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

Abstract

Background

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.

Patients and methods

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.

Graphical abstract

Specifications table

Subject area	Medicine and Dentistry
More specific subject area	Mismatch repair-deficient locally advanced rectal cancer
Name of your trial in progress	The VOLTAGE-2 study (EPOC2201)
Reagents/tools	The 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 design	The 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 registration	jRCT2031220484
Ethics	The 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.

Highlights

• •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.

Description of protocol

Introduction

Background and rationale

Neoadjuvant radiotherapy and chemotherapy, followed by surgical resection, have become standard treatments for locally advanced rectal cancer (LARC).^1,2 These approaches result in pathological complete response (pCR) in 10%-30% of patients. However, surgical resection often results in bowel, urinary, and sexual disorders, significantly impacting the quality of life (QoL). Owing to the functional disorders of surgery, organ-sparing non-operative management (NOM) is positively conducted in patients with clinical complete response (cCR) or near-complete response (nCR).³ Given the responsiveness of anti-programmed cell death protein 1 (anti-PD-1) therapy in patients with mismatch repair-deficient (dMMR) colorectal cancer in the context of metastatic disease, several ongoing clinical trials are assessing the efficacies of anti-PD-1 therapy in patients with dMMR LARC, and they have indicated outstanding responses.⁴

Objectives

This trial aims to demonstrate that anti-PD-1 antibody contributes to cCR and improves long-term outcomes. In addition, we will investigate the surrogacy of ctDNA assay as a cCR by using whole-genome sequencing (WGS)-based molecular residual disease (MRD) assay and will evaluate the biomarkers of the response to anti-PD-1 antibody by using whole-exome sequencing (WES)- plus whole-transcriptome sequencing (WTS)-based tumor genomics and immune microenvironment evaluations.

Methods

Trial design and treatment

The VOLTAGE-2 study (EPOC 2201) is a non-randomized, single-arm, phase II trial (Figure 1). Case registration is carried out via an electronic data capture system called RAVE EDC. Eligible patients will be enrolled and undergo treatment with 12 cycles of nivolumab monotherapy, administered at a dose of 240 mg every 2 weeks. After 12 cycles (∼6 months) of nivolumab, a comprehensive tumor assessment and restaging process will be initiated. This includes evaluations based on colonoscopy; pelvic magnetic resonance imaging (MRI); digital findings; and chest, abdominal, and pelvic computed tomography (CT) scans, according to the Memorial Sloan Kettering (MSKCC) Regression Schema⁵ and RECIST version 1.1. Patients with cCR or nCR based on MSKCC Schema will be placed under observation with a NOM approach and will be treated with an additional 12 cycles of nivolumab (24 cycles). In contrast, those with incomplete response (IR) will undergo chemoradiotherapy (CRT) with capecitabine (1650 mg/day) and 50.4/28 Gy of radiation. In the event of residual disease following CRT, tumor resection including total mesorectal excision (TME) or local excision will be carried out based on the residual lesion. The assessment of cCR, nCR, or IR will be determined at the investigator’s discretion, guided by recommendation from a designated NOM committee composed of experts.

Figure 1.

Phase II single-arm, multicenter study.cCR, clinical complete response; CR, complete response; CT, computed tomography; ctDNA, circulating tumor DNA; DFS, disease-free survival; dMMR, mismatch repair-deficient; ECOG, Eastern Cooperative Oncology Group; i.v., intravenous; MRI, magnetic resonance imaging; OS, overall survival; PS, performance status; W, weeks.

Eligibility criteria

The eligibility criteria are listed in Table 1. The major eligibility criteria is as follows: treatment-naive patients with rectal cancer located ∼12 cm from the anal verge; confirmed dMMR; clinical stage II or III for primary cohort, and stage I in exploratory cohort; age ≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; and presence of sufficient organ function.

Table 1.

Inclusion and exclusion criteria

Inclusion criteria
1.Histologically confirmed diagnosis of adenocarcinoma of the rectum
2.Distance from the anal verge <12 cm
3.Microsatellite instability-high or mismatch repair deficient
4.Age ≥ 18 years
5.Clinical stage II (T3–4, N–) or stage III (any T, N+) in primary cohort and clinical stage I (T1-2 N0 M0)a in exploratory cohort according to the tumor–node–metastasis eight edition
6.Expected curative resection according to imaging diagnosis
7.Provided written informed consent
8.ECOG performance status of 0 or 1
9.No pelvic radiation history
10.For women of childbearing potential (including those who do not menstruate for medical reasons such as chemical menopause),b patients consent to double contraceptionc and limited egg donation (including egg collection for own use) for at least 5 months (for at least 7 months during CRT and after the last dose of capecitabine, if CRT is administered) after the last dose of nivolumab from the time of informed consent. In addition, patients must consent not to breastfeed for at least 5 months after the last dose of nivolumab from the time of informed consent (or during CRT and for at least 7 months after the last dose of capecitabine if CRT is administered).
11.Men who undergo CRT should use appropriate contraceptiond as defined in this study during CRT and for at least 7 months after the last dose of capecitabine and agree not to cryopreserve or donate sperm.
12. Adequate organ function, as defined below a. Hemoglobin level: ≥8.0 g/dl b. Neutrophil count: ≥1500/mm3 c. Platelet count: ≥75 000/mm3 d. PT/INR: ≤1.5 × ULN e. Albumin level: ≥2.5 g/dl f. T-Bil: ≤1.5 × ULN (allows up to ≤2.5 × ULN for Gilbert syndrome) g. AST/ALT: ≤3.0 × ULN h. Serum creatinine level: ≤1.5 mg/dl or creatinine clearancee: ≥45 ml/min
Exclusion criteria
1.More than one type of active cancer (double cancer or a disease-free period of <5 years at enrollment). However, carcinoma in situ that are determined to be cured via local treatment are not considered an active cancer. Patients with multiple cancers in the colon and rectum are eligible if there is no distant metastasis and all lesions can be surgically resected
2.History of inflammatory bowel disease
3.History of pneumonitis or ILD
4.Active or history of autoimmune disease
5.Requirement of systemic adrenocortical hormones or immunosuppressants (excluding temporary use for testing, prophylaxis against allergic reactions, or reduction of edema associated with radiation therapy)
6. Patients with active or a history of cardiovascular risks, such as the following: • Left ventricular EF <50% • History or evidence of clinically significant uncontrolled arrhythmia • History of acute coronary syndrome (including myocardial infarction and unstable angina), coronary angioplasty, or stent placement within 6 months before enrollment • History of or evidence of congestive heart failure grade II or higher according to the NYHA classification of cardiac function • Refractory hypertension (hypertension >140 mmHg systolic and >90 mmHg diastolic and uncontrolled with antihypertensive therapy) • Presence of implantable cardioverter-defibrillators or permanent pacemakers
7.Uncontrolled diabetes or other illnesses that may interfere with evaluation of toxicity
8.HIV-1 antibody and HIV-2 antibody positive, HTLV-1 antibody positive, HBs antigen positive, or HCV antibody positive. In addition, patients with HBs antigen negative but either HBs antibody positive or HBc antibody positive with HBV-DNA above the detection sensitivity are excluded.
9.Pregnant or lactating patients and those who may be pregnant
10.Serious, unstable psychiatric disorders, or other medical conditions that may interfere with the patient’s safety, informed consent, or adherence to study procedures
11.Use of anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody, anti-CTLA-4 antibody, or other therapy for the purpose of controlling T cells
12.Receipt of a live or attenuated vaccine within 28 days before enrollment
13.Unwillingness or inability to comply with protocol-specified procedures
14.Unsuitable for the study, as judged by the investigator

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRT, chemoradiotherapy; CTLA-4, cytotoxic T-lymphocyte associated protein 4; ECOG, Eastern Cooperative Oncology Group; EF, ejection fraction; HBc, hepatitis B core; HBs, hepatitis B surface; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ILD, interstitial lung disease; INR, international normalized ratio; NYHA, New York Heart Association; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PT, prothrombin time; ULN, upper limit of normal.

^aNo expectation of a curative resection via endoscopic or local resection.

^bA woman of childbearing potential is any woman who has experienced menarche, has not undergone surgical sterilization (such as hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), and has not undergone menopause. Postmenopause is defined as ≥12 consecutive months of amenorrhea for no other reason. Women using oral contraceptives or mechanical contraceptive methods, such as intrauterine devices and barrier methods, are of childbearing potential.

^cThe patient must agree to use double contraception with either a vasectomy or a condom for the male partner, tubal ligation, a contraceptive diaphragm, an intrauterine device, or oral contraceptives.

^dFor contraception, the patient must agree to double contraception with any two of the following: personal vasectomy or condoms, partner tubal ligation, contraceptive diaphragm, intrauterine device, or oral contraceptives.

^eFor creatinine clearance, both calculated values using the Cockcroft and Gault formula and 24-h urine collection values are acceptable.

Follow-up

After the completion of the study treatment, a follow-up evaluation will be conducted, consisting of endoscopy, chest, abdominal, and pelvic CT, and pelvic MRI, scheduled every 12 weeks for up to 96 weeks from time of patient enrollment. If rectal region regrowth is observed during NOM within the protocol treatment period (96 weeks from patient enrollment), CRT-naive patients will be transitioned to CRT, and CRT-experienced patients will be transitioned to salvage surgery.

Outcomes

The primary endpoint is the investigator-determined 2-year cCR rate of nivolumab monotherapy, which is defined as the proportion of patients who achieved and maintained cCR at 2 years with nivolumab monotherapy according to both the MSKCC Regression Schema and the RECIST ver.1.1, as determined by the investigator.

The secondary endpoints of the study include the following: 2-year cCR rate across protocol treatments (including CRT), 2-year cCR + pathological complete response (pCR) rate, centrally adjudicated 2-year cCR rate for nivolumab monotherapy, protocol treatment completion rate, recurrence form, progression-free survival (PFS), event-free survival (EFS), disease-free survival (DFS), 2-year TME-free rate (2-year TME-free rate), TME-free survival, TME-free PFS, distant metastasis-free survival (DMFS), local recurrence-free survival (LRFS), overall survival (OS), rate of treatment-related adverse events (AEs) assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, perioperative safety assessment (intraoperative and surgical complications accessed by CTCAE v5.0 and Clavien-Dido classification v 2.0), QoL evaluation during treatment and up to 5 years after treatment, and a circulating tumor DNA (ctDNA) negative conversion rate. The secondary endpoints in patients who undergo NOM include the following: local regrowth rate, time to local regrowth, and the rate of radical resection in patients who undergo salvage surgery (Table 2).

Table 2.

Primary and secondary endpoints

Primary endpoint

Investigator-determined 2-year cCR rate of nivolumab monotherapy

Secondary endpoints

Two-year cCR rate across protocol treatments (including CRT)

Two-year cCR + pCR rate

Centrally adjudicated 2-year cCR rate for nivolumab monotherapy

Protocol treatment completion rate

Recurrence form

PFS

EFS

DFS

Two-year TME-free rate

TME-free survival

TME-free PFS

DMFS

LRFS

OS

Rate of treatment-related AEs accessed by the CTCAE ver5.0

Perioperative safety assessment (intraoperative and surgical complications accessed by CTCAE ver5.0 and Clavien-Dido classification ver. 2.0)

QoL evaluation during treatment and up to 5 years after treatment

ctDNA-negative conversion rate

Endpoints in patients with NOM

Local regrowth rate

Time to local regrowth

Percentage of radical resection of salvage surgery

AEs, adverse events; cCR, clinical complete response; CTCAE, Common Terminology Criteria for Adverse Events; ctDNA, circulating tumor DNA; CRT, chemoradiotherapy; DMFS, distant metastasis-free survival; EFS, event-free survival; DFS, disease-free survival; LRFS, local recurrence-free survival; NOM, non-operative management; OS, overall survival; pCR, pathological complete response; PFS, Progression-free survival; QoL, quality of life; TME, total mesorectal excision.

Planned sample size and study period

The primary cohort will comprise 35 patients with stage II-III disease. Additionally, 20 patients with stage I disease will be included in the exploratory cohort. The enrollment period commenced in January 2023 and is expected to continue until March 2025. The follow-up period extends for 2 years following the completion of enrollment, and the entire trial period is scheduled to conclude in March 2027.

Statistical methods

This study should include 35 patients with resectable dMMR/MSI-H rectal cancer in the full analysis set (FAS).

The sample size was calculated based on an exact binomial distribution method, taking into account the primary endpoint (2-year cCR rate) with a threshold of 23%, an expected value of 45%, a one-sided significance level of 5%, and a power of 80%. To fulfill the requirements of 34 patients with stage II/III resectable rectal cancer and dMMR, the target number was set at 35, accounting for potential ineligibility among patients. If 34 patients are included and ≥13 achieve 2-year cCR with nivolumab therapy alone, the results will be statistically significant. However, if the FAS includes <34 patients after enrolling 35 patients, additional patients will be enrolled to meet the desired sample size.

Translational research

Primary tumor tissues for translational research (TR), including WES/WTS-based tumor genomics and immune microenvironment evaluations using ImmunoID NeXT® (Personalis, Inc., CA), will be collected at five different time points: (i) at the time of enrollment, (ii) 6 weeks after enrollment, (iii) 12 weeks after enrollment, (iv) 24 weeks after enrollment, and (v) 48 weeks after enrollment. Moreover, peripheral blood samples for liquid biopsy using NeXT Personal® (Personalis, Inc., CA) will be collected at 10 different points: (i) at the time of enrollment, (ii) 6 weeks after enrollment, (iii) 12 weeks after enrollment, (iv) 24 weeks after enrollment, (v) 36 weeks after enrollment, (vi) 48 weeks after enrollment, (vii) 60 weeks after enrollment, (viii) 72 weeks after enrollment, (ix) 84 weeks after enrollment, and (x) 96 weeks after enrollment. Additional blood samples will be collected during local tumor regrowth and/or recurrence. NeXT Personal is a tumor-informed MRD assay that uses up to 1800 variants identified across WGS for each patient. In addition, we plan to conduct single call-based spatial transcriptome and microbiome analyses using serially collected tissues and fecal samples.

Integrated analysis of spatiotemporal trans-omics using artificial intelligence (AI) and deep learning (DL)

The data collected in this trial (including clinical data, CT, MRI, colonoscopic images, pathological images, WGS/WES/WTS, liquid biopsy, and QoL data) will be integrated into a single database. To identify predictive markers for the response to nivolumab, the decision of NOM, and the prediction of recurrence or regrowth, we plan to employ spatiotemporal and trans-omics analyses using AI- and DL-driven genomics, transcriptomics, radiomics, pathomics, colonoscopic images, QoL, and clinical features.

Committee associated with the trial

Non-operative management Committee

A NOM committee has been established for consultation when the co-investigator overseeing the facility encounters uncertainties regarding restaging evaluations or local regrowth during NOM. This committee is responsible for evaluating relevant cases and then providing appropriate advice to the co-investigator based on the results of the evaluation.

Conclusion

Here, we describe the methodology of the VOLTAGE-2 study, which aims to investigate the efficacy and safety of nivolumab monotherapy in patients with dMMR LARC. Previous MSKCC trial investigated the efficacy and safety of 6 months of dostarlimab monotherapy in patients with stage II/III dMMR LARC.⁴ The main differences between MSKCC trial and our trial are as follows: We carry out 1-year nivolumab monotherapy because we expected longer consolidation therapy will be desirable to ensure cCR. In addition, 2-year cCR rate is the primary endpoint of our trial because the regrowth of primary LARC will reach a plateau according to several registry data in patients with microsatellite stable LARC.^6,7 We also carry out both WES/WTS-based tumor genomics/immune microenvironment evaluations and a WGS-based tumor-informed MRD assay as translational researches. Our approach involves the integration of spatiotemporal trans-omics data, using AI and DL techniques that will enable the precise prediction of the efficacy of nivolumab and facilitate informed decisions regarding NOM.