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). Two independently powered cohorts are enrolled based on treatment pathway. Cohort A evaluates APG-157 administered as neoadjuvant therapy before curative-intent surgery in participants with resectable oral cavity or oropharyngeal cancer who are medically ineligible for perioperative pembrolizumab. Cohort B evaluates APG-157 administered as induction therapy before definitive chemoradiotherapy and as maintenance therapy after chemoradiotherapy in participants with unresectable or medically inoperable disease. Participants are randomized 1:1 within each cohort to receive APG-157-based treatment or standard-of-care therapy. The primary hypothesis is that APG-157 given before definitive surgery followed by (chemo)radiotherapy improves event-free survival (EFS) compared to surgery and adjuvant (chemo)radiotherapy alone (Cohort A), and that APG-157 given as induction therapy prior to definitive chemoradiotherapy (CRT) followed by maintenance APG-157 improves EFS compared to definitive CRT alone (Cohort B).

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)

1. Adults ≥18 years

2. Histologically or cytologically confirmed, previously untreated locally advanced head and neck squamous cell carcinoma (LA-HNSCC) of the oral cavity or oropharynx.

3. Resectable disease appropriate for curative-intent surgery.

4. 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)

5. Objectively medically ineligible for perioperative pembrolizumab according to protocol-defined objective criteria.

6. HPV/p16 testing available for stratification.

7. Measurable or evaluable disease.

8. Life expectancy ≥12 months.

9. ECOG Performance Status ≤2.

10. Negative pregnancy test for women of childbearing potential and agreement to use effective contraception.

11. Ability to comply with study procedures.

Cohort B (Unresectable / Medically Inoperable Disease)

1. Adults ≥18 years

2. Histologically or cytologically confirmed, previously untreated LA-HNSCC of the oropharynx. Disease not suitable for curative-intent surgery.

3. 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)

4. HPV/p16 testing available for stratification.

5. Presence of evaluable tumor burden.

6. Eligible to receive definitive chemoradiotherapy.

7. Life expectancy ≥12 months.

8. ECOG Performance Status ≤2.

9. Adequate organ function.

10. Contraception requirements met.

11. 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.

The sponsor does not currently plan to make individual participant data available to researchers outside the study sponsor and its designated representatives. Study results will be made publicly available through ClinicalTrials.gov and scientific publications as appropriate.