FDA Grants Priority Review for Pembrolizumab, Chemotherapy Combination in NSCLC

The FDA granted priority review to Merck’s supplemental biologics license application (BLA) for pembrolizumab (Keytruda) in combination with pemetrexed (Alimta) and platinum chemotherapy as first-line treatment for patients with metastatic nonsquamous non—small cell lung cancer (NSCLC), the company announced April 16, 2018.

The Prescription Drug User Fee Act action date has been set for September 23, 2018. The FDA’s acceptance of the application is based on overall survival (OS) and progression-free survival (PFS) data from the phase 3 KEYNOTE-189 trial. The trial is the confirmatory trial for KEYNOTE-021, a phase 2 study that led to pembrolizumab being the first FDA-approved anti—PD-1 therapy in combination with chemotherapy for the first-line treatment of patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression.

In the double-blind, phase 3 KEYNOTE-189 trial,1 616 patients with NSCLC without EGFR or ALK mutations who had no previous treatment were randomized 2:1 to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembroli- zumab or placebo for up to 35 cycles plus pemetrexed maintenance therapy.

After a median follow-up of 10.5 months, the estimated rate of OS at 12 months was 69.2% in the pembrolizumab cohort compared with 49.4% in the placebo cohort. Median PFS in the pembrolizumab cohort (8.8 months) was nearly double that of the placebo cohort (4.9 months).

“Keytruda is the first immunotherapy to significantly extend [the] survival of patients with NSCLC in combination with chemotherapy as a first-line treatment, including in patients whose tumors are either PD-L1 negative

or are untested,” said Roger M. Perlmutter, MD, president, Merck Research Laboratories, in a statement.

If approved by the FDA, this would represent the third indication for pembrolizumab in metastatic NSCLC in the United States based on OS data.

In early April, pembrolizumab monotherapy as first-line treatment in locally advanced or metastatic NSCLC met its primary endpoint of overall survival in the phase 3 KEYNOTE-042 trial compared with platinum-based chemotherapy.

Outside of NSCLC, the anti—PD-1 therapy has indications for melanoma, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, and gastric cancer. In March, the FDA accepted a new supplemental BLA and granted a priority review to pembrolizumab as treatment for advanced cervical cancer, which marked the first filing acceptance and priority review granted for an anti–PD-1 therapy in cervical cancer.

Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemo- therapy in metastatic non-small-cell lung cancer [published online April 16, 2018]. 

2. FDA grants priority review to Merck’s sBLA for Keytruda (pembrolizumab) in combination with pemetrexed (Alimta) and platinum chemotherapy based on results from phase 3 KEYNOTE-189 trial as first-line treatment of metastatic nonsquamous NSCLC [press release]. Kenilworth, NJ: BusinessWire; April 30, 2018. businesswire. com/news/home/20180430005480/en/FDA-Grants-Priority-Review-Merck%E2%80%99s-sBLA-KEYTRUDA%C2%AE. Accessed May 1, 2018.

Keytruda (pembrolizumab) monotherapy met primary endpoint in phase 3 KEYNOTE-042 study, significant- ly improving OS as first-line therapy in locally advanced or metastsatic NSCLC patients expressing PD-L1 in at least 1 percent of tumor cells [press release]. Kenilworth, NJ: Merck; April 9, 2018. mrknewsroom.com/news-re-lease/oncology-newsroom/keytruda-pembrolizumab-monotherapy-met-primary-endpoint-phase-3-keyno. Accessed May 1, 2018.

Rosenberg J. Pembrolizumab granted priority review for treatment of cervical cancer. 

 website. ajmc.com/newsroom/pembrolizumab-granted-priority-review-for-treatment-of-cervical-cancer. Published March 13, 2018. Accessed April 16, 2018.

Researchers Identify New Gene That Predisposes People to ALL

Researchers have identified a fourth gene that may predispose individ- uals to develop acute lymphoblastic leukemia (ALL), according to findings of a study published in 

—which have been identified as predisposing carriers to develop B-cell ALL. 

indicating individuals who have an increased susceptibility to ALL, variants in the gene can influence patient response to treatment.

“This finding adds to the growing body of evidence that, while germline variations still account for a small percentage of pediatric ALL cases overall, more children than previously recognized inherit a predisposition to develop ALL,” Charles Mullighan, MBBS, MD, a member of the St. Jude Department of Pathology, said in a statement.

A decade ago, Mullighan and colleagues first reported that

 was often mutated in leukemic cells, which indicated that the individual would have poor treatment outcomes.

Although not everyone carrying a germline

 variant will develop ALL, the findings mean families can be informed about the potential risk to develop leukemia, added co-author Kim Nichols, MD, director of the St. Jude Cancer Predisposition Division.

 includes 3 generations of a German family with a germline variation of the gene and a family history of B-cell ALL. Researchers found that 2 of the 5 family members with the variant developed ALL as children and died.

 and the other ALL predisposition genes, cells may require an additional cooperating mutation to develop into leukemia,” Mullighan said. “While familial ALL is rare, these cases can point to genes and novel biology to examine in a larger patient population.

Churchman ML, Qian M, Kronnie G, et al. Germline genetic 

 variation and predisposition to childhood acute lymphoblastic leukemia [published online April 19, 2018]. Cancer Cell. doi: 10.1158/2159-8290.CD- RW2018-073.

Discovery adds to evidence that some children are predisposed to develop leukemia [press release]. Memphis, TN: St. Jude Children’s Research Hospital; April 19, 2018. stjude.org/media-resources/news-releases/2018-med- icine-science-news/discovery-adds-to-evidence-that-some-children-are-predisposed-to-develop-leukemia. html. Accessed May 1, 2018.

Articles

Medical World News: Managed Care Updates

New Test Could Make Multiple Myeloma Diagnosis as Easy as Drawing a Blood Sample

may be diagnosed without subjecting patients to a painful bone biopsy, according to research on a new blood test published in 

For the last 10 years, researchers at Kansas University (KU) have been developing a blood-based test for a variety of cancer diagnoses, including multiple myeloma. The blood test uses a small plastic chip that delivers the same diagnostic information through a simple blood draw.

“We’ll be able to eliminate the need for bone-marrow biopsies and allow the clinician to determine the best way to treat the disease using a blood draw,” Steven Soper, PhD, foundation distinguished professor of Chemistry and Mechanical Engineering at KU and a member of The University of Kansas Cancer Center, said in a statement.

 “From this test, the clinician will be able to determine the stage of the disease, what type of drug will best treat the disease, and monitor for signs of recurrence if the disease goes into remission.”

The new chip improves accuracy over previous chips developed to test for multiple myeloma, according to the researchers. Previous chips picked up regular blood cells instead of multiple myeloma cells. The chip test from KU identified circulating plasma cells in all patients with smouldering and symptomatic multiple myeloma, 78% of patients with monoclonal gammopathy of undetermined significance (a precursor to multiple myeloma), and none of the control patients.

The chip is also cheaper than previous versions and can be produced for a couple of dollars per unit, according to Soper, who led the research.

The goal, he said, is that screening for cancer will one day be routine and widespread so there can be a diagnosis long before symptoms present themselves. He added that integrating the test into care can be as easy as screening blood drawn during an annual physical for cancer.

The new test for multiple myeloma will be brought to market by BioFluidica. The technology is already being tested at Children’s Mercy Hospital in Kansas City on pediatric patients with acute leukemia, Soper explained. The test is being used to identify tumor cells in blood to see signs of disease recurrence.

“We’ve demonstrated the utility of this technology in a variety of cancer diseases,” Soper said. “Here, we’re homing in on multiple myeloma, but we’ve developed tests for 2 forms of leukemia and for pancreatic cancer, prostate cancer, ovarian cancer, colorectal cancer, and breast cancer. With our technology, we’ll be able to see if patients are developing cancers before they have overt symptoms and help improve survival.”

Kamande JW, Lindell MAM, Witek MA, Voorhees PM, Soper SA. Isolation of circulating plasma cells from blood of patients diagnosed with clonal plasma cell disorders using cell selection microfluidics.

 (Camb). 2018;10(2):82-91. doi: 10.1039/c7ib00183e.

Chip-based blood test for multiple myeloma could make bone biopsies a relic of the past [press release]. Lawrence, KS; The University of Kansas; April 16, 2018. news.ku.edu/2018/04/16/chip-based-blood-test-multi- ple-myeloma-could-help-make-bone-biopsies-relic. Accessed May 1, 2018.

Novel Drug Shows Promise in Acute Myeloid Leukemia by Suppressing 2 Proteins

The first in a new class of anticancer agents has shown promise against acute myeloid leukemia (AML), according to findings published in 

 The findings led to a phase 1/2 clinical trial for patients with advanced AML and advanced myelodysplastic syndrome.

The research, from investigators at Albert Einstein College of Medicine, describes how an experimental drug, ALRN-6924, targets p53, a protein that is inactivated in AML. The drug inhibits the proteins MDMX and MDM2, both of which inactivate p53 when they are overexpressed. When p53 is activated, it suppresses tumors.

In preclinical studies, ALRN-6924 tripled the median AML survival rate in mice transplanted with human leukemia cells from 50 days to approximately 150 days.

“This is a very striking response,” study leader Ulrich Steidl, MD, PhD, professor of cell biology and of medicine and the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research at Einstein and associate chair for translational research in oncology at Montefiore Health System, said in a statement.2“Most experimental drugs for leukemia achieve an increase in survival of only a few days in these preclinical models. Even more importantly, ALRN-6924 effectively cured about 40% of the treated mice, meaning they were disease free more than 1 year after treatment—essentially a lifetime for a mouse.”

AML is an often-lethal cancer, with only 27% of people who are diagnosed surviving for 5 or more years. Furthermore, in the past half century, the outcomes for AML have not significantly improved, according to a press release from Albert Einstein College of Medicine.

The research found that not only did ALRN-6924 block interaction of both MDMX and MDM2 with p53 in more mature AML cells, but the effect was also seen in the immature stem cells that produce AML cells.

“This is important because AML is driven by stem cells—and if you don’t target stem cells, the disease will come back very quickly,” Steidl said.

He added that some other cancers driven by overexpression of MDMX and MDM2 and inactivation of p53, such as some forms of breast cancer and lung cancer, could be treated with ALR-6924.

Carvajal LA, Ben Neriah D, Senecal A, et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia [published online April 11, 2018]. 

Novel drug shows promise against acute myeloid leukemia [press release]. Bronx, NY: Einstein Medical Center; April 11, 2018. einstein.yu.edu/news/releases/1292/novel-drug-shows-promise-against-acute-myeloid-leuke- mia/. Accessed May 1, 2018.

Coverage of the latest clinical updates in cancer research.

Medical World News: Clinical Updates

Foundation Medicine's FoundationOne CDx was the second product to pursue FDA/CMS dual review, paving the way for comprehensive genomic profiling in advanced cancer patients.

Keeping up with the ongoing changes in oncology is becoming a difficult task for clinicians and payers. New relevant biomarkers and biomarker-driven treatments are introduced each year, and many more are in late-stage development. For example, 8 new biomarker-driven oncology treatments were approved in 2017 alone.

Although many patients have benefited from this revolution in precision medicine by using comprehensive genomic profiling (CGP) of their tumors to help direct therapy, many others have missed this opportunity by receiving conventional testing or, worse, by failing to receive any molecular testing.

CGP refers to next-generation sequencing (NGS)—based testing of tumors that has been optimized to identify all types of cancer-relevant molecular alterations and complex genomic signatures in known cancer-related genes in a single test, using complex (often proprietary) bioinformatics. There has been substantial debate of the value of CGP in both the clinical oncology and managed care communities. Regardless, the demand for the technology exists among patients, providers, and biopharmaceutical companies alike.

A key rationale for using CGP is the well-documented problem of low molecular testing rates and slow adoption rates for new biomarkers.

Patients who receive incomplete or partial testing per guidelines may miss the opportunity to receive potentially life-extending therapies that, for some patients, have been shown to improve quality of life compared with cytotoxic chemotherapy. Alternatively, even if single-assay tests are performed, there is a high likelihood of having insufficient tissue or there being a need for repeated invasive biopsies.

 One study looking at diagnosis patterns in non—small cell lung cancer found that only 8% of patients received testing for all guideline-recommended biomarkers prior to therapy.

 Not receiving targeted therapy resulted in poorer outcomes. This is a significant area of opportunity for quality improvement in patients with advanced cancers. Unfortunately, the few established quality measures related to biomarker testing seem to be written in the reverse order, measuring if a certain test was used for patients who had received a certain drug.

 The more relevant measure might be to assess if a patient with cancer about to receive anti-oncologic therapy had received complete testing.

A CGP approach with FoundationOne CDx offers a potential solution for slow testing adoption rates and tissue exhaustion, and a 1-stop diagnostic to best leverage the rapidly changing treatment landscape. By using a platform that can accommodate additional biomarkers and companion diagnostics, FoundationOne CDx is well suited to keep pace with precision oncology. Testing patients with a CGP approach improves quality of care and offers the opportunity for patients to receive an evidence-based therapy or enroll into a clinical trial, which can be life extending but is often biomarker driven. FoundationOne CDx provides a comprehensive profile of 324 genes and is suitable for use in all solid tumors.

 It encom- passes guideline-recommended genes for testing in solid tumors and has FDA approval as a companion diagnostic for 17 targeted therapies in 5 solid tumor types. In addition, FoundationOne CDx assesses complex genomic signatures to help inform immunotherapy decisions. A comprehensive genomic profile is essential for quantifying these genomic signatures.

FoundationOne CDx is an efficient way of navigating all of these established and emerging biomarkers, potentially limiting the amount of tissue and time needed to assess for multiple clinically relevant alterations compared with sequential single-gene testing.

FDA's Risk-Based Regulation of Diagnostics

Foundation Medicine, Inc, was founded on the premise that no mechanism existed whereby clinicians, in the day-to-day practice of clinical oncology, could systematically obtain tumor information and efficiently interpret the specific molecular alterations associated with each patient’s disease.

 This mission was a driving force in its decision to participate in the parallel review process after being approached by the FDA and CMS.

Laboratory developed tests (LDTs) traditionally have not been required to receive approval by the FDA prior to being used. Additionally, the FDA process for medical devices (including LDTs) is somewhat less well defined and slightly more complex compared with the well-established regulatory path for small molecules and biologic therapies. The 1976 Medical Device Amendment provided a comprehensive regulatory framework for medical devices and established a risk-based regulatory classification system, as described in Figure 1.11 Diagnostics are medical devices and are classified based on the risk posed to the patient using the device. The lowest risk devices are deemed Class I and are mostly exempt from any requirements prior to marketing within the United States. Examples of Class I devices include arm slings, latex examina- tion gloves, and most hearing aids.

Most medical devices and diagnostics fall in the Class II category, and manufacturers of such devices are required to notify the FDA prior to marketing those devices via a 510(k) submission (premarket notification [PMN]).

The 510(k) application allows the manufacturer to demonstrate that its device is “substantially equivalent” in terms of its intended use, safety, and effectiveness to an already legally marketed “predicate” medical device in the United States.

Class III is reserved for devices deemed high risk and subject to a premarket approval (PMA) procedure, like that for new drugs. By statute, the PMA process is reserved for medical devices that “support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury.”13 For this reason, almost all companion diagnostics that may direct treatment are also categorized as Class III and require FDA approval, based on clinical experience, before a product can be marketed.

Pre-market approval is the most involved and expensive process that a medical device manufacturer typically pursues. This type of approval is based on a determination by the FDA that the applicant has submitted sufficient valid scientific evidence to assure that the device is safe and effective for its intended use(s). For example, Figure 2 shows the types of evidence submitted by Foundation Medicine for FoundationOne CDx.

Rigorous FDA evaluations, as shown in Figure 2, are in stark contrast to the path to market for LDTs, although many valuable diagnostic assays have come to market via the LDT pathway. To date, the FDA has exercised a policy of enforce- ment discretion wherein LDTs have not been required to seek authorization in advance of being clinically offered as a test. LDTs are regulated by CMS’ Clinical Laboratory Improvement Amendments (CLIA), which is administered through various accreditation bodies, including the College of American Pathologists. Additionally, various state agencies, including the New York State Department of Health, have their own requirements for laboratories accepting patient samples originating in their states. Although CLIA establishes quality standards for laboratories to ensure the accuracy, reliability, and timeliness of patients’ test results, they do not cover how to perform a pre-market review of analytic validation or require clinical validity data. This contrasts with the FDA review process for Class III PMAs where both analytic and clinical validity are evaluated. Moreover, whereas medical devices and diagnostics must register with the FDA and are also required to submit adverse events, recalls, and user complaints, LDTs have no such requirement. This can lead to lack of awareness of potential safety signals with a given LDT.

To be covered by CMS, medical products must fall into one of the statutorily defined “benefit categories” and be “reasonable and necessary” for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. To meet the “reasonable and necessary” standard, a product or service must improve health outcomes, be safe and effective, and not be deemed experimental or investigational. The reasonable and necessary provisions are not defined explicitly in regulation and remain at the discretion of Medicare. For Medicare, FDA-approved devices with therapeutic indica- tions are presumed to meet this definition unless directly addressed through a Local Coverage Determination (LCD) or National Coverage Determination (NCD). Public payers are often subject to requirements to develop their coverage policies in an open and transparent manner. For example, LCDs and NCDs must undergo opportunities for public comment and are open to more political scrutiny given the nature of publicly funded programs.

The FDA and CMS have clearly different objectives: safety and effectiveness of a device and whether the device is reasonable and necessary, respectively. Therefore, neither agency is usually influenced by the other’s findings or decisions, nor has there been coordination between the individual review processes. To support medical device innovation, the FDA and CMS entered a memorandum of understanding, which led to a pilot FDA/CMS parallel review process.

 The purpose of this program was mainly to minimize the time between regulatory authorization and reimbursement, an important barrier to patient access for the latest medical device innovation.

Creating accelerated approval processes or breakthrough device designations would be insufficient if there was no comparable innovation in reimbursement policies. This is particularly unique to the medical device/diagnostic space in contrast to the oncology therapeutic space where FDA approval of a drug or biologic is sufficient for reimbursement and therefore access by the patient. Medical device/diagnostics must pursue reimbursement separately via an LCD or NCD following FDA review.

 The pilot project has since been made permanent.

Careful evaluation of the National Coverage Analysis process and the resulting NCD can provide valuable insight. CMS assessed CGP technology through the parallel review process using the ACCE (analytical validity, clinical validity, clinical utility, and ethical, legal and social implications of genetic testing) model for assessment. For analytic validity and clinical validity, FDA approval of FoundationOne CDx signifies assurance of safety and effectiveness and that there is an acceptable evidence base for analytic and clinical validity requirements for coverage.

 A key area of focus for CMS in the parallel review was to evaluate clinical utility.

 When these processes are undertaken in parallel, the product’s complete clinical value can be assessed (Figure 3).

Paving The Way in Advanced Cancer: FoundationOne CDx

Through the parallel review process for FoundationOne CDx, CMS identified and reviewed over 250 studies to assess the clinical utility of NGS testing in advanced cancer, demonstrating the breadth of available evidence. The clinical outcome measures CMS considered included overall survival, progression-free survival, partial response, complete response, stable disease, time to progression, overall response rate, and time to treatment failure. Systematic evidence reviews and meta-analyses of clinical trial data provide a strong level of evidence, and observational and other study designs provide additional supportive evidence across a broad population of patients with cancer.

 Meta-analyses of data from therapeutic clinical trials, including randomized controlled trials, which have traditionally been the gold stan- dard in evidence generation; data from nonran- domized studies utilizing CGP; and real-world evidence support the use of a genomically guided treatment approach to improve outcomes.

From this evidence review, CMS concluded that there is sufficient clinical utility demonstrating that FDA-approved and FDA-cleared laboratory in vitro companion diagnostic tests using NGS improve health outcomes for patients with advanced cancer when used by the treating physician and patient to guide selection of proven treatments.20 In addition, in the final NCD, CMS encouraged the community of stakeholders to continue to develop and publish evidence related to the meaningful endpoints assessed in the coverage analysis. Foundation Medicine is committed to publishing evidence as it is generated, as evidenced by more than 300 Foundation Medicine—authored publications.

The parallel review process has served as an incentive for 2 LDTs to pursue regulatory approval: Exact Sciences’ Cologuard for colorectal cancer screening and, more recently, FoundationOne CDx.

 These have been characterized as “single- site PMAs” where both diagnostic tests are offered from a single laboratory. The NCD for NGS-based diagnostics provides confirmed national coverage for FDA-approved or -cleared diagnostics, while LDTs without FDA approval or clearance may still be reimbursed at the discretion of the local Medicare Administrative Contractors.

Translating Parallel Review to Commercial Payers

The parallel review process culminated in FDA approval of FoundationOne CDx and a CMS NCD that provided Medicare beneficiaries with advanced cancer broad access to CGP as a path to precision oncology treatment, as outlined by the coverage criteria in Table.

Although CMS coverage of NGS tests in advanced cancer does not automatically translate into commercial coverage, as reported in a recent survey of some major commercial payers,

 it would seem prudent for commercial payers to seize this moment and re-evaluate the role of CGP in providing important and tangible benefits for the sickest cancer patients regardless of age or insurer. The parallel review process provides the oppor- tunity to recognize and integrate the outcomes of the rigorous FDA regulatory and CMS coverage pathways in order to further pave the path forward for higher quality oncology care.

Commercial payers may be challenged to rethink the approach to coverage determination for non—Medicare Advantage members. With some exceptions, commercial policies have historically described CGP tests as investigational or experimental. These policies often cite lack of clinical utility as a reason for noncoverage; however, there are several considerations for determining clinical utility for genomic panel tests in oncology that differ from single gene testing, including:

Supporting data are often scattered across multiple publications encompassing a diverse range of tumor types, because the clinical utility of CGP varies based on tumor type, stage, and line of therapy.

Not all genomic alterations are directly correlated with a specific therapy; genomic alterations also often impact decision making due to their role in a critical signaling pathway or as a prognostic indicator.

Randomized clinical trials for CGP testing have ethical and design limitations.

To further validate this, a CGP approach has been integrated into many large innovative clinical trials, such as the American Society of Clinical Oncology’s TAPUR and Genentech’s MyPathways; into numerous clinical guidelines; and is used routinely across academic centers and advanced community practices. The evidence base supporting the clinical utility of this approach stems from data across multiple types of studies conducted in the oncology setting using biomarker-driven therapies. Collectively, these studies demonstrate that:

A clinically validated NGS CGP test facilitates the accurate identification of patients with genomic alterations across tumor types.

The presence or absence of these alterations helps inform treatment decisions.

Health outcomes are improved overall when patients are treated with genomically matched FDA-approved drugs or biologics or genomically matched investigational agents.

Thus, genomic testing has a significant role in fulfilling the promise of precision medicine in oncology to improve outcomes for patients, and the NCD is a landmark event for patients with advanced cancer.

Future of the Parallel Review Process in Precision Oncology

When it comes to broad commercial coverage, private payers are often faced with the challenge of addressing or creating a significant disparity in oncology care between patients with Medicare and other commercially covered patients with advanced cancers. Because the analytic validity, clinical validity, and clinical utility evidence reviewed by the FDA and CMS are not limited to patients ≥ 65 years, this same evidence base should be considered by commercial insurers. Cancer is not a disease affecting only the Medicare population. US epidemiology data (Figure 430) estimate the median age at cancer diagnosis to be 66 years, yet 46.8% of cancer diagnoses and 30.7% of cancer deaths occur before age 65.30 In addition, the proportion of cancer cases that are reported as advanced stage (have spread locally or distant) for the Medicare and non-Medicare population are nearly equal (45.3% for <65 years vs and 45% for >65 years). Coverage for commercial lives is imperative so that patients with advanced cancer are provided the greatest opportunity to receive genomically matched or biomarker-driven therapies regardless of age or insurer.

Now that CMS has released the NCD that addresses all NGS-based oncology assays used in advanced cancer, and with the subsequent announcements by multiple CGP diagnostics providers, it is expected that more laboratory tests will undergo the FDA approval process via the PMA pathway.

 Although commercial payers are only directly affected by a new NCD if they offer Medicare Advantage plans, the data supporting the NCD will offer the chance for payers to consider the same information used by CMS to ultimately determine for themselves that outcomes are improved by CGP utilization. If CGP is only accessible to the Medicare population, there is a risk of creating additional disparity in the US healthcare ecosystem. Given the numerous new biomarkers, novel biomarker-driven treatments, tumor-agnostic biomarkers (ie, microsatellite instability), and genomic signatures that require a large panel test, there is no doubt that CGP is not only here to stay but will become mainstream.

In many cases, testing is treated passively by payers (eg, by only asking if a patient was tested if a biomarker-driven therapy is requested). However, CGP offers an opportunity for payers to proactively require that all appropriate patients undergo guideline-driven testing to improve quality of care and decrease waste by assuring the right patients receive the right treatment at the right time. Payers who embrace CGP could be afforded the opportunity to not only improve quality of care but also to better manage and predict cancer drug spend. It would not be hard to imagine a payer taking it one step further and requiring CGP for certain patients, which undoubtedly would increase the utilization of biomarker-driven treatments. The predictable increase in use of biomarker-driven treatments, for both on-label and off-label use, could allow for improved value-based agreements based on the volume of patients receiving CGP, thus off setting possible cost increases for payers while improving quality of care for patients.

Because FoundationOne CDx completed the parallel review process, the path to CMS coverage has been paved for future NGS tests. The broad nature of the NCD means other NGS test providers will only need to pursue companion diagnostic FDA approval or clearance status to obtain coverage from CMS. As outlined in the CMS NCD, the FDA assesses analytic validity and clinical validity as part of the approval process. FDA approval or clearance, therefore, assures market access to high-quality CGP assays. While the CMS NCD ensures access to these approved assays to qualifying Medicare beneficiaries with advanced cancer, the CGP access created by this parallel review will undoubtedly lead to more patients with advanced cancers receiving life-extending precision medicine based therapies. It is fully expected that the understanding of the clinical utility of CGP will continue to evolve, the evidence will continue to grow, and the parallel review process will provide a sound starting place for reasonable assessment of clinical utility for other technologies in this unique space. Lastly, commercial payers will have the opportunity to move from passive to active management of biomarker-driven therapies in a way they have not in the past. Ultimately these decisions will catalyze the paradigm shift for the treatment of advanced cancers as a disease of the genome at all levels of patient care, from the lab to the provider to the payer. If value is defined in part by the therapy’s efficacy, it is hard to see how we can achieve value in oncology without CGP.Author Information

All authors are affiliated with Foundation Medicine, Inc, Cambridge, Massachusetts. Lakshman Ramamurthy, &#1113100;PhD&#1113091;, is the global regulatory lead;&#1113090; K&#1113113;risti Ma&#1113098;well, MS, CGC, is a certified genetic counselor&#1113090;; Bethany Sawchyn, P&#1113100;harmD&#1113091;, is associate director for P&#1113100;ayer &#1113100;Policy and Health Outcomes;&#1113090; and Rachel Anhorn, &#1113100;PharmD&#1113091;, is the director, &#1113100;Payer &#1113100;Policy and Health Outcomes.References:

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Decision memo for next generation sequencing (NGS) for Medicare beneficiaries with advanced cancer (CAG-00450N). CMS website. cms.gov/medicare-coverage-database/details/nca-decision-memo. aspx?NCAId=290&bc=AAAAAAAAACAA&. Published March 16, 2018. Accessed March 21, 2018.

HHS. CMS’ process for making a national coverage determination.Fed Regist. 2013;78(152):48164-48169. cms.gov/Medicare/Coverage/ DeterminationProcess/Downloads/FR08072013.pdf. Published August 7, 2013. Accessed March 21, 2018.

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Schwaederle M, Zhao M, Lee JJ, et al. Impact of precision medicine in diverse cancers: a meta-analysis of phase II clinical trials. 

. 2015;33(32):3817-3825. doi: 10.1200/JCO.2015.61.5997.

Schwaederle M, Zhao M, Lee JJ, et al. Association of bio- marker-based treatment strategies with response rates and progression-free survival in refractory malignant neoplasms: a meta-analysis. 

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Wheler JJ, Janku F, Naing A, et al. Cancer therapy directed by comprehensive genomic profiling: a single center study. 

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Haslem DS, Van Norman SB, Fulde G, et al. A retrospective analysis of precision medicine outcomes in patients with advanced cancer reveals improved progression-free survival without increased health care costs. 

. 2017;13(2):e108-e119. doi: 10.1200/ JOP.2016.011486.

Decision memo for screening for colorectal cancer- stool DNA test- ing (CAG-00440N). CMS website. cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=277. Published October 9, 2014. Accessed April 2, 2018.

Ray T. Commercial payors unlikely to follow CMS policy on NGS cancer panels in short term, survey suggests. GenomeWeb website. genomeweb.com/reimbursement/commercial-payors-unlikely-follow-cms-policy-ngs-cancer-panels-short-term-survey#. WsuwmPmnG1t. Published and Accessed April 9, 2018.

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Ray T. Lab industry says CMS draft national coverage decision for NGS cancer tests bad for patients. GenomeWeb website. genomeweb.com/reimbursement/lab-industry-says-cms-draft-national-coverage-decision-ngs-cancer-tests-bad-patients#.WsBNjdP- wb-Y. Published December 22, 2017. Accessed April 3, 2018.

Authors from Foundation Medicine explain the regulatory path that led to approval of FoundationOne CDx.

Perspective: FDA/CMS Parallel Review Advances Coverage for Cancer Comprehensive Genomic Profiling

While Godard's pronouncement on the cinema may have been uttered with more than a hint of irony, the sensibilities he captured do have relevance in regard to the delivery of cancer care. When patients discuss what

is of the greatest value in their care, many describe their relationship with their physician as an essential, indispensable part of their cancer journey. Similarly, most physicians describe their relationship with their patients as the grounding core of their profession. As the “truth” of these key human interactions are disrupted by the technical and workflow disruptions that, tragically, increasingly permeate and undermine the quality of the time spent in direct patient care, both physicians and patients note the toll that these disruptions take their experience of healthcare.

As cancer care becomes increasingly technology driven, the relationship between the patient and the physician is increasingly subject to “cuts” that undermine the patient centricity of care. In addition, as the increasing number of “cuts” become an inescapable part of the oncologist’s work day (including the innumerable clicks necessary to navigate electronic health records, the interruptions of having to obtain authorization for diagnostic studies, the paperwork associated with obtaining access to cutting edge oral therapeutics, interpreting genomic testing data, seeking clinical trials for patients), the complexity and work burdens of physicians are leading to greater clinician work stress and burnout. Inasmuch as advances in diagnostic technologies, such as genomic testing, promise to improve patient outcomes, the addition of reviewing, interpreting the results, developing care plans based upon genomic data further test the time limits and technical skills of many oncologists. In an article in Healthcare Informatics, the authors quote Jeremy Warner, MD, MS, in noting:

Integrating genomics into clinical workflow is a step into unknown territory, he added. Health systems have to make sure the report is not interruptive of the patient- doctor relationship. “I can’t imagine reading a 30-page PDF in front of a patient in the office.”

The importance of bringing effective point-of-care tools to the practice of oncology cannot be overstated. With the confluence of the increasing complexity of delivering state-of-the-art cancer care to patients and the finite limits of physician time, focus, and human sustainability, the importance of more effective point-of-care resources seems to be self-evident. Advances in information technologies, coupled with greater engagement of an increasingly diverse set of health care stakeholders, has helped to grow point-of-care tools from a core suite of technologies that include evidence-based guidelines and clinical pathways tools to a growing breadth of assets that bring genomic information, reimbursement support, and patient education tools closer toward meeting the needs of the patient and the clinician. These tools may take the form of more effective authorization policies by private and government payers, telehealth support to ensure more effective patient engagement and education, and apps to assess patient-reported outcomes.

, we review some of the point-of-care tools that may help to improve physician work life while also enhancing the patients’ care experience. Authors from Flatiron Health share offer an update on what is working and what’s not with the Oncology Care Model from the perspective of the technology provider and how changes could mitigate the burdens of the electron health record upon physicians’ time with their patients. Authors from Foundation Medicine describe how changes to the FDA/CMS approval process can reduce the pre-authorization burden imposed upon physicians seeking genomic testing for their cancer patients. Matt Lashey from chemoWave writes about how an app to track patient-reported outcomes can help empower better care. Heather Zierhut, PhD, MS, CGC, and Adam Buchanan, MS, MPH, LGC, explore how Medicare reimbursement for telehealth for genetic counseling could more effectively meet patient care needs while helping physicians bring additional expertise to the care of their patients.

Raths D. The ongoing struggle to get actionable genomic data to the point of dare. HealthCare Informatics website. healthcare-informatics.com/blogs/ david-raths/ongoing-struggle-get-actionable-genomic-data-point-care. Published October 26, 2016. Accessed May 8, 2018.

Film is truth 24 times a second, and every cut is a lie – Jean-Luc Godard

From the Editor in Chief: Making Disruptive Technology Less Disruptive

In software development, there’s a concept of a “retro.” Short for a retrospective, the process asks the engineering and product teams to review what’s been working, what hasn’t, and what they’ll commit to improving in the future. As we near the 2-year mark of the Oncology Care Model (OCM),

 we’ve had a chance to reflect on the results and reactions from the first performance period. The completion of the first performance period cycle presents an opportune time to step back to do a retro on how the model has reshaped participating practices and influenced the technology developers supporting them.

The OCM now covers 150,000 Medicare beneficiaries in 200,000 to 300,000 episodes per year,

 and we believe the sustained success and potential expansion of the model can best be driven by incremental iteration that reflects ongoing stakeholder feedback. The OCM, or any future model, will continue to have significant implications for technology developers and participating practices, as requirements become increasingly complex, practices try to mutually optimize quality and cost, and risk-sharing decisions (or obligations) loom. There’s no doubt the model has accelerated the transition from volume to value, particularly in more agile community practices, and its innovation will continue to serve as the foundation of newly proposed models. These include the Making Accountable Sustainable Oncology Networks model,

 which has been submitted to the Physician-Focused Payment Model Technical Advisory Committee.

Although oncologists may feel they’re straddling 2 divergent payment systems, only 1 is here to stay. HHS Secretary Alex Azar recently pointed out, in remarks to US hospitals, that the value-based transformation of our healthcare system

is one of his department’s top priorities.

 Given this, let’s look at what’s been working, what hasn’t, and what could improve in the near term for the OCM specifically and value-based care more broadly.

To kick off the retro process, let’s start with reflecting on the successes of the OCM thus far, namely greater collaboration with CMS, investment in foundational infrastructure, and the implementation of care processes that can be consistently measured and adapted.

While the program continues to evolve with each consecutive reporting period, CMS has worked to cultivate collaborative partnerships, both with oncology practices and electronic health record (EHR) developers. As oncologist Barbara McAneny, MD, president-elect of the American Medical Association, said at the Association of Community Cancer Centers Annual Meeting in March,

 CMS’ constant communication and willingness to incorporate feedback from practices is fostering a more collaborative relationship with oncologists. Through their monthly EHR vendor calls or regular “Support Lunch Hours” sessions with practices, CMS has built and maintained an entire apparatus to seek program feedback and consider program adjustments. This willingness to not only seek, but also implement, feedback has materialized most recently with the adaptation of quality measure criteria (eg, the removal of the OCM-7 measure) and the adjustment of patient-level clinical data submission requirements. This partnership among practices, EHR developers, and CMS will be imperative for the development of required technology infrastructure, to make performance more predictable, and ultimately assuage practice concerns about risk sharing.

Further, although the scope seemed insurmountable when the 160-page OCM Final Rule document was released, practices have made substantial progress within all 3 areas of foundational transformation, discussed in an earlier issue in 

: program administration, care process development, and performance measurement.

 In many cases, given the OCM’s rigorous quality and infrastructure requirements, practices have created new roles that focus on the program’s administration. For example, according to Toni Perry, director of quality and regulatory affairs at Tennessee Oncology, “To ensure success in accurately reporting quality metrics, Tennessee Oncology’s Quality and Regulatory Department added 4-5 full-time data abstractor positions, specifically devoted to validating, mining, and reporting quality data.”

The Monthly Enhanced Oncology Services (MEOS) payments have also enabled practices to expand both administrative and clinical resources to their broader population. “As a practice, we have increased our investment in organizational staff resources in areas such as patient advocates and navigators in order to implement the OCM principles to both OCM and non-OCM patients,” Perry said.

Within Flatiron’s network of over 50 OCM practices, we observed that many began administering their OCM program like a clinical trial: Patients must be screened for eligibility, they must be closely monitored, and detailed clinical data must be captured and reported on a regular basis. To support this imple- mentation, Flatiron leveraged its clinical trial technology to develop a screening tool that allows practices to identify, track, and manage OCM patient episodes. From this, all reporting and EHR-linked identification flows (Figure 1).

With the ability to more precisely identify patients and manage episodes, practices and EHRs have made significant investments in optimizing and codifying necessary processes for quality measurement and care planning. These workflows range from the familiar, like capturing pain, to the new and complex, like ensuring each provider referral loop is closed. EHR developers have deployed technology to make these processes as measurable, actionable, and frictionless as possible. For example, Flatiron’s OCM practices are able to quantify and track screening for pain and depression directly from clinical workflows. Similarly, practices have been able to standardize and streamline delivery of the required care plan to their patients. Flatiron’s care plan is autocompleted from existing data in the EHR, allowing physicians to focus more on patient engagement. Since the start of the program, Flatiron practices have delivered over 68,000 unique patient care plans.

Redesigning products and workflows to enable practices to more effectively implement the OCM has the added benefit of encouraging data capture with maximum ease of use and reporting efficiency. This is evident in our network; for breast cancer alone, structured data completeness doubled less than 2 years from the start of the OCM program compared with a marginal increase in structured data completeness for non-OCM Flatiron practices (Figure 2).

Although there’s been progress integrating foundational components of the OCM, the nuances of the model’s logic requirements and administrative burdens have tempered the pace of transformation, hindering a full pivot to cost-reduction initiatives.

To date, practices have focused on the program elements that are well defined though not easily achieved: identifying patients, billing and collecting MEOS, and reporting registry data. These requirements have created management duties that previously did not exist, and have significantly increased administrative burdens. In particular, practices struggle with the OCM patient identification and clinical data submission components; they have trouble tracking patients on oral oncolytics, a task compounded by inconsistent access to prescription fill data outside the purview of the clinic. This pain point will continue to be burdensome with the increasing adoption of oral therapies.

From July 2016 to July 2017, the percent of Flatiron network OCM episodes initiated by an oral therapy increased by about 10% to over 24,000 episodes (Figure 3). Besides patient identification, CMS has outlined significant requirements for data completeness. To avoid penalties, practices have invested significant resources in abstraction and data backfill, an operational burden that is now necessary but costly.

 study revealed that “administrative costs of care (activities relating to planning, regulating, and managing health systems and services) accounted for 8% in the [United States] versus a range of 1% to 3% in the other countries.”

This is evident across Flatiron’s OCM network: Over 2 million data elements were reported for almost 41,000 OCM patients to the OCM registry during the last submission period. Based on an analysis of the timing of data entry, we estimate that over 36% of breast cancer staging data were entered into the EHR via data abstraction and backfill. While executing these processes is imperative to enable the focus on more esoteric objectives of the model, these administrative components have taken over a year to fully implement for sites and have distracted practices from understanding how to approach the components that more directly affect patient care. The reality is that while collecting, reporting, and measuring high-fidelity data is arduous, much like the adoption of an EHR, they are fundamental enablers of administering value-based models. With the significant administrative investments in the program focused on tackling the OCM on ramp, the vast majority of practices have not yet demonstrated savings below their target spend.

The focal shift away from the administrative execution of the model toward higher-value activities, including gaining a deeper understanding of the financial model and exploring practice-specific opportunities to reduce costs, will be key to the OCM’s durability and ongoing practice success. This shift requires administrative and physician engagement to align on care coordination opportunities, enable productive conversations with the local healthcare ecosystem, and tailor care to each patient’s goals. Anne Marie Rainey, the compliance and quality control officer at Clearview Cancer Institute in Huntsville, Alabama, agrees. “Everyone at the practice—from the concierge to the physician board&mdash;needs to be aware of the program and future implications. Through the use of data-driven tools, detailed clinical reporting, and individual education we are beginning to notice shift in physician engage- ment. We’re now investing in more clinical staff and supportive care services to better address the needs of our patient population and provide higher quality, patient-centered care.”

The OCM, among other quality programs, has shown that point-of-care technology is where and how clinicians experience alternative payment models (APMs) and can be an effective means to engage physicians. They’re where policy is translated into technology that is used to manage patients in value-based models. As such, EHRs must be held accountable for doing their part to reduce the administrative and bureaucratic friction that clinicians experience so they can better spend their time optimizing patient outcomes. During the first year of the model, our clinical team received significant feedback on the cumbersome nature of diagnosing conditions and staging patients in the EHR. Shortly after, the team employed a physician-centric approach when conducting user research with doctors and redesigned the interface to ensure these workflows were intuitive, user friendly, and encouraged structured data capture for programs like the OCM. Now it takes less time to diagnose a patient’s disease, clinicians see consolidated clinical information, and content is more easily updatable for when standards or reporting requirements inevitably change.

However, developing more physician-centric products to enhance usability isn’t enough. Point-of- care data products that leverage the scale of cancer networks must be developed with the data that’s being so meticulously captured for these models. For every patient with cancer who walks into a clinic, a cohort of the most similar patients in a network, and their treatments and outcomes, could be generated. These types of predictive cohorts could enable physicians

to make more personalized treatment decisions by learning from the experience of every patient with cancer. Outcomes of similar patients with cancer could become the evidence required to make a more value-based decision or the stories physicians use to have difficult end-of-life discussions with their patients.

The onus will continue to be on EHR developers to gain an empathetic understanding of users and build intuitive products they need to succeed in this new paradigm. Meanwhile, policymakers must see healthcare technology providers not merely as secondary constituents or APM facilitators, but rather as key stakeholders who must be engaged early and often throughout model design and implementation.

In examining the OCM through the lens which engineering and product teams use to reflect on their performance, the retro, it becomes clear just how much value-based care itself is a team effort. It starts with the care team and goes far beyond, relying upon novel partnerships between payer and provider, government and health information technology, and hospital and clinic. As we enter the second, and more trying, half of the OCM, we’ll soon know if this experiment is a collective win: if patients with cancer across the country have access to higher-quality, more affordable care.

All authors are affiliated with Flatiron Health, a healthcare technology and services company focused on accelerating cancer research and improving care based in New York, New York. Ryan Holleran is a manager of product marketing and strategy; Arif Gilani is a manager of product operations; Abigail Orlando is a data insights engineer; and Brenton Fargnoli, MD, is the medical director of value-based care and director of product marketing and strategy.References:

Oncology Care Model. CMS website. innovation.cms.gov/initiatives/ Oncology-Care. Updated April 5, 2018. Accessed April 11, 2018.

Kline R, Adelson K, Kirshner JJ, et al. The Oncology Care Model: perspectives from the Centers for Medicare Medicaid Services and participating oncology practices in academia and the community. 

Educ Book. 2017;37:460-466. doi: 10.14694/EDBK_174909.

Flatiron Health recently conducted a retrospective review of the Oncology Care Model, discovering what's working, what isn't, and what this could mean for the future.

June 2018

Medical World News: Managed Care Updates

Medical World News: Clinical Updates

Perspective: FDA/CMS Parallel Review Advances Coverage for Cancer Comprehensive Genomic Profiling

From the Editor in Chief: Making Disruptive Technology Less Disruptive

A Retrospective on the Oncology Care Model

Population Health Council Discusses Progress in Payment Reform, Ongoing Barriers in Oncology Care

With the Oncology Care Model, "Everyone Has to Be Engaged," Including Patients

Riding the Wave Through Chemo: Cancer Journey Leads to chemoWave App for Reporting PROs

National Comprehensive Cancer Network, American Association of Clinical Urologists, and Large Urology Group Practice Association Endorse Biomarkers in Prostate Cancer

The Impact of New CMS Rules for Telehealth on Cancer Genetic Counseling