Balancing Innovation and Value in Cancer Care: Spotlight on Non–Small-Cell Lung Cancer Treatment

The rising cost of healthcare, including cancer care, is an established trend in the United States. In 2015, Americans spent $3.2 trillion (nearly $10,000 per person) on healthcare, including hospital inpatient and outpatient care, physicians’ services, and prescription drugs.^1,2 The National Cancer Institute estimates that by 2020, the annual cost of healthcare for Americans with cancer will reach $156 billion; based on current trends, this means that cancer care will represent approximately 20% of the country’s annual healthcare expenditures.³

Higher expenditures for cancer care are attributed, in part, to successes associated with advancements in its diagnosis and treatment, as well as the growing need for survivorship programs.^3,4 Patient outcomes, including survival, have improved, such that the number of cancer survivors in the United States exceeds 14 million.³ Continued drug discoveries also fuel these cost trends; in 2015, the US Food and Drug Administration (FDA) approved 33 new drugs or new indications for cancer.⁴ In addition, sophisticated molecular and genetic tests, which have been approved by the FDA as companion diagnostics, serve as gateways to personalized treatment in oncology.⁴

National Emphasis on Value and Quality in Cancer Care

Despite many breakthroughs in the treatment of cancer, including the discovery of novel drugs and diagnostic tests that can improve patient outcomes, the overall performance of the cancer care system in the United States has been called into question.^5,6 The Institute of Medicine (IOM) has reported that cancer treatment in the United States is not always patient-centric and well-coordinated. For some patients and their families, high-quality cancer care remains difficult to access and afford.^5,6

As reimbursement models for cancer care and chemotherapy delivery have shifted in the past decade, medical oncologists and hematologists, as well as advanced care providers with whom they work, can encounter challenges in delivering high-quality care.⁷ Care providers’ ability to balance individual patient needs while delivering consistent cancer care is called into question as each novel therapy and companion diagnostic test is introduced. The fragmentation of care remains a concern across the cancer care delivery continuum.⁷

As they search for economic predictability and sustainable business models, oncology providers have used and evaluated multiple strategies to improve the delivery of cancer care, including⁷:

• Development of pathways programs and/or cancer treatment guidelines, which are decision-support tools that incorporate evidence-based treatment protocols to ensure high-quality care across all sites of delivery
• Association of independent private practices with larger regional or national networks of medical oncologists for payer and wholesaler negotiating purposes, including regional consolidation as single, privately owned business entities
• Contractual alignment with community hospitals and academic institutions
• Association with integrated delivery systems, including accountable care organizations
• Engagement in oncologist-directed cancer care transformation.

Tenets of Value-Based Cancer Care

The IOM defines quality as “the degree to which health services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge.”⁸ Based on this definition, value-based cancer care represents quality care for patients with cancer that is delivered with the proper allocation of resources.⁹

The use of well-recognized quality performance metrics and the latest clinical evidence are critical to value-based practice approaches.⁹ Oncologists can access current summaries of clinical evidence and treatment standards from multiple independent sources, including the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the Commission on Cancer.⁹ Validated process standards are also provided by the National Committee for Quality Assurance (NCQA), the American College of Physicians, and the National Coalition for Cancer Survivorship, with the goal of driving quality, cost, service, and practice efficiencies.⁹

Evolution of Oncology Medical Home Initiatives

In 2008, the NCQA adopted standards for the primary care patient-centered medical home (PCMH) program, an initiative that continues to drive reforms in healthcare delivery.¹⁰ Evidence consistently shows that PCMHs reduce hospital and emergency department visits, mitigate health disparities, and improve patient outcomes.¹⁰ The medical home model also cultivates patient engagement and expands access and delivery options to align patients’ preferences with payer and provider capabilities.^10,11

Using the PCMH model as a template, John D. Sprandio, MD, and colleagues established an oncology PCMH model in 2010.^10,11 The oncology PCMH model controlled cancer care costs, while improving the management of patients with cancer, as demonstrated by the following outcomes⁷:

• 68% reduction in emergency department visits
• 51% reduction in annual hospital admissions for each patient who receives chemotherapy
• 21% shorter length of stay for hospitalized patients
• 22% reduction in outpatient visits per patient annually in the general hematology/oncology patient population
• 12% reduction in outpatient visits per patient annually in the chemotherapy subpopulation.

The overall cost-savings associated with an oncology PCMH have been estimated at $1 million per physician annually.⁷

In addition to the oncology PCMH model, which was a demonstration project primarily driven by cancer care providers, another medical home model was funded by the Centers for Medicare & Medicaid Services (CMS).^9,12 Known as COME HOME, this initiative was designed to demonstrate that community oncology practices can refine patient management processes while generating high patient satisfaction and favorable health outcomes in a cost-effective manner.¹² In that initiative, 7 US-based community oncology practices that managed patients who were covered under Medicare instituted a cancer care approach that included centralized, protocol-driven triage nurses; 24/7 access to clinical staff; treatment pathways; and laboratory and molecular diagnostics efficiency.^9,12 After 3 years, the COME HOME initiative documented lower overall costs of care, which was primarily attributed to fewer hospital admissions and emergency department referrals.¹²

In 2016, based largely on the success of the COME HOME initiative, CMS launched the Oncology Care Model (OCM).¹³ Under the OCM, oncology group practices enter into payment arrangements that include financial and performance accountability for episodes of care surrounding chemotherapy administration to patients with cancer.¹³ These oncology group practices are responsible for the total cost of care for each patient with cancer, regardless of the origin of that cost. In return for additional monthly payments for each CMS beneficiary who qualifies, oncology practices agree to the following specific quality and reporting standards^13,14:

• Provide patient navigation
• Document a care plan with 13 components, as outlined by the IOM
• Provide 24/7 patient access to an appropriate clinician who has real-time access to the practice’s medical records
• Provide patients therapies that are consistent with nationally recognized clinical guidelines
• Use data to drive continuous quality improvement
• Use an Office of the National Coordinator for Health Information Technology–certified electronic health record.

This 5-year project began in July 2016 and included approximately 200 physician groups, 16 national and regional private payers, and CMS.¹³

Balancing Innovation with Value-Based Cancer Care

The ability of oncology practices to provide value-based cancer care—multidisciplinary and guideline-based patient care while controlling costs—requires the cooperation of all stakeholders, including patients, payers, employers, and care providers. Payers who impose inappropriate limits on access to diagnostic testing or medications, employers who prioritize health benefit plans with high deductibles for patients with cancer, physicians who do not adhere to guidelines, and patients who do not take responsibility for their care can all be disruptive to the success of the OCM and other value-based cancer care initiatives.

The delivery of value-based cancer care is also hampered by the difficulty that providers face as they try to keep abreast of important advances. Although treatment guidelines for individual malignancies are updated routinely by the experts who advise the NCCN, ASCO, and other guideline promoters, robust clinical trial data demonstrating efficacy and viability of novel and innovative approaches to cancer management are published and reported nearly daily. As oncology providers review and select therapies for patients with cancer, they can feel torn between a need to follow the established cancer treatment guidelines and a desire to prioritize a precision medicine approach that is logical and evidence-based but that may not yet be incorporated into standardized treatment guidelines.

Precision Medicine in the Spotlight

Precision medicine in oncology involves the identification and use of unique information about a patient’s tumor cells, including the results of genomics and biomarker testing, to develop a customized treatment plan and specific therapeutics tailored for the individual patient.¹⁵ The Cancer Genome Atlas, a publicly funded project that was launched in 2005 to create a comprehensive “atlas” of cancer genomic profiles, opened the door to this new era of precision cancer care.¹⁵ The overarching theme of precision medicine is the use of drugs that can attack the right targets in the right patient at the right dose to obtain the desired outcome.¹⁵

The concept of precision medicine is not theoretical; it has been crystalized into a governmentwide initiative.¹⁶ In January 2015, President Barack Obama announced the Precision Medicine Initiative (PMI), a comprehensive research effort designed to revolutionize how diseases, including cancer, are managed.¹⁶ Launched with a $215-million investment, the PMI is tasked with accelerating biomedical discoveries and giving clinicians new tools and knowledge to select treatments that will work best for their patients. Public and private stakeholders will be able to leverage advances in genomics, big data, and health information technology. The treatment of cancer is a high priority for the PMI; the National Cancer Institute was granted $70 million to expand its efforts to identify genomic drivers in cancer and to develop effective targeted treatments.¹⁶

The debate as to whether precision medicine and value-based care in oncology are at odds with each other takes shape based on one’s perspective. Those who take an individual patient view contend that value-based care—the delivery of quality care with the proper allocation of resources—is realized when a patient receives the right (albeit often expensive) medication as soon as possible. In this paradigm, biomarker test results rather than standardized treatment guidelines often direct drug selection.¹⁷

Although a personalized treatment approach can be more costly than a nonpersonalized approach, it can also be more cost-effective than using a novel agent only after less effective, guideline-driven treatments have been tried and ruled out. The personalized approach was strengthened by the results of a meta-analysis of more than 13,000 patients who participated in phase 1 clinical trials of targeted agents, which was presented at the 2016 annual meeting of ASCO.¹⁸ Researchers determined that the use of biomarker-driven treatments strongly correlated with improved outcomes, including overall response and progression-free survival (PFS).¹⁸

The counterview embraces a “population perspective,” suggesting that unrestricted access to high-cost targeted agents, in addition to their companion diagnostic tests, will lead to confusion among providers, inappropriate use of costly targeted agents, and ultimately, bankruptcy—for patients as well as for the US healthcare system.¹⁷ In an environment characterized by unrestricted access to diagnostic tests and medications, providers can order multiple biomarker and genetic panels without having a clear understanding of their clinical relevance. In this scenario, treatments may be selected without sufficient clinical evidence of likely benefit.¹⁷

As provider reimbursement models shift away from fee-for-service toward risk-sharing, the relevance of questions about the compatibility of precision medicine and value-based care is heightened.¹⁷ Risk-sharing approaches prioritize efficient achievements of favorable patient outcomes over approaches such as chemotherapy delivery. Oncology providers are rewarded for optimizing patient care based on their knowledge of the latest medical developments, as well as their ability to deliver care in a cost-efficient manner.¹⁷

Innovation in Non–Small-Cell Lung Cancer

Lung cancer is the second most frequently diagnosed cancer in the United States, with an estimated 222,500 new cases projected for 2017.¹⁹ Non–small-cell lung cancer (NSCLC) accounts for approximately 85% of all cases of lung cancer.²⁰ Lung cancer claims more lives than any other type of cancer, including colon, breast, and prostate cancer combined, accounting for approximately 25% of all cancer deaths in the United States.¹⁹

Although the 5-year survival rate for localized (ie, early-stage) lung cancer is 55%, only 16% of patients with lung cancer are diagnosed at such an early stage.²¹ Among lung cancer cases of all stages that were diagnosed between 2005 and 2011, the 1-year and 5-year survival rates were 44% and 17%, respectively.²¹ In addition, one of the deadliest cancers, lung cancer is also the fifth costliest cancer in the United States; the total estimated national expenditure for 2015 exceeded $13 billion.²²

NSCLC is one example of a malignancy in which the concept of precision medicine has evolved most dramatically.^23,24 The discovery and clinical application of knowledge about driver mutations (Figures 1 and 2) have largely transformed oncologists’ approach to the management of patients with NSCLC.^23,24 EGFR mutations, ALK gene rearrangements, and ROS1 rearranged tumors are identified as different NSCLC subtypes and managed with unique drug therapies.^25,26 The identification of several new mutations, although not yet clinically actionable, are expected to continue to alter the classification and management of NSCLC.^24,25

Genetic mutations are not the only actionable biomarkers in NSCLC. Proteomics, epigenomics, transcriptomics, metabolomics, microbiomics, and other “omics” methods are becoming increasingly cost-efficient, and exploration of their clinical utility is underway.²⁴

Proteomics—the large-scale study of proteins that are expressed in and on cancer cells—has identified important targets for research and development in NSCLC. Programmed death (PD)-1 and cytotoxic T-lymphocyte antigen (CTLA)-4 are antigenic proteins expressed on the surfaces of lung cancer cells and immune cells, and represent targets for the development of immunotherapeutic antibodies.^23-25 The efficacy and safety of checkpoint inhibitors, including antibodies to the CTLA-4 drug ipilimumab (Yervoy), the PD-1 inhibitors nivolu­mab (Opdivo) and pembrolizumab (Keytruda), and the PD ligand 1 (PD-L1) inhibitor atezolizumab (Tecentriq), have been extensively evaluated in NSCLC.^24,25

Novel Diagnostics and Therapies for PD-L1–Positive Metastatic NSCLC

Based on the demonstrations of clinical benefit and tolerability in particular subsets of patients with NSCLC, 3 checkpoint inhibitors—atezolizumab, nivolumab, and pembrolizumab—have been recently approved by the FDA and are currently routinely used in selected patients with metastatic NSCLC.^26-29 In addition, 3 immunohistochemistry (IHC) assays to detect PD-L1 expression—Ventana PD-L1 (SP142), PD-L1 IHC 22C3 pharmDx, and PD-L1 IHC 28-8 pharmDx—have obtained regulatory approval by the FDA.^30-33 Each assay includes studies that demonstrate a positive correlation between PD-L1 expression and clinical outcomes after treatment with PD-1 or PD-L1 checkpoint inhibitors.^30-33

After assessing the data that support these diagnostic and therapeutic agents, including the most recent evidence demonstrating activity in metastatic NSCLC, the NCCN recommends the use of checkpoint inhibitors in the following settings²⁶:

• Pembrolizumab as first-line therapy for patients with metastatic NSCLC whose tumors express PD-L1 at levels of ≥50% and with negative or unknown test results for EGFR mutations, ALK rearrangements, and ROS1 rearrangements (category 1)
• Nivolumab as subsequent therapy for patients with metastatic NSCLC that relapsed during or after first-line therapy, regardless of PD-L1 expression levels (category 1)
• Pembrolizumab as subsequent therapy for patients with metastatic NSCLC whose tumors express PD-L1 at levels of ≥1% or higher (category 1)
• Atezolizumab as subsequent therapy for patients with metastatic squamous or nonsquamous NSCLC that relapsed during or after first-line therapy, regardless of PD-L1 expression levels (category 2A).

In the context of PD-L1 expression testing in the first-line setting, NCCN recommends IHC evaluation of PD-L1 expression levels for all patients with metastatic NSCLC who have negative or unknown test results for EGFR mutations, ALK rearrangements, and ROS1 rearrangements (category 2A).²⁶ Although the NCCN recognizes that IHC testing of PD-L1 expression is less than optimal, based on concerns regarding specificity and sensitivity,³⁴ available assays are recognized as the best available options to assess whether patients are candidates for first-line therapy with pembrolizumab.^26,35 Testing for PD-L1 expression is not required in patients with relapsed NSCLC, but the NCCN states that such testing may provide useful information.²⁶

In addition to the NCCN, oncologists and pathologists have elucidated concerns about PD-L1 testing.³⁴ Pathologists have called for the standardization of testing for PD-L1 by IHC.³⁴ Specific considerations regarding these assays include³⁴:

• Each available biomarker assay uses different monoclonal IHC antibody clones produced by 1 of 2 diagnostics companies
• Each assay has proprietary staining platforms
• Different definitions of a “positive” test for PD-L1 expression and inconsistent PD-L1 expression reporting. For most tests, PD-L1 expression is reported on tumor cells; in 1 test, it is also reported on tumor-infiltrating immune cells
• Variability in test accuracy across different sample types (ie, large tumor samples, small biopsies, cytology)
• Intralaboratory and interlaboratory reproducibility
• Intraobserver and interobserver variability
• Epitope stability in stored materials.

Until further research has been completed, considerable knowledge gaps remain about the technical aspects of PD-L1 IHC testing, as well as the biologic implications that can be confidently made based on the expression of any dynamically changing biomarker, including PD-L1.³⁴

First-Line Therapy for PD-L1–Negative Metastatic NSCLC

Because an actionable driver mutation cannot be identified for the majority of patients with metastatic NSCLC,²³ and because the majority of these patients do not express PD-L1 at levels of ≥50%,^35,36 the initial use of chemotherapy remains the standard of care.²³ The efficacy and tolerability of platinum-based doublet chemotherapy has been established in patients with a good performance status (ie, Eastern Cooperative Oncology Group performance status 0 or 1) across multiple clinical trials and meta-analyses.²³

For patients with metastatic NSCLC who do not qualify for initial use of mutation-targeted therapies or pembrolizumab, the NCCN recommends cisplatin or carboplatin in combination with a taxane (ie, docetaxel, paclitaxel, albumin-bound paclitaxel), gemcitabine, etoposide, or pemetrexed.²⁶ Doublet chemotherapy combination therapies for metastatic NSCLC have demonstrated objective response rates of 25% to 35%, a median PFS of 4 to 6 months, and overall survival (OS) of 8 to 10 months.²³

For patients with nonsquamous NSCLC, bevacizu­mab (Avastin), an inhibitor of vascular endothelial growth factor (VEGF), and pemetrexed improved survival outcomes when added to first-line platinum-based chemotherapy.^37,38 When added to paclitaxel and carboplatin, bevacizumab demonstrated improved OS. The median OS was significantly higher with paclitaxel and carboplatin plus bevacizumab (12.3 months) compared with paclitaxel and carboplatin alone (10.3 months; hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.68-0.94; P = .013).³⁷ Bevacizumab is recommended in patients with nonsquamous NSCLC whose performance status is good and who do not have a recent history of hemoptysis.²⁶

Pemetrexed is a folate analog that disrupts processes essential for cell replication.³⁸ For patients with nonsquamous NSCLC, the use of pemetrexed as maintenance therapy immediately after first-line, platinum-based chemotherapy has demonstrated superior OS and PFS compared with placebo.³⁸ In a study of 663 patients with NSCLC, the median OS was 15.5 months with pemetrexed compared with 10.3 months with placebo (HR, 0.70; 95% CI, 0.56-0.88) in patients with nonsquamous NSCLC.³⁸ The median PFS was 4.4 months with pemetrexed versus 1.8 months with placebo (HR, 0.47; 95% CI, 0.37-0.60).³⁸ Neither bevacizumab nor pemetrexed is recommended for patients with squamous NSCLC.^37,38

Subsequent Treatment of Metastatic NSCLC without Mutations

Second-line and subsequent therapies for patients with metastatic NSCLC without mutations includes the use of additional cytotoxic chemotherapy, the combination of ramucirumab (Cyramza) and docetaxel, PD-1 or PD-L1 inhibitor (presuming pembrolizumab was not used as first-line therapy), and palliative care.²⁶

When considering the question of cost-effective therapy sequencing in patients with NSCLC without mutations that relapsed after initial cytotoxic chemotherapy, it can be argued that the clinical benefit rate associated with all available therapies, including checkpoint inhibitors, remains suboptimal.³⁵ For example, responses to available checkpoint inhibitors in patient cohorts selected based on the results of PD-L1 expression testing are observed in less than 50% of patients.³⁵ Response rates to checkpoint inhibitors used as single agents in unselected patients with relapsed NSCLC ranged from 15% to 20%, and the median OS ranged from approximately 12 months to 15 months.^26,35

Cautions about testing of PD-L1 expression have been outlined by the NCCN and by others.^24,26,33,34 Unlike HER2 and estrogen receptors in breast cancer, PD-L1 is an inducible and dynamic biomarker that needs to be considered in a different way.^39,40

Routine use of PD-L1 assays, as well as other ‘omics’ methods, is limited by challenges associated with the technical reproducibility of testing platforms, variability among laboratories, statistical reproducibility, heterogeneity within and between samples, and a lack of longitudinal cohorts for use in validation.²⁴ From a practical perspective, if biopsy procedures are needed to obtain these biomarkers of risk and treatment response, access to tissue in the clinic will remain a challenge.²⁴

Because a high proportion of patients with NSCLC do not respond to PD-1 or PD-L1 inhibitors, the discovery of a biomarker that can accurately identify patients who do not respond to these agents remains an important goal of therapy in NSCLC. The hope is that future PD-L1 companion diagnostics will have improved clinical sensitivity and specificity than the currently available PD-L1 expression assays.³³

The combination of ramucirumab plus docetaxel is a recognized treatment alternative to checkpoint inhibitors in the NCCN guidelines, based on the demonstration of survival benefits in the second-line therapy in the NSCLC setting.^26,41,42 Ramucirumab is a fully human monoclonal antibody that binds to the VEGF receptor 2 extracellular domain to inhibit angiogenesis, a mechanism that is known to promote tumor growth and metastasis.^41,43

The REVEL clinical trial, a phase 3, randomized, double-blind study of ramucirumab plus docetaxel versus placebo plus docetaxel, enrolled more than 1200 patients with squamous or nonsquamous NSCLC that progressed during or after 1 platinum-based therapy for locally advanced or metastatic disease.^41,42 The OS and PFS were significantly improved in patients who received ramucirumab plus docetaxel compared with placebo plus docetaxel (Table).⁴¹ The objective response rate, including complete response and partial response, was also significantly better with ramucirumab plus docetaxel (23%; 95% CI, 20-26) than with placebo plus docetaxel (14%; 95% CI, 11-17).⁴¹ The effect of ramucirumab plus docetaxel on PFS was consistent across most patient subgroups, including patients with squamous or nonsquamous histology, making ramucirumab the first VEGF inhibitor to demonstrate a PFS benefit in squamous NSCLC.^23,42

The combination of ramucirumab and docetaxel has also been shown to be cost-effective as a second-line treatment for NSCLC.⁴⁴ A 2015 analysis of direct medical care costs in the United States and clinical trial outcomes data demonstrated that ramucirumab plus docetaxel is cost-effective in the second-line treatment of patients with nonsquamous NSCLC, presuming a willingness-to-pay threshold of $200,000 per life-year gained.⁴⁴ The incremental cost-effectiveness ratio for ramucirumab plus docetaxel was $192,833 versus docetaxel alone.⁴⁴ These data suggest that ramucirumab plus docetaxel exemplifies the tenets of value-based cancer care: it is an active and cost-effective regimen for appropriately selected patients with relapsed, metastatic NSCLC.

Conclusions

Despite breakthroughs in the diagnosis and treatment of cancer, high-quality cancer care can be difficult to access and afford for some Americans and their families. Recognizing this fact, oncology providers continue to restructure their approach in an effort to deliver value-based cancer care—high-quality patient care at an acceptable cost. The ongoing OCM initiative, in which oncologists enter into payment arrangements that include financial and performance accountability for episodes of care related to chemotherapy administration to patients with cancer, strives to enhance relevant patient outcomes rather than strictly enforce treatment guidelines or promote activities related to chemotherapy delivery.

As concepts, precision medicine and value-based cancer care may initially not appear to be fully aligned. Open access to evidence-based personalized treatments that are selected based on genetic mutations and other biomarkers suggest higher costs of care, but further research must be conducted to determine whether they are ultimately more cost-efficient than nonpersonalized therapies.

NSCLC is one of the most striking examples of how precision medicine discoveries can revamp treatment. Tumors with EGFR, ALK, or ROS1 mutations are recognized as distinct NSCLC subtypes that respond in a unique way to novel targeted therapies.

For patients with squamous or nonsquamous NSCLC without mutations whose tumors express high levels of PD-L1, pembrolizumab extends OS when used as first-line therapy. For patients in the second-line setting whose NSCLC relapsed after initial chemotherapy, guidelines recommend that oncologists offer checkpoint inhibitor therapy only after obtaining results from an approved PD-L1 IHC test.

However, some experts have voiced concerns about the predictive value and the lack of standardization associated with PD-L1 IHC assays. For patients with unmutated squamous or nonsquamous NSCLC that relapsed after first-line chemotherapy and whose tumors do not express PD-L1, ramucirumab plus docetaxel represents the principles of value-based cancer care; this combination therapy is an active and cost-effective regimen for appropriately selected patients in this setting.

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