The cost of metastatic triple-negative breast cancer (mTNBC) continues to rise; before the use of immune checkpoint inhibitors in mTNBC, cumulative costs of treatment ranged from $51,070 for patients not treated with chemotherapy, up to $143,150 for patients who received three or more regimens. For those with programmed death ligand 1 (PD-L1)−positive mTNBC, expanding treatments continue to be approved for combination first-line therapy. Both combination atezolizumab with nab-paclitaxel and pembrolizumab with chemotherapy have been recently approved for this population under accelerated approval. Managed care pharmacists should continue to emphasize evidence-based treatment that is consistent with National Comprehensive Cancer Network guidelines, as non-concordance has been associated with increased costs and worsened outcomes. There are several tools that can be used to assess the value of treatment, with significant heterogeneity among frameworks. Innovative programs that have the potential to decrease costs should be considered when evaluating payment models.
Am J Manag Care. 2021;27(suppl 5):S97-S103. https://doi.org/10.37765/ajmc.2021.88627
In the United States, breast cancer accounts for 30% of all cancers in women and is the second leading cause of cancer-related mortality. An estimated 284,200 new cases and 44,130 deaths associated with breast cancer are expected in 2021.1 Triple-negative breast cancer (TNBC) refers to a subtype of breast cancer that does not express estrogen, progesterone, or human epidermal growth factor receptor (HER2) and represents approximately 20% of all breast cancers.2 Owing to the aggressive nature ofmetastatic TNBC (mTNBC), median overall survival in this population is estimated at 18 months or less and represents an urgent need for novel treatments to improve survival.3
Atezolizumab was approved for use on March 8, 2019, in combination with nab-paclitaxel (protein-bound) for adults with locally advanced or mTNBC whose tumors express programmed death ligand 1 (PD-L1) (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering ≥1% of the tumor area). It should be noted that atezolizumab is not approved in combination with paclitaxel. Interim analysis from the IMpassion131 trial showed that treatment with atezolizumab plus paclitaxel did not significantly reduce progression-free survival compared with placebo plus paclitaxel. Additionally, overall survival results also favored paclitaxel plus placebo as well.4 Pembrolizumab in combination with chemotherapy was approved before completion of the KEYNOTE-355 phase 3 trial for locally recurrent unresectable or mTNBC whose tumors express PD-L1 combined positive score (CPS) greater than or equal to 10. KEYNOTE-355 investigators found that pembrolizumab and chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) provided a significant increase in progression-free survival compared with chemotherapy and placebo. Longer-term clinical follow-up trial data are planned to establish full benefits.5 Each of the regimens described above is indicated in the front line or subsequent setting of mTNBC both per FDA-labeled indication and National Comprehensive Cancer Network (NCCN) guidelines, changing the landscape of treatment in significant ways both clinically and economically. PD-L1 testing is now considered necessary per NCCN guidelines for all patients diagnosed with either hormone-receptor or HER2-negative breast cancer based on these new indications.6
Rising Cost of Cancer Therapy
Costs associated with mTNBC have continued to increase with evolving treatments. One study by Aly and colleagues utilized the Surveillance, Epidemiology, and End Results (SEER)-Medicare database from 2004 to 2011 to estimate overall survival, treatment, and economic burden of elderly patients (mean, 76.8 years old) with mTNBC.7 Patients were divided into the following groups: no chemotherapy (NC), one regimen (1R), two regimens (2R), or three or more regimens (3R+). A total of 625 patients met the study inclusion and exclusion criteria. Forty-nine percent (n = 308) of patients in this study did not receive any chemotherapy treatment. Of the remaining patients, 161 received 1 regimen, 88 patients received 2 regimens, and 68 patients received 3 or more regimens.
As the line of therapy increased, the rate of single-agent use decreased for both 2R (47%) and 3R+ (59%). The cumulative cost of treating patients continued to increase from $51,070 for patients not treated with chemotherapy, up to $143,150 total cumulative costs for patients who received 3R+. Inpatient and physician office visits were the main driver of per-patient per-month costs across all groups.7
While per-patient per-month costs were lower in the higher regimen groups compared with NC, median overall survival was lowest in the NC group and increased with later lines of treatment. Median overall survival for NC was 3.5 months and increased as the number of regimens increased from 1R (7.1 months), 2R (16.0 months), and 3R+ (25.3 months).7 It should be noted that this study was conducted before the approval of immune checkpoint inhibitor (ICI)-based regimens, which are associated with higher costs when compared with the chemotherapy regimens identified in this study.
Another retrospective study that reviewed the monthly cost of treating mTNBC used the electronic medical record and billing data from the Vector Oncology Data Warehouse, which stores data from 9 oncology practices throughout the United States.8 Unlike the previous study, this study included patients who were on average much younger (mean, 56.6 years old) and were diagnosed with mTNBC from 2010 to 2016. This evaluation was divided similar to the previous study: first line (1L), second line (2L), and third or later line (3L+). A total of 505 patients were included in this analysis. The mean cost of treatment was calculated with all patients eligible for each line of treatment, and included inpatient, outpatient, and all cancer-related medication. Total mean 1L costs were $21,908 per month and increased to $24,891 in the 2L group and $25,845 in the 3L+ group. A majority (>50%) of monthly costs were attributed to hospitalizations and emergency department visits, while less than one-third of the total cost was associated with anticancer therapy. The mean monthly patient costs are summarized in the Figure.8 The time period in which these data were assessed was also before the approval of atezolizumab and pembrolizumab combination regimens in mTNBC and may not be truly reflective of the costs that eligible patients with mTNBC may presently experience.8
Other studies have also supported hospitalizations as a major cost driver in patients with mTNBC. One claims-based study of 4617 patients from 2012 to 2019 found that these patients had a mean of 2.4 hospitalizations per patient per year, with an associated cost of $57,115 per patient per year. Reasons for hospitalization included chemotherapy-related adverse effects (AEs), disease progression, and breast-related surgeries.9
Cost-effectiveness of ICI Treatment for mTNBC
The cost-effectiveness of PD-L1 agents in combination with chemotherapy in mTNBC is limited. No cost-effectiveness data were identified regarding pembrolizumab combination with chemotherapy due to its recent approval. Several different cost-effective analyses have been conducted with regard to atezolizumab plus nab-paclitaxel, but traditional cost-effectiveness thresholds may not complete the whole picture, as methodologies differed in these studies.10,11
In one study, investigators looked at the cost-effectiveness of atezolizumab plus nab-paclitaxel compared with nab-paclitaxel alone. In patients who were PD-L1 positive, atezolizumab plus nab-paclitaxel increased overall cost by $120,800 and 0.11 quality-adjusted life-year (QALY) gained compared with just nab-paclitaxel. This corresponded to an incremental cost-effectiveness ratio (ICER) of $1,101,000 per QALY gained, which was higher than the traditionally accepted ICER threshold of $150,000 per QALY gained. Study authors concluded that atezolizumab plus nab-paclitaxel was not cost-effective compared with nab-paclitaxel for treatment of mTNBC positive for PD-L1.10
A second cost-effectiveness analysis noted that atezolizumab plus nab-paclitaxel added an additional $149,465 and 0.762 QALY gained on top of nab-paclitaxel in patients with PD-L1−positive mTNBC. This resulted in an ICER of $196,073 per QALY gained. This number, while lower than other calculations, is still above traditional ICER thresholds of cost-effectiveness. In patients who had an unknown PD-L1 status, the cost-effectiveness of atezolizumab plus nab-paclitaxel increased to an ICER of $281,448 per QALY gained. These results support that atezolizumab plus nab-paclitaxel was more cost-effective in a population that was PD-L1 positive compared with one that was PD-L1 status unknown.11 Notably, treatment guidelines only support the use of this combination in patients with PD-L1−positive disease.6
Current NCCN guidelines recommend atezolizumab and nab-paclitaxel combination therapy and pembrolizumab in combination with chemotherapy as category 1 preferred regimens for the initial treatment in patients with PD-L1−positive mTNBC.6 As previously noted, this addition of atezolizumab to nab-paclitaxel increased the mean cost by approximately $120,800.
Treatment adherence to NCCN guidelines is critical for high-quality care. A 2020 retrospective cohort study of 16,858 women with TNBC between 2004 and 2016 found patients with nonadherent care had worse disease-specific survival compared with those who received NCCN-adherent treatment. In this cohort using the California Cancer Registry, 32.5% of patients with TNBC received NCCN-adherent care (P <.0001). Nonadherent care was associated with an increase in disease-specific mortality (HR, 1.21; 95% CI, 1.11-1.31; P <.0001). Patient populations less likely to receive guideline-adherent care included non-Hispanic Black patients, Hispanic patients, and patients of lowest and lower-middle socioeconomic status.12
Managed care organizations can consider clinical pathways to ensure adherence to guideline recommendations. Clinical pathways are management tools defined as protocols that are evidence-based specific to type of cancer and stage.13 Pathways have been successful in optimizing guideline-concordant care through either internal or external incentivization. In one example of Anthem’s Cancer Care Quality Program, providers receive an additional financial incentive for each patient who is treated in accordance with approved clinical pathways. It was noted that within the first 6 months after implementation, the clinical pathway adherence was 63% for breast, 72% for colorectal, and 63% for lung cancers.14 Evidence-based clinical pathway adherence has been the cornerstone of many programs that seek to encourage providers to prescribe regimens consistent with appropriate guidelines both in terms of outcomes and cost mitigation; an example of this will be discussed in relation to the Oncology Care Model (OCM).
Cost of Supportive Care: A Driver of Total Costs
One major consideration of cost in patients receiving chemotherapy includes immune-related AEs (irAEs), which can include a wide range of systemic effects including, but not limited to, colitis, pneumonitis, neurological conditions, and endocrinopathies.15 The irAE rates known per clinical trials are noted first. Authors of IMpassion130 noted that between study arms, the overall incidence of treatment-related AEs was well balanced; however, the study arm that included atezolizumab and nab-paclitaxel saw an increased rate of grade 3-4 events (40% vs 30%) and serious AEs (13% vs 7%) when compared with nab-paclitaxel and placebo. Notably, 16% of patients in the study arm experienced an AE leading to treatment of any study drug, whereas only 8% of patients discontinued treatment for this reason in the placebo arm. With specific mention to irAEs, while these did occur at a higher rate in the atezolizumab arm, there were only a few patients who required discontinuation for irAEs alone. KEYNOTE-355 authors noted, not surprisingly, a higher rate of irAEs with an overall rate of 26% in the study arm compared with 6% in the placebo arm. Similarly, rates of grade 3-4 irAEs were seen in 5% of patients in the study arm compared with none in the placebo arm. Authors noted that treatment-related AEs grade 3 or higher were similar across study and placebo arms (68% and 67%, respectively). While treatment discontinuation due to AEs was not captured in KEYNOTE-355, both this study and IMpassion130 appear to demonstrate a unique but overall reasonably tolerated AE profile with regard to the approved study arms. There are presently limited data to assess the frequency with which irAEs occur in the setting of mTNBC and it is with anticipation we look to real-world evidence and publication of the irAEs as these regimens are used with increasing frequency. In the absence of this specific evidence in this setting owing to each regimen’s relatively recent approval, we will further attempt to quantify some of these real-world irAEs.3,5
In an observational study that used the Premier Healthcare Database, a total of 13,030 patients on an ICI were identified from 2015 to 2017. These patients had non−small cell lung cancer, renal cell carcinoma, urothelial carcinoma, or Merkel cell carcinoma. Of the patients identified, 51% experienced at least 1 irAE, with a total of 15,277 distinct irAEs. Health-related costs were assessed up to 90 days after a reported irAE. The mean cost for inpatient irAEs was $21,219 and the mean cost for outpatient irAEs was $5951. The most expensive irAEs on average included transverse myelitis ($80,976), toxic epidermal necrolysis ($69,115), and myocarditis ($45,341). Although this study did not include patients with mTNBC treated with atezolizumab or pembrolizumab, it does illustrate the increased cost burden associated with treating patients with an ICI. This may be an increasingly burdensome problem in the midst of the COVID-19 pandemic and patients who are in geographically rural areas. Limited access to specialist care may decrease timely referrals for irAEs. It is especially crucial that patients who start ICI therapy are appropriately monitored to ensure timely referral to care.16
Another concern regarding irAEs has been the rate of ICI discontinuation. From clinical trials of ICI monotherapy, discontinuation associated with irAEs was noted to be up to 13%.17 One small study demonstrated an interesting interpretation of study discontinuation with 61 patients with non−small cell lung cancer, 22.4% of patients on nivolumab (n = 9/40) and 42.9% of patients on pembrolizumab (n = 9/21) had to discontinue therapy due to irAEs. Importantly, in this small study, the majority of irAEs appeared to be related to the presence of interstitial lung disease that then was associated with the development of drug-related interstitial lung disease and death in some cases, underscoring the need for consideration of this diagnosis in combination with treatment decisions. None of the patients in this study went on to rechallenge with an ICI after the onset of drug-related interstitial lung disease; however, the study goes on to note that the patients who required treatment discontinuation due to irAE development had significantly better outcomes than those who discontinued treatment for other reasons. The paradoxical outcomes of this study highlight the need to better understand how efficacy of ICI relates to treatment discontinuation and underlying patient- and disease-specific medical history.18
Current American Society of Clinical Oncology (ASCO) and NCCN guidelines for the management of irAEs are comprehensive and include monitoring recommendations for each type of potential irAE. In general, ICI therapy should be continued in mild cases of irAEs. For those that progressed to grade 2 or higher, ICIs were recommended to be stopped temporarily or discontinued indefinitely depending on type of irAE and severity.17,19 Providers may also consider rechallenging ICI treatment after an irAE after individualized assessments of risk versus benefit. A study evaluated the rate of subsequent irAEs after an initial grade greater than or equal to 2 irAEs in 180 patients with varied types of cancer. After the rechallenge on an ICI, 38.9% experienced a subsequent grade greater than or equal to 2 irAEs. It was also observed that lower rates of irAE were associated with rechallenge with the same ICI.20 For patients who use an ICI, irAEs not only have the potential to increase costs but may also drive the need for a new treatment dependent on the severity of the irAE.
Due to the rapidly changing treatment landscape for mTNBC, managed care pharmacists should be cognizant of current treatment guidelines published through the NCCN. When selecting an agent for formulary inclusion, agents for cancer treatment are generally covered for appropriate indications and guideline recommendations. However, in the case of preferring one ICI over the other for the treatment of mTNBC, no comparative head-to-head studies have been conducted to determine which regimen may be superior. Although both agents have demonstrated efficacy in mTNBC, longer-term follow-up and real-world efficacy and safety data are needed to help providers and patients make the best-informed decision on treatment selection.
Besides cost to payers, managed care pharmacists should take into consideration the financial burden and quality-of-life impacts on the patient. Financial toxicity has been associated with psychological stress, potential delay of care, nonadherence to therapy, and worsening outcomes. Proactive identification of these patients is crucial to risk mitigation of treatment failure. Patients who are identified as higher risk for financial toxicity through evaluation of social determinants to health should be provided appropriate resources and follow-up to ensure adherence.21
The Managed Care Pharmacist’s Role in Cost Management
The cost of treating mTNBC will continue to increase as new treatment modalities are developed. Managed care pharmacists may assist with many functions such as optimization of evidence-based prescribing, formulary management, and ensuring adherence to NCCN guidelines. Through innovative payment models such as the OCM, managed care organizations strive to improve clinical care of patients while simultaneously managing costs.22
Strategies to Address Costs of Therapy
The cost of treating mTNBC will continue to increase as new treatment modalities are approved and improve overall survival and progression-free survival. Managed care pharmacists should focus not just on the direct drug spend on anticancer agents, but also on how to optimize treatment in a way that improves patient efficacy and safety outcomes while managing cost. Means of optimizing treatments include the previously discussed clinical pathways to incentivize concordance with evidence-based guidelines. As non-concordance with NCCN and evidence-based guidelines are associated with overall more costs, clinical pathways may help to encourage appropriate utilization.23 As mentioned previously, the managed care pharmacist may also play a role in ensuring that AEs are minimized through the proactive treatment planning to prevent neutropenia or nausea/vomiting and through close monitoring for the development of irAEs that may lead to hospitalization if not managed assertively.
Value-based frameworks may be of assistance to patients and providers when discussing treatment options. These frameworks attempt to incorporate values and outcomes that are patient centered but relevant to various stakeholders such as additional years of life, disease-free survival, functionality, AEs, and total cost of care.
The ASCO Value Framework was initially developed to help form the shared decision between provider and patient that weighed clinical benefit versus risk of treatment. Additionally, the European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) has been used by clinicians to estimate the magnitude of clinical benefit observed in trials from a score of 0 (negligible) up to 4-5 (substantial).24 It has been observed that the ASCO and ESMO tools are similar in how they assess benefit and incorporate toxicity. The major difference is that ESMO does not incorporate cost whereas ASCO does.25 NCCN evidence blocks are easy to visualize and interpret snapshots of data that reflect treatment, quality of data, and cost. This tool can be used by providers with patients to help determine preference of treatments.26
The Memorial Sloan Kettering Cancer Center DrugAbacus is a tool that is aimed at providers to allow them to compare drug prices weighted by preference (eg, toxicity, rarity, unmet need). Another tool that allows for cost comparisons between agents are Institute for Clinical and Economic Review (ICER) evaluations. These evaluations target managed care organizations and policymakers to provide a value-based price assessment. It presents data as an ICER, or cost per QALY gained. This helps managed care organizations determine the cost-effectiveness of regimens based on study outcomes and cost.26 The Table26 provides a brief summary of key characteristics of these tools.
Challenges of Implementing New Payment Models
One of the most storied payment models for oncology is the OCM, which began its 5-year pilot in 2016. This model is a fee-for-service payment model with additional monthly enhanced oncology service (MEOS) payments and performance-based payments incentives. Some successes of OCM implementation were that many practices that participated implemented or considered treatment pathway software that was guideline concordant. Additionally, providers noted that practices adopted from the OCM (eg, increased palliative care specialists, enhanced advance care planning, enhanced outpatient services) have improved patient care, and believed patients were better informed regarding their treatment. Results of available data have demonstrated no significant impact on spending, hospitalizations, or emergency department visits for those patients who received active treatment.27 The Oncology Care First (OCF) program is slated to launch following the completion of OCM and is intended to improve on specific elements of OCM to further incentivize the prescription of high-value, evidence-based care.
A recent study attempts to quantify whether OCM episodic cost savings may be realized and maximized through the use of voluntary pathways from quarter 1 of 2017 through quarter 1 of 2019. Authors concluded that a reduction in spend when utilizing evidence-based clinical pathways within a value-based care model is possible after seeing a less-rapid increase in drug spend (18.6% vs 34.4%) and a percentage decrease in drug spend (13.5% vs 0.1%) in a non-OCM center compared with an OCM center, respectively. While the study did include patients receiving ICIs, this was more in populations with diseases other than mTNBC in which reasonable substitutions could be made that decreased costs such as combinations utilizing paclitaxel instead of nab-paclitaxel in appropriate patients.28
There are, as mentioned throughout this article, very little data that tie back to ICI use in mTNBC owing to the recent approvals; however, cost savings could be realized through implementation of and adherence to evidence-based clinical pathways. For example, ensuring that these ICI-based regimens are only utilized in those patients known to benefit with the aforementioned PD-L1 levels could provide significant cost savings owing to the specificity with which these regimens must be used and the extraordinary costs associated with each. Further, both KEYNOTE-355 and IMpassion130 have demonstrated that not all patients diagnosed with mTNBC will benefit from these interventions owing to PD-L1 expression. Ensuring that only patients presently known to benefit from these treatments will receive them results in myriad benefits: the patient is kept from receiving a treatment that will likely not help them or provide a survival benefit; the patient avoids costs for the aforementioned treatment and any resulting AEs; lastly, a reduction in healthcare utilization costs overall are only a small sample of the many ways in which treatment that is prescribed on-evidence produces better results for a variety of stakeholders across the medical spectrum and society overall.
Future considerations may include a hospital at-home program or other innovative practices in appropriate patients. Regardless of the type of payment model used, managed care pharmacists should continue to evaluate the cost savings and potential decrease of healthcare resource utilization.22
As the cost of mTNBC treatment rises, combination ICIs are recommended for first-line therapy in patients who are PD-L1 positive. Both combination atezolizumab with nab-paclitaxel and pembrolizumab with chemotherapy are FDA approved for this population. Treatment decisions should be based on evidence-based guidelines, as non-concordance with them has been associated with increased drug costs and worsened outcomes. Care must be taken to validate that these new and novel ICI-based regimens are appropriately utilized based on available literature and evidence. Real-world evidence especially seeks to further explain the nuances with which these treatments may be implemented effectively. With set costs, it becomes imperative as clinicians to focus on the appropriate use of these drugs in patients with specific PD-L1 expression in order to both streamline use and ensure the avoidance of costly off-label prescribing practices that result in tremendous cost both financially and clinically. Pharmacists should be aware that costs will continue to increase for the treatment of mTNBC and use the tools available to help the provider and patient understand their choices through utilization of value frameworks and adherence to evidence and guidelines where applicable.
The FDA is holding a public meeting of the Oncologic Drugs Advisory Committee (ODAC) on April 27-29 to discuss multiple indications from different drugs granted accelerated approval that have since reported results from a confirmatory trial that have not verified clinical benefit.One of the indications listed on the agenda for discussion is atezolizumab in combination with nab-paclitaxel for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1.29
Author affiliation:Rebecca Tombleson, PharmD, BCOP, is director of pharmacy operations, Oncology Analytics, Inc, Atlanta, GA.
Funding source: This activity is supported by an educational grant from Merck Sharp & Dohme Corp.
Author disclosure: Dr Tombleson has no relevant financial relationships with commercial interests to disclose.
Author information: Concept and design; analysis and interpretation of data; drafting of the manuscript.
Address correspondence to: firstname.lastname@example.org
Medical writing and editorial support provided by:Andrew M. Abe, PharmD
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