A randomized phase 2 study of an individualized neoantigen-targeting immunotherapy in patients with newly diagnosed metastatic microsatellite stable colorectal cancer (MSS-CRC).

LBA13 Background: Neoantigen-targeting immunotherapy aims to provide therapeutic benefit to patients by generating potent neoantigen-specific T cells. GRANITE is an immunotherapy regimen that uses chimpanzee adenovirus and self-amplifying mRNA vaccines encoding patient-specific neoantigens in combination with immune checkpoint inhibitors. Preliminary efficacy was noted in MSS-CRC (Palmer et al Nature Medicine 2022) and this regimen is being assessed in a randomized Phase 2 study in 1L metastatic MSS-CRC (NCT05141721). Methods: Patients (pts) with 20 neoantigens based on the EDGEÔ prediction model were randomized 1:1 to receive the GRANITE regimen in addition to 1L standard of care (SOC) (GRANITE vaccine arm), or 1L SOC alone (control arm). Results: Baseline demographics and disease characteristics were balanced between arms. As of 15 Oct 2024, GRANITE pts had an improvement in PFS relative to control pts (HR=0.73, 90% CI [0.44, 1.21]). In this study, high and low disease burden groups were identified using baseline ctDNA assessed by Gritstone’s validated, highly sensitive, tumor-informed assay. Patients with low disease burden benefited more than those with high disease burden, consistent with emerging data suggesting neoantigen-targeting immunotherapy having greater activity in minimal disease settings (e.g., adjuvant setting). Furthermore, in the low disease burden group at the most recent study visit, more patients were free of progression with very low ctDNA levels (ie, below the limit of quantification of the assay) in the GRANITE arm, 41% (7/17), versus the control arm, 21% (3/14). The greater proportion of GRANITE patients both free of progression and with very low ctDNA, suggests potential further separation of PFS cuves with additional follow up. Neoantigen-specific T cell responses were observed in 100% of patients in the GRANITE arm with evaluable PBMC samples (17/17 assessed by ex vivo and in vitro stimulation ELISpots). Molecular responses based on a reduction in ctDNA at a single timepoint was similar between arms (39% in GRANITE and 40% in control arms). Most common (≥20%) treatment-related adverse events (TRAE) included pyrexia and influenza like illness and no pts discontinued due to a TRAE. Conclusion: This randomized study shows GRANITE may benefit patients, especially those with low burden disease, in this front line setting of metastatic MSS-CRC that has not benefitted from immunotherapy. Updated analysis will be presented. Clinical trial information: NCT05141721 .