Randomized phase 2 study to evaluate the efficacy and safety of silevertinib in combination with temozolomide in newly diagnosed patients with EGFRvIII-positive IDHwt MGMT unmethylated glioblastoma.

TPS2098 Background: Targeted therapy for patients with newly diagnosed glioblastoma (ND-GBM) has made little progress. First-line therapy remains surgery, adjuvant radiotherapy with temozolomide (TMZ), and maintenance TMZ. This treatment paradigm is even less effective for the ~60% of patients with MGMT unmethylated status. Oncogenic epidermal growth factor receptor (EGFR) alterations are identified in ~ 50% of ND-GBM tumors irrespective of MGMT status. EGFRvIII is present in ~30% of ND-GBM and is nearly always expressed with other EGFR mutations and/or EGFR amplification. Prior clinical trials of EGFR targeting drugs have shown limited benefit primarily due to poor CNS penetrance and/or lack of potency across EGFR variants and EGFR amplification. Silevertinib (BDTX-1535) is a 4th generation covalent EGFR tyrosine kinase inhibitor (TKI) with high CNS penetrance targeting the full spectrum of oncogenic EGFR alterations in GBM, including variants (EGFRvIII, vII, vVI), mutations, and amplification. Silevertinib has shown additive antitumor effects with TMZ in an intracranial GBM tumor model expressing EGFRvIII with EGFR amplification. A phase 0/1 window-of-opportunity study in patients with recurrent GBM showed that silevertinib reached therapeutic levels in infiltrative GBM tissue with associated biomarker suppression (NCT06072586). Silevertinib was well tolerated and demonstrated promising clinical activity in a phase 1 study in patients with recurrent GBM (ASCO 2024). This randomized phase 2 study will evaluate efficacy and safety of silevertinib in combination with TMZ in adults with EGFRvIII-positive (EGFRvIII) unmethylated MGMT ND-GBM. Methods: This multicenter study (NCT05256290) will be conducted in the US and consists of 2 sequential parts. Part 1 (Safety Run-in) will enroll up to 12 patients to evaluate the safety of two doses of silevertinib (150mg QD, 200mg QD) in combination with TMZ and will inform the selected dose for Part 2. In Part 2 (Efficacy Evaluation), patients will be randomized 1:1 to receive adjuvant silevertinib in combination with TMZ or TMZ alone. Patients with EGFRvIII ND-GBM who have completed surgery and adjuvant chemoradiation are eligible (Table). The primary endpoint for Part 2 is progression free survival by blinded independent central review using Response Assessment in Neuro-Oncology (RANO2.0) criteria. Clinical trial information: NCT05256290 . Key inclusion criteria. Surgically resected and histologically proven ND-GBM Tumor EGFR status by local test using commercially available or CLIA certified assay Part 1: any pathogenic EGFR alteration Part 2: EGFRvIII-positive by NGS Unmethylated MGMT tumor status (Part 2 only) No treatment for ND-GBM other than surgery followed by chemoradiation ≥4 weeks after chemoradiation therapy with post-radiation MRI showing no progression