APG-157 in Locally Advanced Head and Neck Squamous Cell Carcinoma

This Phase 3, multicenter, randomized, open-label study evaluates APG-157 in adults with newly diagnosed locally advanced head and neck squamous cell carcinoma (LA-HNSCC). The study consists of two independently powered cohorts designed to evaluate APG-157 in distinct treatment settings. Cohort A enrolls participants with resectable oral cavity or oropharyngeal squamous cell carcinoma who are objectively medically ineligible for perioperative pembrolizumab according to protocol-defined criteria. Participants are randomized 1:1 to receive APG-157 administered orally at 600 mg/day for 6 weeks prior to curative-intent surgical resection followed by protocol-directed adjuvant therapy, or standard-of-care surgery followed by adjuvant therapy alone. Cohort B enrolls participants with unresectable or medically inoperable locally advanced oropharyngeal squamous cell carcinoma. Participants are randomized 1:1 to receive APG-157 induction therapy for 4 weeks before definitive chemoradiotherapy, followed by APG-157 maintenance therapy initiated within 60 days after chemoradiotherapy and continued for up to 1 year, or standard-of-care definitive chemoradiotherapy alone.The primary objective is to determine whether APG-157-based treatment improves event-free survival compared with standard-of-care treatment. Key secondary objectives include overall survival, objective response, pathological response, ctDNA clearance, safety, treatment feasibility, and patient-reported outcomes.

Inclusion criteria

Cohort A (Resectable Disease)

• Adults ≥18 years
• Histologically or cytologically confirmed, previously untreated locally advanced head and neck squamous cell carcinoma (LA-HNSCC) of the oral cavity or oropharynx.
• Resectable disease appropriate for curative-intent surgery.
• Stage III-IVA disease according to AJCC criteria:

• Oropharynx, p16-positive: Stage III (T4, N0-N3, M0)
• Oropharynx, p16-negative: Stage III or IVa (T3-T4, N0-N2, M0)
• Oral cavity: Stage III or IVa (T3-T4, N0-N2, M0)
• Objectively medically ineligible for perioperative pembrolizumab according to protocol-defined objective criteria.
• HPV/p16 testing available for stratification.
• Measurable or evaluable disease.
• Life expectancy ≥12 months.
• ECOG Performance Status ≤2.
• Negative pregnancy test for women of childbearing potential and agreement to use effective contraception.
• Ability to comply with study procedures.

Cohort B (Unresectable / Medically Inoperable Disease)

• Adults ≥18 years
• Histologically or cytologically confirmed, previously untreated LA-HNSCC of the oropharynx. Disease not suitable for curative-intent surgery.
• Stage III-IVA disease according to AJCC criteria:

• p16-positive Stage III (T4, N0-N3, M0) with >10 pack-year smoking history
• p16-negative Stage III or IVa (T3-T4, N0-N2, M0)
• HPV/p16 testing available for stratification.
• Presence of evaluable tumor burden.
• Eligible to receive definitive chemoradiotherapy.
• Life expectancy ≥12 months.
• ECOG Performance Status ≤2.
• Adequate organ function.
• Contraception requirements met.
• Ability to comply with study procedures.

Exclusion criteria

Cohort A Specific:

• Stage I-II disease
• Stage IVb or Ivc disease
• T4b unresectable disease
• N3 disease where applicable
• Medically eligible for perioperative pembrolizumab

Cohort B Specific:

• Stage I-II disease
• Disease not appropriate for curative-intent CRT
• Active autoimmune disease requiring systemic therapy
• Prior solid organ or allogeneic stem cell transplant
• Ongoing immunosuppression >10 mg/day prednisone equivalent

Common Exclusion Criteria:

• Primary tumor arising from the nasopharynx, hypopharynx, larynx, paranasal sinus, or unknown primary site.
• Prior treatment for current head and neck squamous cell carcinoma.
• Prior malignancy unless protocol exceptions met
• Distant metastatic disease
• Live vaccine within 30 days
• Known hypersensitivity to APG-157 or its components.
• Unresolved clinically significant toxicity
• Recent participation in another investigational study
• Active uncontrolled infection
• Significant uncontrolled cardiovascular disease
• Pregnancy or breastfeeding.
• QTcF >500 msec or congenital long QT syndrome
• Any condition compromising safety, compliance, or study interpretation

Randomization ratio: 1:1 within each cohort

Stratification Factors:

Cohort A:

• HPV/p16 status,
• Planned platinum strategy,
• PD-L1 CPS category

Cohort B:

• HPV/p16 status
• Planned platinum strategy
• Geographic region.