In cancer treatment, time is of the essence. Our Curious Dr. George asks Kevin B. Knopf, MD, MPH, Chief Medical Officer at Cadex Genomics, how his company’s new test, Alibrex, could rapidly reveal how well a given treatment is working for a given patient.
Curious Dr. George: The U.S. Food and Drug Administration has approved about 270 anti-cancer drugs. The National Comprehensive Cancer Network publishes guidelines for treatment of about 61 major cancer types. Although there is consensus on first- and second-line therapy, there may be a substantial delay before a patient’s oncologist can determine whether the therapy chosen is working for them. Your company Cadex Genomics has a new test to evaluate whether an agent is active against a tumor in a given patient. You claim that your test, Alibrex, is agnostic to tumor type, tissue of origin, and the name of the drug and can give an answer quickly. Can you describe the test, how it works, and how it is performing at this early time?
Kevin B. Knopf, MD, MPH: Alibrex is being developed to identify stage IV cancer patients who are not responding to treatment, allowing for an early switch to more effective therapy. Specifically, the test identifies patients whose tumor is rapidly growing during treatment. Alibrex requires a blood draw prior to therapy being administered, and another prior to the next cycle of treatment. Using quantitative polymerase chain reaction qPCR technology, cell-free DNA (cfDNA) concentration levels are measured in each blood draw to determine if the tumor is growing.
The concept is straightforward: as tumors grow, the amount of cfDNA the tumor sheds into the blood increases. Alibrex takes advantage of this by picking up the increase in cfDNA and determining whether the patient has disease progression. The advantage of evaluating cfDNA versus circulating tumor DNA (ctDNA) is that all tumors shed cfDNA with increasing amounts as the tumor grows. Compared to cfDNA, ctDNA is a far more complex approach in that different tumors shed different types of ctDNA.
A concern with this approach is that increases in cfDNA may be seen from other non-cancer-related sources, such as infections, white blood cell lysis, injury, or a number of other events unrelated to tumor growth. It is possible for a patient with such an event, prior to a blood draw, to have a result that is a false positive or negative due to the impact of changing levels of non-cancer cfDNA.
To overcome this problem, Alibrex assesses short cfDNA fragment lengths; it has been published and recognized that short cfDNA fragments are specific to cancer. By focusing on short cfDNA fragments, Cadex Genomics has developed a tumor-agnostic biomarker that is uniquely fit for purpose as a therapy monitoring tool.
To be able to detect small changes in cfDNA, Alibrex must be highly reproducible and have very low limits of detection to meet the performance necessary for clinical utility. We achieve this by targeting a non-coding region of DNA that has 1,800 copies in every cell and is located across all 23 chromosomes. Alibrex can detect differences in cfDNA levels in less than what is in a single cell.
Alibrex has been analyzed in two patient cohorts. The first, a study of 32 stage IV colorectal cancer patients at MD Anderson Cancer Center, demonstrated a sensitivity of 63% and specificity of 100%. A later multi-center study (74 lung, breast, and colorectal cancer patients) on an optimized version of the assay, demonstrated that Alibrex has a sensitivity of 88% and a specificity of 100%. By the end of August of 2023, we will have expanded this 74-patient analysis to 150 patients. Prior to making the test available to patients in the clinical setting, we will validate the assay in a 100-patient lung cancer study.
In clinical practice, we anticipate Alibrex being used monthly to determine if a patient is developing progressive disease and not responding to therapy. We do not anticipate Alibrex to be an imaging replacement; rather, we see the potential of imaging being used in significantly longer intervals.
In the future, with additional studies, Alibrex may potentially be used to monitor therapy in the neoadjuvant setting and to monitor prostate cancer patients who are in active surveillance.
Dr. Knopf is also Chief Medical Officer and Division Chief of Hematology and Oncology at Highland Hospital in Oakland, CA. He can be reached at firstname.lastname@example.org.
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