Joseph Alvarnas, MD, discusses the history of cancer care and what the future might look like in the space.
One can get an excellent sense of the pace of cancer care innovation and the controversies and failures that are part of this grand narrative by tracking cancer-related cover stories in TIME magazine.1-10 Dating back 70 years, these cover stories have told the dynamic story of the failed promises, bold advances, and unintended consequences of advances in cancer treatment and their impact upon patients affected by this diverse set of disorders. In ready this series of stories, it is difficult not to wonder how this narrative will continue to evolve over the next 10 to 20 years.
In the early 1970s and 1980s, stories in the popular media embraced the idea of anticancer “magic bullets” that would prove the key to providing cures for all types of cancer. In the end, there was no magic, just a growing appreciation for the fact that curing cancer is not based upon some underlying simplicity in cancer biology or fortune in identifying a universal cure. Instead, there was a growing realization that conquering cancer would require a deep level of scientific inquiry into the genetic and molecular underpinnings of each type of cancer, so that individual cures could potentially be crafted to manipulate the underlying biology of the disease. The requisite quantum intellectual leap from a belief in magic bullets toward a mindset that embraced the inherent complexity of cancer biology led to the “precision medicine” mindset. The future of cancer care lies in this continuing, dynamic journey of discovery while ensuring that our systems of delivering care can match this clinical promise, so that patients can benefit equitably from these advances in care.
The promise of targeted anticancer therapeutics was first demonstrated through the extraordinary success of imatinib (Gleevec) and the tyrosine kinase inhibitors (TKIs) in the treat- ment of patients with chronic myelogenous leukemia (CML). By exploiting the mechanism of action of the unique fusion protein created by gene fusion specific to CML, daily dosing of the TKIs could produce a significant percentage of molecular complete remissions for a population of patients whose prognosis prior to the advent of these innovative therapeutics was poor, with a median survival of less than 3 years.11
Although the information derived from convention cytogenetic studies on cancer have had some impact upon the development of targeted anticancer therapeutics, the Human Genome Project has produced a veritable Rosetta Stone for identifying unique tumor-related mutations in the cancer cell genome and leveraging this information in the pursuit of innovative targeted therapeutics.12 This process has been accelerated by increasing numbers of patients with cancer whose tumors have undergone genomic testing, including whole exome sequencing, as well as the availability of supercomputer analysis of these data. The availability of supercomputer-based analytics allows for very high throughput of immense amounts of unstructured genomic data that can help identify potentially relevant cancer-related mutations.13 These advances in our understanding of tumor genomics and the identification of new tumor neo-antigens as marks for targeted therapeutics and immune-oncologic therapeutics have accelerated the pace of development for these therapeutics.
In a relatively short period of time, these data and other data obtained from basic science research directed at identifying tumor genomics and potential targets for innovative immuno-onco- logical treatments have produced significant, tangible results for patients with previously unmet cancer care needs. Earlier this year, in a randomized phase III trials of checkpoint inhibitors added to the standard treatment of non—small cell lung cancer (NSCLC) for patients without mutations of EGFR or ALK produced a significant prolongation of survival and improvements in progression-free survival.14 The standard of care for patients with NSCLC has evolved dramatically during this period, with inclusion of genomic testing as part of the assessment of patients with advanced disease prior to treatment. Moreover, these treatment guidelines also reflect increasing therapeutic options, including targeted therapeutics for patients with selected mutations of EGFR, ALK, BRAF, MET, ROS1.15 Many types of cancer that have proven historically refractory to standard chemotherapeutic approaches may respond dramatically to targeted immune-oncological agents, often producing an excellent quality of life for patients affected by these diseases.16 This pace of innovation continues to increase at a previously unprecedented pace. Between 2014 and 2017, there were more than 50 FDA approvals for targeted anticancer therapeutics.17 Although some of these reflect approval of a single agent for multiple indications, most reflect a breadth of therapeutics that include bispecific molecules, checkpoint inhibitors, small molecules, and monoclonal antibodies that demonstrated effectiveness in a broad array of tumors, including many cancers that have been refractory to standard chemotherapeutic approaches. Moreover, the future pipeline for new, targeted anticancer therapeutics looks robust.18 As more potential therapeutic targets are identified through genomic, molecular, proteomic, and metabolomic investigation and data analysis, there is enormous hope that the promise of precision medicine will translate into greater opportunities for patients with historically refractory and poor-prognosis cancers.19 These advances portend a future in which cancer survival rates will continue to rise and the number of cancer survivors in the United States will continue to grow.
Yet, inasmuch as the future is likely to bring enormous progress and innovative treatments for patients with unmet care needs, it is also likely to bring a series of increasingly complex challenges to our healthcare system. The first of these relates to concerns about the financial sustainability of delivering these innovations, given their rapidly escalating price tags. In a recent study, the average cost of an anticancer drug approved between 2006 and 2015 rose more that 5-fold to an average of $13,176 per month.20 Although the challenge of paying for new therapeutics with an average annual cost of $160,000 sounds daunting, the example of chimeric antigen receptor (CAR) T-cell therapeutics stands as a bellwether for some of the expected cost challenges to come. Thus far, 2 CAR T-cell products have been approved, with the possibility of a third in the near term. These genetically modified agents are manufactured on a per-patient basis for the treatment of young patients with relapsed, refractory B-cell acute lymphoblastic leukemia (ALL) and patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), respectively. Both products have demonstrated clinical activity that is superior to historical approaches, and the Institute for Clinical and Economic Review report on
CAR T-cell therapies found that these products met the threshold for cost-effectiveness for both treatment indications.21 Yet the line-item procurement costs of the 2 commercially available therapeutics ($373,000 for DLBCL and $475,000 for B-cell ALL) has been met with significant concern.22 These represent some of the most expensive therapeutics released to date in the United States. This has led policymakers to wrestle publically with the question of how to deal with therapeutics whose cost is seen as a challenge to the sustainability of our government-based payment systems. In the 2019 Inpatient Prospective Payment System (IPPS) rule, a large part of the cost of delivering these treatments was left unreimbursed, thus leaving the hospitals and healthcare systems that offered these therapeutics to cover half or more of the cost of product procurement alone.23 This issue seems to have had a chilling effect upon the availability of these therapeutics to patients who may need them. Recently, FDA Commissioner Scott Gottlieb, MD, said the failure to resolve the issue of CAR T-cell reimbursement could stifle future therapeutic innovations for patients with cancer.24
Although the rising costs of pharmaceuticals and engineered therapeutics pose a challenge, it is inappropriate to consider the issue of therapeutic cost in isolation. In one study, a review of the cost of care for third- and fourth-line treatments for patients with relapsed or refractory DLBCL ranged from $600,000 to $750,000.25 This is a sum that may actually exceed the cost of much more effective care for this population of patients. The difference is that the transactions costs associated with CAR T-cell procurement have created a perception of greater overall costs where that may not, in fact, be true.
The idea of shifting toward payment for value, rather than volume, is a concept that is routinely cited as an essential principle in gaining control over care-related costs. Experts and national leaders— from Michael E. Porter, PhD, MBA, and Thomas H. Lee, MD, both of Harvard, to former HHS Secretary Sylvia Mathews Burwell—have all embraced this as an essential principle of creating a high-quality, financially sustainable system of care delivery.26,27 Yet we have made amazingly little global progress in this regard in creating a national value-based care model in the oncology domain. There are some important pilot projects, including the Oncology Care Model (OCM) from the Center for Medicare and Medicaid Innovation, but we have yet to see the creation of a national ecosystem that consistently fosters and rewards high-value oncology care, especially a system that can support and reward the appropriate and effective use of high-cost therapeutics.
Whereas it is easy to become enthralled with the unprecedented pace of innovation around genomic diagnostic technologies and advances in targeted therapeutics, these things risk becoming intellectual curiosities unless we can create an ecosystem that aligns financial incentives with providing patients with the most effective suite of services throughout their cancer journey. For some this might entail treatments with a recently approved therapeutic, while for others this might be a system that ensures that compassion and palliation are equally valued when they represent the most patient-centered options for a particular patient. One of the benefits of the OCM is that it has brought the idea that cancer care is delivered throughout a series of episodes that should align around the needs of patients and their families. As knowledge is gleaned from this pilot project, the hope is that the concept of value-based care may grow from an aspirational platitude to a fully realized ecosystem that provides patient-centered care and sustainable reimbursement for physicians and healthcare systems across the breadth of a patient’s entire cancer journey. Creating this system will require that big data science and information technology can be fully leveraged to carefully define clinical risk through rigorous patient segmentation (based upon demographic, diagnostic, genomic, and goals of care data) in order to reimburse a system of care that is focused upon the patient’s needs throughout the continuum of care. Key elements of this ecosystem, including the creation of big data analytic models and care delivery frameworks, are in progress.28-32 Data gleaned from this set of experiences can help to create the scaffolding upon which a better, more effective, sustainable system can be created.
It will be impossible to deliver the transformational level of care that genomics and innovative therapeutics equitably, effectively, or sustainably promise unless we create a transparent, data-rich system of care that can sustain and deliver these consistently. This linkage between the needs and voice of the patient, genomic testing data, and the creation of a care ecosystem that aligns clinical risk, goals of care, the patient experience, and meaningful outcomes with reimbursement, is perhaps the best finish line for the end of the beginning of our road toward sustainable, patient-centered oncology care.AUTHOR INFORMATION
Joseph Alvarnas, MD, is the editor-in-chief of Evidence-Based OncologyTM. A hematologist/oncologist, Dr Alvarnas is the vice president of government affairs and senior medical
director for employer strategy at City of Hope in Duarte, California. He is an expert in bone marrow and stem cell transplantation and an associate clinical professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope.REFERENCES