Pathologists and medical lab scientists may do more consults with interdisciplinary teams in connection with biomarker-based phase I clinical trial selection
Scientists are beginning to incorporate next-generation gene sequencing into a growing number of clinical trials. This is an important development because knowledge developed in clinical trials often forms the foundation for the evidence-based medicine guidelines issued following a successful clinical trial.
Further, these new uses for gene sequencing can directly lead to new opportunities for clinical laboratories and pathology groups. That’s because the increased use of gene sequencing for patients participating in clinical trials may well provide the necessary evidence to support new molecular diagnostics assays and genetic tests that physicians would use in support of therapeutic drugs cleared for market.
Significantly, genetic analysis of patients enrolled in advanced cancer clinical trials may be poised to replace traditional enrollment approaches. This is because researchers using next-generation gene sequencing are demonstrating that a “molecular triage” model for a clinical trial can increase efficiency, reduce costs, and shorten early pharmaceutical development time.
Phase I Trial Relies Exclusively on Molecular Screening for Enrollment
Separate clinical studies have demonstrated that molecular screening can optimize treatment for advanced-stage cancer patients in Phase I clinical trials. For example, a completed prospective clinical trial in the United States assigned cancer treatment for patients using genetic analysis exclusively. The trial, called CUSTOM, involved patients diagnosed with advanced-stage non-small cell lung cancer, small cell lung cancer, or thymic cancer, according to a press release issued by Georgetown University Medical Center, where this clinical trial was conducted.
The molecular approach showed multiple advantages over the traditional histology-based approach. “The traditional methodology used to design and execute clinical trials is dated, inefficient and expensive,” wrote Giuseppe Giaccone, M.D., PhD., and his colleagues in the abstract that was published on the American Society for Clinical Oncology website.
“The CUSTOM’s clinical trial design is one approach to increase the efficiency, reduce the cost, and increase the speed of the early phase pharmaceutical development process,” stated Giaccone, who is Associate Director for Clinical Research at Georgetown Lombardi Comprehensive Cancer Center, Georgetown University. He led the CUSTOM trial while at the National Cancer Institute, where he served as Chief of the Medical Oncology Branch, prior to joining Georgetown. Researchers at Oregon Health & Science University also participated.
Opportunity for Molecular Portraits of Tumors
Patients in the CUSTOM clinical study submitted additional biopsies in order to find and target the genetic mutations driving their cancer. Surprisingly, they and their physicians proved eager to have the tumors genetically analyzed—in spite of the requirement of an additional biopsy.
“We expected it would take five years to enroll 600 patients into CUSTOM,” stated Giaccone in the press release. “But in less than two years, 668 patients were recruited.”
Study Points to Use of Molecular Screening in Clinical Practice
Researchers in France are conducting an ongoing study called MOSCATO (Molecular Screening for Cancer Treatment and Optimization). They presented their findings thus far at the 24th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Dublin, Ireland, in November.
More than 95% of the eligible patients agreed to enroll in the trial, according to a story published in ScienceDaily. Molecular analysis proved feasible in more than 85% of the patients. Molecular alterations were detected in 50%. Of those, 30% were allocated to a specific trial on the basis of the analysis.
Increased Rates of Partial Response Rates
Phase I trials with all-comers typically have partial response rates of between 7% and 10%, wrote Christoffe Massard, M.D., and colleagues in the abstract accompanying the presentation. By contrast, the partial response rate in Phase I trials stemming from more molecularly targeted trial enrollment is currently closer to 20%, they observed.
Massard is a medical oncologist and senior consultant at Institut Gustave-Roussy in Villejuif, France, a suburb south of Paris.
Clinical Trial Patients Are Willing to Undergo Molecular Analysis
“The most important findings at the moment are that this approach is feasible in the context of daily practice, and the patients are very keen to participate [in] this program,” stated Massard in the ScienceDaily piece. “For some patients, the results of the [molecular] analyses changed the Phase I trials and treatments for which they were being considered.”
The MOSCATO investigators attributed the success of molecular screening in Phase I trials to:
1) advances in the ability to characterize genomic changes that drive an individual patient’s tumor in a timely manner; and
2) patient and physician interest in this type of personalized medicine.
Pathologists Have Role in These Clinical Trials
Further, Massard noted that the availability of a multi-disciplinary panel of experts is crucial for molecular screening. In MOSCATO, a team of clinicians, interventional radiologists, pathologists, biologists, bioinformaticians, and statisticians meet regularly to discuss the results and implications of the molecular analyses.
“Characterization of the genomic alterations that could drive tumor growth of an individual patient is now critical to better select targeted therapies in Phase I trials,” Massard and colleagues concluded in the abstract.
For pathologists and clinical laboratory managers, there are two significant takeaways from this e-briefing. First, accelerating stakeholder acceptance means that we may see more molecular marker-based clinical trials launching in the near future. Second, if major clinical trials for drug approvals are increasing their use of genetic testing and analysis, regular clinical use of genetic testing as part of the therapeutic drug selection process may not be far behind.
—Pamela Scherer McLeod