ĎADAPTí or fail?
IRVING, Texas—Aimed toward targeting the ideal candidates to improve the results of cancer patient study outcomes, Caris Life Sciences, a leading molecular science innovator, has announced new data supporting the use of its revolutionary ADAPT Biotargeting System to drive clinical trial success. The results, presented June 21 at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer 2018 in Barcelona, Spain, showed that an assay built using the ADAPT platform was able to identify responders and non-responders from the unsuccessful MAESTRO Phase 3 clinical trial in advanced pancreatic cancer.
Researchers found that if the assay had been used to stratify patients, the study would have had a significant probability of meeting the primary endpoint—rather than the low percentage actually achieved in the threshold trial.
“Clinical studies that do not use biomarkers or use single biomarkers to identify potential drug responders are evaluating investigational drugs on molecularly heterogeneous populations,” says Dr. W. Michael Korn, chief medical officer at Caris Life Sciences. “These studies can often result in failed clinical trials and limit patient access to potentially useful drugs.”
“However, with our ADAPT Biotargeting System, we are able to simultaneously identify multiple targets and develop a molecular signature tuned to those patients that will likely benefit from the therapy and those that will not,” adds Korn. “Specifically for this study, we set out to demonstrate that a clinical trial leveraging the ADAPT Biotargeting System would be more likely to succeed.”
This is the first time “that our ADAPT Biotargeting System was applied to tumor samples from a clinical trial,” says David Spetzler, Caris Life Sciences’ president and chief scientific officer. “Our analysis suggests that if ADAPT had been used to enroll patients in the MAESTRO study, the probability of success would have been 98 percent.”
ADAPT “is a revolutionary new technology that creates new opportunities to make molecular medicine a reality and further our understanding of complex diseases like cancer, and help a countless number of patients,” Spetzler tells DDNews. “There are multiple ADAPT products in our pipeline, spanning diagnostic, responder/non-responder and drug target identification in prostate, pancreatic, ovarian and colon cancers.”
“In the threshold study, we found that the assay was also able to predict gemcitabine response, thus we are performing analytic validation of the assay for this purpose and evaluating the need for a follow-on clinical study,” he adds.
The MAESTRO Phase 3 clinical trial randomized patients with locally-advanced or metastatic pancreatic cancer to receive gemcitabine plus placebo or gemcitabine plus evofosfamide, according to the presentation. The clinical trial failed to meet the primary endpoint of 33 percent improvement in median overall survival (OS).
The hypothesis of the study states that biomarker-based selection of patients for study accrual might have led to success. That’s because Caris’ ADAPT Biotargeting System employs poly-ligand profiling to survey a vast array of potential biomarkers and create a molecular profile that can identify patients most likely to derive clinical benefit from a given therapeutic regimen.
Biopsy samples from known responders and non-responders in the study were used to train a library of more than one trillion oligodeoxynucleotides with aptameric-binding properties. The resulting trained library was then tested on specimens from a fully blinded cohort of 172 patients from the MAESTRO study (122 primary tumors and 49 metastatic tumors).
The original MAESTRO study demonstrated a median OS increase of 17.4 percent for the combination arm compared to gemcitabine monotherapy. Based on the ADAPT assay results in the test cohort of 172 patients where tissue was available, 1,000 trial simulations were performed to model the assay impact for the 693 patients enrolled in the study by randomly assigning all patients to either study arm and generating Kaplan-Meier plots.
The ADAPT patients resulted in a predicted 37.6 percent median OS increase for all patients and a predicted 54.9 percent increase in median OS for patients whose specimens came from primary tumors. Aptamers from the trained library were used as affinity purification probes to isolate biomarkers from FFPE specimens. High-resolution mass spectrometry detected 20 proteins, 11 of which were previously associated with pancreatic cancer and six of which have been reported to play roles in gemcitabine resistance.
In the near future, the ADAPT Biotargeting System “will have a significant impact on the approval rates for new drugs, as the subset of patients that benefit from the new therapy can be identified and targeted,” Spetzler says. “ADAPT creates the opportunity for the creation of companion diagnostics without the need to know the biomarkers ahead of time. It can also find new drug targets, creating novel opportunities to improve patient outcomes. We have also shown that ADAPT works in blood plasma and is able to identify patients with early-stage cancer, so it can be used to create non-invasive diagnostics tests as well.”
“We anticipate that this study, along with work evaluating patient benefit of trastuzumab therapy in HER2+ breast cancer, will lead to additional collaborations with biopharmaceutical companies, and ultimately to the prospective incorporation of ADAPT in cancer drug development,” he concludes.