Patricia Deverka, Principal Researcher, Health Care Group
American Institutes for Research, Chapel Hill, NC; Adjunct Associate Professor, Center for Pharmacogenomics & Individualized Therapy, University of North Carolina at Chapel Hill

Q: Paying for Precision Oncology – Who Decides?
A: There is tremendous enthusiasm for the scientific rationale and clinical promise of precision oncology amongst researchers, oncologists, industry and subgroups of cancer patients. Nearly three-quarters of the compounds in the oncology pipeline have the potential to become personalized medicines and over 90% of the $25 billion personalized medicine market in 2015 came from the sale of oncology drugs that required use of a companion diagnostic, such as Herceptin and Her2 testing. The typical companion diagnostic analyzes single gene mutations or abnormal gene expression profiles, in contrast to next generation tumor sequencing (NGTS), which assays genomic alterations in tens to hundreds of genes simultaneously. Tumor profiling using NGTS now occurs frequently at major cancer centers across the U.S., however reimbursement for both the test and the off-label use of targeted therapies is unpredictable and challenging for most molecular tumor board staff, oncologists and their patients. Without coverage by either private or public insurers, most patients will not have access to NGTS tests and targeted therapies.
Payers typically use a stepwise approach for coverage decision-making when evaluating the evidence supporting the technical and clinical aspects of new molecular diagnostic tests. Based on published studies, technology assessments and professional guidelines, payers assess:
1) analytic validity – whether a new test is accurate and reliable,
2) clinical validity – if the result is medically meaningful, and
3) clinical utility of the test – whether results affect clinical decisions and improve health outcomes.
Payers are one of key stakeholder groups that require evidence of clinical utility for decision-making, however clinical utility cannot be demonstrated until analytic and clinical validity are established. As compared to “ single test/single result” assays, each of the two validation steps are inherently more difficult for payers to assess with NGTS tests, due to the complexity of the technology, as well as variation in informatics analyses and procedures for interpretation and reporting of sequence variants. Economic considerations such as whether use of the test will lead to cost offsets (e.g., reductions in hospitalizations) are potential factors in test evaluations, but they also depend on evidence of clinical utility since changes in resource utilization must be linked to an alteration in patient outcomes, such as improved response or avoidance of side effects compared to an alternative approach.
When determining medical policy for an insured group, assessment of the evidence base typically leads to a determination of whether a test is “medically necessary” and therefore covered, or “experimental/investigational” and not covered. NGTS tests create particular challenges for payers given that they include both established and novel targets and test results are used to guide the use of off-label therapy, thereby challenging the standard approach to evidence evaluations. There is growing recognition that the traditional reliance on randomized controlled trials to demonstrate clinical utility is not feasible and that use of basket trials, observational studies, registries, n-of-1 studies and modeling may be required. These study methods are less familiar to payers and will require education and published examples. Nevertheless, more payers are acknowledging that flexibility in evidence requirements is required and oncology is one of the most likely areas for innovation.
However while many payers view NGTS clinical applications as a reasonable hypothesis, they still consider this approach to be investigational. What is needed now is stronger evidence to support the proof of concept of using NGTS to guide treatment decisions. One example is the National Cancer Institute’s basket trial, Molecular Analysis for Therapy Choice (NCI-MATCH), which pairs patients’ genomically profiled tumors with a treatment regardless of anatomical location. The study has recently expanded the number of targeted therapy treatment arms and is actively enrolling patients. In the meantime, the current model of health care delivery encourages standardization and use of treatment pathways as a mechanism to promote quality of care and reduce unnecessary costs. Thus the purported advantages of NGTS tests such as individual patient customization run counter to current system incentives.
Without convincing evidence that NGTS tests lead to better outcomes through better decision-making, payers will continue to struggle in the near-term to develop transparent, evidence-based affirmative coverage decisions. One example of how the Blue Cross Blue Shield Association is addressing the problem is a new subscription service called Evidence Street. Researchers in this group conduct technology assessments of new drugs, devices and tests, including molecular diagnostics. They work with test developers, commercial laboratories, drug companies and professional societies to ensure more consistent and transparent evidence standards for their technology assessments. Evidence Street does not make coverage decisions, but provides evidence to support Blues plans in their technology evaluations throughout the country.
So what is the path forward? There needs to be a combination of efforts from all stakeholders. Researchers in both for-profit and academic settings need to design and publish context-specific NGTS clinical utility studies, using a variety of appropriate methods. They should involve patients, caregivers and payers in study planning to ensure relevancy of results and use a range of outcome measures, including those developed by various research groups supported by NHGRI, such as the Clinical Sequencing Exploratory Network (CSER). Whenever possible studies should be conducted in practice-based research networks to reduce data collection costs and reflect usual care.
There are efforts underway to collect test use and patient outcomes data more systematically as part of multi-stakeholder supported registries (ASCO’s Targeted Agent and Profiling Utilization Registry; Molecular Evidence Development Consortium) and through third party oncology data aggregators (Syapse, Flatiron). Medicare’s MolDX (molecular diagnostics) program administered by Palmetto GBA allows the option of provisional coverage for tests under its Coverage with Data Development program which is used for promising tests that meet evidence standards for analytic and clinical validity but lack sufficient proof of clinical utility.
While NGTS tests are potentially disruptive technologies, if they are to be widely covered by private and public payers, stakeholders will need to demonstrate evidence of test accuracy, medical relevancy and ability to improve the process and/or outcomes of care. Assessment of clinical utility answers practical questions such as “Can and will we take action on the NGTS test results?” and “Does the outcome change in a way in which patients and other stakeholders find value relative to the outcome without the test?” Given the opportunity costs for patients, families and the health care system, we must work together to answer these questions.
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Razelle Kurzrock, MD, Chief, Division of Hematology and Oncology, UCSD School of Medicine; Senior Deputy Director, Clinical Science; Director, Center for Personalized Cancer Therapy; Director, Clinical Trials Office, UCSD Moores Cancer Center, San Diego, California

Q: Some workers in the field of precision oncology are growing despondent because of observed limitations of therapeutic effectiveness. What do you believe are now the best approaches to consider in order to move towards potential cures?
A: The pillars of precision oncology are genomically-targeted and immune-targeted therapies. Of interest, the fields of immunotherapy and genomics, often considered to be separate, are actually married to each other. Inhibiting checkpoints exploited by the tumor to shield itself from the immune machinery can reactivate the immune system. But, once reactivated, the immune system must be able to differentiate tumor cells from normal elements. The mutanome produces neo-antigens that permit this differentiation—and the more genomically aberrant the cancer, the more likely that the reactivated immune system will eradicate it. In contrast, with genomically-targeted therapies, the fewer the aberrations, the less likely that resistance will occur.
Yet, in treating patients, we are using old clinical trial paradigms rather than adjusting to the realities unveiled by genomic interrogation.
For instance, we administer genomically targeted therapies, mainly as monotherapy, to patients with heavily-pretreated, advanced metastatic disease—ie., the equivalent of heavily-pretreated chronic myelogenous leukemia (CML) blast crisis (where the response rate to imatinib is vanishingly low) (see Table). These patients have highly complex molecular portfolios and we should not expect that genomically targeted monotherapies will be curative.
We should not be then wringing our hands and talking about the limitations of our therapy–but rather the limitations of our approach.
The real eye opener is that so many patients with such late-stage disease respond at all.  The response rate of metastatic solid tumors to genomically targeted agents is actually much higher than that for imatinib in late-stage CML (see Table). Yet, CML is considered the poster child for successful genomically-targeted therapy, with the median survival increasing from about 4-5 years to a near normal life expectancy.
The key ingredients for transforming CML included:

1. Identifying the driver (Bcr-Abl)
2. Identifying matched targeted therapy (imatinib)
3. Moving from late-stage disease (blast crisis—the biologic equivalent of metastatic solid tumors) to newly diagnosed disease.

In solid tumors, as in CML, the cancer evolves with time and becomes more genomically complex. If we therefore want to use genomically targeted treatments to cure more patients with solid tumors, we need to fundamentally change our approach:

1. Move to newly diagnosed disease
2. Use customized combinations rather than monotherapy or random combinations for metastatic disease, which inevitably harbors complicated molecular alterations that differ from patient to patient.

Intriguingly, for patients whose tumors have highly chaotic genomes, immunotherapy is most effective. Indeed, in diseases such as melanoma, characterized by high tumor mutational burden, the long-term disease-free survival with immunotherapy may now be about 50%–an incredible improvement over the ~18% two-year survival seen with traditional chemotherapy.
In summary, we should be elated with the results yielded to date by precision oncology. If we, however, want to leap from improvements to cures, we need to stop relying on age-old clinical trial designs and adjust our strategy to the biology of each patient’s cancer.
 

Table: Precision Treatments and Response Rates

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Srivani Ravoori, PhD, Associate Director, Science Communications; American Association for Cancer Research

Intro: The American Association for Cancer Research (AACR) publishes a forecast blog post at the start of each year to ask prominent cancer research leaders what they envision the new developments will be in areas like immunotherapy, precision medicine, cancer prevention, and health disparities.

In this excerpt from the 2017 post in Cancer Research Catalyst, we interviewed precision medicine expert George Demetri, MD, Professor of Medicine at Harvard Medical School, Director of the Ludwig Center at Dana-Farber/Harvard Cancer Center, and Director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute. Dr. DeMetri is a founding member of the CollabRx Editorial Advisory Board and Chief Editor for CollabRx Sarcoma. Here’s what he had to say about developments in precision medicine for treating cancer – as well as his thoughts on aspects of the 21st Century Cures Act, federal support for cancer research, and the value in supporting basic science.

Q: The American Association for Cancer Research (AACR) is arguably the World’s most important professional organization of volunteers in the cancer research field. As we enter 2017, what does AACR consider the field’s greatest challenges and opportunities?

A: “The good news is that we are still uncovering virtually monogenic diseases – diseases that are driven by single oncogenic fusions or mutations,” says Demetri, a board member of the AACR. Therapies targeting single mutations, such as NTRK fusions, lead to durable and dramatic responses, he notes.For the vast majority of common cancers, however, it is not a simple monogenic problem. We need more combination therapies and more research to find where the Achilles’ heel is, Demetri says. “This is where we, as professionals, need to be careful about overstating the value of precision targeting to the public without also getting too negative.”
“Cancer diagnostics are going to get better and better,” says Demetri, and predicts that we may be on the verge of putting together a composite set of predictive and prognostic biomarkers. “Our diagnostic tools are getting so sophisticated that we can put cancers into different bins at different times in a patient’s treatment course.” With treatment, cancers acquire new mutations to thrive, and with technological advances we can now, in many cases, track the different mutations that are likely driving the disease and match them with different drugs.
While Demetri notes that we have to be intellectually honest about the fact that most patients treated with targeted therapies develop resistance, he is not yet giving up on our aim of finding cures. It may appear as not achievable now, but we are getting there through combination therapies, he adds.
We really need to hone our ability to pick combinations that are not cross-resistant and truly synergistic or complementary, he notes. One of the many approaches is to tie targeted therapies with less-targeted, more multifunctional modalities such as immuno-oncology, which can trigger the immune system. “Even though checkpoint inhibitors are a multibillion dollar market, I would say they are still in their infancy as far as our extent of understanding goes,” notes Demetri.

 
We are likely to see more efforts in developing very potent epigenetic drugs, according to Demetri. Drugs that target EZH1, EZH2, and bromodomain inhibitors are an alternative way to addressing the bad wiring in cancer cells, notes Demetri, who expects to see more studies testing combinations of epigenetic therapies with targeted therapies and immunotherapies.
This year, Demetri predicts, we will gain further understanding into the smaller, molecularly defined subsets of cancer, and develop even better, more precisely targeted therapies.
A recent development is the work on protein degradation technologies, which make it possible to bring the ubiquitin-proteasome system to degrade a protein of interest in a very catalytic way, Demetri says. “This could be a real game changer,” he predicts. Researchers are still trying to understand how to use the protein degradation system appropriately to target undruggable proteins such as Myc and Ras. “I think this is an exciting area of research and this year we are likely to see some proof-of-concept studies. I feel it is just about to hit the mainstream,” Demetri notes.
Progress with cancer genomic medicine depends on a key element, data sharing—large genomic datasets made available to all so the significance of the genetic alterations present in patients’ tumors could be gleaned through collective evidence. However, data sharing comes with many challenges, such as protection of patients’ privacy and ownership of the data.
Progress with breaking the barriers of genomic data sharing will come from continued advocacy from the patients rather than the professionals, Demetri says. “It is vital to leverage our interactions with patients and patient advocates who want the same things that we do to push the kind of data sharing that will advance the field.”
In the event that the efforts from the federal government to further data-sharing initiatives are insufficient, we may see the private sector jumping in to build databases, he notes. “A lot of this will depend on the next heads of the NIH and the NCI,” he adds.
Regarding the provisions in the 21st Century Cures Act to roll back FDA regulations to accelerate drug development, “I like the idea that we can streamline and simplify and have more transparency in the rules for therapeutic development in cancer,” Demetri says. “I’m optimistic that we will keep the focus on both safety and efficacy.” Ultimately, if a drug does not work sufficiently well to justify its use or if it is prohibitively expensive compared to other equally effective options, Demetri says he would trust our community of professionals would have the integrity to not use it, and to explain these choices and options to our patients.
We are in the post-genomic era where we need to overlay other elements (such as epigenetic compensatory mechanisms, metabolic or anatomic resistance mechanisms, etc.) on top of simple genotyping and basic interpretation of the genotype, Demetri says. Adding this is more complicated and will take a lot of effort and money to fund the necessary research. “I feel that the advances against cancer are very powerful and will go forward no matter what, but the question is, how fast can we get there and at what scale and scope?” Demetri asks.
“Reading the tea leaves of the new administration, we may be facing less than optimal federal support for cancer research, but I’m hopeful that we will see more private sector-based and philanthropy-based partnerships that will step up to support cancer researchers at this important juncture,” Demetri says.
“What I’d like to see this year is some time for positive reflection to realize the importance of public funding of science, which is tied to the importance of funding investigators who can follow their instincts to make new discoveries,” says Demetri. He adds, “Fundamental, curiosity-driven research is the only way we are going to get to unthinkable breakthroughs – real paradigm shifters akin to kinase inhibitors in the late 90s and immuno-oncology drugs more recently.”
“We need to recognize that there is a social good to funding basic research: without fundamental scientific understanding, applied medical research is limited to moving already existing therapies around the chessboard. We need science-based novel agents and new approaches to change the therapeutic approach and help patients in ways we might not be able to conceive of today,” Demetri notes and adds, “We have not told that story well enough and I’d like 2017 to be the year where we make that a little clearer to the public so there’s more support for basic science. That is critical.”

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Val Jones, MD, Medical Director of Admissions, Saint Luke’s Rehabilitation Institute, Spokane, WA

Q: Your principal practice in Spokane, Washington is Physical Medicine and Rehabilitation. What do you find to be the best uses of PM&R in patients with cancer at your facility?
A: Rehabilitation medicine is one of the best-kept secrets in healthcare. Although the specialty is as old as America’s Civil War, few people are familiar with its history and purpose. Born out of compassion for wounded soldiers in desperate need of societal re-entry and meaningful employment, “physical reconstruction” programs were developed to provide everything from adaptive equipment to family training, labor alternatives and psychological support for veterans.
Physical medicine and rehabilitation (PM&R) then expanded to meet the needs of those injured in World Wars I & II, followed closely by children disabled by the polio epidemic. In time, people recognized that a broad swath of diseases and traumatic injuries required focused medical and physical therapy to achieve optimal long term function. Today, cancer patients frequently benefit from comprehensive rehabilitation as they recover from the effects of chemo (neuropathy, weakness, and cognitive impairments), radiation (scarring and range of motion limitations), surgery (flaps, plastics procedures, tumor resection, amputations), and brain injuries (edema, debulking, gamma knife and neurosurgery).
Rehabilitation is a phase of recovery occurring after any major life-changing medical or surgical event. Our bodies are designed to regenerate and repair, though optimizing this process takes skilled guidance. PM&R physicians (also known as physiatrists) are trained to use physical modalities (stretching, strengthening, heat, cold, etc.) to mechanically enhance healing. They prescribe medications to manage pain, spasticity, nerve injury, and cognitive impairments, while also leveraging the power of physical therapy to increase cardiopulmonary fitness, muscle strength and flexibility. PM&R physicians are also experts in neurologic injury, and can adapt exercises to coax spinal cord, brain and peripheral nerve injuries to construct new pathways for movement and repair.
Inpatient rehab’s prime directive is to get patients back home. To succeed at home, patients need to be able to function as independently as possible, using trained assistants for managing the activities that cannot be performed without help. Admission to a rehab hospital or unit offers the patient home practice opportunities – with simulated challenges that can include everything from terrain parks, test kitchens, medication management trials, driving simulators, balance tests, electric wheelchairs and even exoskeletons that allow paralyzed patients to walk again. It is like a robotic Disney World, with endless aquatic and equipment possibilities for restoring movement and independence.
When I discuss admission to inpatient rehab with my cancer patients, I ask them about their goals, motivation, and energy levels. Timing of rehab is important, because it must dovetail with treatment, so that the physical exertion strengthens, not saps, the patient. Often times when a person is newly diagnosed with cancer, they want “everything done” – intensive chemo/radiation/surgery as well as rehab/exercise. But staggering these interventions can be more effective.
In other cases when care is palliative, learning new skills and being fitted with battery or electric-powered equipment can mean the difference between living at home or in an assisted environment. Some successful cancer patients come to inpatient rehab to practice managing their activities of daily living with varied amounts of assistance, preparing for increased needs as time goes on so they can enjoy being at home for as long as possible.
For the physiatrist, cancer is a cause of impairments that can be overcome with creativity and practice, no matter the long-term prognosis. Adaptive equipment, physical exercise, and cognitive retraining may be applied intensively (3 hours a day in the inpatient setting), or at a slower outpatient pace, depending on individual need. Rehab physicians desire to support and sustain patient function at the highest level, and “add life to years.” As such, rehabilitation should be considered an integral part of successful cancer care and management.
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David S. Priemer, M.D., Resident Physician in Anatomic Pathology and Neuropathology, Indiana University School of Medicine Department of Pathology and Laboratory Medicine, Indianapolis, IN; priemerd@iu.edu

Q: The numbers show that American physicians are ready to cast the medical/hospital autopsy into some relic or trash bin. Yet some physicians believe that the low tech autopsy still has much to contribute. Do you believe that the autopsy still can be useful in cancer deaths? And, if so, in what ways?

A: As an aspiring autopsy pathologist, it has been disappointing to learn of the decreasing role of autopsy in medicine. Many in pathology do not care for autopsies because they are dirty, time-consuming, and not reimbursed. Issues also exist amongst clinicians who trust that modern diagnostic modalities provide equivalent value, fear exposing mistakes, fear litigation, and are growing increasingly uncomfortable with approaching patient families. This medical environment which has largely forgotten the autopsy is also that in which trainees are developing habits as future practitioners. As a result, we may be facing further decline in the use of autopsies in the years to come.
Despite diminishing emphasis on the autopsy, data suggests that it has retained its value. This is as true for cancer patients as it is for any. Below I have highlighted what I think are the most important ways in which autopsies are useful for cancer patients:

1. Establishing cause of death. This reason for performing autopsies does not change because an individual has cancer. According to recent studies, major discrepancies (missed major diagnoses relating to the death that would have had a positive or equivocal impact on survival) between pre-and post-mortem findings occur in approximately one quarter of critically ill cancer patients. This rate is within the range of those observed in recent studies that used generalized patients. Therefore, it does not appear that deaths in critically ill cancer patients are any less likely to involve discrepant diagnoses than deaths in other settings. In addition to confirming the events that led to a death from cancer, the autopsy may also be the only way to discover that a patient died independently of their cancer. In other words, autopsy may be the only way to truly confirm a cancer death at all.
2. Assessing diagnostic accuracy. Autopsy is the gold-standard for assessing the accuracy of medical imaging. In the cancer setting, autopsy can confirm or deny imaging results and may discover lesions that were not clinically noted. In addition, autopsy allows for histopathologic confirmation of the malignancy; this may be particularly important in patients who had limited tissue sampling prior to death.
3. Evaluating effectiveness and potential adverse effects of treatment. The autopsy allows access to the entirety of a patient’s tissues, and therefore can serve as the ultimate tool for the determination of treatment effect and harmful side effects in the sickest of cancer patients, those who die. This should be especially considered in patients undergoing chemotherapeutic trials, which is where these outcomes are being studied. However, it is not required that research protocols in the United States include autopsies for patients who die while on trial therapies.
4. Research. Perhaps the most notable modern example of the use of autopsy in research is actually in cancer research. Tumor molecular biology has been of growing research interest as we move toward targeted cancer therapies. However, tumor harvested for these purposes from living patients is often suboptimal for the purposes of comprehensive molecular analysis. Because of this, autopsy has emerged as a method to collect large amounts of tumor from deceased patients, and the field of “rapid autopsy” has been born. Rapid autopsies, which are performed within 6 hours of death to sample viable tumor, are now being performed in a handful of American institutions. The number is expected to grow in the coming years.

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