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).
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.
Oropharynx, p16-positive: Stage III (T4, N0-N3, M0)
Stage I-II disease
Stage IVb or Ivc disease
T4b unresectable disease
N3 disease where applicable
Parallel
APG-157
DrugAPG-157 is a first-in-class investigational drug product, formulated as 100 mg soft hydrogel pastille to dissolve in the mouth
Surgery
Procedure/SurgeryDefinitive Surgery
Radiation/Chemotherapy
RadiationProtocol-specified risk-adapted postoperative radiotherapy, with concurrent platinum-based chemotherapy (e.g., cisplatin or carboplatin) administered when indicated based on pathological risk factors
Radiation/Chemotherapy
RadiationDefinitive radiotherapy with concurrent protocol-specified platinum-based chemotherapy.
Event-Free Survival (EFS)
EFS is defined as the time from randomization to the earliest occurrence of a protocol-defined EFS event, including radiographic and/or clinical disease progression that precludes initiation or completion of planned definitive curative-intent therapy; locoregional recurrence, progression, or distant metastasis following definitive treatment, confirmed by imaging, pathology, salvage intervention with viable tumor or other protocol-defined assessments, where applicable, or death from any cause. EFS will be analyzed by blinded independent central review (BICR) using RECIST v1.1 and protocol-defined pathology criteria, as applicable. The primary analysis will be conducted in the intent-to-Treat ( ITT) population using stratified log-rank testing and Cox proportional hazards models.
Overall Survival (OS)
Overall survival is defined as the time from randomization until death from any cause.
Objective Response Rate (ORR)
Proportion of participants achieving confirmed response (CR) or partial response (PR) according to RECIST v1.1 as assessed by BICR.
ctDNA Clearance Rate
Change in circulating tumor DNA (ctDNA) levels over time and proportion of participants achieving ctDNA clearance from the baseline assessed using a tumor-informed assay.
Clinically Meaningful Pathological Response(Cohort A):
Proportion of participants achieving ≤50% residual viable tumor in the resected specimen as assessed by BICR.
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