Phase 2/3, randomized, open-label study of an individualized neoantigen vaccine (self-amplifying mRNA and adenoviral vectors) plus immune checkpoint blockade as maintenance for patients with newly diagnosed metastatic colorectal cancer (GRANITE).

Abstract

TPS3635 Background: Treatment options for most patients with metastatic colorectal cancer (mCRC) are largely limited to cytotoxic chemotherapy, with little advancement in the last decade. Encouragingly, a small subset of patients deficient in mismatch repair (dMMR/MSI-hi) benefit from checkpoint inhibitors (CPI) whereas those proficient in mismatch repair (pMMR/MSS) do not. The absence of clinical benefit in patients with pMMR/MSS mCRC may relate to a lack of neoantigen-specific T cells and immune infiltration. An individualized neoantigen vaccine that induces CD8 T cells capable of tumor lysis has the potential to expand the number of patients with mCRC who may benefit from immunotherapy. Data from a Phase 1/2 study evaluating neoantigen vaccines in combination with CPIs in patients with previously treated mCRC demonstrated a 44% molecular response (MR) rate (≥50% decrease in ctDNA relative to baseline) in 4/9 patients; this correlated with improvement in OS relative to those without a MR. To further investigate neoantigen vaccines in earlier lines of treatment, a Phase 2/3 study in the1L maintenance setting in mCRC was initiated. Methods: GO-010 is a Phase 2/3, randomized, open-label, multi-center study evaluating the efficacy and safety of 2 neoantigen-containing vectors (GRT-C901-adenoviral vector plus GRT-R902-self-amplifying mRNA vector) as prime/boost in combination with CPIs as an add-on to fluoropyrimidine/bevacizumab (bev) following 1L therapy with FOLFOX/bev in patients with mCRC. During Phase 2, up to 90 patients will be randomized 1:1 to the vaccine or control arm with a primary objective of assessing efficacy by MR. During Phase 3, up to 226 patients will be randomized with a primary objective of assessing PFS per iRECIST in a blinded, independent manner. There are two stages to the study. In the vaccine production stage, while patients receive FOLFOX/bev 1L therapy, neoantigen prediction is performed using a tumor biopsy and Gritstone’s EDGE™ neoantigen prediction model. For patients in the vaccine arm the top 20 predicted neoantigens are included in the vaccine vectors. After completing oxaliplatin, patients will enter the study treatment stage. Patients in the control arm will continue with maintenance therapy whereas patients in the vaccine arm will add the vaccine regimen to maintenance therapy. The vaccine regimen consists of GRT-C901/GRT-R902 as well as SC ipilimumab (30 mg) and IV atezolizumab (1680 mg). Over the first year of treatment, 6 vaccinations will occur. Ipilimumab will be administered SC with the first doses of GRT-C901 and GRT-R902. Atezolizumab will be administered every 4 weeks for up to 2 years. Study assessments include imaging, ctDNA, safety, immunogenicity and exploratory biomarker analysis. Clinical trial information: NCT05141721.

mRNA vaccines in the prevention and treatment of diseases

“…Furthermore, the 1‐year OS rates were 96% for melanoma, 83% for NSCLC, and 67% for bladder cancer, all of which were superior to the historical data obtained from programmed death‐1 inhibitor monotherapy 271 . The existing clinical data suggest that in the treatment of tumor types with a high mutational burden (e.g., melanoma and NSCLC) and mismatch repair‐deficient colorectal cancer, neoantigen vaccines used in combination with immune checkpoint inhibitors should be the focus of future research, because they may provide synergistic effects to enable a higher response rate and PFS 228,258,259,271 …”

“…Neoantigens originate from random somatic mutations in tumor cells and do not exist in normal cells. Therefore, neoantigens are recognized as nonself by the immune system and are presented to T cells by human leukocyte antigen (HLA), which makes them the most promising target for tumor vaccines 252–259 . Compared with a TAA‐targeted vaccine, a neoantigen‐based vaccine provides inspiring advantages: first, due to the constrained expression of neoantigens in tumor cells only, neoantigen vaccines elicit a true tumor‐specific T‐cell response, and avoid off‐target damage to nontumorous tissues.…”

“…271 The existing clinical data suggest that in the treatment of tumor types with a high mutational bur-den (e.g., melanoma and NSCLC) and mismatch repairdeficient colorectal cancer, neoantigen vaccines used in combination with immune checkpoint inhibitors should be the focus of future research, because they may provide synergistic effects to enable a higher response rate and PFS. 228,258,259,271 Although neoantigen vaccines have great prospects, the design of such vaccines depends heavily on the continuous optimization of algorithms, including HLA typing, binding strength of neoantigens and MHC, and T cell receptor (TCR) analysis. They are further limited by the median time from screening neoantigens to vaccine preparation of 103 days (ranging from 89 to 160 days), which is too long for patients with advanced tumors who urgently demand individualized treatment.…”

“…Therefore, neoantigens are recognized as nonself by the immune system and are presented to T cells by human leukocyte antigen (HLA), which makes them the most promising target for tumor vaccines. [252][253][254][255][256][257][258][259] Compared with a TAA-targeted vaccine, a neoantigen-based vaccine provides inspiring advantages: first, due to the constrained expression of neoantigens in tumor cells only, neoantigen vaccines elicit a true tumor-specific T-cell response, and avoid off-target damage to nontumorous tissues. Next, a substantial fraction of nonsynonymous neoantigens causes strong immunogenicity, 260 this is perhaps due to the fact that somatic mutated neo-epitopes manage to bypass the central tolerance.…”

Cancer vaccines in the clinic

“…Gritstone's most advanced trial is a Phase 2/3 trial for metastatic colorectal cancer (NCT05141721), which is buoyed by positive results from a Phase 1/2 trial (GRANITE).Results showed that four of nine patients experienced a molecular response to the therapy, defined by a > 50% reduction in circulating tumor DNA (ctDNA). Median survival in this group exceeded 18 months, compared with 7.8 months among non-responders, with median overall survival (OS) not yet reached at the time of last report 77. Among all viral trials, the majority exclusively target TAAs (23/38, 60.5%), while some target exclusively neoantigens (7/38, 18.4%) (Figure6c).…”