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

A Multicenter, Randomized, Open-Label Phase 3 Study of APG-157 as Neoadjuvant Therapy or as Induction and Maintenance Therapy 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).

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.