Gan, Jinping

2526 Background: Tumor necrosis factor receptor-2 (TNFR2) is expressed on effector CD8+, CD4+, and regulatory T (Treg) cells, natural killer (NK) cells, and myeloid cells. Activation of TNFR2 is anticipated to yield effective anti-tumor immunity by stimulating T-cell and NK-cell activation and proliferation in the tumor microenvironment. HFB200301 is a first-in-class anti-TNFR2 agonistic monoclonal antibody that triggers both innate and adaptive immune stimulation by binding to a specific epitope on TNFR2. We report initial results of an ongoing Phase I dose escalation, multicenter study (NCT05238883) of HFB200301 in monotherapy and in combination with tislelizumab (TIS) in patients (pts) with advanced refractory solid tumors. Methods: A Phase I trial designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and initial efficacy of HFB200301 in monotherapy and in combination with TIS. Eligible pts, ≥18 years with an ECOG PS 0-1 and advanced solid tumors, will be enrolled in dose escalation at 5 different dose cohorts in monotherapy (Q4W), 3 different dose cohorts in combination with TIS (Q4W), or in dose expansion following determination of safety. Radiographic response is assessed every 8 weeks. Results: A total of 39 pts have been enrolled, 27 pts in monotherapy and 12 pts in combination. All pts received prior systemic therapy (median 2, range 1-4); 23 pts (59%) had prior checkpoint inhibitor treatment. No dose limiting toxicities were observed in either the monotherapy or combination arms. Treatment-related adverse events (TRAEs) occurred in 44% of monotherapy and in 50% of combination pts, with pruritis (11%), tremor (7%), fatigue (7%), asthenia (7%) and nausea (7%) being the most common TRAEs. No ≥ Grade 3 TRAEs were reported, and there were no drug discontinuations due to TRAEs. Preliminary HFB200301 PK analysis demonstrated non-linear clearance of HFB200301, with dose-proportional maximum concentration [Cmax], achieving sufficient exposures for peripheral target engagement in all tested doses. Emerging PD data demonstrates evidence of immune activation and expansion of CD8+ T cells, but not Tregs, in the tumor microenvironment and peripheral blood. Single cell RNAseq analysis of peripheral blood mononuclear cells demonstrated PD modulation in TNFR2 positive immune cell types post-HFB200301 treatment. Early response evaluation reveals ongoing durable clinical responses (> 6 months) in a PD-L1+ pleural mesothelioma pt and an EBV+ gastric cancer pt from combination cohorts. Conclusions: HFB200301 demonstrates a favorable safety profile, dose-dependent PK, with PD and preliminary clinical activity in monotherapy and in combination with TIS in pts with heavily pre-treated refractory solid tumors. Clinical trial information: NCT05238883 .

TPS2670 Background: Tumor necrosis factor receptor-2 (TNFR2) is expressed on effector CD8+ T cells, CD4+ T cells, T regulatory cells, natural killer cells, and myeloid cells. Targeting TNFR2 is anticipated to yield effective anti-tumor immunity by stimulating T-cell and NK-cell activation and proliferation in the tumor microenvironment. HFB200301 is a first-in-class anti-TNFR2 agonistic monoclonal antibody that triggers both innate and adaptive immune stimulation by binding to a specific epitope on TNFR2. HFB200301 has demonstrated dose-dependent anti-tumor activity in human TNFR2 knock-in mice bearing MC38 and Hepa1-6 syngeneic tumors. Methods: HFB200301 is being evaluated in a first-in-human, open-label, multi-center, dose escalation and expansion study in adult patients with advanced solid tumors. A single-cell immune profiling platform, DIS, was deployed to identify unique tumor-infiltrating T cell signatures that could help optimize patient selection for HFB200301 treatment. It is hypothesized that the presence of an effector T cell subpopulation that express both TNFR2 and CD8A in solid tumors may represent a tumor microenvironment favorable to TNFR2 agonism. The following cancer indications have been identified based on the prevalence of a TNFR2 high/CD8 high signature: Epstein-Barr Virus positive (EBV+) gastric cancer, clear cell renal cell carcinoma (ccRCC), cutaneous melanoma, testicular germ cell tumor (TGCT), soft tissue sarcoma (STS), and PD-L1+ cancers: cervical cancer, pleural mesothelioma, lung adenocarcinoma, and head and neck squamous cell carcinoma (HNSCC). The escalation portion of the study explores increasing doses in cohorts of up to six patients, utilizing mTPI-2 design to determine recommended dose(s) for expansion (RDE(s)). Based on pharmacokinetic modeling to maximize HFB200301 activity, 60-minute intravenous infusions of HFB200301 are administered every 4 weeks. Once RDE(s) is determined, expansion into three indication-specific cohorts is planned to determine the recommended phase 2 dose (RP2D). Key eligibility criteria include histologically documented advanced or metastatic solid tumors in the above listed indications. Patient enrollment opened in February 2022 in the USA, with plans for additional clinical sites in Spain and China. The primary objective is to identify the RDE, characterize safety and tolerability of HFB200301, and determine RP2D. Secondary objectives include pharmacokinetic parameters, preliminary evidence of anti-tumor efficacy (e.g., ORR, DCR, DOR) and pharmacodynamic evaluation (e.g., T cell subsets) in the blood and in the tumor. Furthermore, a potential predictive biomarker signature derived based on the DIS single-cell immune profiling approach will be investigated retrospectively. Clinical trial information: NCT05238883.