A Cost-effectiveness Analysis Comparing Pembrolizumab-Axitinib, Nivolumab-Ipilimumab, and Sunitinib for Treatment of Advanced Renal Cell Carcinoma.

OBJECTIVES: The US Food and Drug Administration (FDA) approved nivolumab-ipilimumab and pembrolizumab-axitinib as first-line treatments for metastatic, clear-cell, renal cell carcinoma (mRCC) based on results from CheckMate 214 and KEYNOTE-426. Our objective was to compare the adjusted, lifetime cost-effectiveness between nivolumab-ipilimumab, pembrolizumab-axitinib, and sunitinib for patients with mRCC. MATERIALS AND METHODS: A 3-state Markov model was developed comparing nivolumab-ipilimumab and pembrolizumab-axitinib to each other and sunitinib, over a 20-year lifetime horizon from a US medical center perspective. The clinical outcomes of nivolumab-ipilimumab and pembrolizumab-axitinib were compared using matching-adjusted indirect comparison. Costs of drug treatment, adverse events, and utilities associated with different health states and adverse events were determined using national sources and published literature. Our outcome was incremental cost-effectiveness ratio (ICER) using quality-adjusted life years (QALY). One-way and probabilistic sensitivity analyses were conducted. RESULTS: Nivolumab-ipilimumab was the most cost-effective option in the base case analysis with an ICER of $34,190/QALY compared with sunitinib, while the pembrolizumab-axitinib ICER was dominated by nivolumab-ipilimumab and was not cost-effective (ICER=$12,630,828/QALY) compared with sunitinib. The mean total costs per patient for the nivolumab-ipilimumab and pembrolizumab-axitinib arms were $284,683 and $457,769, respectively, compared with sunitinib at $241,656. QALY was longer for nivolumab-ipilimumab (3.23 QALY) than for adjusted pembrolizumab-axitinib (1.99 QALY), which was longer than sunitinib's (1.98 QALY). These results were most sensitive to treatment cost in both groups, but plausible changes did not alter the conclusions. CONCLUSIONS: The base case scenario indicated that nivolumab-ipilimumab was the most cost-effective treatment option for mRCC compared with pembrolizumab-axitinib and sunitinib.

Cost-effectiveness of Nivolumab-Ipilimumab Combination Therapy for the Treatment of Advanced Non-Small Cell Lung Cancer.

Importance: Treatment with nivolumab-ipilimumab combination therapy was found to improve overall survival compared with chemotherapy among patients with advanced non-small cell lung cancer (NSCLC) in the CheckMate 227 clinical trial. However, these drugs are substantially more expensive than chemotherapy and, given the high incidence of advanced NSCLC, the incorporation of dual immune checkpoint inhibitors into the standard of care could have substantial economic consequences. Objective: To assess whether nivolumab-ipilimumab combination therapy is a cost-effective first-line treatment for patients with advanced NSCLC. Design, Setting, and Participants: This economic evaluation designed a Markov model to compare the cost-effectiveness of nivolumab-ipilimumab combination therapy with platinum-doublet chemotherapy as first-line treatment for patients with advanced NSCLC. The Markov model was created to simulate patients with advanced NSCLC who were receiving either nivolumab-ipilimumab combination therapy or platinum-doublet chemotherapy. Transition probabilities, including disease progression, survival, and treatment toxic effects, were derived using data from the CheckMate 227 clinical trial. Costs and health utilities were obtained from published literature. Data analyses were conducted from November 2019 to September 2020. Exposures: Nivolumab-ipilimumab combination therapy. Main Outcomes and Measures: The primary study outcomes were quality-adjusted life-years (QALYs) and cost in 2020 US dollars. Cost-effectiveness was measured using an incremental cost-effectiveness ratio (ICER), with an ICER less than $100 000 per QALY considered cost-effective. Model uncertainty was assessed with 1-way and probabilistic sensitivity analyses. Results: Treatment with nivolumab-ipilimumab combination therapy was associated with an increase in overall cost of $201 900 and improved effectiveness of 0.50 QALYs compared with chemotherapy, yielding an ICER of $401 700 per QALY. The study model was sensitive to the cost and duration of immunotherapy. Treatment with nivolumab-ipilimumab combination therapy became cost-effective when monthly treatment costs were reduced from $26 425 to $5058 (80.9% reduction) or when the maximum duration of immunotherapy was reduced from 24.0 months to 1.4 months. The model was not sensitive to assumptions about survival or programmed cell death 1 ligand 1 status. A probabilistic sensitivity analysis indicated that, at a willingness-to-pay threshold of $100 000 per QALY, nivolumab-ipilimumab combination therapy was less cost-effective than chemotherapy 99.9% of the time. Conclusions and Relevance: In this study, first-line treatment with nivolumab-ipilimumab combination therapy was not found to be cost-effective at current prices despite clinical trial data indicating that this regimen increases overall survival among patients with advanced NSCLC.

Immune checkpoint inhibitors-associated risk of immune-related hypothyroidism in older patients with advanced melanoma: a real-world analysis of US SEER-Medicare data.

Background: The risk of immune-related(ir)-hypothyroidism in older patients with advanced melanoma treated with anti-CTLA4 or anti-PD1 therapies is poorly understood, especially in the real-world setting.Research design and methods: We identified older patients (≥65 years) diagnosed with advanced melanoma between 2011-2015 and treated with anti-CTLA4 or anti-PD1 agents in the SEER-Medicare database. Applying probability-of-treatment-weighting for confounder adjustment and proportional hazards models, we estimated the risk of ir-hypothyroidism between treatment initiation and up to 90 days from last dose between anti-PD1 and anti-CTLA4 users.Results: Of 210 older patients with advanced melanoma identified, 164 received anti-CTLA4 (ipilimumab) and 46 anti-PD1 agents (11 nivolumab, 35 pembrolizumab). There was no statistically significant difference in ir-hypothyroidism risk between anti-PD1 and anti-CTLA4 users (HR=2.15, 95%CI=0.83-5.53). Pairwise medication comparisons showed a lower risk among ipilimumab versus nivolumab (HR=0.15, 95%CI=0.06-0.40) and pembrolizumab versus nivolumab users (HR=0.13, 95%CI=0.03-0.55). Sensitivity analyses using an all-stages melanoma cohort did not show a difference in ir-hypothyroidism risk between medication classes and individual medications.Conclusions:This retrospective claims data analysis revealed no statistically significant difference in ir-hypothyroidism risk between anti-CTLA4 or anti-PD1 users. However, patients with advanced melanoma treated with ipilimumab or pembrolizumab may have a lower ir-hypothyroidism risk compared to nivolumab users.

Cost-effectiveness of nivolumab in advanced melanoma: a drug review.

Introduction: The immune checkpoint inhibitors, including nivolumab, and targeted agents have dramatically improved the outcome for patients with unresectable advanced melanoma. Areas covered: This is a narrative review of the published evidence on nivolumab in metastatic melanoma. Expert opinion: In ipilimumab pre-treated patients (CheckMate 037), nivolumab was associated with a higher response rate and a longer duration of response when compared to chemotherapy. In previously untreated patients, nivolumab improves survival when compared to chemotherapy (CheckMate 066) or to ipilimumab (CheckMate 067). The combination of nivolumab and ipilimumab also improves survival when compared to ipilimumab (CheckMate 067). CheckMate 067 was not designed to compare the nivolumab-ipilimumab combination to nivolumab alone. A modified regimen using a lower dose of ipilimumab in combination with standard dose nivolumab is better tolerated than nivolumab in combination with standard dose ipilimumab (CheckMate 511). In patients with previously untreated metastatic melanoma, the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab improve survival when compared to ipilimumab. Nivolumab is equally active in BRAF mutated and BRAF wild type melanoma. The optimal sequence of checkpoint inhibitors and BRAF/MEK inhibitors in BRAF mutated patients has not been established.

Cohort versus patient level simulation for the economic evaluation of single versus combination immuno-oncology therapies in metastatic melanoma.

Background: Model structure, despite being a key source of uncertainty in economic evaluations, is often not treated as a priority for model development. In oncology, partitioned survival models (PSMs) and Markov models, both types of cohort model, are commonly used, but patient responses to newer immuno-oncology (I-O) agents suggest that more innovative model frameworks should be explored. Objective: A discussion of the theoretical pros and cons of cohort level vs patient level simulation (PLS) models provides the background for an illustrative comparison of I-O therapies, namely nivolumab/ipilimumab combination and ipilimumab alone using patient level data from the CheckMate 067 trial in metastatic melanoma. PSM, Markov, and PLS models were compared on the basis of coherence with short-term clinical trial endpoints and long-term cost per QALY outcomes reported. Methods: The PSM was based on Kaplan-Meier curves from CheckMate 067 with 3-year data on progression free survival (PFS) and overall survival (OS). The Markov model used time independent transition probabilities based on the average trajectory of PFS and OS over the trial period. The PLS model was developed based on baseline characteristics hypothesized to be associated with disease as well as significant mortality and disease progression risk factors identified through a proportional hazards model. Results: The short-term Markov model outputs matched the 1-3 year clinical trial results approximately as well as the PSMs for OS but not PFS. The fixed (average) cohort PLS results corresponded as well as the PSMs for OS in the combination therapy arm and PFS in the monotherapy arm. Over the lifetime horizon, the PLS produced an additional 5.95 quality adjusted life years (QALYs) associated with combination therapy relative to ipilimumab alone, resulting in an incremental cost-effectiveness ratio (ICER) of £6,474 per QALY, compared with £14,194 for the PSMs which gave an incremental benefit of between 2.2 and 2.4 QALYs. The Markov model was an outlier (∼ £49,000 per QALY in the base case). Conclusions: The 4- and 5-state versions of the PSM cohort model estimated in this study deviate from the standard 3-state approach to better capture I-O response patterns. Markov and PLS approaches, by modeling state transitions explicitly, could be more informative in understanding I-O immune response, the PLS particularly so by reflecting heterogeneity in treatment response. However, both require a number of assumptions to capture the immune response effectively. Better I-O representation with surrogate endpoints in future clinical trials could yield greater model validity across all models.

Cost-effectiveness of immune checkpoint inhibitors for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer.

BACKGROUND: Patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) show a significant response to checkpoint inhibitor therapies, but the economic impact of these therapies is unknown. A decision analytic model was used to explore the effectiveness and cost burden of MSI-H/dMMR mCRC treatment. METHODS: The treatment of hypothetical patients with MSI-H/dMMR mCRC was simulated in 2 treatment scenarios: a third-line treatment and an exploratory first-line treatment. The treatments compared were nivolumab, ipilimumab and nivolumab, trifluridine and tipiracil (third-line treatment), and mFOLFOX6 and cetuximab (first-line treatment). Disease progression, drug toxicity, and survival rates were based on the CheckMate 142, study of TAS-102 in patients with metastatic colorectal cancer refractory to standard chemotherapies (RECOURSE), and Cancer and Leukemia Group B/Southwest Oncology Group 80405 trials. The analyzed outcomes included survival (life-years), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: Ipilimumab with nivolumab was the most effective strategy (10.69 life-years and 9.25 QALYs for the third line; 10.69 life-years and 9.44 QALYs for the first line) in comparison with nivolumab (8.21 life-years and 6.76 QALYs for the third line; 8.21 life-years and 7.00 QALYs for the first line), trifluridine and tipiracil (0.74 life-years and 0.07 QALYs), and mFOLFOX6 and cetuximab (2.72 life-years and 1.63 QALYs). However, neither checkpoint inhibitor therapy was cost-effective in comparison with trifluridine and tipiracil (nivolumab ICER, $153,000; ipilimumab and nivolumab ICER, $162,700) or mFOLFOX6 and cetuximab (nivolumab ICER, $150,700; ipilimumab and nivolumab ICER, $158,700). CONCLUSIONS: This modeling analysis found that both single and dual checkpoint blockade could be significantly more effective for MSI-H/dMMR mCRC than chemotherapy, but they were not cost-effective, largely because of drug costs. Decreases in drug pricing and/or the duration of maintenance nivolumab could make ipilimumab and nivolumab cost-effective. Prospective clinical trials should be performed to explore the optimal duration of maintenance nivolumab.

Economic Evaluation of Talimogene Laherparepvec Plus Ipilimumab Combination Therapy vs Ipilimumab Monotherapy in Patients With Advanced Unresectable Melanoma.

Importance: A phase 2 trial comparing talimogene laherparepvec plus ipilimumab vs ipilimumab monotherapy in patients with advanced unresectable melanoma found no differential benefit in progression-free survival (PFS) but noted objective response rates (ORRs) of 38.8% (38 of 98 patients) vs 18.0% (18 of 100 patients), respectively. Objective: To perform an economic evaluation of talimogene laherparepvec plus ipilimumab combination therapy vs ipilimumab monotherapy. Design, Setting, and Participants: For PFS, cost-effectiveness and cost-utility analyses using a 2-state Markov model (PFS vs progression or death) was performed. For ORRs, cost-effectiveness analysis of the incremental cost of 1 additional patient achieving objective response was performed. In this setting based on a US payer perspective (2017 US dollars), participants were patients with advanced unresectable melanoma. Main Outcomes and Measures: The PFS life-years and PFS quality-adjusted life-years were determined, and the associated incremental cost-effectiveness ratios (ICERs) and incremental cost-utility ratios (ICURs) were estimated. Also estimated was the ICER per 1 additional patient (out of 100 treated patients) achieving objective response. Base-case analyses were validated by sensitivity analyses. Results: In PFS analyses, the cost of talimogene laherparepvec plus ipilimumab ($494 983) exceeded the cost of ipilimumab monotherapy ($132 950) by $362 033. The ICER was $2 129 606 per PFS life-years, and the ICUR was $2 262 706 per PFS quality-adjusted life-year gained. Probabilistic sensitivity analyses yielded an ICER of $1 481 208 per PFS life-year gained and an ICUR of $1 683 191 per PFS quality-adjusted life-year gained. In 1-way sensitivity analyses, the PFS hazard ratio and the utility of response were the most influential parameters. Talimogene laherparepvec plus ipilimumab has a 50% likelihood of being cost-effective at a willingness-to-pay threshold of $1 683 191 per PFS quality-adjusted life-year gained. In ORR analyses, talimogene laherparepvec plus ipilimumab ($474 904) vs ipilimumab alone ($132 810), a $342 094 difference, yielded an ICER of $1 629 019 per additional patient achieving objective response. In subgroup analyses by disease stage and BRAFV600E mutation status, ICERs ranged from $1 069 044 to $17 104 700 per 1 additional patient achieving objective response. Conclusions and Relevance: The cost to gain 1 additional progression-free quality-adjusted life-year, 1 additional progression-free life-year, or to have 1 additional patient attain objective response is about $1.6 million. This amount may be beyond what payers typically are willing to pay. Combination therapy of talimogene laherparepvec plus ipilimumab does not offer an economically beneficial treatment option relative to ipilimumab monotherapy at the population level. This should not preclude treatment for individual patients for whom this regimen may be indicated.

Early cost-effectiveness of tumor infiltrating lymphocytes (TIL) for second line treatment in advanced melanoma: a model-based economic evaluation.

BACKGROUND: An emerging immunotherapy is infusion of tumor infiltrating Lymphocytes (TIL), with objective response rates of around 50% versus 19% for ipilimumab. As an Advanced Therapeutic Medicinal Products (ATMP), TIL is highly personalized and complex therapy. It requests substantial upfront investments from the hospital in: expensive lab-equipment, staff expertise and training, as well as extremely tight hospital logistics. Therefore, an early health economic modelling study, as part of a Coverage with Evidence Development (CED) program, was performed. METHODS: We used a Markov decision model to estimate the expected costs and outcomes (quality-adjusted life years; QALYs) for TIL versus ipilimumab for second line treatment in metastatic melanoma patients from a Dutch health care perspective over a life long time horizon. Three mutually exclusive health states (stable disease (responders)), progressive disease and death) were modelled. To inform further research prioritization, Value of Information (VOI) analysis was performed. RESULTS: TIL is expected to generate more QALYs compared to ipilimumab (0.45 versus 0.38 respectively) at lower incremental cost (presently €81,140 versus €94,705 respectively) resulting in a dominant ICER (less costly and more effective). Based on current information TIL is dominating ipilimumab and has a probability of 86% for being cost effective at a cost/QALY threshold of €80,000. The Expected Value of Perfect Information (EVPI) amounted to €3 M. CONCLUSIONS: TIL is expected to have the highest probability of being cost-effective in second line treatment for advanced melanoma compared to ipilimumab. To reduce decision uncertainty, a clinical trial investigating e.g. costs and survival seems most valuable. This is currently being undertaken as part of a CED program in the Netherlands Cancer Institute, Amsterdam, the Netherlands, in collaboration with Denmark.

Cost Estimate of Immune-Related Adverse Reactions Associated with Innovative Treatments of Metastatic Melanoma.

BACKGROUND AND OBJECTIVE: Immuno-oncology therapies represent a new treatment opportunity for patients affected by metastatic melanoma. The purpose of this study was to estimate the costs of immune-related adverse events (irAEs) associated with the new anti-PD1 immuno-oncology therapies, with the anti-CTLA-4 immuno-oncology therapy and with the combined therapy (CTLA4 + anti-PD1) in patients affected by metastatic melanoma. MATERIALS AND METHODS: A probabilistic cost-of-illness (COI) model was developed to estimate the management costs of grade ≥ 3 adverse events associated with the new anti-PD1 therapies (pembrolizumab and nivolumab), the anti-CTLA-4 therapy (ipilimumab) and the combined therapy CTLA4 + anti-PD1 (nivolumab + ipilimumab) for the treatment of patients with metastatic melanoma from the National Health Service (NHS) perspective in Italy. Identification of the epidemiological and cost parameters was carried out through a systematic literature review (SLR). Univariate and probabilistic sensitivity analyses were performed to account for uncertainty and variation in the model results. RESULTS: The model estimated a cost associated with the management of grade ≥ 3 immune-related adverse events in patients with metastatic melanoma equal to €176.2 (95% CI 63.5-335.0) for anti-CTLA-4 therapy, €48.6 (95% CI 40.1-58.5) for the new anti-PDI therapies and €276.8 (95% CI 240.4-316.2) for the combined therapy. Among the innovative therapies for the considered metastatic melanoma, the combined therapy was the most expensive innovative treatment in terms of event management of immune-related grade ≥ 3 adverse events. CONCLUSION: This study may represent a useful tool to understand the economic burden associated with the management of irAEs associated with patients affected by metastatic melanoma.

Analysis of survival of patients treated with vemurafenib, ipilimumab and dabrafenib for advanced skin melanoma in daily clinical practice (Real-World Data): retrospective analysis of patients treated under drug/reimbursement programmes in Poland in 2013-2016.

Vemurafenib, ipilimumab and dabrafenib were registered for the treatment of advanced skin melanoma pursuant to the results of randomized phase III clinical trials. Real-world data on survival time for patients treated with those drugs in daily clinical practice are so far limited. Patients with advanced skin melanoma treated under reimbursement programmes (drug programmes), for which they were qualified pursuant to uniform inclusion criteria in force in all oncology centres in Poland. Data were obtained from the electronic databases of the national payer (NFZ) responsible for the implementation and monitoring of reimbursement (drug) programmes. The analysis included all patients included for treatment with vemurafenib (since March of 2013), ipilimumab (since March of 2014) and dabrafenib (since July of 2015) until December 2016. The end date of the observation was set to 31 December 2016. The total survival analysis was performed using the Kaplan-Meier estimator. Until 31 December 2016, 759 patients were treated with vemurafenib, 370 with ipilimumab and 181 with dabrafenib. The overall survival (OS) median was 9.8 months for patients treated with vemurafenib (95% confidence interval: 8.8-10.6) and 6.9 months for patients treated with ipilimumab (95% confidence interval: 5.7-9.2). For patients treated with dabrafenib, the OS median was not reached because of an overly short observation period. The probability of surviving 12 months in the group of patients treated with vemurafenib was 40.5%, ipilimumab was 35.1% and dabrafenib was 60.7%. The probability of surviving 24 and 36 months in the group of patients treated with vemurafenib or ipilimumab amounted to, respectively, 20.1, 15.4 and 21, 18.8%. OS of patients with advanced melanoma treated in daily clinical practice may be comparable to the ones achieved in registration trials. The use of appropriate treatment inclusion criteria may affect the obtained OS.

Modelling the Survival Outcomes of Immuno-Oncology Drugs in Economic Evaluations: A Systematic Approach to Data Analysis and Extrapolation.

BACKGROUND: New immuno-oncology (I-O) therapies that harness the immune system to fight cancer call for a re-examination of the traditional parametric techniques used to model survival from clinical trial data. More flexible approaches are needed to capture the characteristic I-O pattern of delayed treatment effects and, for a subset of patients, the plateau of long-term survival. OBJECTIVES: Using a systematic approach to data management and analysis, the study assessed the applicability of traditional and flexible approaches and, as a test case of flexible methods, investigated the suitability of restricted cubic splines (RCS) to model progression-free survival (PFS) in I-O therapy. METHODS: The goodness of fit of each survival function was tested on data from the CheckMate 067 trial of monotherapy versus combination therapy (nivolumab/ipilimumab) in metastatic melanoma using visual inspection and statistical tests. Extrapolations were validated using long-term data for ipilimumab. RESULTS: Modelled PFS estimates using traditional methods did not provide a good fit to the Kaplan-Meier (K-M) curve. RCS estimates fit the K-M curves well, particularly for the plateau phase. RCS with six knots provided the best overall fit, but RCS with one knot performed best at the plateau phase and was preferred on the grounds of parsimony. CONCLUSIONS: RCS models represent a valuable addition to the range of flexible approaches available to model survival when assessing the effectiveness and cost-effectiveness of I-O therapy. A systematic approach to data analysis is recommended to compare the suitability of different approaches for different diseases and treatment regimens.

Pharmacovigilance Assessment of Immune-Mediated Reactions Reported for Checkpoint Inhibitor Cancer Immunotherapies.

STUDY OBJECTIVE: Ipilimumab, pembrolizumab, and nivolumab are checkpoint inhibitors (CPIs) that activate T-cell-mediated immune response. CPI can provide durable benefits to some cancer patients with melanoma, renal cell cancer, non-small cell lung cancer, or a growing list of other cancers. However, CPI treatment is also associated with adverse immune-mediated reactions (IMRs) that can be life-threatening. This pharmacovigilance analysis aims to characterize IMR signals in relation to CPI treatment. DESIGN: Retrospective pharmacovigilance disproportionality analysis. DATA SOURCE: U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). MEASUREMENTS AND MAIN RESULTS: Adverse event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were identified by generic names, and IMRs were identified by MedDRA Preferred Terms. Empirical Bayes geometric means with corresponding 95% confidence intervals (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined as metrics with EB05 ≥ 2.0. Overall, 1,018 IMR events were submitted for CPIs, corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab. The period of data collection precluded data on the most recently approved CPI agents. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11% hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs. Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab, respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for pembrolizumab, for which nephritis and infusion-related reactions were not reported. Signals of IMRs were detected for CPIs as a class (EB05 = 12.4) and individual agents: ipilimumab (EB05 = 13.2), nivolumab (EB05 = 15.0), and pembrolizumab (EB05 = 7.3). Colitis and pneumonitis had the strongest signals for CPIs (EB05 = 45.6 and EB05 = 17.6, respectively). Colitis was the strongest signal for ipilimumab (EB05 = 54.2), and pneumonitis was the strongest signal for nivolumab (EB05 = 48.0) and pembrolizumab (EB05 = 21.8). CONCLUSION: Cancer immunotherapy with CPIs is associated with a multitude of IMRs, especially colitis and pneumonitis. Individual CPIs had variable IMR signals, and pharmacoepidemiologic studies are required to evaluate the identified signals.