VOLTAGE-2: multicenter phase II study of nivolumab monotherapy in patients with mismatch repair-deficient resectable locally advanced rectal cancer

• Published in: ESMO Gastrointestinal Oncology Vol. 3; p. 100031
• Main Authors: Bando, H., Tsukada, Y., Kumagai, S., Miyashita, Y., Taketomi, A., Yuki, S., Komatsu, Y., Akiyoshi, T., Shinozaki, E., Kanemitsu, Y., Takashima, A., Shiozawa, M., Shiomi, A., Yamazaki, K., Matsuhashi, N., Hasegawa, H., Kato, T., Oki, E., Fukui, M., Wakabayashi, M., Fuse, N., Nishikawa, H., Ito, M., Yoshino, T.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.03.2024; Elsevier
• Subjects: locally advanced rectal cancer; mismatch repair deficiency; nivolumab; non-operative management; whole-exome- and whole-transcriptome-based tumor immune microenvironment testing; whole-genome-based minimal residual disease testing; whole-genome-based minimal residual disease testing; nivolumab; non-operative management; locally advanced rectal cancer; whole-exome- and whole-transcriptome-based tumor immune microenvironment testing; mismatch repair deficiency
• ISSN: 2949-8198; 2949-8198
• DOI: 10.1016/j.esmogo.2023.100031

Neoadjuvant radiotherapy and chemotherapy, followed by surgical resection, are standard treatments for locally advanced rectal cancer (LARC). Emerging evidence has shown the efficacy of anti-programmed cell death protein 1 (anti-PD-1) therapy for patients with mismatch repair-deficient (dMMR) colorectal cancer, particularly in managing metastatic disease. Several ongoing clinical trials evaluating the efficacy of anti-PD-1 therapy in patients with dMMR LARC have reported outstanding responses. Here, we present the VOLTAGE-2 study (EPOC 2201), a non-randomized, single-arm, phase II trial that aims to investigate the efficacy and safety of nivolumab monotherapy for 1 year in patients with dMMR-resectable LARC. Patients with clinical complete response (cCR) or near-complete response (nCR) will be observed with non-operative management (NOM) using the Memorial Sloan Kettering Regression Schema. The primary endpoint will be investigator-determined 2-year cCR rate for nivolumab monotherapy. We will investigate the surrogacy of circulating tumor DNA assay as a cCR using whole-genome sequencing (WGS)-based molecular residual disease (MRD) assay and will evaluate the biomarkers of the response to anti-PD-1 antibody using whole-exome sequencing (WES) plus whole-transcriptome sequencing (WTS)-based tumor genomics and immune microenvironment evaluations. We plan to carry out spatiotemporal trans-omics analyses using artificial intelligence and deep learning-driven genomics, transcriptomics, radiomics, pathomics, colonoscopic imaging, quality of life, and clinical features. Specifications tableSubject areaMedicine and DentistryMore specific subject areaMismatch repair-deficient locally advanced rectal cancerName of your trial in progressThe VOLTAGE-2 study (EPOC2201)Reagents/toolsThe study treatments will include 12 cycles of nivolumab monotherapy, administered at a dose of 240 mg every 2 weeks, followed by assessments using Memorial Sloan Kettering Regression Schema. If a clinical complete response (cCR) or near-complete response (nCR) is observed, non-operative management (NOM) will be pursued, with an additional 12 cycles of nivolumab. In case of an incomplete response (IR), we will shift to standard chemoradiotherapy, followed by surgical intervention.Trial designThe VOLTAGE-2 study is a non-randomized, single-arm, phase II trial. Eligible patients must be aged ≥18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and have a histological diagnosis of rectum adenocarcinoma (≤12 cm from the anal verge). The trial will include patients with cStage II (cT3-4N0M0), or cStage III (cTanyN1-2M0). The primary endpoint is the 2-year cCR. Assuming null and alternative hypotheses of cCR rates at 23% and 45%, respectively, the required sample size for primary cohort is 35. The statistical analysis will employ a one-sided alpha of 5% and aim for statistical power of 85%. In addition, as an exploratory cohort, 20 patients with cStage I (cT1-2N0M0) will be included, and the same study treatment will be carried out.Trial registrationjRCT2031220484EthicsThe trial protocol was reviewed and approved by the institutional review board of each participating site before study initiation. The study will be conducted in accordance with the tenets of the Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent will be obtained from all patients.Value of the trial in progress•This trial will investigate the efficacy and safety of 1-year of nivolumab monotherapy in patients with dMMR-resectable LARC.•We will investigate the surrogacy of ctDNA assay as cCR by using WGS-based MRD assay and will evaluate the biomarkers of the response of anti-PD-1 antibody using WES/WTS-based tumor genomics and immune microenvironment evaluations.•We are planning spatiotemporal, trans-omics analyses using AI- and DL-driven genomics, transcriptomics, radiomics, pathomics, colonoscopic images, quality-of-life assessments, and clinical features. •The efficacy of anti-PD-1 therapy in dMMR LARC patients is promissing responses.•The VOLTAGE-2 study investigates the efficacy and safety of 1-year nivolumab.•Patients with cCR or nCR will be observed with NOM.•WGS-based MRD assay will be used as the surrogacy of cCR.•WES/WTS-based tumor genomics and immune microenvironment will be evaluated.