Minimal Residual Disease–Directed Adjuvant Therapy for Patients With Early-Stage Colon Cancer: CIRCULATE-US

ABSTRACT

BACKGROUND: The ability to detect circulating tumor DNA (ctDNA), a novel surrogate for minimal residual disease (MRD) for patients with solid tumors, has significantly evolved over the past decade. Several studies have shown that ctDNA may provide clinical insight into the biological dynamics of MRD. The CIRCULATE-US (NRG-GI008; NCT05174169) trial will aim to address the role of ctDNA for risk stratification to intensify and deintensify adjuvant chemotherapy for patients with early-stage colon cancer.

METHODS: CIRCULATE-US, a prospective phase 2/3 randomized trial, is investigating the molecular dynamics and prognostic role of ctDNA (evaluated by Natera’s Signatera assay) for patients with resected colon cancer. Patients with negative postoperative ctDNA will be enrolled in cohort A and randomized to receive either immediate treatment with 5-fluorouracil and folinic acid or capecitabine plus oxaliplatin (FOLFOX6 or CAPEOX; Arm 1) or serial ctDNA surveillance with delayed adjuvant therapy (Arm 2). Patients randomized to Arm 2 with subsequent positive ctDNA results will be enrolled in cohort B for a second randomization to receive either FOLFOX6/CAPEOX (Arm 3) or 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan (FOLFIRINOX; Arm 4) for 6 months. Patients with positive postoperative ctDNA results will be directly enrolled in cohort B and randomized to receive either FOLFOX6/CAPEOX (Arm 3) or FOLFIRINOX (Arm 4). Patients with stage II or stage IIIC colon cancer with positive ctDNA results (tested as standard of care with commercial testing) will be eligible for enrollment in cohort B. The primary end point for cohort A is time to positive ctDNA status for phase 2 and disease-free survival for phase 3 with a noninferiority design. The primary end point for cohort B is disease-free survival for both phase 2 and phase 3 with a superiority design.

DISCUSSION: CIRCULATE-US will aim to understand postoperative ctDNA dynamics in early-stage colon cancer and will investigate escalation and de-escalation approaches by using ctDNA status as a surrogate for MRD status.

Oncology (Williston Park). 2022;36(10):604-608.
DOI: 10.46883/2022.25920976

Rationale

Management of early-stage colon cancer has evolved over the past decade, leading to improved survival outcomes particularly with evolution of adjuvant chemotherapy.^1,2 Historically, whether to use adjuvant therapy—and, if so, which type—was determined by using the tumor/node/metastasis (TNM) staging system and by considering high-risk clinical and pathological factors for recurrence, such as tumor grade, presence of lymphovascular or perineural invasion, tumor perforation, bowel obstruction, and positive margin. However, the TNM staging system and the prognostic factors used to determine adjuvant therapy regimens lack precision. Given that adjuvant chemotherapy is beneficial only for a subgroup of patients with colon cancer and because the long-term toxicities of chemotherapy agents, such as neuropathy, can significantly impact quality of life, a more precise identification of the patient population that would benefit from adjuvant chemotherapy is needed.

Minimal residual disease (MRD) is a well-defined risk factor for inferior outcomes for patients with several cancers. MRD can be detected with different methodologies; these include molecular methods with the use of cell-free tumor DNA (molecular residual cancer) or immunological methods including flow cytometry (used in liquid tumors). Moreover, MRD has long been utilized to determine treatment stratification for patients with acute myeloid leukemia.³ Research on circulating tumor DNA (ctDNA), a surrogate for MRD for patients with early-stage colon cancer, has rapidly evolved within the past decade. When investigating ctDNA in patients with stage II colon cancer, Jeanne Tie, MD, MBChB, and colleagues found that 79% of patients with positive postoperative ctDNA status, but only 9.8% of patients with negative ctDNA status, had recurrent disease (HR, 18; 95% CI, 7.9-40; P < .001).⁴ In another study among patients with stage III colon cancer who underwent serial ctDNA testing, Tie and colleagues again showed a significantly increased risk of recurrence for patients with positive ctDNA status after R0 resection (HR, 3.8; 95% CI, 2.4-21.0; P < .001).⁵ A study by Maximilian Diehn, MD, PhD, and colleagues investigated the role of ctDNA in R0 resected stage II and III colorectal cancer, and the 2-year relapse-free survival rate was 17% vs 88% for patients with positive and negative ctDNA status, respectively (HR, 10.3; 95% CI, 2.3-46.9; P < .00001).⁶ In the same study, time to recurrence was shorter for patients with positive ctDNA status (HR, 20.6; 95% CI, 3.1-139.0; P < .00001).⁶

More recently, the CIRCULATE-Japan study (jRCT1031200006) investigated serial ctDNA testing using Signatera assays.⁷ In this study, patients with positive ctDNA status 4 weeks after surgery had a significantly lower 1-year disease-free survival (DFS) rate compared with patients with negative ctDNA status (55.5% vs 95.2%, respectively; HR, 13.3; 95%, CI 8.0-22.2; P < .001). Notably, patients who remained ctDNA positive at 12 weeks after surgery and who had negative-to-positive seroconversion were found to be at further increased risk of recurrence at 6 months (HR, 15.8; 95% CI, 5.7-44.2; P < .001) compared with patients with negative ctDNA, indicating the greater importance of serial testing vs that of a single ctDNA test. The investigators also found that ctDNA clearance at 12 weeks was significantly higher for patients who received adjuvant chemotherapy for stage III disease (58% vs 11%; P <.001).⁷ Cumulative incidence of ctDNA clearance was also significantly higher for patients who received adjuvant therapy than for those who did not (67% vs 7% by 24 weeks; HR, 17.1; 95% CI, 6.7-43.4; P < .001). How ctDNA clearance correlates with clinical outcomes for these patients will require longer follow-up.

Collectively, these data indicate that ctDNA status is a clinically meaningful surrogate for MRD status for patients with colon cancer who are undergoing adjuvant therapy and that serial ctDNA can be utilized to escalate and de-escalate adjuvant therapy and to deliver adjuvant therapy to the right patient population more precisely than TNM staging.

Hypothesis

The primary hypothesis of this phase 2/3 randomized study is that patients with negative postoperative ctDNA results (considered MRD negative) can undergo serial ctDNA testing in place of immediate adjuvant chemotherapy without significant detrimental effect on the 3-year DFS rate with the introduction of adjuvant therapy at the time of seroconversion to positive ctDNA: phase 3 H0 (null hypothesis): 3-year DFS, 85.0% vs 74.6%; HR, 1.8; and alternative hypothesis (HA): 3-year DFS, 85.0% vs 82.1% (HR, 1.21), with a 90% power at α of 0.025 one-sided. For patients with positive postoperative ctDNA results (considered MRD positive), we hypothesize that escalation of chemotherapy to FOLFIRINOX in place of CAPEOX and FOLFOX will result in an improved 3-year DFS rate with a 33.3% risk reduction (phase 3 HA: HR of 0.667 or a 3-year DFS rate of 40.0% vs 54.3%, with a 90% power at α of 0.025 one-sided). The primary objective for cohort A (ctDNA negative) is to compare time to ctDNA positivity (phase 2) and DFS (phase 3) between immediate and delayed adjuvant chemotherapy arms. The primary objective for Cohort B (ctDNA positive) is to compare DFS between patients in the FOLFOX/CAPEOX and FOLFIRINOX arms for both phase 2 and phase 3 cohorts.

Eligibility

The study will enroll patients with histologically/pathologically confirmed stage IIIA/IIIB mismatch repair–proficient colon adenocarcinoma (T1-3, N1/N1c) with R0 resection and an ECOG performance status of 0 or 1. Patients with mismatch repair–deficient colon cancer or distal tumor extension of 12 cm or less from the anal verge or below the peritoneal reflection will not be enrolled in this study. Patients will be required to undergo Signatera ctDNA testing no longer than 8 weeks after surgical date to allow ctDNA results to be available and to initiate adjuvant therapy within acceptable 12 weeks postoperative period of time. Time interval between surgery (defined as postoperative day 7) and study entry must be within 60 days (ie, 67 days from date of R0 resection). Due to the potential false-negative risk of ctDNA testing and the inherently increased risk of recurrence of T4 or N2 disease, cohort A will not enroll patients with T4 or N2 disease. Patients with pathologic stage II or IIIC colon adenocarcinoma with R0 resection and commercially obtained Signatera ctDNA assay with positive results are eligible for enrollment in cohort B. These patients will require confirmatory central ctDNA testing before randomization in cohort B. Patients should have negative CT or MRI results for metastatic disease and adequate organ function within 28 days prior to enrollment. Patients with tumor perforation, history of prior colorectal cancer, previous systemic therapy or radiotherapy for colorectal cancer, or tumor histology other than adenocarcinoma will be excluded from the trial. Patients with a history of other active cancer within 5 years, bone marrow or solid organ transplant, or grade 2 or greater sensory or motor neuropathy will also be excluded. Patients with HIV who are on antiviral therapy and have a negative viral load are eligible for enrollment.

Interventions

In this randomized phase 2/3 trial, patients with negative ctDNA status will be included in cohort A and then will undergo randomization to either receive the standard of care with immediate adjuvant therapy for 3 to 6 months with FOLFOX6/CAPEOX (Arm 1) or undergo serial ctDNA testing without adjuvant therapy every 3 months (±21 days) over the first year and every 6 months throughout years 2 and 3 until ctDNA becomes positive (Arm 2). Patients randomized to Arm 1 will also undergo ctDNA testing at the same frequency. Patients in Arm 2 with subsequent positive ctDNA results will transition to cohort B and will undergo a second randomization to receive either 6 months of FOLFOX/CAPEOX (Arm 3) or FOLFIRINOX (Arm 4).

Patients with positive postoperative ctDNA status assessed no later than 8 weeks after R0 resection will be included in cohort B and randomized to either the standard-of-care arm with FOLFOX/CAPEOX (Arm 3) or the interventional arm with FOLFIRINOX for 6 months (Arm 4). All patients will undergo routine clinical and radiological surveillance with follow-up restaging scans every 6 months. Patients in cohort B will undergo the same serial ctDNA testing as those in Arm 2.

End Points and Statistical Plan

The primary end point of phase 2 for cohort A is time to ctDNA positivity, which is defined as the time from randomization to the first ctDNA-positive result after randomization to Arm 1 and the second ctDNA-positive result after randomization to Arm 2. The difference in definition of ctDNA positivity for Arm 1 and Arm 2 allows for the possibility that delayed chemotherapy on Arm 2 could seroconvert the patient back to negative ctDNA. Recurrence without a positive ctDNA result will be considered as an event for the primary end point for both arms (Arms 1 and 2). The last ctDNA test will be used to censor patients without any postrandomization positive ctDNA results. Patients with only 1 positive ctDNA result in Arm 2 will be censored at the last ctDNA test. The primary end point of phase 3 for cohort A and of phase 2/3 for cohort B is DFS, which is defined as time from randomization to recurrence or death from any cause.

The stratification factors for cohort A include disease stage (IIIA vs IIIB) and intended fluoropyrimidines chemotherapy (5-FU vs capecitabine). The stratification factors for Cohort B include intended fluoropyrimidines chemotherapy (5-FU vs capecitabine) and the initial postoperative ctDNA status (positive vs negative). The statistical design for cohort A is powered to prove the noninferiority of delayed adjuvant therapy with serial ctDNA testing compared with immediate adjuvant therapy (no more than a small detriment with delayed adjuvant chemotherapy under HA; phase 2: 1-year event-free rate for immediate and delayed adjuvant arms, 88.0% vs 85.7%, respectively [HR, 1.21]; phase 3: 3-year DFS rate, 85.0% vs 82.1%, respectively [HR, 1.21]).^5,8 The statistical design for cohort B is powered to prove the superiority of treatment intensification with FOLFIRINOX compared with standard arm with regard to 3-year DFS rate (HA for phases 2 and 3: 54.3% vs 40.0%, respectively [HR, 0.667]).⁵ The 1-sided type I errors of the noninferiority tests (Cohort A) are set to be 0.05 and 0.025 for phases 2 and 3, respectively. The type I errors of the superiority tests (Cohort B) are set to be 0.15 (1-sided) and 2.5% (1-sided) for phases 2 and 3, respectively.

Infographic. CIRCULATE-US

Study Status

The study was activated on March 1, 2022, through the National Cancer Institute’s National Clinical Trials Network and is actively recruiting across the United States. All United States cooperative groups (ALLIANCE, ECOG-ACRIN, SWOG, and NRG) through their network members are actively participating in the trial to enhance study recruitment. The study is expected to open at both community and academic institutions to maximize race, gender, and age diversity in the study cohorts.

ACKNOWLEDGMENTS: We thank Ashli Nguyen-Villarreal, Associate Scientific Editor, and Sarah Bronson, Scientific Editor, in the Research Medical Library at The University of Texas MD Anderson Cancer Center, for providing editorial assistance.

AUTHOR AFFILIATIONS

Ibrahim Halil Sahin, MD¹; Yan Lin, PhD^2,3; Greg Yothers, PhD^2,3; Peter C. Lucas, MD, PhD^3,4; Dustin Deming, MD⁵; Thomas J. George, MD⁶; Scott Kopetz, MD, PhD⁷; Christopher H. Lieu, MD^8*; and Arvind Dasari, MD, MS^7*

¹H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; ²NRG Oncology, Pittsburgh, PA; ³University of Pittsburgh, Pittsburgh, PA; ⁴National Surgical Adjuvant Breast and Bowel Project, Division of Pathology, NRG Oncology Biospecimen Bank, Pittsburgh, PA; ⁵University of Wisconsin Carbone Cancer Center, Madison, WI; ⁶University of Florida Health Cancer Center, Gainesville, FL; ⁷University of Texas MD Anderson Cancer Center, Houston, TX; ⁸University of Colorado Cancer Center, Aurora, CO

^*Denotes equal contribution.

CORRESPONDING AUTHOR

Ibrahim Halil Sahin, MD
Division of Hematology and Oncology University of Pittsburgh School of Medicine
UPMC Hillman Cancer Center
5150 Centre Ave, Pittsburgh, PA 15232
sahinih@upmc.edu
Tel: 412 623 3245; Fax: 412 692 4705

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