KS04.7.A L19TNF IN COMBINATION WITH TEMOZOLOMIDE-BASED CHEMORADIATION FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA SHOWS PROMISING SAFETY AND OVERALL SURVIVAL SIGNALS IN A PHASE I STUDY

Abstract BACKGROUND Targeted cytokine-based therapy is a promising treatment opportunity to potentially convert an immunologically “cold” tumor microenvironment into a “hot” one and trigger a potent antitumor response. L19TNF is a fully human antibody-cytokine fusion protein, comprising the pro-inflammatory cytokine tumor necrosis factor (TNF) fused to the antibody L19 that recognizes the extra domain B of fibronectin, a tumor-specific antigen. This allows targeted delivery of therapeutically relevant doses of TNF to the tumor while sparing healthy organs. Here, we report the results of the phase I dose escalation part of a clinical trial with systemically administered L19TNF in combination with standard chemoradiotherapy for patients with newly diagnosed glioblastoma. MATERIAL AND METHODS The Phase I part of NCT04443010 study was an open-label, non-randomized, multicenter dose escalation to investigate the safety and preliminary efficacy of L19TNF in combination with temozolomide chemoradiotherapy for patients newly diagnosed glioblastoma. Patients were treated with 7, 10 or 13 µg/kg intravenous L19TNF, radiotherapy of 60 Gy in 30 fractions plus daily 75 mg/m2 TMZ, followed by up to 6 maintenance cycles of TMZ 150-200 mg/m2. Tumor responses were assessed by iRANO criteria. RESULTS From 2021 - 2024, we enrolled 18 patients from two centers in Switzerland. Tumors of 11 patients (61%) had an unmethylated O6-methylguanine DNA methyltransferase (MGMT) promoter. L19TNF could be safely administered at a dose of 13 µg/kg in combination with temozolomide-based chemoradiation. Treatment was well tolerated and the most common adverse events were asymptomatic transient increases of ALT, GGT and AST, decreased lymphocyte counts, chills, back pain, nausea, vomiting, headache and decreased platelet and white blood cell counts. With the addition of L19TNF to standard temozolomide-based chemoradiation, we observe a median overall survival of > 20 months. CONCLUSION The intravenous administration of L19TNF is safe in patients with newly diagnosed glioblastoma and shows promising activity. These encouraging results warrant further investigations within the Phase II part of the clinical trial.