Policy Issues in the Development and Adoption of Biomarkers for Molecularly Targeted Cancer Therapies Workshop Summary (2015) / Chapter Skim
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Workshop Summary
Workshop Summary
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There are hundreds of candidate targeted drugs in the development pipeline and several new cancer drugs targeting specific genetic alterations have entered the market in the past 2 years. However, many challenges remain in effectively and efficiently developing new targeted cancer therapies and the biomarker tests that indicate 1
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New paradigms may be needed for assessing the efficacy of targeted therapies as well as the clinical validity and usefulness of biomarker tests. The standard approach of defining treatment based on the anatomic origin of cancer is becoming less tenable now that genomic tests are stratifying cancers into rare subsets defined instead by the molecular drivers of the tumors.
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At the November 2014 workshop, subject-matter experts and members of the public discussed recent trends in the development and implementation of molecularly targeted cancer therapies and explored potential policy actions to address specific challenges. Topics included 1.
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Sloan Kettering Cancer Center, the MD Anderson Cancer Center, S the Broad Institute of the Massachusetts Institute of Technology, Matthias Holdhoff Cancer Research bar for proficiency testing for Research profiling and • Raise the UK, Fred Hutchinson Cancer genomic Center, Princess Margaret Hospital Cancer Center, the Dana-Farber Can make the results public. Mickey Williams • stablish reporting standards both for test methods and results, cer Research Center, and the gene sequencing company Illumina, E the consortium aims to demonstrate clinical utility, democratizenext including minimum reporting requirements for publishing genomic testing sosequencingwidelyMickey Williams generation it is more data.
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Dane Dickson, Federico Monzon • valuate the impact of the changing health care policy environ E ment, such as new current procedure terminology codes for diagnostic tests and the rise in accountable care organizations. Kathryn Phillips Increase Patient and Provider Knowledge About Tumor Profiling Tests • reate publicly available databases of test availability, cost, and C value.
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. MOLECULAR BIOLOGY REVOLUTION IN CANCER DIAGNOSIS AND TREATMENT A molecular biology revolution that has changed the way in which cancer is diagnosed and treated began in earnest in the 1990s and early 2000s when several molecularly targeted therapies became available.
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. By 2010 researchers had identified six genetic variants in the tumors of lung cancer patients that indicated likelihood of responding to specific treatments as well as a KRAS variant that indicated a lack of response to a group of targeted treatments known as tyrosine kinase inhibitors (see Figure 1)
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Roy Herbst, Ensign Professor of Medicine and Professor of Pharmacology, chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital, and associate director for translational research, Yale Cancer Center, added, "We really have taken lung cancer and made it a disease where we are focusing on more and more pieces of the pie." Similar scenarios have evolved in the treatment of many other cancers, including breast, melanoma, lung, and colon cancers. Using tests to identify molecular drivers of tumor growth in these cancers is often key to selecting a treatment.
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RNA Sequencing Tests Next-generation sequencing can determine the sequence of a portion or all of the DNA in a tumor sample, but not all that DNA will be transcribed into RNA and then into proteins that play an active role in tumor cells. To focus sequencing efforts on the genes that are being transcribed and are thus more likely to have an effect on tumors, some researchers do another type of genomic tumor testing, known as RNA sequencing.
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Tests for Circulating Tumor DNA Other innovative biomarker tests on the horizon are those that measure tumor DNA circulating in the blood. Called liquid biopsies, these tests analyze a small blood sample to detect and screen the naked DNA released by tumor cells during cell turnover.
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Now, smaller academic hospitals are expressing interest in doing tumor profiling, which increasingly is being required for clinical trials with targeted agents. In addition, he said the recent Supreme Court ruling that invalidated patents of isolated genes that occur in nature also triggered greater interest in developing genetic tests (U.S.
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Kravis Center for Molecular Oncology at Memorial Sloan Kettering Cancer Center, said that the Actionable Genome Consortium aims to establish various standards for cancer genomics (see Box 2)
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BOX 2 Actionable Genome Consortium The Actionable Gene Consortium was formed in 2014 to cre ate and publicize standards for cancer genetics. Composed of representatives from the National Cancer Institute, the Memorial Sloan Kettering Cancer Center, the MD Anderson Cancer Center, the Broad Institute of the Massachusetts Institute of Technology, Cancer Research UK, Fred Hutchinson Cancer Research Center, Princess Margaret Hospital Cancer Center, the Dana-Farber Can cer Research Center, and the gene sequencing company Illumina, the consortium aims to demonstrate clinical utility, democratize genomic testing so it is more widely available to patients, contain costs, and define and standardize what actionable genes are across institutions.
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Generally, establishing clinical validity for a test involves showing that it is "fit for purpose," a process that relies on data collected from clinical trials or from archived samples that are well annotated with outcomes and other clinical information. More recently, sponsors have been submitting
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Conduct Initial Feasibility Tests These tests should reveal the strengths and weaknesses of the test in a clinical setting. Consult with FDA This is important if the specimens will be collected as part of a clinical trial specifically for assessing the test.
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Several speakers noted that many diagnostic companies and laboratories do not assess the clinical utility of their tests before they are used in the clinic. Next-generation sequencing tests especially tend to provide extensive information on genetic variants in a sample, but little to no supporting information on which of those alterations are "actionable," that is, indicate specific clinical interventions.
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Assessing clinical utility of tests usually requires applying the test to a large number of patients or patient samples, which can be challenging to do given the rarity of some of the mutations that the tests are designed to detect. Some relevant mutations, such as those in BRAF, occur in only 1 percent or less of lung cancer patients.
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For example, Oncotype Dx, a biomarker test for breast cancer that measures the expression of 21 genes, has a large gray zone of results called "intermediate" for which there is no one clear treatment recommended. For patients given this result, the test currently has no clinical utility (a clinical trial called TAILORx is ongoing to assess the utility of the test for this patient population)
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Eberhard gave an example of a root-cause analysis under taken to address the problem that diagnosis of non-small-cell lung cancer based on how it appears under a microscope is imprecise and does not recognize subtypes. The root-cause analysis of this problem identified that accurate and reproducible subtyping can be compromised by samples that are too small, by inexperienced interpretation, or by being unable to distinguish poorly differentiated adenocarcinomas from squamous cell carcinomas (Grilley-Olson et al., 2013; Thunnissen et al., 2014)
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She also noted that some patients have been uploading their own data onto websites that researchers can access, so more progress can be made in treating their disease. Johnson pointed out that the Lung Cancer Mutation Consortium, a group of 16 centers across the United States, is assembling detailed sequencing information (BAM files3)
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There are tens of thousands of LDTs in clinical use, and most cancer diagnostics are LDTs, Monzon said. According to FDA, LDTs are supposed to be simple, well-understood pathology tests, tests used to diagnose rare diseases, or those for which testing outside the institution would be prohibitive to patient care due to delays between test ordering and delivery of test results.
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The test cannot enter the market until FDA reviews and approves this application. In its review of tests, FDA considers analytical and clinical validity, but not clinical utility (IOM, 2010a, 2012)
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This letter noted the problems that FDA has identified with several highrisk LDTs, including claims not adequately supported with evidence, lack of appropriate controls in studies to evaluate the test, erroneous results, and falsification of data. This has resulted in faulty LDTs that could have led to patients being over- or undertreated for heart disease, cancer patients being exposed to inappropriate therapy or not receiving effective therapy, and incorrect diagnoses of serious conditions, such as autism, FDA stated.
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In addition, nextgeneration sequencing is revealing new mutations in HER2 that previous tests could not detect, Monzon and Solit pointed out. Litwack noted that the use of different FDA-approved tests can affect the quality of clinical trials, which often use local test results for patient accrual and subgroup analyses.
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That validation was done using cellline samples for normal controls and a representative set of samples with characteristic genetic variants to assess the performance capabilities of the instrument under different scenarios, such as sequencing regions rich in certain bases, sequences from different chromosomes with different proximities to the centromere, etc. After this testing was accomplished successfully, FDA cleared the sequencing device to be used for detecting hereditary disorders from genetic sequences in blood samples.
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SOURCES: Litwack presentation, November 10, 2014; http://www.cftr2.org (accessed March 18, 2015)
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Companion Diagnostics Often biomarker tests in oncology are designed to be used in conjunction with specific targeted treatments, and both the test and the experimental treatment can be co-developed and tested simultaneously in clinical trials. Safety and efficacy of the new drug and of the new diagnostic are typically demonstrated in the same clinical trial, with the goal of simultaneous FDA registration for both the drug and diagnostic.
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SOURCE: Adapted from http://www.fda.gov/MedicalDevices/ProductsandMedical Procedures/InVitroDiagnostics/ucm301431.html (accessed March 18, 2015)
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• Scientific Studies Lab TestingService Development Device Development PMA U.S. Approval Feasibility VerificaƟon ValidaƟon Submission Assay OpportuniƟes for partnership span the range of research, clinical trials, and commercializaƟon FIGURE 2 High-level strategy for drug and test co-development.
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Monzon pointed out that after a test for a specific genetic variant is approved as a companion diagnostic for one type of cancer, evidence often surfaces suggesting it is also likely to be effective as a companion diagnostic for the same treatment used in a different type of cancer. But manufacturers have to clinically validate the tests for this new use in order for it to be listed on the drug's label.
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Long agreed, stressing, "We develop one product that is sold worldwide so we are dealing with many regulatory bodies around the world." However, the multiple agencies worldwide that regulate biomarker tests use different approaches to regulating products, Long said. For example, some countries approve a companion diagnostic without any clinical utility data, but once those data accrue from studies of clinical use, the label for
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approval along with a technical file submitted to a regulatory authority. CLINICAL IMPLEMENTATION CHALLENGES Speakers at the workshop noted several challenges to effectively implementing molecularly targeted cancer diagnostics and therapies in the clinic, including • Insufficient or inadequate tissue specimens; • An overwhelming amount of data that are difficult to interpret and relay to patients; • A lack of standards for and comparative effectiveness data on diagnostics; • Time delays in acquiring test results; • Lack of financial resources and a testing infrastructure; and • Uncertainty over how to address incidental findings and report them to patients.
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To increase that awareness, her institution, Princess Margaret Hospital, created a spreadsheet for each cancer patient that delineates all the individual genetic alterations detected in the tumor and the currently available and relevant clinical trials the patient could be enrolled in based on that genotyping. "We send this to our clinicians on a regular basis so they are constantly reminded that if they have a patient with this profile, they need to think about the clinical trial," Siu said.
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" asked Patricia Ganz, Distinguished Professor, University of California, Los Angeles (UCLA) , Fielding School of Public Health, and director, Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center, UCLA.
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study, which compares various targeted therapies for lung cancer. Time Delays As previously noted, because many tumor profiling tests must be performed in reference laboratories that are not located at the point of care, delays may occur that can limit the usefulness of some tests.
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LoRusso noted that incidental findings may be of medical value or utility to the ordering physician and patient. One survey LoRusso cited found that most breast cancer patients would want genomic profiling if it
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We have to be proactive and think about this now rather than later," she said. In 2013, ACMG published recommendations for the reporting of incidental findings in genomic sequencing tests, but there were no oncologists or members from cancer professional societies in the working group that developed these recommendations, LoRusso pointed out.
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Clinics will need to have the expertise and resources to provide follow-up care for those patients found to have incidental findings outside the realm of cancer. "You either have to refer that patient out to another institution or to another investigator within your own institution, or you have to start developing a team approach to treating these cancer patients," LoRusso said.
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In addition, genetic findings from tumors can change over time as the cancer evolves with new mutations, yet "when you give the patients the results, many of them stick to them as if they are the Bible for their survival, so we really have to watch how we end up reporting these data to the patients and what we promise them as a result of getting these data," LoRusso said. Another challenge is when a test shows an unexpected genetic variant suggesting that a patient's tumor is likely to respond to a treatment that is not yet approved for that indication, such as Herceptin for lung cancer, and thus may not be reimbursed by an insurer.
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But many biomarker tests are LDTs that do not undergo regulatory
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Messner reported on a 2012 study of payer policies which concluded that "the low number of disease-related genomic tests considered for coverage by insurers is likely due to the few studies published demonstrating clinical utility, the often small role of genetics in complex diseases, and availability of alternative effective screening methods." Sean Tunis, President and Chief Executive Officer, Center for Medical Technology Policy, added, "It's not that payers are looking for a way to not pay for these tests as much as they are looking for some kind of consensus that there is an evidentiary framework that distinguishes tests that are useful from tests that are not. If there were more regulation of tests by the FDA, there probably would be a lot more willingness for payers to reimburse them.
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"It depends on the protocol," he said. This is a dilemma because academic institutions and cancer centers often require screening biomarker tests to determine eligibility for clinical trials of targeted cancer treatments, but payers will often not reimburse such testing, noted Jennifer Malin, medical director of oncology for WellPoint, Inc.
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" Incidental Findings Schilsky said that payers often will not pay for follow-up of incidental findings on genomic tests, and he questioned why this is so, giving the example of computerized tomography (CT) abdominal scans for cancer that often reveal incidental findings in organs other than the original organ of interest.
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However, Malin said that for WellPoint-affiliated health plans, the costs of drugs for cancer patients comprise about one-quarter of the total cost of cancer care, while physician visits only comprise about 3 percent, so there is a great need to figure out if the resources being spent on biomarker tests and the associated targeted treatments are contributing to greater value and outcomes for patients. Part of the reason more genetic tests have not been reimbursed may be because most of the "actionable" genetic alterations these tests uncover do not yet translate into better clinical outcomes, Gradishar noted.
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GATHERING THE EVIDENCE: INNOVATIVE CLINICAL TRIALS The ability to detect numerous genetic anomalies in cancers is not equally matched by the ability to understand what those molecular flaws mean clinically, several presenters pointed out. Clinical studies are needed to assess this, but few studies are being conducted.
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. At her own institution, Princess Margaret Hospital in Ontario, only about 6 percent of the 2,000 cancer patients enrolled in the genetic profiling programs known as IMPACT or COMPACT ultimately are entered into early-phase clinical trials of a targeted therapy.
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Advanced solid tumors NOTE: BI = Boehringer Ingelheim; GI = gastrointestinal; GSK = GlaxoSmithKline; NCI = National Cancer Institute; NCTN = National Clinical Trial Network; NIH = National Institutes of Health. SOURCE: Siu presentation, November 10, 2014.
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NOTE: EGFR = epidermal growth factor receptor; HER = human epidermal growth factor receptor; MSKCC = Memorial Sloan Kettering Cancer Center; OS = overall survival; PFS = progression-free survival. SOURCE: Solit presentation, November 10, 2014.
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Patients whose cancers progress while on experimental therapy have the option of being rebiopsied and being placed in a different treatment arm if the mutations detected suggest that another treatment arm would be appropriate. Williams said all four participating clinical laboratories at different institutions will be running the same next-generation sequencing tests on the tumor samples.
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, NCI. Lung-MAP Umbrella Trial Herbst described the Lung-MAP trial as a Phase II/III trial that entails a public-private collaboration among institutions participating in NCI's National Clinical Trials Network, nonprofit organizations such as the Foundation for the National Institutes of Health and the Friends of Cancer Research, and several drug companies, all of which will provide funding for the $150 million trial.
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• Patient benefit -- the goal is to bring safe and effective drugs to patients sooner than they might otherwise be available. Following discussions with more than 20 drug companies, a drug selection committee (composed of lung cancer experts and stakeholders not employed by the drug companies developing the experimental therapies being considered)
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Challenges with Basket and Umbrella Trials Basket and umbrella trials present several challenges that researchers are trying to overcome, including • The difficulty of finding enough patients who have the rare molecu lar subtypes of cancers likely to respond to experimental targeted treatments; • The need for competing drug sponsors and research institutions to collaborate; • The difficulty in treating a moving target, given the heterogeneous and dynamic nature of tumors; and • The uncertainty about how to prioritize genetic targets for treatment. Sufficient Patients for Trials Most cancer patients are not aware their tumors have rare mutations that might respond to certain targeted therapies.
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Solit estimates that to complete the neratinib study outlined in Figure 3, 30,000 to 40,000 patients will have to be screened, an enormous undertaking that cannot be accomplished at a single institution. Consequently, in addition to screening cancer patients at his own institution, Memorial Sloan Kettering Cancer Center, he is collaborating with the MD Anderson Cancer Center, Foundation Medicine, and other institutions or companies that do genomic profiling of large numbers of patients regularly.
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Commercialization of tests in the future could then be expediently accomplished using the same labs in the network once the associated targeted therapies achieve regulatory approval. Need for Collaboration Basket and umbrella trials require collaboration across institutions, companies, and areas of expertise.
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Dabrafenib + BRAF HER2 HER2 BM X BLA Drug X + BM X cMET cMET BM X Other Rx Rx/Dx data PMA claim partners sharing Dx Develop/analyƟcally PMA validated panel • Panel contains genes relevant to current and future assets PMA claims to support drug across cancer types and pipeline approvals • IniƟal screening effort focuses on NSCLC Panel would be used commercially to support adopƟon of the Rx associated with the panel FIGURE 6 Proposed collaborative multipharma network to advance multibiomarker diagnostics. NOTE: BLA = biologic license application; Dx = diagnostic; NDA = new drug application; NSCLC = non-small-cell lung cancer; PMA = premarket R02799, Figure 6, portrait or broadside approval; Rx = drug.
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. "Obviously if you profiled only one sample, it is possible that you would not be catching what is actually active and relevant at the present time," Siu said, and noted that the emerging drug resistance that commonly occurs after treatment with targeted therapies is probably due to new mutations, which perhaps could be detected early on in circulating tumor DNA.
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That is the only way we are going to make sure that it is not just the payers dictating what the standard should be, but the payers in dialogue with all the other key stakeholders who have equally legitimate social objectives," Tunis concluded. Coverage with Evidence Development Several speakers suggested that one useful option for gathering the evidence needed to assess the clinical utility of molecular diagnostics would be Coverage with Evidence Development (CED)
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Medicare has used CED for a number of indications, including gene testing for warfarin sensitivity and molecular diagnostics for prostate cancer. To be considered for CED, a medical diagnostic or treatment must address an important health need and/or specific payer priority, and the existing evidence on the intervention must be adequate to conclude that the technology is promising.
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As Dickson reported, MolDx recognizes the new paradigms posed by genomic tests, including the likelihood that large clinical trials of these tests are not likely to be conducted or duplicated due to the difficulty of enrolling enough patients now that many targeted treatments are directed at rare patient subsets, as well as the often low or negative return on investment on research in advanced molecular testing. This has resulted in "less than perfect science" for molecular diagnostics in areas where there are substantial unmet needs, Dickson said.
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Company Request for Redetermination * Analytical and Clinical Validity MolDx Executive Committee still required for coverage Final Review Final Clinical Utility Decision (Full, Limited, Coverage with Data Development, Non-Coverage)
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Another alternative it proposed was conducting high-quality prospective observational studies, in which patient outcome measures are determined prior to the start of the study and there are sufficient numbers of patients to power the study so that conclusions drawn from the data are reliable. In situations in which there are multiple data sources, the Collaborative recommended modeling techniques in which it might be possible to "connect the dots to infer patient benefit," even if there is no direct evidence of clinical utility, Messner said.
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In addition, the Collaborative will consider standards for interpretation and integration with other data, and whether standards should be established for reporting to payers the breadth of sequencing in genetic panels and the types of variants detected. GATHERING THE EVIDENCE: DATABASES AND REGISTRIES High-quality genetic databases that are well annotated with clinical outcomes data and patient characteristics are a valuable resource for gathering the evidence needed to assess the clinical utility of genetic tests and targeted treatments, several speakers noted.
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clinical trial database for physicians and patients who want to find experimental treatments that target specific genetic alterations in tumors. This NCI database lists more than 40,000 clinical trials for more than 135 different cancer diagnoses and 500 cancer genes.
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For such test results, it lists the genetic variants with therapeutic significance for the patient's tumor, the types of drugs that target those mutations, and potentially relevant clinical trials. In closing, Levy stressed, "We need to be able to aggregate all of our data together on the clinical outcomes of patients and their genomic alterations because the number of patients with these very rare alterations is just staggeringly small, and no one institution is going to have enough patients with each of these variants to be able to do any real discovery with it." To address that challenge, she advocated for learning health care systems in which the care of a patient seen today is informed by data collected on all similar patients treated before, and the data collected on today's care is then used to inform future care (IOM, 2010b)
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Another participant noted that the Affordable Care Act requires reimbursement of routine clinical care costs of patients enrolled in clinical trials. Schilsky said the study protocol does not specify a particular test for genomic profiling; the treating physician can choose a test offered by any laboratory that is accredited by CAP, is CLIA-certified, and has a McKesson Bioscience Z-code indicating it is a unique and vetted test.
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Challenges in Using Databases Speakers noted several challenges in using databases or registries to support clinical utility assessments. For example, databases may not capture all relevant outcomes or may not be well annotated with high-quality data, and
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• ther genes of interest that have appropriate justification for O selection based on published scientific evidence regarding susceptibility to a specific molecularly targeted therapy Criteria for Drug Selection • evel 1: Agent met a clinical end point (objective response, L progression-free survival or overall survival) in a clinical trial testing the agent in the patient's tumor type harboring the mutation of interest • evel 2: Agent is commercially available for use in any L tumor type with the specific genomic variant identified in the patient's tumor • evel 2: Agent has demonstrated evidence of clinical activ L ity against the patient's tumor type based on published literature • evel 3: Agent has demonstrated preclinical evidence of L antitumor activity and evidence of target inhibition in model systems of patient's tumor type SOURCE: Schilsky presentation, November 10, 2014.
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"Not collecting additional data about the host in which the cancer occurs seems to be a missed opportunity." Martin responded, "The key element in the future will be the ability to tie the genomic data back to electronic health record data where you have much more information along the lines of what you are suggesting." Siu noted that in a recent clinical trial with genetic profiling, she included a companion epidemiological survey that was completed by more than 95 percent of the patients because "this is information they realize is very important to collect." A few participants suggested that registries are best developed in academic settings. "Academic settings are the better place to develop these resources when we are so early on in this process, as they have few conflicts of interest, clear oversight mechanisms, and more open access," Anderson said.
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EDUCATION AND CLINICAL DECISION SUPPORT NEEDS Studies suggest that a lack of awareness or understanding of tumor biomarker tests has impeded their use by patients and their physicians. "Patients want tests when they understand them," Phillips said.
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LoRusso added that she relies on genetic counselors in her clinical trials to educate patients on the meaning of their genetic test results. Jane Perlmutter, patient advocate, who is involved in the I-SPY trial for targeted breast cancer treatments, said that when they return incidental results from that trial, investigators will also rely on genetic counselors, who provide patient educational materials and are developing a webinar to train clinicians on how to convey that information.
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But Ganz noted that palliative care is a worthwhile option that can be discussed with end-stage cancer patients instead of "promising them a genetic test is going to be the key to their survival. We need to have an open discussion about what our care can and cannot do.
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The guidelines cover the full spectrum of cancer care, from detection to end-of-life care, and rate the strength of the supporting evidence based on the quality, extent, and consistency of clinical studies for each intervention. In 2012, NCCN also launched a compendium for biomarker tests, including genetic tests, that are used to make clinical decisions related to screening, diagnosis, monitoring, or providing predictive or prognostic information in oncology.
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New guidelines suggest more than 50 treatment options for lung cancer, for example. Treatment pathways tend to be more specific and are another option for guiding physicians to use cancer biomarker tests and targeted treatments appropriately.
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RESEARCH NEEDS In addition to gathering the evidence needed to assess the clinical validity and utility of biomarker tests, speakers suggested a few other research opportunities. Phillips suggested that prospective studies should also gather data on the entire pathway of events, including who is using the tests, how patients and providers feel about the tests, and the information the tests provide, in addition to the outcomes, benefits, and costs.
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Holdhoff noted that circulating tumor DNA tests are in an early stage of development and there is a need for large-scale clinical prospective studies to assess their value in clinical practice. He suggested providing funding and resources to enable the inclusion and evaluation of circulating tumor DNA tests within large-scale prospective clinical trials, and involving experts in that technology early in clinical trial design.
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2012. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: Updated results from a Phase 1 study.
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1996. Tumor marker utility grading system: A framework to evaluate clinical utility of tumor markers. Journal of the National Cancer Institute 88(20)
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2014. Ensuring patient access to affordable cancer drugs: Workshop summary.
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2010. Overall survival with cisplatin gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non small-cell lung cancer: Results from a randomised Phase III trial (AVAiL)
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2007. Statistics in medicine -- reporting of subgroup analyses in clinical trials.
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