Evaluating Immune Checkpoint Inhibition in Solid Tumor Patients with Homologous Recombination Repair Deficiency.

TPS3108 Background: Recent studies have shown that patients with mismatch repair deficiency have an increased response rate to immune checkpoint inhibitors (ICI). This led to the tissue-agnostic FDA approval of pembrolizumab (PEM). Stemming from this, we are investigating the interplay between homologous recombination (HR) repair deficiency, another mechanism of DNA repair, and solid tumor response to ICI using an all-inclusive functional immunofluorescence assay of the Fanconi Anemia pathway (FATSI) that we developed and which can be performed in paraffin embedded tumors. Methods: This is a phase 2 open-label single center trial evaluating the role of PEM in patients with metastatic solid tumors who have progressed on first-line standard of care chemotherapy and for whom PEM does not have an FDA approved indication. FATSI will be performed in all patients, as well as stool analyses for microbiome composition evaluation. We hypothesize that FATSI negative tumors will be associated with improved responses. Other eligibility criteria include measurable disease by imaging, 18 years of age or older and no previous exposure to ICI. Patients with known microsatellite instability (MSI) high tumors are not eligible. The primary objective is to evaluate the immune-related objective response rate (iORR) achieved in patients with FA Repair Pathway functionally competent and functionally deficient tumors. Secondary objectives include 20-week progression free survival and overall survival. Other exploratory objectives include evaluation of the mutation load, markers of neo-antigenicity, T cell receptor clonotype analyses (before and after treatment) and alterations in HR repair genes. We will utilize a two-stage phase II trial design to detect an iORR ≥ 20% in the whole population tested vs. the null hypothesis that the true iORR ≤5%, representing a response by chance alone, or other infrequent unknown mechanism. An interim analysis requires that at least 2 of the first 20 evaluable patients enrolled have an objective response. If this occurs, we will accrue 19 additional patients for a total of 39. Enrollment is ongoing and seven patients are currently on treatment. Clinical trial information: NCT03274661.