The role of ctDNA, or liquid biopsy, as a predictive tool to guide and monitor cancer treatment, remains unclear after the first prospective randomised phase II trial evaluating clearance of ctDNA as a primary endpoint using adjuvant chemotherapy in patients with stage II colon cancer did not meet its endpoint.

The NRG-GI005 (COBRA) phase II/III study was halted after the results of the pre-planned phase II analysis found that the use of chemotherapy did not increase the rate of ctDNA clearance among patients who had detectable ctDNA after surgery when compared to patients who did not receive chemotherapy. The research was presented at the 2024 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, taking place January 18-20 in San Francisco, California and online.

In the COBRA study, 635 patients with resected stage II colon cancer without traditional high-risk features – including, but not limited to, presence of perineural invasion, tumour perforation, and/or obstruction at initial presentation – were randomised 1:1 to two arms: 318 patients in Arm A received the current standard-of-care (close observation without chemotherapy); 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 six months of adjuvant (CAPOX or FOLFOX) chemotherapy. The primary endpoint was clearance of ctDNA after six months.

The researchers compared ctDNA clearance between Arm A and Arm 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 3/7 patients (43%) in Arm A and in 1/9 pts (11%) in Arm B (p=.98).

The study was stopped per protocol after the phase II endpoint was not satisfied.

“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 six months. While the investigators’ pre-planned 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, ASCO Expert in Gastrointestinal Cancers.

“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 Van K. Morris, MD from the University of Texas MD Anderson Cancer Center.

The authors plan to continue to follow the study participants for survival and recurrence outcomes.

The study was sponsored by the National Cancer Institute and received funding from Guardant Health.

Source: ASCO