Cancer Vaccine Shows Efficacy and Safety Potential in PDAC and CRC

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Investigators of the AMPLIFY-201 trial hypothesized that ELI-002 2P may induce the expansion of functional tumor-directed KRAS-mutated specific T cells following tumor resection.

“In this first-in-human phase 1 trial, we demonstrated that lymph-node-directed ELI-002 2P vaccination targeting KRAS driver oncogenes present in one quarter of solid tumors is immunogenic in 84% of patients with minimal residual disease [MRD]–positive relapse after locoregional treatment,” according to the study authors.

“In this first-in-human phase 1 trial, we demonstrated that lymph-node-directed ELI-002 2P vaccination targeting KRAS driver oncogenes present in one quarter of solid tumors is immunogenic in 84% of patients with minimal residual disease [MRD]–positive relapse after locoregional treatment,” according to the study authors.

ELI-002 2P, a cancer vaccine, showed promising efficacy and tolerability in patients with KRAS-mutated pancreatic and colorectal cancers (CRC), according to results from the phase 1 AMPLIFY-201 trial (NCT04853017).

In 84% of patients, ex vivo KRAS-mutated specific T-cell responses were seen; 24% had biomarker clearance; and the median relapse-free survival was 16.33 months.

The cancer vaccine is made up of 3 components that target lymph nodes. The makeup of ELI-002 2P includes amphiphile-modified G12D and G12R KRAS-mutated peptides plus amphiphile-modified TLR9 agnostic CpG-7909 DNA.

The investigators hypothesized that using ELI-002 2P would induce the expansion of functional tumor-directed KRAS-mutated specific T cells, increase the potential for tumor activity by avoiding human leukocyte antigen loss during later disease stages, and reduce tumor biomarkers through T cell action.

“In this first-in-human phase 1 trial, we demonstrated that lymph-node-directed ELI-002 2P vaccination targeting KRAS driver oncogenes present in one quarter of solid tumors is immunogenic in 84% of patients with minimal residual disease [MRD]–positive relapse after locoregional treatment,” the study authors wrote.

A total of 25 patients were enrolled and dosed between October 2021 and April 2023. The fixed dose of the vaccine was 0.7 mg; however, doses could be escalated to 0.1 mg, 0.5 mg, 2.5 mg, 5.0 mg, and 10.0 mg in cohorts 1 through 5 with the use of a modified 3+3 design. To be enrolled on the trial, patients needed to have the presence of a KRAS mutation, be negative for overt disease, and have MRD that was adjudicated through circulating tumor DNA (ctDNA) positivity, and/or elevated serum tumor antigen, or CA19-9.

A tumor-informed ctDNA assay was used for 21 patients, and the remaining 4 patients had a serum-based assay. Of note, 13 patients discontinued treatment because of disease progression, but no patients discontinued due to toxicity. While on treatment, patients were not allowed to receive anti-tumor therapy, and subsequent therapy was reported during the 2-year follow-up.

The median patient age was 61.0 years, with a majority of patients being female (60%) and White (84%). Most patients had pancreatic adenocarcinoma (PDAC; 80%) compared with CRC (20%). Surgical pathology was considered, and most patients had stage III or resected oligometastatic stage IV disease (68%), and a minority of patients were node negative (24%). Overall, all patients were given previous chemotherapy, and 28% had prior radiation.

Grade 1/2 treatment-emergent adverse effects (TEAEs) were observed in 48% of patients, and no grade 3 or higher TEAEs were noted. TEAEs included fatigue (24%), injection site reaction (16%), and myalgia (12%). A grade 3 abdominal wall hematoma was considered a serious AE and resolved 8 days after onset. This serious AE was considered related to a biopsy that was conducted per protocol in relation to disease progression.

Injection site reactions were monitored through patient-reported outcomes. A total of 92% of patients reported mild symptoms, 56% had moderate symptoms, and 12% had severe symptoms.

The primary end point was met in determining the recommended phase 2 dose of 10.0 mg.

The secondary end point of tumor biomarker response was also evaluated. This was determined by any decrease in baseline ctDNA and/or serum tumor antigen levels and did not include subsequent biomarker values. A total of 84% of patients had a decline from baseline, 44% had a 30% or more drop, 32% had a 50% or more drop, and 24% had complete biomarker clearance. Of note, 5 of 6 clearances were determined through subsequent undetectable ctDNA values.

Biomarker declines were observed in 80% of patients with PDAC and 100% with CRC. There was a biomarker decline for 100% of patients with G12R mutations and 80% with G12D mutations. Biomarker responses were observed in all patients with G12D and G12R mutations.

Responses were recorded across all durations from prior surgery to chemotherapy with a median of 5.7 months. The median duration of study treatment was 20.1 weeks, 23 patients completed the prime series, 11 patients proceeded to the booster phase, and 11 completed all specified protocol therapy. Additionally, 1 patient continued treatment after cutoff.

Reference

Pant S, Wainberg ZA, Weekes CD, et al. Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial. Nat Med. Published online January 9, 2024. doi:10.1038/s41591-023-02760-3

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