PI3K Inhibition and PD-1 Blockade in Advanced Anal Canal Carcinoma

durable responses in patients with locally advanced or metastatic BCC.Imiquimod, a topical toll-like receptor 7 agonist, induces local innate and adaptive immune activation and has shown activity in superficial and selected high-risk BCC.Fractional CO laser has been shown to enhance topical drug penetration and increase local immunogenicity.The combination of systemic immune checkpoint inhibition with locally enhanced immune stimulation may synergistically augment antitumor immune responses.Methods: CEMIQUID (IOR-REG-2501; EUCT 2025-520698-38-00) is a multicenter, open-label, phase Ib/II investigator-initiated clinical trial evaluating neoadjuvant cemiplimab with or without topical imiquimod and fractional CO laser in patients with highrisk, potentially resectable BCC.In the Phase Ib safety run-in, six patients will receive cemiplimab 350 mg intravenously every 3 weeks in combination with imiquimod 5% cream, self-applied five days per week after fractional CO laser treatment, for a total of four neoadjuvant cycles (12 weeks).The primary objective of Phase Ib is to assess safety and feasibility and to identify dose-limiting toxicities.If no more than one of six patients experiences a dose-limiting toxicity, the study will proceed to Phase II.In Phase II, twelve patients will be randomized in a 3:1 ratio to receive cemiplimab monotherapy or cemiplimab combined with imiquimod and fractional CO laser.Definitive surgical resection will be performed following completion of neoadjuvant therapy.Resected tumor specimens will undergo centralized histopathologic evaluation to assess pathologic response and will be used for predefined translational analyses.The primary endpoint of Phase II is 3-year relapse-free survival.Secondary endpoints include pathologic complete response rate, objective response rate, clinical benefit rate, overall survival, surgical resectability, and safety.Exploratory objectives include the evaluation of immune biomarkers and tumor microenvironment changes, including IFN- and ICAM-1 expression, lymphocytic infiltration, tertiary lymphoid structures, and immune-related gene expression signatures.The trial is currently open and recruiting at four academic centers in Spain, with Phase Ib enrollment ongoing.