Andtbacka, Robert H.I.

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 .

2531 Background: The immune co-stimulatory receptor OX40 is expressed on CD4+ T cells, including regulatory T cells (Tregs). First generation OX40 agonists faced limitations from interference with endogenous OX40-OX40L binding, leading to decreased surface OX40 levels on T cells. Distinguished by its unique epitope on OX40, the novel next generation IgG1 monoclonal antibody (mAb) HFB301001 facilitates agonistic activity without impeding endogenous OX40 ligand binding. This allows for effective co-stimulation of T cells without diminishing OX40 levels. Additionally, HFB301001 exhibited superior in vivoanti-tumor activity and ability to enhance effector CD8+ T cell function compared to a benchmark first generation OX40 agonist in preclinical studies. Here, we report initial data of an ongoing dose-escalation study (NCT05229601) of HFB301001 in patients (pts) with advanced solid tumors. Methods: A Phase I trial designed to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of HFB301001. Eligible pts ≥18 years old (ECOG PS 0-1) with advanced solid tumors are enrolled in 4 different dose cohorts in monotherapy (Q4W) dose escalation. Solid tumor types were selected using Drug Intelligent Science (DIS®), employing integrative bulk and single cell RNAseq (scRNAseq) analyses to confirm and prioritize prospective targets in specific immune cell types. Sequential analysis of peripheral blood and tumor tissue biomarkers is performed. Radiographic response is assessed every 8 weeks. Results: As of January 06, 2024, 26 pts were enrolled, all having received prior systemic therapy (median 2, range 1-4); 81% received prior checkpoint inhibitor treatment. The majority of pts (77%) were male, median age was 62.5 years (range 41-78). Treatment-related adverse events (TRAEs) occurred in 34.6% of pts, none ≥ grade 3. Common TRAEs included rash (19%), pruritis (12%) and arthralgia (8%). No dose-limiting toxicities were observed. Preliminary results demonstrate dose-proportional increases in maximum concentration, typical mAb volume of distribution, and nonlinear clearance. On treatment biopsies revealed expansion of both natural killer and cytotoxic CD8+ T cells, with no notable expansion of Tregs. Analysis of peripheral blood by scRNAseq and immunophenotyping revealed expansion of cytotoxic CD8+T cells relative to CD4+ T cells post treatment. Preliminary efficacy analysis indicates a disease-control rate (DCR) of > 60% with greatest effect seen in hepato-cellular and renal cell carcinoma. Median time on treatment was 1.9 months (range 0.9-17 months). Conclusions: HFB301001 demonstrates a favorable safety profile, dose-dependent PK and PD immunomodulation, and DCR in heavily pretreated solid tumors. HFB301001 warrants further evaluation and expansion in specific tumor types is planned. Clinical trial information: NCT05229601 .

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10 6 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 10 8 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.