P2.03b-016 Tesevatinib in NSCLC Patients with EGFR Activating Mutations and Brain Metastases (BM) or Leptomeningeal Metastases (LM): Topic: Brain Meta

Abstract

Tesevatinib is a potent reversible EGFR inhibitor with strong preclinical evidence of brain penetration: brain:plasma ratios of 1-4 and brain:meninges ratios of 10-15 in rodents (AACR 2015 Abstract 2590). Tesevatinib was previously shown to have significant clinical activity in patients presenting with EGFR mutant NSCLC, but not in patients with T790M mutation. Approximately 25% of patients with EGFR activating mutations progress in the CNS, and metastases there have a low rate (10%) of T790M mutations. Patients with NSCLC driven by activating EGFR mutations who had BM or LM occurring or progressing while receiving erlotinib, gefitinib, or afatinib were treated with 300 mg of tesevatinib daily. Patients with BM had RECIST 1.1 measurable disease in the brain, and RECIST 1.1 evaluated response. Patients with symptomatic LM were diagnosed by either CSF cytology or MRI findings. Response was measured by improvement in symptoms, CSF cytology, and MRI. Patients with both BM and symptomatic LM were enrolled in the LM cohort. Target accrual is 20 patients in each cohort. To date, 7 patients have been enrolled [2M:5F; median age 61 (36-66); 1 Asian], all with CNS symptoms. Four were in the BM cohort and 3 in the LM cohort. All had prior CNS radiotherapy, either WBRT or SRS or both. All had prior systemic therapy (median 3; range 1-6). Three patients had EGFR del 19, 3 had L858R, and 1 had L861Q. Gr ≥ 3 adverse events, regardless of relationship to study drug, have included Gr 3 prolonged QTc, Grade 3 hypokalemia, Gr 3 dehydration, Gr 3 UTI, and Gr 3 ALT elevation. Three patients had dose reductions due to asymptomatic QTc interval prolongation. Six out of the 7 patients had CNS symptom improvement, often occurring within 14 days of tesevatinib initiation. Two patients decreased steroids. One BM patient had marked improvement in right leg strength and a 19% reduction in the target BM on Study Day 23. One patient with BM and LM had resolution of LM symptoms, a 57% reduction in BM target lesion, and clearance of LM enhancement on MRI at Study Day 41. Early data from the first 7 patents in this ongoing clinical trial indicate that tesevatinib has clinical activity in the CNS in EGFR mutant disease manifesting as BM or LM in patients previously treated with erlotinib, gefitinib, or afatinib. An additional cohort of 20 treatment-naïve patients who have initial presentation with brain metastases is being added.