Preliminary results from a phase IIa trial of APG-157 in oral cavity and oropharyngeal dysplasia.

e18119 Background: Oral and oropharyngeal squamous cell carcinoma affects over 678,900 people annually and is often preceded by potentially malignant lesions such as leukoplakia and erythroplakia. These lesions have a malignant transformation rate of over 12% and are usually removed surgically, but some patients have widespread dysplasia unsuitable for resection. Currently there are no FDA approved chemopreventive treatments to overcome this. APG-157 is an oral immuno-oncology drug based on zinflavonoid skeleton. Previously evaluated in a Phase 1B trial for Head and Neck Cancer, it showed reduced mutated p53, increased wild-type p53, enhanced CD8+ T-cell recruitment to the tumor microenvironment, reduced salivary proinflammatory cytokines (IL-1β, IL-8, TNF-α), and significant reversal of oral dysbiosis. Methods: Phase IIA will enroll 32 participants for a minimum of two 4-week treatment cycles of APG-157 200 mg PO TID. Participants with stable disease or positive response may opt for a third cycle. Follow-up is every three months for two years. The primary outcome is pathological response, measured by the proportion of patients with mild or no dysplasia after treatment. The secondary outcome is clinical response, assessed by lesion size in two dimensions and categorized as complete, partial (≥30% reduction), no change, or progressive (≥25% increase or appearance of new lesion). Major inclusion criteria include biopsy-proven mild to severe oral or oropharyngeal dysplasia and a visible lesion ≥8x3 mm. Major exclusion criteria include recent oral surgery, untreated head and neck cancer, and recent chemotherapy or radiation. Correlative studies will analyze CD44, p16, EGF, and other cancer markers. Results: The study has enrolled 14 participants: six are off-study (one early termination, one non-adherence, three screen failures, one withdrawal), three are in treatment, and five have completed treatment (four completed two cycles, one completed three cycles). One participant had a partial clinical response and went from severe to no dysplasia on pathology. Another participant with partial clinical response went from severe to mild dysplasia. Another had partial clinical response and went from at least carcinoma in situ to invasive cancer on pathology. Two other participants refused or postponed end-of-treatment biopsy – one had no clinical change and one had progressive disease. There were no serious adverse events. Of the 22 reported adverse events, 4 were deemed ‘Possible,’ 7 ‘Unlikely,’ and 11 ‘Not Related’ to the study. Possible treatment-related events were diarrhea, oral pain, and oral dysesthesia. Conclusions: Preliminary pathological and clinical results suggest APG-157 is a well-tolerated and promising treatment for oral and oropharyngeal dysplasia. Early evidence highlights its safety and potential therapeutic value in a disease where early treatment is vital for survival. Clinical trial information: NCT05865028 .