Dose Escalation Trial of the Combination of Osimertinib and Quaratusugene Ozeplasmid Gene Therapy in Patients with Advanced NSCLC.

[BACKGROUND] Expression of TUSC2, a tumor suppressor gene, is decreased in 82% of patients with NSCLC. Quaratusugene ozeplasmid gene therapy consists of a plasmid containing the TUSC2 gene encapsulated in lipid nanoparticles that restores TUSC2 expression, and thus is a new approach to cancer treatment.

[PATIENTS AND METHODS] Patients had NSCLC with EGFR mutations and progression on osimertinib regimens. Quaratusugene ozeplasmid was administered IV every 21 days at 3 dose levels with osimertinib 80 mg PO daily. Dexamethasone, acetaminophen, and diphenhydramine were administered prophylactically. Dose limiting toxicities (DLTs) were generally defined as ≥ Grade (Gr) 3 adverse events (AEs).

[RESULTS] Twelve patients were enrolled (3M/9F), median age 59.5, with 3 at 0.06 mg/kg, 4 at 0.09 mg/kg, and 5 at 0.12 mg/kg. There were no DLTs. There was a delayed infusion-related reaction with muscle aches, headache, and pyrexia. One patient at the 0.06 mg/kg dose level had a partial response (PR) and no progression for more than 32 months. Two other patients had stable disease (SD) for 22 and 9 months before disease progression.

[CONCLUSION] Among the 12 patients treated with escalating doses of quaratusugene ozeplasmid and standard doses of osimertinib there were 3 patients with prolonged time to progression, including 1 with continuing PR. Quaratusugene ozeplasmid administration was associated with a delayed infusion-related reaction managed with prophylactic steroids, acetaminophen and diphenhydramine. There were no DLTs. The recommended phase II dose of quaratusugene ozeplasmid in combination with osimertinib in patients with NSCLC progressing after osimertinib treatment is 0.12 mg/kg.