Treatment stores

MRD-guided treatment approach generates excitement in stage II-III colon cancer

Using a circulating tumor DNA test to detect the presence of minimal residual disease may provide an opportunity to better inform treatment decisions in patients with early-stage colon cancer.

The use of a circulating tumor DNA (ctDNA) test to detect the presence of minimal residual disease (MRD) may provide an opportunity to better inform treatment decisions in patients with colon cancer at an early stage, according to Georges Azzi, MD.

Specifically, in the Phase 2/3 CIRCULATE-US study (NRG-GI008; NCT04089631), which plans to enroll approximately 2,000 patients with stage II or III colon cancer who have undergone resection, researchers will rely on the Signatera custom MRD test to determine status.1

Those determined to have MRD negativity will be randomized to receive standard of care (SOC) adjuvant chemotherapy or undergo observation unless ctDNA is subsequently detected. Those who test positive for MRD will be randomized to receive SOC chemotherapy or an intensified regimen of mFOLFIRINOX (oxaliplatin, leucovorin, irinotecan, and 5-fluorouracil).

“I encourage everyone to enroll in this study,” Azzi said. “This is an important study for our patients. He also gives [us] the potential to help advance science, and [for patients to] potentially skip chemotherapy and be closely monitored. If they are positive, [patients have] the ability to intensify therapy under study.

In an interview with Live®Azzi, co-director of the department of hematology/oncology, prostate cancer, at Holy Cross Health, discussed the promise of personalized, tumor-informed cDNA tests used for the detection of MRD and how this approach can potentially alter the management of patients with colon cancer.

Live®: What was the purpose of the CIRCULATE-US study?

Azzi: We know that adjuvant chemotherapy, as it stands today, does not cure all patients. The premise [of this research is] try and improve [upon what is seen with] the current adjuvant chemotherapy regimens that we give to patients after surgery. [We want] to be able to climb [treatment] in those patients who are [at] the highest risk [for recurrence].

The clinic’s most valuable tool for assessing where patients [fall] on this risk spectrum is the tumour-informed ctDNA, [which we use to assess] MRD. [We know that] patients who test positive 4 weeks after their surgery have a much higher risk of recurrence. This will be the premise of randomization in CIRCULATE-US, where there will be the ability to defuse [treatment] for negative patients and intensify for positive patients.

Could you tell us more about the design of the study and the methods that will be used? What are the main inclusion criteria?

From the published design of the study, we see that the plan is to perform a tumour-informed ctDNA test within 6-8 weeks of surgery. [The test results] will [help to] randomize [those with] stage [II or III disease]. They need an R0 resection, as well as a stable MMR and microsatellite [disease].

The ctDNA test used in this study will be Natera’s Signatera test. If ctDNA is detected, then there is randomization between the current standard of care, which is FOLFOX or CAPOX for 6 months, vs FOLFOXIRI. Yes [it is] not detected, there will be randomization between CAPOX or FOLFOX vs surveillance with serial ctDNA.

If the ctDNA is not detected, the patient will not continue to receive chemotherapy. However, if detected during follow-up, the patient will be randomized to receive 6 months of FOLFOX vs. FOLFOXIRI. They will join the second part of the study if the ctDNA is detected throughout the monitoring. This first arm will test chemotherapy given immediately versus delayed accelerated chemotherapy.

The ctDNA test you mentioned was also put to use in the CIRCULATE Japan study. What have been the results that have been reported from this study so far?

The study, which was the largest prospective tumor-based cDNA study performed [to date]enrolled 1200 patients. [Data] on the first [approximately] 800 patients were analyzed and presented. [We saw] high performance of the tests, with a preoperative detection rate of 95% in these patients.

After 4 weeks, [postoperative ctDNA positivity] was associated with [inferior disease-free survival] in patients with stage I to III disease, with a relative risk of 24.4. Yes [a patient] was positive, [ctDNA] was able to detect a relapse. [We saw] the ability to distinguish high-risk patients from patients who will fare better.

How did this ctDNA test become the test of choice for this study? Have we seen it approved for other indications?

Currently, this ctDNA test has the most validation data currently available and it has good performance for the detection of metastatic disease. In CIRCULATE Japan, we found a sensitivity of 93% [rate] for the detection of recurrences. I think that’s why this test was selected for [CIRCULATE-US].

[Beyond this, we have also] saw Medicare approval for follow-up immunotherapy [with the] tumour-informed tcDNA assay. The, [the assay is] used in advanced cancer to monitor molecular tumor burden. If patients respond [to treatment], you would see a decrease in molecular tumor burden whereas if they are unresponsive you would see an increase. To predict that at 6 weeks after treatment versus several months of imaging, [represents] the ability to detect response or progression, as well as the ability to differentiate pseudo-progression from progression, which is important with immunotherapy.

How could this test fill an unmet need?

If we don’t use a test like this, we’re in a black box setting, unable to tell who is high risk and who isn’t. We see the pathological criteria, even positive lymph nodes, and the hazard ratio is not as good for DFS prediction as the ctDNA test with the tumor-based approach. This is the best test we have to do [help us] differentiate the highest risks from the lowest risks.

The unmet need is the ability to identify patients who will relapse, potentially enrolling them in trials, such as CIRCULATE-US, and scaling up treatment to hopefully show a difference. On the other hand, in the future, [this may also be leveraged] to show that many patients can skip chemotherapy if they [test] negative.

Reference

  1. Natera’s Signatera Test Selected for NRG Oncology’s Landmark CIRCULATE-US Study of MRD-Guided Treatment in Stage II-III Colon Cancer. Press release. Natera, Inc.; September 7, 2021. Accessed February 22, 2022. https://bit.ly/3EOTJ2c