Circulating tumor DNA (ctDNA) has become an established biomarker of measurable or molecular residual disease (MRD) after curative-intent surgery in patients with colorectal cancer. The research focus is now on linking ctDNA to long-term outcomes and using it to guide treatment decisions—which was the aim of several studies presented at the 2024 ASCO Gastrointestinal Cancers Symposium.

Pashtoon M. Kasi, MD, MS

Hiroki Yukami, MD, PhD

Jeanne Tie, MD

Van Karlyle Morris, MD

The first results from the BESPOKE CRC trial were presented by Pashtoon M. Kasi, MD, MS, of Weill Cornell Medicine in New York.¹ “We found that ctDNA detection of MRD is a powerful prognostic and predictive tool in patients with stage II and III colorectal cancer,” Dr. Kasi said.

A disease-free survival analysis of the prospective, observational GALAXY study in stage II to IV colorectal cancer, part of the CIRCULATE-Japan project, was presented by Hiroki Yukami, MD, PhD, of the Cancer Chemotherapy Center and Osaka Medical and Pharmaceutical University in Takatsuki, Japan.² “Our data demonstrate the prognostic value and predictive capabilities of ctDNA detection analyzed in almost 3,000 patients at 24 months. Sustained ctDNA clearance was significantly associated with more than 90% disease-free survival,” Dr. Yukami said.

The phase II AGITG DYNAMIC-Rectal trial examined the utility of ctDNA after surgery for locally advanced rectal cancer.³ “The ctDNA-informed approach to adjuvant therapy following neoadjuvant chemoradiation and surgery was associated with a reduced rate of chemotherapy,” said Jeanne Tie, MD, of the Peter MacCallum Cancer Centre in Australia.

In contrast to those three positive studies, the phase II/III NRG-G1005 (COBRA) study, which sought to validate the clinical utility of plasma-only ctDNA as a predictive biomarker in a randomized trial, failed to demonstrate its benefit in guiding adjuvant therapy selection,⁴ according to Van Karlyle Morris, MD, of The University of Texas MD Anderson Cancer Center in Houston.

BESPOKE CRC

BESPOKE CRC enrolled more than 1,700 patients with stage II/III colorectal cancer who underwent surgery and either started adjuvant therapy or were followed with observation.¹ Data are now complete for 623 patients, of whom 280 had stage II colorectal cancer, 343 had stage III disease, and 93 had detectable MRD by ctDNA between 2 and 12 weeks postsurgery (defined as the MRD-time point in this study—18 (6.43%) MRD-positive for stage II and 75 (21.87%) MRD-positive for stage III). Dr. Kasi described the following key findings:

• ctDNA positivity at any MRD testing point was prognostic for inferior disease-free survival.
• Adjuvant chemotherapy benefited patients with detectable MRD but not those with undetectable MRD.
• ctDNA positivity during surveillance was prognostic of inferior disease-free survival, regardless of the receipt of adjuvant chemotherapy.
• ctDNA positivity was predictive of the ­benefit of chemotherapy; ctDNA-positive patients followed with ­observation were significantly more likely to have a recurrence.
• Sustained ctDNA clearance was associated with superior disease-free survival compared with transient or no clearance.
• ctDNA testing was associated with an increased use of therapies directed at oligometastasis (in up to 40% of the instances).
• Patients appreciated the use of ctDNA and the information it produced in guiding their treatment.

The prognostic power of ctDNA for long-term outcomes was clear. Median disease-free survival was not reached in the undetectable-MRD cohort and was approximately 16 months in the detectable-MRD cohort; the 2-year disease-free survival was 92% vs 30%, respectively (hazard ratio [HR] = 12.1; P < .0001). Patients with detectable MRD treated with chemotherapy had a median disease-free survival of almost 18 months, vs 8 months with observation (HR = 3.06; P < .0025). Median disease-free survival was not reached in the undetectable-MRD group.

Despite receiving adjuvant therapy during surveillance, just 22% of ctDNA-positive patients were disease-free at 2 years, compared with 98% of the ctDNA-negative group (HR = 59.9; P < .0001). In the observation group, this rate was 13% vs 97%, respectively (HR = 80.0; P < .0001). Sustained clearance was important: 85% of patients with only transient clearance had disease recurrence within 15 months.

GALAXY Trial

GALAXY evaluated patients with stage II to IV resected colorectal cancer for up to 24 months after surgery.² Of 2,998 patients, 1,130 (38%) received adjuvant chemotherapy, and 1,868 (62%) were followed with observation. The primary endpoint was disease-free survival.

The clearance of ctDNA, especially if sustained, heralded significantly improved outcomes. Transient clearance on chemotherapy correlated with improved disease-free survival, compared with patients without such clearance, but prognosis remained poor. Dr. ­Yukami reported these key outcomes after 16 months’ median follow-up:

• 24-month disease-free survival was 85.9% for patients with no detectable ctDNA at 2 to 10 weeks after surgery and 28.9% for those with detectable ctDNA (HR = 10.53; P < .0001). In patients with stage II/III disease, this rate was 89.3% vs 33.5% (HR = 12.05; P < .0001), and ctDNA was the strongest predictor.
• Receipt of adjuvant chemotherapy for ctDNA positivity led to clearance in 66.3%.
• For patients with sustained ctDNA clearance, 24-month disease-free survival was 90.1% vs 2.3% for those with transient clearance (HR = 25.1; P < .0001) and 2.0% for those with no clearance (HR = 87.1; P < .0001).
• Return to positive status after transient clearance happened within 18 months for 98% of the patients who became ctDNA-positive again.
• A ≥ 50% reduction in ctDNA concentration at 6 months was associated with a 24-month disease-free survival of 51% vs 29% with less clearance.

AGITG DYNAMIC-Rectal Trial

The phase II AGITG DYNAMIC-Rectal trial examined the utility of ctDNA in guiding adjuvant therapy in 230 patients with locally advanced rectal cancer (cT3–4 and/or cN+) following treatment with neoadjuvant chemoradiation and total mesorectal excision.³ Of these patients, 75 underwent treatment of clinician’s choice, and 155 underwent ctDNA-informed management in which chemotherapy was delivered to those with a positive ctDNA test at weeks 4 and/or 7 after surgery. Patients with a negative ctDNA result received no chemotherapy if node-negative or clinician’s choice of treatment if node-positive. The ctDNA analysis was positive in 28% of patients.

The use of ctDNA to select patients for adjuvant chemotherapy resulted in a reduction in its use, as it was delivered to 46% of the ctDNA-guided arm (27% of ctDNA-positive patients, 16% of ctDNA-negative patients, and 3% of those with unknown status) vs 77% of the control arm, Dr. Tie reported.

The 3-year recurrence-free survival rates for ctDNA-guided management and standard management were 76% and 82%, respectively; however, the study’s sample size was too small to compare this outcome. A difference in 3-year recurrence rates was seen, however, between ctDNA-negative and ctDNA-positive patients—83% vs 53% (HR = 0.29; P < .001). The ctDNA-positive patients (all of whom were treated with adjuvant chemotherapy) were twice as likely as ­ctDNA-negative patients (only 23% received chemotherapy) to experience a relapse in a distant site and/or a locoregional site. Lung-only relapses predominate in ctDNA-negative patients, whereas the liver is the most common site of relapse in ctDNA-positive patients.

Dr. Tie cautioned: “The study’s small sample size precludes any conclusions to be drawn about the noninferiority in recurrence-free survival of ctDNA-informed vs standard management.”

COBRA Study

In contrast, the randomized phase II/III NRG-G1005 (COBRA) trial failed to show clinical utility in guiding adjuvant therapy and was closed early for futility.⁴ The study randomly assigned 635 patients with resected stage IIA colon cancer to active surveillance or assay-directed therapy in which patients received chemotherapy if ctDNA-positive (5.5% of the population) or active surveillance if negative. The primary endpoint was the rate of ctDNA clearance in the ctDNA-positive cohorts at 6 months after randomization to active surveillance or treatment.

Among the first 16 patients with ctDNA detected at baseline, 7 were randomly assigned to standard-of-care surveillance, and 9 were randomly assigned to adjuvant chemotherapy. The rate of ctDNA clearance after 6 months was 43% vs 11%, respectively (P = .98), indicating adjuvant chemotherapy was not more successful in clearing MRD, Dr. Morris reported.

“Using the selected ctDNA assay [LUNAR] in this clinically low-risk population, we did not observe an improvement in ctDNA clearance with 6 months of adjuvant chemotherapy,” he said. The “steady enrollment” to the study, Dr. Morris added, “confirms that prospective randomized controlled trials assessing ctDNA as an integral biomarker and as a surrogate for MRD are not only feasible but remain necessary for us to test and confirm clinically relevant hypotheses.” 

DISCLOSURE: Dr. Kasi has a leadership role with Precision Biosensors; has stock or other ownership interests in Elicio Therapeutics; has served as a consultant or advisor to Bayer, BostonGene, Daiichi Sankyo/AstraZeneca, Delcath Systems, Eisai, Elicio Therapeutics, Exact Sciences, Foundation Medicine, Guardant Health, Illumina, Ipsen, Eli Lilly, MSD Oncology, Natera, NeoGenomics Laboratories, QED Therapeutics, SAGA Diagnostics, Seagen, Servier, Taiho Oncology, Taiho Pharmaceutical, and Tempus; has received institutional research funding from Advanced Accelerator Applications, Boston Scientific, and TerSera; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca. Dr. Yukami reported no conflicts of interest. Dr. Tie has received honoraria from Astra Zeneca, Haystack Oncology, Merck Serono, Merck Sharp & Dohme, Pierre Fabre, Bristol Myers Squibb, Servier, Daiichi Sankyo, Gilead, Beigene, Illumina, and Takeda; and has received institutional research funding from Astra Zeneca, Pfizer, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Genentech, and Grail. Dr. Morris has served as a consultant or advisor to Incyte and Regeneron; and has received institutional research funding from Bicara Therapeutics, BioNTech, Bristol Myers Squibb, EMD Serono, Novartis, and Pfizer.

REFERENCES

1. Kasi P, Aushev VN, Ensor J, et al: Circulating tumor DNA for informing adjuvant chemotherapy in stage II/III colorectal cancer. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract 9. Presented January 20, 2024.

2. Nakamura Y, Mishima S, Ando K, et al: Circulating tumor dynamics in colorectal cancer patients with molecular residual disease. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract 6. Presented January 20, 2024.

3. Tie J, Cohen JD, Wang Y, et al: Circulating tumor DNA analysis informing adjuvant chemotherapy in locally advanced rectal cancer. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract 12. Presented January 20, 2024.

4. Morris VK, Yothers G, Kopetz S, et al: Phase II results of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract 5. Presented January 20, 2024.