Genomics-Driven Clinical Trials Scarce in Cancer Therapy

Davendra Sohal, MD, MPH

The promise of precision oncology remains largely unfulfilled because of a shortage of clinical trials, according to a Cleveland Clinic prospective cohort study.

The study of tumor genetics from 250 patients found actionable alterations in two-thirds of samples, but in the end, only about 10 percent of the patients received tumor genomics-driven targeted therapies.

“There’s a lot of talk of genomics in cancer care, and this is one of the first prospective studies to evaluate whether it is feasible, No. 1 and, No. 2, if it leads to an improvement in clinical outcomes, based on tumor genomics,” said Cleveland Clinic medical oncologist Davendra P.S. Sohal, MD, MPH, the study’s principal investigator.

The study’s findings were featured at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

Clinical trials lacking

The problem, according to Dr. Sohal, is that there simply aren’t enough clinical trials. Their scarcity results from the significant expense, resources and regulatory steps that a trial entails, he said. Thus, patient access is limited.

“We need more clinical trials here and at other institutions,” he said. “All institutions have trials for three or four of these drugs, whereas there are about 30 to 40 targets for which there are drugs out there. If every institution has access to only three or four, then patients have very limited options.”

Cancers are increasingly seen as diseases of the genome, according to Harold Varmus, the former director of the National Cancer Institute, writing in NCI’s “Update” blog. The characterization of genetic and protein abnormalities now often determines how cancers are diagnosed and treated. Precision medicine uses genetic information from an individual’s cancer to determine the most effective treatment, and allows the use of an agent targeted to that specific genetic abnormality.

Study assesses feasibility

Cleveland Clinic’s study was intended to identify the presence of actionable alterations in a limited cohort, and to determine their impact on management decisions.

To be eligible, patients were required to have pathologic diagnosis of select solid tumor malignancies without a known curative option. They had to be 18 years or older and with an ECOG PS 0-2 (The Eastern Cooperative Oncology Group’s scale of Performance Status [PS] is a recognized method to quantify the functional status of cancer patients).

Test results in less than a month

Tumor samples were sequenced using an advanced molecular panel (FoundationOne™, Cambridge, MA) to detect as many as 315 candidate genes. Cleveland Clinic’s Genomics Tumor Board reviewed the results with an eye toward biologically actionable alterations which would ideally correspond to an approved therapy in the solid tumor under study or another solid tumor, a clinical trial, or a contraindication to a targeted therapy. Trial outcomes were feasibility and clinical impact of tumor sequencing. All patients gave written informed consent, and the median time from consent to genomic test was 26 days.

“So we showed ultimately that in less than one month from patient consent, we can get the result and make a recommendation,” said Dr. Sohal.

Actionable alterations, but a shortage of trials

Enrollment of the 250 patients took place between August 2013 and October 2014. They were a median of 60 years old, 122 (49 percent) were male, and 220 (88 percent) were white. They had a variety of cancers including head and neck (10 percent), pancreatobiliary (12 percent), lung (13 percent), breast (18 percent) and colorectal (25 percent).

Twenty-seven of the samples (11 percent) had insufficient tissue for analysis. Of the remaining 223, an alteration was found in 96 percent (n = 214). The Genomics Tumor Board declared 141 (63 percent) of alterations to be biologically actionable. However, only 11 percent (n = 24) of patients received tumor genomics-driven targeted therapies: 12 went on clinical trials, three received on-label drugs, and nine received off-label drugs. Lack of clinical trial access was the most common reason for non-recommendation/receipt of genomics-driven therapy.

A step toward better results

“I want to say that precision oncology is feasible, but clinical impact requires better access to clinical trials,” said Dr. Sohal. “So in theory it sounds all great, and we have shown the first practical test of this, and there is still work to be done.”

Nevertheless, many lessons were learned, he said.

“I think it raises awareness as to how to do this right, and how to incorporate Genomics Tumor Boards in these decisions, because these are complicated decisions — what to recommend to a patient,” Dr. Sohal said. “And it raises awareness that we need more clinical trial access for patients before we can have better results.”