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). 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).

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.