head of developmental therapeutics at Georgetown University’s Lombardi Comprehensive Cancer Center. “Under normoxic conditions, the molecule remains inactive. Under conditions of hypoxia, such as those found in malignant tumors, tarloxotinib undergoes single electron reduction and fragments to the cell permeable tarloxotinib-E, which is the active drug.”
In preclinical studies, tarloxotinib exhibited promising activity in patients with NSCLC and EGFR exon 20 mutations and HER-2 mutations, as well as oncogenic alterations in the ERBB gene family. Liu and colleagues enrolled patients in the RAIN-701 and stratified them into three cohorts based on disease mutations:
Patients with NSCLC and EGFR exon 20 insertions (Cohort A; n = 11);
Patients with NSCLC and HER-2 activating mutations (Cohort B; n = 11); and
Patients with any solid tumor harboring an NRG1, EGFR, HER-2 or HER-4 fusion (Cohort C; n = 1).
Patients in Cohorts A and B had progressive disease following treatment with platinum-based chemotherapy. The researchers assigned them to a weekly intravenous dose of tarloxotinib (150 mg/m2 per week). Objective response rate by RECIST criteria served as the study’s primary endpoint.
With 20 evaluable patients, Liu reported an overall disease control rate of 60% (n = 12). In Cohort A, 55% of patients (n = 6) achieved stable disease as the best response. The remaining patients (45%; n = 5) had progressive disease.
Among nine evaluable patients in Cohort B, four experienced tumor reduction by RECIST criteria, and two patients achieved a confirmed partial response (objective response rate, 22%). Four patients had stable disease and three patients had progressive disease.
In addition, three patients in Cohort B received treatment lasting beyond 6 months, with treatment still ongoing in three patients.
The majority of treatment-emergent adverse events observed were low-grade, including grade 1-2 QT prolongation (60.9%), rash (45.3%), nausea (21.7%) and diarrhea (21.7%). Grade 3 or higher adverse events included QT prolongation (34.8%), rash (4.3%), diarrhea (4.3%) and increased alanine aminotransferase (4.3%). Five patients required dose reductions.
“No arrhythmias were observed in this or any prior tarloxotinib studies,” said Liu. “Only one patient discontinued therapy due to an adverse event, which was an infusion reaction.”
Enrollment in RAIN-701 remains ongoing in Cohorts B and C.
