Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Has Tumor Molecular Profiling Enabled More Effective and Less Toxic Cancer Treatment?

The Cancer Moonshot Blue Ribbon Panel in its 2016 report recommended the development of a federated, large-scale patient participation network through which patients will be offered comprehensive tumor profiling.

Information about tumor profiles and treatment outcomes in a linked network of databases would, the panel said, enable more precise knowledge about effective therapies, identify the patients in whom they will work, and in which types of cancer, as well as allow patients to “pre-register” for clinical trials. The information would also permit patients or their physicians to be contacted if their tumor’s molecular characteristics made them eligible for clinical trials that match their cancer profile.

Skepticism remains, however, about whether molecular profiling of individual tumors leads to more effective cancer treatment. Companies and organizations continue to push molecular profiling of individual tumors to determine the best treatment options while physicians, absent definitive data correlating profiles with specific treatments, have plenty of reservations about using them, and so do managed care organizations.

According to Michael J. Mike Pishvaian, MD, PhD, assistant professor at Georgetown in the Hematology/Oncology Department at Lombardi Comprehensive Cancer Center, in a 2014 interview with MedScape, “We are in an era in which we are able to profile not just the genes but the tumor cell in general, either by genomics, proteomics, or phosphoproteomics and with newer technologies, such as RNA sequencing and metabolomics to try and understand what is driving the cancer cell. Many of these tests are ready for prime time and are even in the retail market.”

But he adds, while the ability to order these tests has become easy, that doesn’t mean that “We should order them all the time, because part of being able to order them is being able to act upon the results.”

Caution Reigns

Ira Klein, MD, of Aetna, expressed industry concerns in a Managed Care Magazine interview. “The insurance industry is somewhat cautious; we like evidence from scientific peer-reviewed literature, and these tests are still in the evaluation stage.”

Physicians worry that tumor profile reports may overload them with a complex list of possible causes of a cancer. The occurrence of many of these genetic alterations may be generally low but it has become a common practice for profiling laboratories to suggest that the results may guide treatment. Test reports often say some of the alterations may be “potentially actionable targets,” some reports listing drugs that could be used. But stronger evidence to support concept of using molecular profiling to guide treatment decisions is needed.

Leveraging lessons learned through the NCI-MATCH (Molecular Analysis for Therapy Choice) clinical trial, in which agents developed by different companies are tested alone or in combination under a single study, NCI is forming public-private partnership with 20 to 30 pharmaceutical and biotechnology companies to expedite cancer researchers’ access to investigational agents and approved drugs.

Researchers will be able to obtain compounds through one pre-approved formulary list and test them for new purposes or in new combinations, eliminating the need to negotiate with each company independently for individual research projects, which can take as long as 18 months. Ultimately this approach will expedite the start of clinical trials and will bring new options to cancer patients faster.

To this end the NCI started enrolling patients in its Molecular Analysis for Therapy Choice (NCI-MATCH) launched in August 2015 as part of the Precision Medicine Initiative announced by President Obama. The NCI describes the study as a phase II precision medicine trial to find out whether matching certain drugs or drug combinations in adults whose tumors have specific gene abnormalities will effectively treat their cancer, regardless of its tissue of origin or cancer type. The study will, it is hoped. provide evidentiary underpinnings to treating cancers according to their molecular identities rather than according to the tissue in which they initially were found.

 The trial, co-developed by the ECOG-ACRIN Cancer Research Group and the NCI, is a
“basket” study, designed to determine patient responses to drugs based on the specific mutations in patients' tumors rather than where their cancer originated.

The cancer treatment drugs currently number about 30, with more being added in new study arms. Drugs include approved drugs as well as investigational agents. Most of the trial arms in the trial test single-agent drugs that are either commercially available or are still being tested in clinical trials; a few arms contain combinations of drugs for which there are enough safety data and evidence that they might be active against a genetic abnormality.

Each targeted therapy is assessed in a single-arm phase II trial, with NCI-MATCH functioning as an umbrella protocol for these trials. Patients with a match to a drug treatment will stay on that drug treatment until their disease progresses (or the treatment becomes toxic), at which point they will, if they desire, undergo another biopsy to look for additional molecular features that could match them to a new targeted drug. 

DNA Sequencing Test

NCI-MATCH uses a single DNA sequencing test to identify gene mutations in patients’ tumors. Developed at the Frederick National Cancer Research Institute, the test detects about 4,000 different variants across 143 cancer-associated genes that can be targeted by drugs in the trial. The NCI and its collaborators say many patients with rare cancers who were ineligible for most clinical trials that typically require large numbers of participants to ensure reliable study results will now be eligible because they, and patients with more commonly seen cancer types, share the same gene mutation.

To ensure biopsy sample quality control, biopsy specimens from all screened patients is sent to a single location, the ECOG-ACRIN Central Biorepository and Pathology Facility at the University of Texas MD Anderson Cancer Center. The DNA sequencing analysis will be done at one of four CLIA-certified facilities using a standardized process, including Frederick National Laboratory for Cancer Research, MD Anderson Cancer Center, Yale Cancer Center, and Massachusetts General Hospital.

The study’s primary endpoint is the overall response rate, the proportion of patients in the trial whose tumors shrink by a predefined amount over a specific time period. The secondary endpoint is 6-month progression-free survival, a measurement of whether a patient’s disease remains stable.

“For our purposes, a response rate of 5 percent or less in a molecularly-defined population will not be considered promising, whereas a response rate of 16 percent to 25 percent will be encouraging,” said NCI study co-chair Barbara A. Conley, M.D., associate director of the NCI’s Cancer Diagnosis Program. 

Researches presented data from an interim analysis at the annual meeting of the National Association for Cancer Research (AACR). Patient enrollment in the trial was paused in November 2015 for a planned interim analysis. Data as of March 9, 2016 were included in the analysis which established that a trial of therapy based on genetic characteristics of the tumor is feasible on a national scale in the NCI-sponsored networks and further, the investigators said, that the entire process of tumor characterization from accrual to biology read-out is feasible, having been accomplished in 87 percent of patients. The study also showed that a high proportion of less common malignancies in this early analysis opens options for advances in rarer cancers.

The interim analysis the investigators say also permitted implementation of several improvements to the study’s structure and allowed planning for the realistic needs of additional trials/drugs that can be analyzed in specific gene abnormalities.

The planned pause in enrollment, Robert Gray, PhD, ECOG-ACRIN group statistician and a professor of biostatistics at Dana-Farber/Harvard Cancer Center, said during an interview with Cancer Discovery, was consistent with an interim data analysis required by the trial's protocol after the first 500 patient screening.

The pause began earlier than expected due to the rapid pace of enrollment, according to Dr. Gray. The organizers expected to reach their enrollment threshold over the course of the first year, and were “caught by surprise” when nearly 800 people signed up during the first 3 months. The trial re-opened May 31, 2016, with 24 treatment arms.

Jeffrey S Abrams, MD, Acting Director for Clinical Research, Division of Cancer Treatment and Diagnosis (DCTD) and Associate Director for DCTD’s Cancer Therapy Evaluation Program (CTEP), in a November 2, 2016 presentation, pointed out some lessons learned by investigators during the earlier phase of the trial.

In particular, they found that 20% of biopsies as currently performed “Are not really fit for rapid turnaround,” slowing down the entire process. They noted, “It takes several months to add arms, even though we thought we designed a “nimble trial”. And rapid pace of accrual on MATCH means “We won’t have results for a while.” The trial also needs more drug combinations for testing, he noted. One change to the trial that emerged from the interim analysis is mandatory needle aspiration in all cases and allowance of tumor samples obtained up to six months prior to registration.

 Trial researchers had expected that only a small number of screened patients would have one or more molecular abnormalities that match one of the 30 or more treatment options being studied. Interim results appear to support that expectation with 5 percent of tested patients received treatment assignments (33) and 16 patients enrolled; 19 patients did not enroll in treatment for reasons including ineligibility, starting other treatment, disease progression, and death.

But, despite the challenges in the NCI-MATCH trial, there is little doubt, researchers say, that over time NGS-based cancer diagnostics will be a key component in guiding personalized drug selection.

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