Disclosures: Morris reports an advisory board role with Array Biopharma/Pfizer and a data safety monitoring board role with Incyte, as well as research support from Array Biopharma/Pfizer, AstraZeneca, Bristol-Myers Squibb, EMD Serono and Immatics.
May 06, 2020
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COBRA trial to assess whether circulating tumor DNA can guide colon cancer treatment

Disclosures: Morris reports an advisory board role with Array Biopharma/Pfizer and a data safety monitoring board role with Incyte, as well as research support from Array Biopharma/Pfizer, AstraZeneca, Bristol-Myers Squibb, EMD Serono and Immatics.
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Van K. Morris, MD
Van K. Morris

Circulating tumor DNA has shown great promise as a blood-based, prognostic biomarker for patients with colon cancer, with detectable levels after resection considered an indicator of elevated risk for recurrence.

However, research has not yet established a definitive role for circulating tumor DNA (ctDNA) in the customization of therapy for these patients, particularly in terms of postoperative or adjuvant chemotherapy.

To evaluate the potential of ctDNA as a predictive tool to identify patients who may or may not benefit from adjuvant chemotherapy, NRG Oncology launched the GI005 trial, also known as the COBRA trial.

The NCI-led trial, which opened to accrual in December, is projected to enroll more than 1,400 patients with resected stage IIA colon cancer that is considered low risk and, under current practice standards, would not typically necessitate adjuvant chemotherapy.

Participants will be randomly assigned to either close observation — the standard of care — or prospective testing for ctDNA.

Those whose upfront testing reveals detectable ctDNA would be deemed at high risk for recurrence and would then receive 6 months of adjuvant chemotherapy. Patients who are tested but have no detectable ctDNA will be categorized as lower risk and will be managed with active surveillance.

Additionally, blood samples will be collected from patients in the observation group and assessed years later for ctDNA. These ctDNA levels then will be compared with the ctDNA clearance rate of those who undergo chemotherapy.

“Current clinical criteria used to define low-risk or high-risk stage II colon cancer are not great in identifying who benefits from adjuvant chemotherapy,” Van K. Morris, MD, assistant professor of gastrointestinal oncology at The University of Texas MD Anderson Cancer Center, principal investigator of the COBRA trial and a HemOnc Today Next Gen Innovator, said in an interview with Healio. “This study may help to define more precisely those patients at higher or lower risk for recurrence in order to inform us better on when adjuvant chemotherapy should be used.”

Morris spoke with Healio about his hopes for the study and what the results could mean for future indications of adjuvant chemotherapy.

Question: What do you hope to learn as far as predicting the efficacy of adjuvant chemotherapy following resection among these patients with colon cancer?

Answer: Recommendations in the NCCN Guidelines for Colon Cancer list observation, single-agent fluorouracil and FOLFOX as acceptable adjuvant treatment options for patients with stage II colon cancer. There currently is no predictive biomarker for patients with stage II colon cancer that definitively guides clinicians in distinguishing those at high risk for recurrence, who would benefit from adjuvant chemotherapy, from those at low risk for recurrence, who should not experience the otherwise unnecessary toxicity of chemotherapy. Although ctDNA has shown prognostic importance in distinguishing the likelihood of recurrence for patients with resected colon cancer, we hope to provide level one evidence that ctDNA status can serve as a beneficial predictive biomarker that can help guide the decision-making process for oncologists when considering adjuvant chemotherapy for stage II colon cancer.

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Q: Will the fact that this population has low-risk disease that would otherwise not warrant adjuvant chemotherapy influence how well they do with this treatment?

A: We deliberately chose a population of patients with stage IIA colon cancer who would not receive adjuvant chemotherapy under current practice patterns in order to eliminate the possibility that standard therapies otherwise would be withheld from these patients. The study design was discussed carefully with patient advocates and bioethicists, who agreed that the concept of equipoise was being upheld.

Q: How do you hope to use the information you glean from this trial in clinical practice?

A: This is the first prospective study supported by the NCI for any solid tumor that seeks to investigate ctDNA as a predictive biomarker for adjuvant chemotherapy following definitive resection. We hope to demonstrate utility with this approach, which could then refine further the indications for adjuvant chemotherapy in stage II colon cancer.

Q: Do you think ctDNA testing is on its way to becoming standard practice for guiding treatment of patients with resected colon cancer?

A: Our understanding is that CMS/Medicare does not plan to cover this technology until there is level one evidence for its use as a predictive biomarker. Although there have been other prognostic assays in the past for patients with stage II colon cancer, none has distinguished which patients do or do not benefit from adjuvant chemotherapy. It is our hope that this trial will change that.

Q: What is unique about the LUNAR-1 assay, which will be used for this trial, and how do you expect it to increase sensitivity in detecting residual disease?

A: In addition to capturing somatic mutation information, the LUNAR-1 assay (Guardant Health) is also able to identify colorectal cancer-specific methylation patterns. Given that patients with minimal residual disease will have very low tumor burden after surgery, the ability to uncover both genomic and epigenetic features of these tumors will help to improve the needed sensitivity for assay performance. – By Jennifer Byrne

For more information:

Van K. Morris, MD, can be reached at 1400 Holcombe Blvd. #463, Houston, TX 77030.

Disclosure: Morris reports an advisory board role with Array Biopharma/Pfizer and a data safety monitoring board role with Incyte, as well as research support from Array Biopharma/Pfizer, AstraZeneca, Bristol-Myers Squibb, EMD Serono and Immatics.