20P Efficacy and safety of AZD3759 in previously untreated EGFR-mutant non-small cell lung cancer with central nervous system metastases in a multi-center, phase II umbrella trial (CTONG1702)

Non-small cell lung cancer (NSCLC) had poor prognosis in patients with central nervous system (CNS) metastases. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has changed the treatment paradigm of advanced EGFR-mutant patients. However, limited benefit has been observed in patients with EGFR mutation and CNS metastases with available EGFR-TKIs. We initiated an umbrella trial (CTONG1702), in the 8th arm to access the efficacy and safety of AZD3759, an EGFR-TKI with high capability to penetrate the blood-brain barrier, in untreated EGFR-mutant NSCLC with brain or leptomeningeal metastases. Patients received AZD3759 200 mg or 300 mg BID. The primary objective was objective response rate (ORR). To determine whether AZD3759 has sufficient activity, we used Simon’s minimax two-stage to calculate sample size. 30 patients were enrolled and received AZD3759 at 200 mg (n = 15) or 300 mg (n = 15) BID. As of June 30 2022, the median follow-up is 31.6 months. The ORR was 70% (21/30), which was 80% (12/30) in 200 mg group and 60% (9/30) in 300 mg group, respectively. The median progression-free survival (PFS) was 13.9 months and median overall survival (OS) was 37.0 months. The survival benefit was greater in 200 mg than in 300 mg groups. Treatment-related adverse events with grade ≥3 occurred in 21 (70%) patients, which was (60.0%) in 200 mg group and 13 (86.7%) in 300 mg group, respectively. The most common adverse events are rash and diarrhea. Of 16 patients who had tumor or liquid biopsy to analyze acquired resistant mechanism, 10 (62.5%) developed EGFR T790M. Of 30 enrolled patients, 13 received osimertinib as 2nd-line therapy. This is the first report to present phase II study outcome of AZD3759 with promising efficacy and tolerable safety in the selected population with CNS metastases. We suggested 200 mg BID was a better dose with superior response and lower toxicity. EGFR T790M was the most common resistant mutation, and these patients still have the opportunity to receive osimertinib after progression of AZD3759.