Neoadjuvant APG-157 monotherapy in patients with locally advanced squamous cell carcinoma of head and neck: A phase IIA, single arm trial.

6087 Background: Newly diagnosed, locally advanced squamous cell carcinoma of the head and neck (SCCHN) poses significant treatment challenges due to its infiltrative nature, and high recurrence risk. From diagnosis to definitive curative-intent therapy, patients may experience rapid disease progression leading to a poor prognosis. A safe and effective therapy to halt tumor growth during this period is critical to improve patient outcomes. Methods: APG-157, a first-in-class immuno-oncology drug was evaluated in Phase 2A trial (NCT05312710) of 24 patients with stage I–IVA SCCHN in oral cavity (54.2%) and oropharynx (45.8%). Fifty percent had stage III & IVA disease. 91% of oropharyngeal cases were HPV+. APG-157 was administered orally as a soft lozenge - 200 mg, 3X a day before meals - for 4-6 weeks between initial diagnosis and definitive therapy. The primary and secondary endpoints included overall response rate (ORR) using RECIST v1.1 and safety, respectively. The exploratory endpoints included changes in tissue biomarkers, circulating tumor DNA (ctDNA), salivary cytokines, and post-hoc analysis of Event-Free Survival (EFS). Results: APG-157 was well tolerated with no treatment-related Grade 3 or 4 adverse events. There was no delay in subsequent definitive therapy. Of 13 oral cavity patients, 10 completed surgery, 3 had post-operative radiotherapy, and all achieved R0 resection. 11 patients with oropharyngeal cancer had chemoradiation (n=10) or radiation alone (n=1). APG-157 showed antitumor activity as 77% of the subjects achieved pathological responses (23% near-complete, 23% major, 31% partial), while 15% had stable disease and 8% showed progression. Among the patients undergoing surgery as definitive therapy, 46% demonstrated clinical-to-pathological downstaging, while 8% experienced upstaging. The (ORR) was 16.7% (n=24), with tumor reduction observed in 45% of the patients. No primary tumor progression occurred, achieving a 100% disease control rate (DCR) with 2 complete responses (CRs), 2 partial responses (PRs), and 20 cases of stable disease (SD). Median EFS was not reached at 2 years. All patients remain alive with no recurrence except one subject who died from a non-cancer-related cause. Pre- and post-treatment multiplex IHC analysis showed APG-157 reduced Ki-67+ tumor cells, increased CD8+ infiltration, and reprogrammed macrophages to the M1 phenotype. Post-treatment ctDNA clearance correlated with complete (30%) and partial (70%) disease control, resulting in ORR of 100% (Gouda MA, et al. Liquid Biopsy Response Evaluation Criteria in Solid Tumors (LB-RECIST). Ann Oncol. 2024 Mar;35(3):267-275). Conclusions: APG-157 is a safe and effective oral therapy addressing a critical unmet need in SSCHN. It is a convenient neoadjuvant treatment option with a strong safety profile and durable long-term outcomes after curative-intent therapy. Clinical trial information: NCT05312710 .