Targeting minimal residual disease (MRD) in resected RAS mutated pancreatic cancer with vaccine TG01/QS-21+/- PD-1 inhibitor, balstilimab: A randomized phase II study (TESLA).

TPS4205 Background: MRD detected by presence of circulating tumor DNA (ctDNA) after intended curative treatment is associated with high risk of relapse in pancreatic cancer. Early treatment of patients with presence of ctDNA after completion of surgery +/- adjuvant therapy may offer an opportunity to clear ctDNA and improve outcomes. TG01 is a RAS-neoantigen peptide vaccine adjuvanted by QS-21 (Stimulon) targeting the seven most frequent codon 12-13 RAS mutations. TG01 has previously demonstrated ability to activate mutant RAS specific CD4+ and CD8+ T-cell responses in vaccinated patients and repeated TG01 dosing in resected pancreatic cancer was found to be well tolerated and associated with a median OS of 33.4 months (95% CI 24.0, 45.8) 1,2 . Checkpoint inhibitors as single agents have not shown anti-tumor activity in pancreatic cancer, suggesting that a priming agent inducing tumor-specific T-cells may be required to support efficacy. Balstilimab is a human monoclonal antibody targeting programmed cell death protein 1 (PD-1) which is intended to reverse the immunosuppressive effects of this signaling pathway in the context of tumor immuno-surveillance by T-cells. Methods: Design: A two-arm, open-label, phase II randomized trial of TG01/QS-21 vaccine or TG01/QS-21 vaccine plus balstilimab (n=12 per arm, N=24) with surgically resected Stage 1-3 RAS mutant PDAC who are MRD+ following completion of standard adjuvant chemotherapy. Assay: MRD is detected by a commercially available ctDNA assay (Signatera, Natera). Somatic variants are identified by whole–exome sequencing of the primary tumor and the matched normal (whole blood) sample and a bespoke assay of up to 16 clonal, somatic variants are generated for each patient. This “tumor signature” will be monitored in plasma throughout the study. Treatment schedule: A priming phase of six vaccine administrations once every two weeks followed by a maintenance phase of administrations once every 8 weeks for up to 51 weeks. Balstilimab will be administered every 2 weeks for up to 51 weeks beginning at week 3. Imaging assessment will be done every 12 weeks. Eligibility: Surgically resected pancreatic adenocarcinoma with pathogenic RAS mutation, and no evidence of recurrent disease on baseline imaging. Inclusion criteria also include ECOG PS 0-1, and positive Signatera ctDNA MRD. Objectives: The primary objective is to assess the 6-month molecular disease control rate as defined by ctDNA stable, decreased or cleared. Secondary objectives include safety of TG01/QS-21 with or without balstilimab, 6 and 12-month DFS rate in each cohort, as well as correlation between the depth of molecular response and DFS. Exploratory: changes in clonality of RAS mutations and assess immune response. Enrollment is ongoing. 1) Gjertsen MK et al. Int J Cancer 1997, 72(5) 784-90. 2) Palmer DH et al. Br J Cancer 2020 122:971-77. Clinical trial information: NCT05638698 .