Cost-effectiveness and Budgetary Consequence Analysis of Durvalumab Consolidation Therapy vs No Consolidation Therapy After Chemoradiotherapy in Stage III Non–Small Cell Lung Cancer in the Context of the US Health Care System | Lung Cancer | JAMA Oncology | JAMA Network
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Figure 1.  Microsimulation Model Schematic for Treatment Strategies
Microsimulation Model Schematic for Treatment Strategies

PFS indicates progression-free survival.

Figure 2.  Detailed Microsimulation Model Schematic for Treatment Strategies in Patients Whose Cancer Has Not Progressed After Definitive Chemoradiotherapy
Detailed Microsimulation Model Schematic for Treatment Strategies in Patients Whose Cancer Has Not Progressed After Definitive Chemoradiotherapy

PD-L1 indicates programmed cell death 1 ligand 1.

Figure 3.  Sensitivity Analysis of Key Variables for Durvalumab Consolidation Therapy vs No Consolidation Therapy in Order of Magnitude of Association
Sensitivity Analysis of Key Variables for Durvalumab Consolidation Therapy vs No Consolidation Therapy in Order of Magnitude of Association

ICER indicates incremental cost-effectiveness ratio; KM, Kaplan-Meier; OS, overall survival; PD-L1, programmed cell death 1 ligand 1; PDS, progressive disease survival; PFS, progression-free survival; and QALY, quality-adjusted life-year.

aDurvalumab consolidation therapy dominated no consolidation therapy.

Table 1.  Summary Results for the Base-Case Model
Summary Results for the Base-Case Model
Table 2.  Incremental Budgetary Consequence Analysis
Incremental Budgetary Consequence Analysis
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Original Investigation
December 13, 2018

Cost-effectiveness and Budgetary Consequence Analysis of Durvalumab Consolidation Therapy vs No Consolidation Therapy After Chemoradiotherapy in Stage III Non–Small Cell Lung Cancer in the Context of the US Health Care System

Author Affiliations
  • 1Institute for Technology Assessment, Massachusetts General Hospital, Boston
  • 2Massachusetts General Hospital Cancer Center, Boston
  • 3Harvard Medical School, Boston, Massachusetts
JAMA Oncol. 2019;5(3):358-365. doi:10.1001/jamaoncol.2018.5449
Key Points

Question  Is it cost-effective to treat patients with unresectable stage III non–small cell lung cancer whose cancer has not progressed after definitive chemoradiotherapy with durvalumab consolidation therapy?

Findings  Using a decision analytic microsimulation model among 2 million simulated patients, this study found that durvalumab in this indication was cost-effective at a $100 000 per QALY willingness-to-pay threshold. Using this treatment strategy for all eligible patients could add an additional $768 million to national cancer spending in year 1; the annual budgetary consequence would then decrease to $241 million in year 5.

Meaning  Results of this study suggest that durvalumab consolidation therapy is a cost-effective treatment, although budgetary implications warrant consideration by health policy decision makers.

Abstract

Importance  In early 2018, durvalumab became the first immunotherapy to be approved for adjuvant treatment of patients with unresectable stage III non–small cell lung cancer (NSCLC) whose cancer has not progressed after definitive chemoradiotherapy. However, the cost-effectiveness and potential economic implications of using this high-priced therapy in this indication are unknown to date.

Objective  To explore the cost-effectiveness and potential budgetary consequences of durvalumab consolidation therapy vs no consolidation therapy after chemoradiotherapy in stage III NSCLC in the context of the US health care system.

Design, Setting, and Participants  A decision analytic microsimulation model was developed in an academic medical setting to compare the following 2 postchemoradiotherapy strategies: all patients receive no consolidation therapy until progression vs all patients receive durvalumab consolidation therapy until progression or for a maximum of 1 year. The potential budgetary consequence was calculated by applying the proportion of patients with NSCLC who were diagnosed in stage III and received chemoradiotherapy to the projected number of annual new cases for 2018 to 2022 to find total eligible patients and then multiplied by the mean difference in annual cost between the strategies over this 5-year period. Simulated conditions were matched to those of the PACIFIC phase 3 randomized clinical trial and reasonable treatment strategies for metastatic NSCLC. All simulated patients begin disease free after having received radical treatment with chemoradiotherapy and are followed up as they progress to metastatic disease first-line treatment, metastatic disease second-line treatment, end-stage progressive disease, and death.

Main Outcomes and Measures  The main outcome of this study was the incremental cost-effectiveness ratio of durvalumab consolidation therapy vs no consolidation therapy, given as aggregate cost of treatment per quality-adjusted life-year gained.

Results  Among 2 million simulated patients, durvalumab consolidation therapy was cost-effective compared with no consolidation therapy at a $100 000 per quality-adjusted life-year willingness-to-pay threshold, with an estimated incremental cost-effectiveness ratio of $67 421 per quality-adjusted life-year, and would contribute an additional $768 million to national cancer spending in year 1. The annual budgetary consequence would then decrease to $241 million in year 5.

Conclusions and Relevance  Durvalumab consolidation therapy represents an indication where expensive immunotherapies can be cost-effective. Treating with immunotherapy earlier in the course of cancer progression can provide significant value, despite having a substantial budgetary consequence.

Introduction

For almost 3 decades, lung cancer death rates for both men and women in the United States have surpassed those of all other cancers.1 These formidable death rates are driven primarily by a combination of high lung cancer incidence and poor survival outcomes for patients with lung cancer diagnosed in later stages: the 5-year survival rate for patients with distant metastases is approximately 5%.2 Treatments for advanced-stage lung cancer are seldom curative, with the goal in most cases being to delay progression and maintain quality of life. Recent advances in the use of immunotherapy have led to historical developments in the treatment of advanced non–small cell lung cancer (NSCLC). Single-agent programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) inhibitors and immunotherapy plus chemotherapy combination therapies have demonstrated improvements in overall survival (OS) in both the first-line and second-line settings.3-11 The adoption of these treatments as standard therapies in the first and second lines has subsequently spurred efforts to move the use of these agents earlier in the disease course.

Although the therapeutic armamentarium of advanced NSCLC has greatly expanded in recent years, progress for locally advanced, unresectable disease has remained stagnant, with definitive chemoradiotherapy representing the standard of care for more than a decade. Advancements in this area are critical because approximately 0.5 million patients worldwide are diagnosed as having unresectable stage III NSCLC annually, and only 15% of patients who receive chemoradiotherapy are alive after 5 years.12 Given the success of checkpoint inhibition in later-stage disease, the incorporation of PD-1/PD-L1 inhibition in cases of unresectable stage III NSCLC has become a recent focus.

In early 2018, durvalumab, a selective PD-L1 inhibitor, became the first immunotherapy to be approved for adjuvant treatment of patients with unresectable stage III NSCLC whose cancer has not progressed after definitive chemoradiotherapy.13,14 The US Food and Drug Administration approved durvalumab based on evidence from the PACIFIC phase 3 randomized clinical trial (ClinicalTrials.gov identifier NCT02125461),15 in which patients with stage III NSCLC who did not have disease progression after 2 or more cycles of platinum-based chemoradiotherapy were randomized in a 2:1 ratio to receive durvalumab or placebo every 2 weeks for up to 12 months.14 A preplanned interim analysis published by Antonia and colleagues14 demonstrated a median progression-free survival (PFS) of 16.8 months for those receiving durvalumab and 5.6 months for those receiving placebo. This statistically significant improvement in PFS (hazard ratio for disease progression or death, 0.52) demonstrated the benefit of immunotherapy in the treatment algorithm of stage III NSCLC and will likely have wide-ranging implications for the treatment of NSCLC more broadly.

Given that almost 30% of patients with NSCLC are diagnosed as having stage III disease and the duration of treatment in the adjuvant setting can be up to 1 year,16 the adoption of durvalumab consolidation therapy after chemoradiotherapy could have a profound financial consequence on cancer treatment spending in the United States. Despite the proven effectiveness of immunotherapy drugs, much concern has been dedicated to the costs associated with these advanced treatments.17-20 In 2017, worldwide sales of immunotherapy drugs used for patients with lung cancer surpassed $9 billion,21-24 with growth projections placing the total market for immunotherapy at $20 to $30 billion in the coming decade.25

With immunotherapy use becoming a standard practice in a continuously increasing number of indications, evaluating the cost-effectiveness of these treatments and projecting their potential budgetary consequences have become instrumental in determining the societal association of implementing these new therapeutic strategies. We aimed to provide a comprehensive economic assessment of durvalumab consolidation therapy after definitive chemoradiotherapy for patients with unresectable stage III NSCLC to better understand its value and budgetary implications at the societal level.

Methods
Simulation Model

To estimate the survival and cost outcomes of patients with unresectable stage III NSCLC without evidence of progression after definitive chemoradiotherapy, we developed a decision analytic microsimulation model in an academic medical setting with a 1-month Markov cycle length that compares different treatment strategies in the context of the US health care system. Given that patients with EGFR mutations made up only 6% of the PACIFIC trial population and other targetable mutations were not studied, these patients were not well represented in the trial and were excluded from our analysis.14 All simulated patients begin disease free after having received radical treatment with chemoradiotherapy and are followed up as they progress to metastatic disease first-line treatment, metastatic disease second-line treatment, end-stage progressive disease, and death, which are all mutually exclusive health states. The main outcome of this study was the incremental cost-effectiveness ratio (ICER) of durvalumab consolidation therapy vs no consolidation therapy, given as aggregate cost of treatment per quality-adjusted life-year gained. Patients who survive for more than 5 years without progression are assumed to follow the mean life expectancy for patients with stage III NSCLC who have lived at least 5 years past their date of diagnosis. Age-stratified life expectancies for these patients were determined from a primary data analysis of the Surveillance, Epidemiology, and End Results (SEER)–Medicare database, a population-based cancer registry, and were used to inform survival rates for cured individuals. A 3% annual discount rate was used for survival and cost estimates, and all patients were followed up until death. We estimated ICERs in terms of incremental costs divided by incremental quality-adjusted life-years (QALYs) gained. The ICERs were compared with a $100 000 per QALY willingness-to-pay (WTP) threshold.26 This study used only nonidentifiable patient data for secondary data analysis and was approved by Partners Institutional Review Board (protocol 2015P002190).

To reduce the statistical fluctuations of the outcomes, 1 million patients were simulated for each of the following 2 postchemoradiotherapy strategies: (1) all patients receive no additional treatment until progression (no consolidation therapy group) and (2) all patients receive durvalumab consolidation therapy until progression or for a maximum of 1 year (durvalumab consolidation therapy group). This is shown in Figure 1.

First-line treatment in the metastatic disease state depended on the postchemoradiotherapy strategy used, PD-L1 expression, and tumor histology. Patients were treated with first-line therapy until their disease progressed, at which point they entered metastatic disease second-line treatment (Figure 2). For the purpose of this analysis, cisplatin-based and carboplatin-based treatments were not differentiated in the model because their prices are similarly low and their survival outcomes are not significantly different,27,28 reflecting common clinical practice in which these drugs are used in similar capacities. Specific details for first-line and second-line treatment strategies are provided in the eMethods in the Supplement. After progression from metastatic disease second-line treatment to end-stage progressive disease, all patients stopped treatment and received best supportive care until death. Additional information on dosing, infusion timing, and patient stratification by PD-L1 expression and histology is listed in eTable 1 in the Supplement.

Survival and Health State Utilities

Kaplan-Meier survival curves and other survival data used to model PFS and OS were obtained from the original clinical trial literature (eTable 2 in the Supplement).7,8,11,14,29,30 Kaplan-Meier estimates were extracted using a web-based tool to extract data from plots, images, and maps (WebPlotDigitizer; https://automeris.io/WebPlotDigitizer/). For PFS, Kaplan-Meier estimates were used directly until months 21 and 19 in the no consolidation therapy and durvalumab consolidation therapy groups, respectively, with exponential curves providing the best fit thereafter.14 After PFS, patients are modeled according to the OS curves for the respective first-line clinical trials,7,8,11,29,30 depending on PD-L1 expression and histology (Figure 2). In modeling OS, a similar approach was used, although fitted exponential curves best preserved the shapes of the Kaplan-Meier curves, while avoiding overfitting. Exponential models were also used in extrapolating progression rates past the end of the clinical trial periods. Health state utilities were sourced from the literature.19,31,32 The QALYs were estimated by multiplying life-years accumulated in each cycle by a utility specific to the patient’s age in that cycle, as well as a utility specific to the patient’s stage of progression. Patients who survive at least 5 years without progression did not incur any lung cancer–specific disutility thereafter. Additional information on health state utilities is listed in eTable 2 in the Supplement.

Costs

This study evaluated the aforementioned 2 treatment strategies from the societal perspective and thus included the following medical costs associated with cancer treatment: drug acquisition, therapy administration, treatment of major adverse events, follow-up scans, immunohistochemical staining, best supportive care, and death costs. Each of these costs was derived from relevant US sources (eTable 2 in the Supplement).33-36 Unit drug costs were acquired from the Centers for Medicare & Medicaid Services (CMS) 2018 Average Sales Price Drug Pricing Files (version updated June 22, 2018).36 Because durvalumab is not included in the CMS 2018 Average Sales Price Drug Pricing Files, the unit cost for durvalumab provided by Truven Health Analytics Red Book Online was reduced by the same percentage discount between the Red Book Online and the CMS stated prices for pembrolizumab.37 Doses administered were calculated using a mean body weight of 70.32 kg and a mean body surface area of 1.79 m2, determined by an analysis of an internal database containing more than 3500 patients with lung cancer treated at Partners HealthCare hospitals. Adverse events considered in the model were those rated at a severity of grade 3, 4, or 5 and must have occurred in at least 1% of patients in the respective clinical trial.5,7,8,14,29,30 Costs for treatment of these adverse events were informed by the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project using International Classification of Diseases, Ninth Revision codes specific to the individual adverse event recorded.35 To estimate best supportive care and cancer-related death costs, we performed a primary data analysis of the SEER-Medicare database. Specific cost information for each input variable is listed in eTable 2 in the Supplement. Costs were adjusted to 2018 US dollars using the Personal Healthcare Price Index provided by the CMS.38,39

Sensitivity Analysis

One-way deterministic sensitivity analyses were performed on model variables to assess the association of uncertainty in variable estimates with the results. For each strategy, 95% CIs or plausible ranges of the selected variables were used, and each variable was tested at the upper and lower limits of its respective interval (eTable 3 in the Supplement). Sensitivity analyses were performed on all model variables; however, only those having meaningful association with cost-effectiveness are presented.

Budgetary Consequence Analysis

In addition to the evaluation of each strategy’s cost-effectiveness, we conducted a budgetary consequence analysis to project the maximum additional health care spending that would result from fully implementing the durvalumab consolidation therapy strategy in the United States.40 To find the potential budgetary consequence, we assumed that the durvalumab consolidation therapy strategy was immediately adopted for all eligible patients, defined as those patients with unresectable stage III NSCLC without evidence of progression after definitive chemoradiotherapy. The total number of eligible patients was estimated by multiplying the proportion of patients with NSCLC who were diagnosed in stage III and received chemoradiotherapy based on a SEER-Medicare primary data analysis (eTable 4 in the Supplement) by the projected number of annual new cases2 for 2018 to 2022. Given that lung cancer incidence is expected to decline in the coming years because of decreasing smoking prevalence in the United States,41,42 we assumed a 2% decrease in incidence per year. We modeled the undiscounted costs per year for the durvalumab consolidation therapy and no consolidation therapy strategies and then multiplied the mean difference in annual cost between the strategies for each year of treatment by the number of eligible patients. We used a 5-year time horizon (2018-2022), with new eligible patients entering the patient population each year based on expected incidence. Simulated conditions were matched to those of the PACIFIC clinical trial (ClinicalTrials.gov identifier NCT02125461) and reasonable treatment strategies for metastatic NSCLC.

Results
Cost-effectiveness

In the cost-effectiveness analysis, no consolidation therapy after chemoradiotherapy resulted in a mean cost per patient of $185 944 and a mean quality-adjusted survival per patient of 2.34 QALYs. Durvalumab consolidation therapy resulted in a mean cost per patient of $201 563 and a mean quality-adjusted survival per patient of 2.57 QALYs, with an estimated ICER of $67 421 per QALY. Table 1 lists additional information on the results for the base-case analysis.

Sensitivity Analysis

One-way deterministic sensitivity analyses of key variables revealed that the price of durvalumab, price of pembrolizumab, health state utilities, and PFS progression rates most altered the cost-effectiveness of the strategies (Figure 3). Durvalumab consolidation therapy surpassed the $100 000 per QALY WTP threshold in 6 scenarios, as shown in Figure 3. In addition, the durvalumab consolidation therapy strategy dominated the no consolidation therapy strategy when the price of durvalumab was tested at its lower limit and when the price of pembrolizumab was tested at its upper limit.

Budgetary Consequence Analysis

We estimated the number of patients eligible for durvalumab consolidation therapy to be approximately 11 982 for 2018 in the United States given that, among the 198 926 projected cases of NSCLC for 2018, approximately 28.4% are diagnosed in stage III and approximately 21.2% of those stage III patients receive chemoradiotherapy (eTable 4 in the Supplement). We assumed an annual decrease in NSCLC incidence of 2% over the next 5 years. Implementing durvalumab consolidation therapy for all eligible patients in the United States would cause a potential incremental budgetary consequence of an additional $768 million to national cancer spending in year 1. The annual budgetary consequence would then decrease to $241 million in year 5. Additional details on the annual projections are listed in Table 2. The Consolidated Health Economic Evaluation Reporting Standards43 were met by our study (eTable 5 in the Supplement).

Discussion

The approval of durvalumab consolidation therapy for unresectable stage III NSCLC after definitive chemoradiotherapy provides an effective treatment alternative to delay and potentially prevent progression to metastatic disease. Using a microsimulation model, we evaluated the cost-effectiveness of durvalumab consolidation therapy and projected its maximum potential consequence on cancer spending in the United States. We found that durvalumab consolidation therapy was cost-effective compared with no consolidation therapy at a $100 000 per QALY WTP threshold, with an estimated ICER of $67 421 per QALY. The incremental budgetary consequence of using durvalumab consolidation therapy for all eligible patients would be $768 million in year 1 and then decrease to $241 million in year 5.

Giving durvalumab earlier in the course of treatment is a cost-effective means of potentially prolonging survival; however, the incremental costs and QALYs associated with durvalumab consolidation therapy vs no consolidation therapy are low. The modest difference between these 2 strategies can be explained by the clinical consequences of immunotherapy combination trials for first-line treatment of metastatic NSCLC, as well as the substantial cost that accompanies long-term immunotherapy use.44,45 While durvalumab consolidation therapy is only given for a maximum of 1 year, treatment with pembrolizumab as part of a combination therapy can extend up to 2 years, depending on the response and performance status of the patient, accruing considerable treatment costs and diminishing the cost difference between the 2 strategies. Durvalumab provides a promising opportunity for delaying recurrence and potentially improving the likelihood of cure in a cost-effective manner, making it the preferred method of treatment from a health economics standpoint.

The potential incremental budgetary consequence of durvalumab consolidation therapy represented a substantial increase in the overall spending on cancer treatment in the United States. According to data from the Agency for Healthcare Research and Quality’s Medical Expenditures Panel Survey for the years 2000 to 2015, total cancer-related expenditures have increased by a mean of 7.0% per year.46 At this rate, approximately $98.3 billion will be spent in 2018 on direct medical costs associated with all cancers,46 meaning that the projected incremental budgetary consequence in year 1 ($768 million) would correspond to a 0.8% increase. However, cost savings realized in the later years of treatment partially offset the high initial costs of new eligible patients entering the treated population, leading to a lower budgetary consequence over time. Given the anticipated growth in the use of immunotherapy for cancer treatment in the coming years, oncologic spending will undoubtedly increase; therefore, it will be essential for overall affordability to continue to search for indications where these drugs may be used most cost-effectively.

Sensitivity analyses showed that the cost-effectiveness of durvalumab consolidation therapy was understandably sensitive to the price of durvalumab. While the base-case analysis showed this treatment strategy to be cost-effective, a decrease in price could minimize uncertainty around its cost-effectiveness and greatly reduce its consequence on national cancer spending. In addition, when durvalumab price was tested at its lower limit, the durvalumab consolidation therapy strategy became less costly than the no consolidation therapy strategy. Therefore, a price reduction would lend considerable confidence to durvalumab consolidation therapy being regarded as an economically sound treatment option. Also, testing pembrolizumab price at its upper limit caused durvalumab consolidation therapy to be less costly than no consolidation therapy. This result reinforces the fact that the cost-effectiveness of durvalumab consolidation therapy is dependent on changes in the first-line immunotherapy combination treatments.

Limitations

Our model includes several simplifying assumptions that limit our study. First, since durvalumab consolidation therapy after chemoradiotherapy in patients with stage III NSCLC was approved by the US Food and Drug Administration in February 2018, it is still uncertain what treatment options will be best for patients who progress to metastatic disease. While our base-case analysis represents a likely set of treatment plans, treatment strategies may differ as more becomes known about how patients will respond in later stages. Second, for the purpose of estimating progression rates in our model, we synthesized survival data from multiple clinical trial populations. This introduces uncertainty into our model because no one trial population followed the treatment regimens specified in our model. Third, the number of eligible patients estimated for the budgetary consequence analysis assumes that patients did not progress during chemoradiotherapy, which may have caused the number of patients eligible to be overestimated. Fourth, OS data for the PACIFIC trial have yet to be published, and our study results may be altered if these data show OS to be significantly longer or shorter than modeled in this analysis. If OS in the PACIFIC trial is significantly greater than projected in our model, the cost-effectiveness of durvalumab will likely improve; however, if durvalumab fails to improve OS, it is unlikely that durvalumab will remain cost-effective.

Conclusions

Our study demonstrates that durvalumab consolidation therapy can be cost-effective for patients with unresectable stage III NSCLC whose disease has not progressed after definitive chemoradiotherapy. Given the substantial consequence on cancer spending that immunotherapy treatments will likely have, it is necessary to find indications where these therapies are of most value. Additional efforts should be focused on searching for the patient populations who respond best to immunotherapy and experience the fewest adverse events, potentially through improved biomarker selection, because this will also reduce the overall financial burden imposed by these high-priced therapies. As we learn more about immunotherapy and as subsequent changes to treatment strategies are implemented, cost-effectiveness analyses will allow us to evaluate the association of newly approved indications for immunotherapies with the economics of cancer treatment in the United States and can provide opportunities for more informed discussions on health care policy and planning.

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Article Information

Accepted for Publication: September 12, 2018.

Corresponding Author: Chung Yin Kong, PhD, Institute for Technology Assessment, Massachusetts General Hospital, 101 Merrimac St, Ste 1010, Boston, MA 02114 (joey@mgh-ita.org).

Published Online: December 13, 2018. doi:10.1001/jamaoncol.2018.5449

Author Contributions: Mr Criss and Dr Kong had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Reynolds and Kong are co–senior authors, with equal contribution to this article.

Concept and design: Criss, Mooradian, Lumish, Gainor, Reynolds, Kong.

Acquisition, analysis, or interpretation of data: Criss, Mooradian, Sheehan, Zubiri, Gainor, Kong.

Drafting of the manuscript: Criss, Mooradian, Reynolds, Kong.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Criss, Kong.

Obtained funding: Kong.

Administrative, technical, or material support: Criss, Mooradian, Sheehan, Kong.

Supervision: Criss, Mooradian, Zubiri, Gainor, Reynolds, Kong.

Conflict of Interest Disclosures: Dr Gainor reported serving as a compensated consultant to or receiving honoraria from Bristol-Myers Squibb, Pfizer, Merck, Genentech/Roche, Ariad/Takeda, Incyte, Agios, Amgen, Loxo, and Theravance. No other disclosures were reported.

Funding/Support: This study was supported by grants R01CA202956 and U01CA199284 from the National Institutes of Health (Mr Criss, Ms Sheehan, and Dr Kong).

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The data for our analysis comply with the Health Insurance Portability and Accountability Act of 1996 regulations.

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