Randomized phase 3 study of first-line AZD3759 (zorifertinib) versus gefitinib or erlotinib in EGFR-mutant (EGFRm+) non–small-cell lung cancer (NSCLC) with central nervous system (CNS) metastasis.

9001 Background: Patients (pts) with EGFRm + NSCLC have high rates of CNS metastasis, few treatment options, and a poor prognosis. So far there are no solid evidence from head to head phase 3 trials in this setting. The potent EGFR TKI AZD3759 has high blood–brain barrier penetration, preliminary data has shown promising intracranial (IC) and systemic antitumor activity, and a tolerable safety profile. Methods: This was the first phase 3, open-label, multicenter, randomized controlled trial to compare the efficacy and safety of first-line AZD3759 with first generation EGFR TKIs specifically in pts with EGFRm + (L858R and/or exon 19Del) NSCLC and CNS metastasis. Adult pts were randomized 1:1 to receive AZD3759 (200 mg twice daily) or first generation EGFR TKIs (the control group, gefitinib 250 mg or erlotinib 150 mg once daily). The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1. Results: Between Feb 1, 2019, and Jan 12, 2021, 439 pts were randomized: 220 to AZD3759 and 219 to the control group. As of July 12, 2022, median follow-up was 20.4 months (mo) for both. Median PFS (95% CI) was significantly superior with AZD3759 vs the control group (9.6 [8.2–9.7] vs 6.9 [6.3–8.0] mo; HR 0.719, 95% CI 0.580–0.893; p=0.0024). The objective response rate (ORR; BICR/RECIST 1.1) was 68.6% for AZD3759 vs 58.4% for the control group ( p=0.027), with a trend toward longer median duration of response (DoR) with AZD3759 (8.2 vs 6.8 mo; p=0.0997). IC PFS, ORR, and DoR with AZD3759 were all superior vs the control group regardless of the assessor or evaluation criteria. The overall survival was immature. The incidence of any-grade treatment-related adverse events (TRAEs) was similar between the two groups (97.7% vs 94.0%). Grade ≥3 TRAEs occurred in 65.9% (AZD3759) and 18.3% (the control group) of pts. The main TRAEs were skin and subcutaneous tissue events, gastrointestinal system events and abnormal liver function. No new safety signals arose. Conclusions: First-line AZD3759 demonstrated superior systemic and IC antitumor efficacy compared with first generation EGFR TKIs in pts with EGFRm + NSCLC and CNS metastasis. Adverse events were as expected and manageable. IC antitumor activity. Clinical trial information: NCT03653546 . [Table: see text]