A randomized, open-label, multicenter, Phase 3 trial of ivonescimab alone or ivonescimab with ligufalimab versus pembrolizumab for the first-line treatment of recurrent and/or metastatic head and neck squamous cell carcinoma(HNSCC)

This Phase 3 randomized, open-label, multicenter trial evaluates treatment regimens in patients with first-line recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) who are PD-L1 positive (Combined Positive Score ≥ 1). The primary objective is to compare overall survival of ivonescimab in combination with ligufalimab versus standard of care pembrolizumab, and of ivonescimab monotherapy versus pembrolizumab. This comparison addresses the clinical need for improved survival outcomes in this patient population with limited first-line treatment options.

The secondary objectives include:

• Comparison of objective response rate assessed by Blinded Independent Review Committee based on Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 for ivonescimab in combination with ligufalimab versus pembrolizumab and for ivonescimab versus pembrolizumab

• Comparison of progression-free survival assessed by Blinded Independent Review Committee based on RECIST v1.1 for ivonescimab in combination with ligufalimab versus pembrolizumab and for ivonescimab versus pembrolizumab

• Comparison of disease control rate and duration of response as assessed by investigator based on RECIST v1.1 for ivonescimab in combination with ligufalimab versus pembrolizumab and for ivonescimab versus pembrolizumab

• Comparison of safety and tolerability of ivonescimab in combination with ligufalimab versus pembrolizumab and for ivonescimab versus pembrolizumab

• Evaluation of the pharmacokinetic profile and performance of exposure/response analysis of ivonescimab

• Evaluation of the pharmacokinetic profile and performance of exposure/response analysis of ligufalimab

• Evaluation of the immunogenicity of ivonescimab and ligufalimab

This clinical trial enrolled a total of **390 participants** diagnosed with **recurrent and/or metastatic squamous cell carcinoma of the head and neck**. The study population included both **male and female** subjects aged **18 to 79 years** at the time of enrolment. Participants were required to have an **Eastern Cooperative Oncology Organization (ECOG) performance status** score of 0 or 1, indicating relatively good functional capacity. The trial population was selected based on **histologically and/or cytologically confirmed** disease with primary tumour location in the **oral cavity**, **oropharynx**, **hypopharynx**, or **larynx**. Eligible participants had **PD-L1 positive** tumours with a **Combined Positive Score (CPS) ≥ 1** and had not received prior systemic anti-tumour therapy for their recurrent or metastatic disease. Participants were required to have adequate **organ function**, including satisfactory **haematology** parameters such as **absolute neutrophil count** ≥ 1.5×10⁹/L, **platelet count** ≥ 100×10⁹/L, and **haemoglobin** ≥ 10 g/dL, as well as adequate **renal function** with calculated **creatinine clearance** ≥ 50 mL/min and **hepatic function** with specific limits for **bilirubin**, **AST**, **ALT**, and **albumin** levels. Patients with **oropharyngeal cancer** were required to have **HPV status** testing performed prior to randomization. An expected survival of at least 6 months at randomization was also required for study inclusion.

This is a **randomized**, **open-label**, **multicenter**, **Phase 3** clinical trial evaluating **ivonescimab** administered alone or in combination with **ligufalimab** compared to **pembrolizumab** as first-line treatment for patients with **recurrent and/or metastatic squamous cell carcinoma of the head and neck**. The trial investigates investigational medicinal products administered via **intravenous infusion**, with ivonescimab given at a maximum daily dose of 10 mg/kg (maximum total dose of 350 mg/kg), ligufalimab at a maximum daily dose of 45 mg/kg (maximum total dose of 1575 mg/kg), and pembrolizumab at a maximum daily dose of 200 mg (maximum total dose of 7000 mg). The maximum treatment period for all investigational products is **104 weeks**. The trial is designed to compare treatment outcomes across three arms, with participants randomized to receive either ivonescimab monotherapy, ivonescimab in combination with ligufalimab, or pembrolizumab as the comparator.

The primary objective of the trial is to compare **Overall Survival** between ivonescimab combined with ligufalimab versus pembrolizumab, and ivonescimab monotherapy versus pembrolizumab in patients with first-line recurrent and/or metastatic head and neck squamous cell carcinoma who are **PD-L1 positive** (Combined Positive Score ≥ 1). Secondary endpoints include **objective response rate**, **progression-free survival**, **disease control rate**, safety assessments, **pharmacokinetic characteristics**, and **immunogenicity assessment**. The trial employs **RECIST version 1.1** criteria for tumor response evaluation, requiring at least one measurable lesion suitable for repeated accurate measurements.

Eligible participants must be adults aged 18 to 79 years with histologically or cytologically confirmed recurrent and/or metastatic squamous cell carcinoma with primary tumor location in the oral cavity, oropharynx, hypopharynx, or larynx. Participants must have an **ECOG performance status** of 0 or 1, expected survival of at least 6 months, and adequate organ function including **absolute neutrophil count** ≥ 1.5×10⁹/L, platelet count ≥ 100×10⁹/L, **hemoglobin** ≥ 10 g/dL, calculated **creatinine clearance** ≥ 50 mL/min, serum total **bilirubin** ≤ 1.5× upper limit of normal, **AST** and **ALT** ≤ 2.5× upper limit of normal (or ≤ 5× upper limit of normal for patients with liver metastases), and serum **albumin** ≥ 28 g/L. Participants must not have received prior systemic anti-tumor therapy for recurrent and/or metastatic disease, although prior adjuvant/neoadjuvant chemotherapy, radiotherapy, or definitive chemoradiotherapy for locally advanced disease is permitted if disease progression occurred more than 6 months after treatment completion. **HPV status** must be determined prior to randomization for patients with oropharyngeal cancer. PD-L1 expression must be confirmed as positive (Combined Positive Score ≥ 1) using a CE-IVD immunohistochemistry assay validated for head and neck squamous cell carcinoma.

The trial recruitment is estimated to begin in December 2025, with an estimated completion date of December 2030. The overall trial duration encompasses the recruitment period, active treatment phase, and follow-up assessments. Participant involvement extends throughout the treatment period of up to 104 weeks plus additional follow-up visits for survival and safety monitoring. Study visits include a screening visit for eligibility assessment and baseline evaluations, regular on-treatment visits for administration of investigational medicinal products and safety monitoring, follow-up visits for disease assessment and evaluation of treatment response, and an end-of-study visit for final assessments. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, participant withdrawal of consent, investigator decision based on participant's best interest, or protocol-defined criteria for treatment discontinuation.

This clinical trial evaluates three investigational medicinal products administered via intravenous infusion for the first-line treatment of recurrent and/or metastatic head and neck squamous cell carcinoma. The study employs a randomized, open-label, multicenter design comparing experimental treatments against a standard-of-care comparator. The maximum treatment period for all medicinal products is 104 weeks.

Ivonescimab (sponsor product code AK112/SMT112) is an experimental medicinal product formulated as an injection for intravenous infusion. The active substance is ivonescimab, a protein-based therapeutic agent. The dosage is administered at 10 milligrams per kilogram body weight, with a maximum daily dose of 10 mg/kg and a maximum total dose of 350 mg/kg over the treatment period. This investigational product serves as a test treatment in the study protocol.

Ligufalimab (sponsor product code AK117) is an experimental medicinal product presented as a solution for infusion administered via the intravenous route. The active substance is ligufalimab, a humanised IgG4-kappa monoclonal antibody against CD47. The dosing regimen consists of 45 milligrams per kilogram body weight as the maximum daily dose, with a maximum total dose of 1575 mg/kg over the treatment duration. This investigational product functions as a test treatment and is evaluated both as monotherapy in combination with ivonescimab.

Pembrolizumab, marketed as KEYTRUDA 25 mg/mL concentrate for solution for infusion, serves as the comparator treatment in this trial. This medicinal product is authorized within the European Union (marketing authorization number EU/1/15/1024/003) and contains pembrolizumab as the active substance, a protein-based therapeutic agent. The pharmaceutical form is a concentrate for solution for infusion, administered via intravenous infusion. The maximum daily dose is 200 milligrams, with a maximum total dose of 7000 mg over the treatment period. This product represents the standard-of-care therapy against which the experimental treatments are compared.

The primary endpoint for efficacy assessment is Overall Survival. Secondary endpoints include objective response rate, progression free survival, disease control rate, safety assessments, pharmacokinetic characteristics, and immunogenicity assessment. Tumor measurements will be performed according to RECIST v1.1 criteria to evaluate measurable lesions suitable for repeated accurate measurements. PD-L1 protein expression is assessed using CE-IVD immunohistochemistry assay with any assay validated for head and neck squamous cell carcinoma in a laboratory compliant with national provisions, based on either archival tissue samples before the diagnosis of recurrent or metastatic tumor or tissue samples obtained after the diagnosis of recurrent or metastatic tumor.