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Precision medicine approach improves outcomes in phase 1 trials
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Patients treated in phase 1 trials designed with a biomarker-based approach for treatment selection demonstrated higher response rates and longer PFS, according to results of a meta-analysis scheduled for presentation at the ASCO Annual Meeting.
Further, genomic biomarkers were associated with better outcomes than treatment selection based on protein biomarkers, results showed.
Maria Schwaederle
“There have been breathtaking advances in our ability to perform genomic [analyses] that help us understand the underlying biology of tumors,” Maria Schwaederle, PharmD, researcher in the Center for Personalized Cancer Therapy and division of hematology and oncology at University of California, San Diego, said during a press briefing. “However, the usefulness of a biomarker-driven approach for treatment selection is still a matter of debate in the community.”
Typically, phase 1 studies are composed of a small group of patients with the primary goal of assessing an experimental drug’s safety, not its efficacy.
“Our analysis shows that this belief is completely outdated, and that with biomarker selection, especially with genomic biomarkers, we can reach high response rates, even in phase 1 trials,” Schwaederle said.
Researchers searched PubMed to identify 351 phase 1 studies published between 2011 and 2013 that reported efficacy endpoints. Fifty-eight of these studies were considered “personalized,” meaning they tested for a biomarker used for treatment selection, or at least 50% of patients are known to harbor the biomarker based on the specific malignancy studied.
The meta-analysis included data from 13,203 patients. Outcome variables included response rate and PFS; OS could not be included because it was rarely reported in phase 1 studies.
The median response rate of personalized trials was significantly higher than that of trials that were not personalized (31% vs. 5%; P < .0001).
Forty-five trials also reported PFS data (personalized, n = 7). Those with biomarker-selected therapies reported significantly longer median PFS rates than trials without a personalized approach (5.7 months vs. 2.95 months; P = .0002).
“One question that is often asked is if this is simply about having a better therapy,” Schwaederle said. “But, our analysis showed this is not just that the therapies are better, but that targeted therapies must be given to the right patients.”
Fifty-seven of the studies assigned therapy based on biomarkers, 177 studies assigned targeted therapies without biomarker selection and 117 studies evaluated cytotoxic treatments.
An analysis based on these subgroups showed the median response rate was significantly higher in trials with targeted arms with biomarker selection vs. without (31.1% vs. 5.1%; P < .0001).
Further, although a biomarker approach with genomic or protein biomarkers improved response compared with no biomarker selection, the effect of genomic biomarkers was more profound. Median response rate was 42% with genomic biomarkers compared with 22.4% with protein biomarkers (P = .001).
“A biomarker-based approach was the most significant independent predictor of improved outcomes in phase 1 studies,” Schwaederle said. “Targeted drugs in and of themselves were not effective — they absolutely need to be given to the right patients.” – by Alexandra Todak
Perspective
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Don S. Dizon, MD, FACP
This is an important study that had a very large dataset for analysis the study included over 13,000 patients in phase 1 trials. The results showed that precision medicine is here, and that we can select patients using changes in the tumors DNA, or genomics changes, or even protein biomarkers and do much better than we have done in the past.
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