A phase 2 study of amivantamab plus lazertinib in patients with EGFR-mutant lung cancer and active central nervous system disease.

8517 Background: Patients (pts) with EGFR-mutant lung cancer (EGFR+LC) with active brain metastases (BrM) or leptomeningeal disease (LM) are often excluded from clinical trials. Despite central nervous system (CNS) disease control with osimertinib, > 50% of pts with EGFR-mutant lung cancer have involvement of the brain (BrM) or leptomeninges (LM). Amivantamab and lazertinib have demonstrated systemic activity in pts with EGFR-mutant lung cancer whose disease progressed after osimertinib and/or platinum-based chemotherapy. This trial evaluated amivantamab +lazertinib in the setting of progressive CNS metastases (NCT04965090). Methods: We evaluated amivantamab and lazertinib in 2 cohorts: pts with 1) progressive or new BrM or 2) LM. All pts with EGFR exon 19 del/L858R/atypical mutations had prior osimertinib. All pts with EGFRexon 20 insertions (ex20ins) had prior chemotherapy. Each cohort was to enroll 20 pts powered to differentiate overall response rate (ORR) of 0.05 vs 0.25. Positive CSF assessment (cytology or circulating tumor cells (CTC)) +/- BrM allocated a pt to the LM cohort. Pts received standard dosing of amivantamab and lazertinib 240 mg daily. Co-primary endpoints were systemic ORR by RECIST v1.1 and CNS ORR by RANO-BM or LM. Paired pre-treatment tumor, blood, and CSF samples had targeted DNA sequencing and cell-free RNA (cfRNA) sequencing. Results: Trial enrolled 20 pts in BrM cohort and 22 pts in LM cohort. Median age 55 (range 31-80), 69% women,. 40% had L858R (n = 17), 40% del19 (n = 17), 12% ex20 ins (n = 5), and 8% atypical EGFR mutations (n = 3). Median lines of prior therapy: 2 (1-7). Except patients with ex20ins, all patients had prior osimertinib, and 55% had chemo. Efficacy Data: . 14 LM pts (64%) had decrease in CSF CTCs and 7 (32%) had improvement in neurologic symptoms. Most frequent treatment-related adverse events (TRAEs) (≥30% in overall population) were rash (71%), infusion-related reaction (59%), paronychia (43%), fatigue (40%), edema (40%), mucositis (33%), and nausea (33%). Most frequent (≥5%) grade ≥3 TRAEs were infusion related reactions (7%), thromboembolic event (5%), elevated AST/ALT (5%), and rash (5%). Three pts (7%) discontinued treatment due to TRAEs. Genomic data comparing concurrent systemic tumor, plasma and CSF samples, and ctDNA and cfRNA dynamics will be presented. Conclusions: The combination of amivantamab+lazertinib is a promising treatment for pts with EGFR-mutant lung cancer and active CNS disease, with clinically meaningful time on treatment and radiographic response. This is the first clinical trial successfully completed in pts with EGFR-mutant lung cancer and progressive CNS metastases. Clinical trial information: NCT04965090 .Table: see text