736MO Personalized, off-the-shelf KRAS neoantigen-specific immunotherapy for the treatment of advanced solid tumors: Clinical benefit associated with decreases in ctDNA (SLATE-KRAS)

Abstract

Targeting neoantigens derived from common driver mutations with a viral-based prime/boost vaccine can induce strong neoantigen-specific CD8 T cell responses and is a promising off-the-shelf immunotherapy. A phase 1/2 study was conducted in patients (pts) with metastatic solid tumors harboring a specific vaccine-targeted neoepitope (HLA class I-restricted). The version 1 (V1) vaccine targeted 20 shared neoantigens from KRAS, TP53, b-catenin, and BRAF. An improved V2 vaccine only targeted KRAS neoantigens (G12C/D/V, Q61H). Pts receive an adenovirus prime followed by boosts with a self-amplifying mRNA with IV nivolumab 480 mg Q4W +/- SC ipilimumab 30 mg with vaccinations. Primary endpoints were safety (Phase 1) and response per RECIST v1.1 (Phase 2). 26 pts with solid tumors were treated with V1. In pts with NSCLC (n=13, post-IO), 1 pt had an unconfirmed partial response (PR), 3 had stable disease (SD; one pt with -18% shrinkage completing 2 years of treatment), and 9 had progressive disease (PD). Molecular response was observed in 3 of 6 ctDNA-evaluable NSCLC pts (defined as > 50% decrease relative to baseline). Analysis of tumors showed increases in IFNg-related genes and vaccine-induced T cells. A V2 vaccine developed to target KRAS neoantigens more effectively induced greater levels of CD8 T cells than V1 in the first pts analyzed. 11 pts have been treated with V2 (NSCLC [n=4, post-IO] and MSS-CRC [n=7]). 1 NSCLC pt had an unconfirmed PR correlating with an 80% decrease in ctDNA. 2 pts with CRC had SD (one ongoing with >85% reduction in ctDNA, CA 19-9, and CEA and -14% shrinkage), and 5 pts with CRC had PD. 3 V2 pts progressed prior to the first boost vaccination at 4 weeks suggesting treating in earlier lines may provide time to generate robust neoantigen-specific CD8 T cells. The most common (>20%) treatment-related adverse events (TRAEs) were low grade, transient pyrexia, fatigue, nausea, injection-site reactions, vomitting, and chills and consistent across V1 and V2. This off-the-shelf, neoantigen-specific vaccine demonstrated promising anti-tumor activity in pts with advanced solid tumors with tumor regression and/or molecular response.