Abstract CT036: Safety and immunogenicity of a first-in-human mutant KRAS long peptide vaccine combined with ipilimumab/nivolumab in resected pancreatic cancer: Preliminary analysis from a phase I study

Background: Novel strategies are needed to decrease the high recurrence rates of pancreatic ductal adenocarcinoma (PDAC) after curative-intent surgery. Mutant KRAS (mKRAS) is an oncogenic driver found in approximately 90% of PDAC that has emerged as a target for neoantigen-specific vaccination. Methods: This is a single-arm, open-label, first-in-human phase I study of a pooled synthetic long peptide (SLP) vaccine targeting six mKRAS subtypes (G12D, G12R, G12V, G12A, G12C, G13D) combined with ipilimumab/nivolumab (ipi/nivo) in patients with resected PDAC (NCT04117087). Key inclusion criteria: presence of a vaccine-targeted KRAS mutation, disease-free status after completing adjuvant chemotherapy within 6 months of enrollment. Priming phase: mKRAS vaccine given on days 1, 8, 15, and 22 along with ipi 1 mg/kg every 6 weeks for 2 doses and nivo 3 mg/kg every 3 weeks for 4 doses. Boost phase: mKRAS vaccine given on weeks 13, 21, 29, 37, and 45 along with nivo 480 mg every 4 weeks for 10 doses. Co-primary endpoints: safety, mKRAS-specific T cell response. Secondary endpoints: disease-free survival (DFS), overall survival (OS). Results: At the time of data cutoff (December 1, 2022), 11 patients were treated with a median follow-up time of 10.7 months. 8/11 patients achieved a mKRAS-specific T cell response, defined as >5-fold change in IFN-gamma-producing mKRAS-specific T cells within 17 weeks post-vaccination, as assessed by serial ELISpot. The median fold change in IFN-gamma-producing mKRAS-specific T cells within 17 weeks post-vaccination was 10.2 (range: 1.5-686.3). The majority of all adverse events were grade 1 (79.5%) or grade 2 (15.2%) in severity per NCI CTCAE v5.0. Four grade 3 immune-related adverse events (pneumonitis, adrenal insufficiency, arthralgias, myalgias) and discontinuation of checkpoint blockade occurred in 2/11 patients. The median DFS for the entire cohort was 6.4 months and not reached for OS. Patients who mounted a mKRAS-specific T cell response demonstrated a significant improvement in median DFS compared to immune non-responders (not reached vs 2.8 months, p = 0.045). Conclusions: The combination of a pooled SLP mKRAS vaccine and dual checkpoint blockade is tolerable and immunogenic in patients with resected PDAC. Induction of an mKRAS-specific T cell response is associated with improved DFS in this cohort. Ongoing correlative studies will apply multi-omic approaches to identify novel biomarkers of immune response and resistance. Cita