Phase I Dose Escalation Trial of the First-in-class TNFR2 Agonist Monoclonal Antibody, HFB200301, in Monotherapy and in Combination with tislelizumab, an anti-PD-1 Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors

BACKGROUND

• Tumor necrosis factor receptor-2 (TNFR2) is primarily expressed on immune cells, including effector CD8+ and CD4+ T-cells, regulatory T (Treg) cells, natural killer (NK) cells, and myeloid cells. In contrast, TNFR1 is expressed ubiquitously across most cell types.

• HFB200301 is a first-in-class, agonistic monoclonal antibody (mAb) targeting TNFR2. It is designed to stimulate both innate and adaptive immune responses. The stimulation of T-cells and NK-cells within the tumor microenvironment (TME) is expected to enhance anti-tumor immunity effectively.

• To enhance the probability of clinical success, we used our Drug Intelligence Science (DIS®) platform to select tumor types most likely to respond to HFB200301, based on target biology and single-cell insights from patient-derived tumors, including refractory tumors.

• Here, we present the initial data of an ongoing multicenter, dose-escalation, Phase I trial of HFB200301 in monotherapy and in combination with tislelizumab (TIS) in patients with advanced refractory solid tumors (NCT05238883).

OBJECTIVES and STUDY DESIGN

Primary Objectives

• Safety and tolerability of HFB200301 in patients

Secondary Objectives

• Establish RDE and RP2D
• Assess PK, PD, and immunogenicity of HFB200301
• Examine preliminary anti-tumor efficacy, ORR using RECIST 1.1, iRECIST, and mRECIST for mesothelioma

Exploratory Objective

• Establish Proof of Mechanism (POM) in paired tumor biopsies and peripheral blood

Key Eligibility Criteria

• Adult patients with advanced or metastatic solid tumors. Tumor types include:

  • Cervical cancer
  • EBV+ gastric cancer
  • Head and neck squamous cell carcinoma
  • Pleural mesothelioma
  • Non-small cell lung cancer
  • Melanoma
  • Renal cell carcinoma
  • Sarcoma

• Measurable disease - RECIST 1.1 or mRECIST

• ECOG PS 0-1

• Patient must have exhausted standard lines of systemic therapy*

*Other protocol-defined inclusion criteria may apply.

RESULTS

PHARMACODYNAMICS

• HFB200301 was well tolerated in monotherapy and in combination with TIS with no DLTs and no ≥ Grade 3 TRAEs.

• 44% Overall Disease Control Rate (DCR) in monotherapy and in combination with tislelizumab in heavily pretreated tumors.

Proof of mechanism in the periphery

• Peripheral single-cell analysis reveals a majority of TNFR2+ CD8+ T cells are reprogrammed to become proliferative and cytotoxic following HFB200301 treatment. This reprogramming persists for at least 28 days. Expression analysis confirms activation of NFκB pathway. Tregs are unaffected by HFB203001.

Proof of mechanism in the tumor

• The baseline and on-treatment patient and tumor characteristics, along with PK and PD data, and our DIS®-informed predictive modeling, indicated that more frequent Q2W dosing of HFB200301 may be beneficial. Initial monotherapy results in a HNSCC patient are promising.

• HFB200301 demonstrates a favorable safety profile and dose-dependent PK with PD and preliminary clinical activity in monotherapy and in combination with TIS in patients with heavily pre-treated refractory solid tumors.