The role of circulating tumor DNA (ctDNA), or liquid biopsy, as a predictive tool to guide and monitor cancer treatment remains unclear, after the first prospective randomized phase II trial evaluating clearance of ctDNA in patients with stage II colon cancer receiving adjuvant chemotherapy did not meet its endpoint. The NRG-GI005 (COBRA) phase II/III study was halted after the results of the preplanned phase II analysis found the use of chemotherapy did not increase the rate of ctDNA clearance among patients who had detectable ctDNA after surgery compared with patients who did not receive chemotherapy. The research will be presented at the 2024 ASCO Gastrointestinal Cancers Symposium by Van K. Morris, MD, and colleagues (Abstract 5).
Van K. Morris, MD
About the Study
In the COBRA study, 635 patients with resected stage II colon cancer without traditional high-risk features—including, but not limited to, the presence of perineural invasion, tumor perforation, and/or obstruction at initial presentation—were randomly assigned 1:1 to two arms: 318 patients in arm A received the current standard-of-care (close observation without chemotherapy), and 317 patients in arm B received ctDNA assay–directed therapy. Patients in arm B without ctDNA detection were allowed to continue with close observation. For arm B, participants with ctDNA detected were treated with 6 months of adjuvant CAPOX (capecitabine and oxaliplatin) or FOLFOX (fluorouracil, leucovorin, and oxaliplatin) chemotherapy. The primary endpoint was clearance of ctDNA after 6 months.
Key Findings
The researchers compared ctDNA clearance between arms A and B among the first 16 patients with ctDNA detected in their postoperative blood analysis. If the P value was greater than .35 (P > .35), the study would be stopped for futility and not continue to the phase III portion.
Among the first 16 patients with detected ctDNA, clearance of ctDNA after 6 months was observed in three of seven patients (43%) in arm A and in one of nine patients (11%) in arm B (P = .98). The study was stopped per protocol after the phase II endpoint was not satisfied.
“The real-world applications of liquid biopsy for patients with gastrointestinal cancers continue to evolve rapidly. While the results of this specific trial are disappointing, continued enhancements to ctDNA assay characteristics and performance coupled with the unmet clinical needs of patients keep future ctDNA trials highly relevant for the foreseeable future,” said lead study author Dr. Morris, of The University of Texas MD Anderson Cancer Center.
The authors plan to continue to follow the study participants for survival and recurrence outcomes.
ASCO Expert Perspective
Cathy Eng, MD, FACP, FASCO
“The consideration of adjuvant chemotherapy in the stage II setting has always remained a shared decision-making process. The consideration of ctDNA positivity was in the hopes as a surrogate marker to guide the use of adjuvant chemotherapy by attaining ctDNA clearance at 6 months. While the investigators’ preplanned interim analysis was unable to determine any improvement in ctDNA clearance, the role of ctDNA must continue to be explored,” said Cathy Eng, MD, FACP, FASCO, an ASCO Expert in gastrointestinal gancers.
Disclosure: The study was sponsored by the National Cancer Institute and received funding from Guardant Health. For full disclosures of the study authors, visit coi.asco.org.
