Early On-Treatment Assessment of T Cells, Cytokines, and Tumor DNA with Adaptively Dosed Nivolumab + Ipilimumab: Final Results from the Phase 2 ADAPT-IT Study.

PURPOSE: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT;NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared with conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported. PATIENTS AND METHODS: Patients with unresectable melanoma received two doses of nivo-ipi. Radiographic assessment at Week 6 informed continuation of ipilimumab before nivolumab maintenance. The primary endpoint was overall response rate at Week 12. Plasma was assayed for circulating tumor DNA and 10 cytokines using a multiplex immunoassay. Flow cytometry of peripheral blood mononuclear cells was performed with an 11-color panel. RESULTS: Among the treated patients, expansion of proliferating T-cell populations was observed in responders and nonresponders. Baseline IL6 levels were low in patients achieving an objective radiographic response (median 1.30 vs. 2.86 pg/mL; P = 0.025). High baseline IL6 levels were associated with short progression-free survival [PFS; HR = 1.24, 95% confidence interval (CI), 1.01-1.52; P = 0.041]. At Week 6, patients with response had lower average tumor variant allele fractions than nonresponders (median 0.000 vs. 0.019; P = 0.014). Greater increases in average variant allele fractions from baseline to Week 6 correlated with short PFS (HR = 1.11, 95% CI, 1.01-1.21; P = 0.023). Week 12 overall response rate was 47% (95% CI, 35%-59%) with a median follow-up of 34 months among survivors. Median PFS was 21 months (95% CI, 10-not reached); 76% of responses (95% CI, 64%-91%) persisted at 36 months. CONCLUSIONS: Adaptively dosed nivo-ipi responses are durable and resemble historical data for conventional nivo-ipi. Baseline IL6 and circulating tumor DNA changes during treatment warrant further study as biomarkers of nivo-ipi response.

Cost-effectiveness of treating advanced melanoma with tumor-infiltrating lymphocytes based on an international randomized phase 3 clinical trial.

INTRODUCTION: In a multicenter, open-label randomized phase 3 clinical trial conducted in the Netherlands and Denmark, treatment with ex vivo-expanded tumor-infiltrating lymphocytes (TIL-NKI/CCIT) from autologous melanoma tumor compared with ipilimumab improved progression-free survival in patients with unresectable stage IIIC-IV melanoma after failure of first-line or second-line treatment. Based on this trial, we conducted a cost-utility analysis. METHODS: A Markov decision model was constructed to estimate expected costs (expressed in 2021€) and outcomes (quality-adjusted life years (QALYs)) of TIL-NKI/CCIT versus ipilimumab in the Netherlands. The Danish setting was assessed in a scenario analysis. A modified societal perspective was applied over a lifetime horizon. TIL-NKI/CCIT production costs were estimated via activity-based costing. Through sensitivity analyses, uncertainties and their impact on the incremental cost-effectiveness ratio (ICER) were assessed. RESULTS: Mean total undiscounted lifetime benefits were 4.47 life years (LYs) and 3.52 QALYs for TIL-NKI/CCIT and 3.33 LYs and 2.46 QALYs for ipilimumab. Total lifetime undiscounted costs in the Netherlands were €347,168 for TIL-NKI/CCIT (including €67,547 for production costs) compared with €433,634 for ipilimumab. Undiscounted lifetime cost in the Danish scenario were €337,309 and €436,135, respectively. This resulted in a dominant situation for TIL-NKI/CCIT compared with ipilimumab in both countries, meaning incremental QALYs were gained at lower costs. Survival probabilities, and utility in progressive disease affected the ICER most. CONCLUSION: Based on the data of a randomized phase 3 trial, treatment with TIL-NKI/CCIT in patients with unresectable stage IIIC-IV melanoma is cost-effective and cost-saving, both in the current Dutch and Danish setting. These findings led to inclusion of TIL-NKI/CCIT as insured care and treatment guidelines. Publicly funded development of the TIL-NKI/CCIT cell therapy shows realistic promise to further explore development of effective personalized treatment while warranting economic sustainability of healthcare systems.

Nivolumab plus ipilimumab versus the EXTREME regimen in recurrent/metastatic squamous cell carcinoma of the head and neck: a cost-effectiveness analysis.

In the CheckMate 651 study, nivolumab plus ipilimumab versus EXTREME (cisplatin/carboplatin + cetuximab + fluorouracil) regimen was compared for effectiveness. It is not known whether these immunotherapy agents are cost-effective for recurrent or metastatic squamous cell carcinomas of the head and neck (R/M SCCHN). The purpose of this study was to compare the cost-effectiveness of nivolumab plus ipilimumab with EXTREME in the first-line setting from the standpoint of third-party payers in the United States. The projecting of costs and outcomes over 15 years was done using a three-state partitioned survival model discounted by 3% per year. Long-term extrapolation of CheckMate 651 was used to model progression-free survival and overall survival (OS). The incremental net health benefit (INHB), incremental net monetary benefit (INMB), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated. The uncertainty and stability of the model were accounted for via one-way and probabilistic sensitivity analyses. As compared with nivolumab plus ipilimumab, EXTREME was associated with an increase of 0.154 life-years and 0.076 QALYs, as well as a cost increase of $572 per patient. The corresponding ICERs were $7545/QALY along with the values of INMB and INHB were $113,267 and 0.076 QALYs, respectively, at a willingness to pay (WTP) threshold of $150,000/QALY. The probability of nivolumab plus ipilimumab being cost-effective was > 99% in patients with combined positive score (CPS) ≥ 1, CPS 1-19, or CPS ≥ 20. Moreover, hazard ratio for OS and body weight were the most sensitive parameters for the model. According to sensitivity analyses, these results were generally robust. In overall populations with R/M SCCHN, the EXTREME regimen is cost-effective compared with nivolumab plus ipilimumab. Given a WTP threshold of $150,000 per QALY, the probability of the EXTREME regiment being cost-effective compared with nivolumab and ipilimumab, was 64%. Importantly, there was heterogeneity in the cost-effectiveness probabilities, based on primary sites and expression levels of PD-L1. Therefore, tailored treatment based on individual patient and clinical characteristics, remains important, and may impact the cost-effectiveness of the regimens under study.

Cost-Effectiveness Analysis of Nivolumab Plus Ipilimumab Combination Therapy as First-line Treatment for Advanced Renal Cell Carcinoma in Japan.

OBJECTIVES: The purpose of this study is to examine the cost-effectiveness of nivolumab (NIVO) plus ipilimumab (IPI) combination therapy (NIVO + IPI) compared with the sunitinib (SUN) therapy for Japanese patients with advanced renal cell carcinoma from the perspective of a Japanese health insurance payer. METHODS: A lifetime horizon was applied, and 2% per annum was set as the discount rate. The threshold was set as $ 75 000 per quality-adjusted life-year (QALY) gained. For the analytical method, we used a partitioned survival analysis model to estimate the incremental cost-effectiveness ratio (ICER), which is calculated by dividing incremental costs by incremental QALYs. Progression-free survival, progressive disease, and death were set as health states. Additionally, cost parameters and utility weights were set as key parameters. We set the intermediate/poor-risk population as the base case. Scenario analysis was conducted for the intention-to-treat population and the favorable risk population. Furthermore, one-way sensitivity analysis and probabilistic sensitivity analysis were conducted for each population. RESULTS: In the base-case analysis, the QALYs of NIVO + IPI and SUN were 4.32 and 2.99, respectively. NIVO + IPI conferred 1.34 additional QALYs. Meanwhile, the total costs in the NIVO + IPI and SUN were $692 288 and $475 481, respectively. As a result, the ICER of NIVO + IPI compared with SUN was estimated to be $162 243 per QALY gained. The parameter that greatly affected the ICER was the utility weight of progression-free survival in NIVO + IPI. CONCLUSIONS: NIVO + IPI for advanced renal cell carcinoma seems to be not cost-effective compared with the SUN in the Japanese healthcare system.

Cost-utility analysis of Pembrolizumab compared to other alternative immunotherapy and chemotherapy treatments for patients with advanced melanoma in Iran.

OBJECTIVES: Immunotherapy drugs like Pembrolizumab have shown significant improvements in treatment outcomes of advanced melanoma. This study aimed to evaluate the cost-utility of Pembrolizumab compared to other immunotherapy and chemotherapy drugs in the first-line treatment of advanced melanoma in Iran. METHODS: A partitioned-survival model, based on data from a recent randomized phase 3 study (KEYNOTE-006) and recent meta-analysis, was used to divide Overall survival (OS) time into Progression-free survival (PFS) and post-progression survival for Pembrolizumab, Nivolumab, Ipilimumab, Dacarbazine, Temozolomide, Carboplatin, and Paclitaxel combination. Quality Life Years (QALY) and Incremental Cost-Effectiveness Ratio (ICER) were considered as the final outcome. RESULTS: The ICER of Ipilimumab, Nivolumab, Nivolumab & Ipilimumab, and Pembrolizumab compared to Temozolomide was calculated as $40,365.53, $19,591.13, $24,578, and $47,324.2 per QALY, respectively. Scenario analysis demonstrated if the price of one vial of Nivolumab 100 is $90.51, each vial of Pembrolizumab is $119.20, and each vial of Ipilimumab is $101.54, they will be cost-effective in Iran. CONCLUSION: None of the immunotherapy drugs studied were found to be cost-effective when considering the cost-effectiveness threshold of $3,532. Therefore, a cost reduction of more than 90% in the prices of immunotherapy drugs would be necessary for them to be considered cost-effective in Iran.

Cost-effectiveness of first-line immunotherapy for advanced non-small cell lung cancer with different PD-L1 expression levels: A comprehensive overview.

BACKGROUND: Immunotherapies can substantially improve treatment efficacy, despite their high cost. A comprehensive overview of the cost-effectiveness analysis (CEA) of immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer based on different tumor proportion scores (TPSs) was conducted. METHODS: PubMed, Embase, Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, and NHS Economic Evaluation databases were searched from their inception until August 24, 2022. Data relevant to the CEA results were recorded, and quality assessments conducted based on the Quality of Health Economic Studies (QHES) process. FINDINGS: Fifty-one original studies from seven countries were included. The mean QHES score was 77.0 (range: 53-95). Twenty-seven studies were classified as high-quality, and the rest as fair quality. Pembrolizumab, nivolumab, ipilimumab, atezolizumab, camrelizumab, cemiplimab, sintilimab, tislelizumab, and durvalumab were identified using three TPS categories. While nivolumab plus ipilimumab and pembrolizumab plus chemotherapy were unlikely to be cost-effective in China, the results for the US were uncertain. Atezolizumab combinations were not cost-effective in China or the US, and tislelizumab and sintilimab were cost-effective in China. For TPSs ≥ 50%, the pembrolizumab monotherapy could be cost-effective in some developed countries. Cemiplimab was more cost-effective than chemotherapy, pembrolizumab, and atezolizumab in the US. For TPSs ≥ 1%, the cost-effectiveness of pembrolizumab was controversial due to the different willingness-to-pay thresholds. CONCLUSIONS: None of the atezolizumab combination regimens were found to be cost-effective in any perspective of evaluations. Camrelizumab, tislelizumab, and sintilimab have lower ICERs compared to atezolizumab, pembrolizumab, and nivolumab in China. Cemiplimab may be a more affordable alternative to pembrolizumab or atezolizumab. However, it remains unclear which ICIs are the best choices for each country. Future CEAs are required to select comprehensive regimens alongside randomized trials and real-world studies to help verify the economics of ICIs in specific decision-making settings.

First-line nivolumab plus ipilimumab for unresectable MPM in China: a cost-effectiveness analysis.

BACKGROUND: The regimen of nivolumab plus ipilimumab (NI) has been recommended by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology-Malignant Pleural Mesothelioma (Version 1.2022) and Chinese Guidelines for the Clinical Diagnosis and Treatment of Malignant Pleural Mesothelioma (2021 edition) as the first-line treatment for Malignant Pleural Mesothelioma (MPM). But whether immunotherapy has a financial advantage over conventional chemotherapy (pemetrexed plus cisplatin/carboplatin, C) is uncertain. METHODS: Based on survival and safety data from the CheckMate 743 clinical trial (NCT02899299), a partitioned survival model was constructed using TreeAge Pro2022 software. The model cycle was set to 1 month and the study period was 10 years. The output indicators included total cost, quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were used to assess the robustness of the results, considering only direct medical costs. RESULTS AND DISCUSSION: The ICER for group NI versus Group C was $375,656/QALY in all randomized patients, $327,943/QALY in patients with epithelioid histology, and $115,495/QALY in patients with non-epithelioid histology. The ICERs of all three different populations all exceeded the willingness-to-pay threshold (three times the per capita gross domestic product of China in 2021). The results of univariate sensitivity analysis showed that the price of pemetrexed and nivolumab had great influence on the analysis results. The results of the probabilistic sensitivity analysis show that the probability of the NI scheme being more economical in all three different populations was 0. WHAT IS NEW AND CONCLUSION: From the perspective of the Chinese healthcare system, in patients with unresectable MPM, NI has no economic advantage over C.

Adverse event costs associated with first-line therapy for advanced non-small cell lung cancer in the United States: An analysis of clinical trials of immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors, such as pembrolizumab, nivolumab, and atezolizumab, have demonstrated substantial survival benefits in patients with advanced non-small cell lung cancer (NSCLC). However, there is limited evidence on their relative safety profiles and adverse event (AE)-related cost burden. OBJECTIVE: To compare the AE management costs of nivolumab plus ipilimumab with and without limited chemotherapy with those of chemotherapy, pembrolizumab plus chemotherapy, and atezolizumab plus chemotherapy in a first-line setting among patients with advanced NSCLC. METHODS: The mean per-patient AE costs were estimated using the incidence of all-cause grade 3/4 AEs with any-grade incidence greater than or equal to 15% and the corresponding costs of AE management in the inpatient setting. AE rates were obtained from individual patient data from the CheckMate 227 and CheckMate 9LA trials for nivolumab plus ipilimumab with/without limited chemotherapy and aggregated data from the KEYNOTE-189 and KEYNOTE-407 trials for pembrolizumab plus chemotherapy and the IMpower130 trial for atezolizumab plus chemotherapy. AE management costs from the third-party payer perspective were estimated based on inpatient medical costs from the 2016 United States Healthcare Cost and Utilization Project National Inpatient Sample. All costs were inflated to 2020 US dollars. RESULTS: Nivolumab plus ipilimumab and nivolumab plus ipilimumab plus limited chemotherapy were associated with lower per-patient grade 3/4 AE costs compared with chemotherapy ($1,708 and $624 lower over the treatment course, respectively). Compared with pembrolizumab plus chemotherapy, nivolumab plus ipilimumab was associated with lower grade 3/4 AE costs in patients with nonsquamous histology (difference: -$4,866) and squamous histology (difference: -$3,795), and nivolumab plus ipilimumab with limited chemotherapy also had lower AE costs for both nonsquamous (difference: -$2,800) and squamous (difference: -$2,753) disease. Similarly, nivolumab plus ipilimumab and nivolumab plus ipilimumab plus limited chemotherapy were also associated with lower AE costs ($11,400 and $8,809 lower, respectively) compared with atezolizumab plus chemotherapy among patients with nonsquamous disease. In particular, nivolumab plus ipilimumab without or with limited chemotherapy were associated with much lower AE costs of hematological AEs compared with chemotherapy and other immune checkpoint inhibitor-based treatments in combination with a full course of chemotherapy. CONCLUSIONS: Nivolumab plus ipilimumab with/without limited chemotherapy was associated with lower AE management costs compared with chemotherapy, pembrolizumab plus chemotherapy, and atezolizumab plus chemotherapy as first-line treatment for advanced NSCLC. The AE cost benefits were largely driven by the lower cost burden for hematological AEs for nivolumab plus ipilimumab with/without limited chemotherapy. DISCLOSURES This study was supported by Bristol-Myers Squibb. The sponsor was involved in all aspects of the work and in the decision to submit the manuscript for publication. Dr Stenehjem has received consulting fees from Bristol-Myers Squibb. Dr Lubinga was an employee of Bristol-Myers Squibb at the time of the study's conduct and holds stock/options. Drs Betts and Wu are employees of Analysis Group, Inc., a consulting company that has received funding from Bristol-Myers Squibb for this research.

Cost-effectiveness of nivolumab and ipilimumab versus pembrolizumab and axitinib in advanced renal cell carcinoma with intermediate or poor prognostic risk: a Brazilian private healthcare system perspective.

OBJECTIVE: Nivolumab plus ipilimumab (NIVO + IPI) and pembrolizumab plus axitinib (PEM + AXI) have demonstrated significant clinical benefits as first-line (1 L) treatments for intermediate/poor-risk advanced renal cell carcinoma (aRCC) patients. This study aimed to assess the cost-effectiveness of NIVO + IPI versus PEM + AXI from a Brazilian private healthcare system perspective, utilizing a novel approach to estimate comparative efficacy between the treatments. METHODS: A three-state partitioned survival model (progression-free, progressed, and death) was developed to estimate costs, life-years (LYs), quality-adjusted LYs (QALYs), and the incremental cost-utility ratio (ICUR) over a 40-year time horizon. In the absence of head-to-head comparisons between NIVO + IPI and PEM + AXI, clinical data for NIVO + IPI was obtained from CheckMate 214 (NCT02231749) and for PEM + AXI from KEYNOTE-426 (NCT02853331). A matching-adjusted indirect comparison was conducted to account for the imbalance of treatment effect modifiers between the trials. Patient characteristics, resource use, health state utilities, and costs were based on Brazilian-specific sources. Costs and health outcomes were both discounted by 5% annually in line with Brazilian guidelines. The robustness of the results was evaluated through extensive sensitivity analysis and scenario analyses. RESULTS: When comparing the matched versus unmatched OS, PFS, and TTD curves there was no noteworthy difference. NIVO + IPI was associated with cost savings (R$ 350,232), higher LYs (5.54 vs. 4.61), and QALYs (4.74 vs. 3.76) versus PEM + AXI, resulting in NIVO + IPI dominating PEM + AXI. Key model drivers were the treatment duration for PEM, NIVO, and AXI. NIVO + IPI remained dominant in all scenario analyses, which indicated that model results were robust to alternative modelling inputs or assumptions. CONCLUSIONS: This analysis shows that NIVO + IPI is estimated to be a life-extending and potentially cost-saving 1 L treatment option when compared with PEM + AXI for intermediate/poor-risk a RCC patients in the Brazilian private healthcare system.

Cost Effectiveness and Budget Impact of Nivolumab Plus Ipilimumab Versus Platinum Plus Pemetrexed (with and Without Bevacizumab) in Patients with Unresectable Malignant Pleural Mesothelioma in Switzerland.

BACKGROUND: Malignant pleural mesotheliomas (MPMs) are aggressive and often unresectable. In the past, chemotherapy was the standard for palliative treatment. However, immunotherapy with nivolumab+ipilimumab has recently received marketing approval. OBJECTIVES: This study evaluated the cost effectiveness of nivolumab+ipilimumab versus pemetrexed+platinum (with/without bevacizumab) for Swiss patients with unresectable MPM, overall and by histological subtype. METHODS: We developed a three-state Markov cohort model with a cycle length of 1 month, a 30-year time horizon, and a discount rate of 3% per year for costs and benefits. The model included the updated survival and treatment-dependent utility results from the Checkmate-743 and MAPS registration trials. A Swiss statutory health insurance perspective was considered with unit costs for 2022 from publicly available and real-world sources. We assumed a willingness-to-pay (WTP) threshold of CHF100,000/QALY. Model robustness was explored in sensitivity and scenario analyses. RESULTS: Compared with chemotherapy, nivolumab+ipilimumab incurred additional costs of CHF109,115 and 0.57 additional quality-adjusted life-years (QALYs), yielding an incremental cost-effectiveness ratio (ICER) of CHF192,585/QALY (i.e. USD201,829/QALY) gained. Relative to their 2022 list price, nivolumab+ipilimumab may be cost effective if priced at 48% across all histologies. Assuming cisplatin-based instead of carboplatin-based chemotherapy reduced the ICER to CHF158,911/QALY (i.e. USD166,539/QALY). For the non-epithelioid subtype, nivolumab+ipilimumab was cost effective compared with chemotherapy (ICER of CHF97,894/QALY, i.e. USD102,593/QALY). Chemotherapy+bevacizumab was often a dominated strategy or would require a bevacizumab cost reduction to 28%. CONCLUSIONS: Our model projected nivolumab+ipilimumab to be cost effective for the non-epithelioid subtype but not for all histologies. Substantial discounts for nivolumab+ipilimumab would be necessary to achieve cost effectiveness for all histologies.

Real-World Outcomes of Latinx Versus Non-Latinx Patients Treated With First-Line Immunotherapy for Metastatic Renal-Cell Carcinoma.

BACKGROUND: There are limited data regarding the impact of ethnicity among patients receiving immune checkpoint inhibitors. We evaluated real-world outcomes between Latinx and non-Latinx patients with metastatic renal-cell carcinoma (mRCC) treated with first-line nivolumab/ipilimumab within 2 different healthcare settings. METHODS: We performed a retrospective analysis of patients with mRCC who received nivolumab/ipilimumab within the Los Angeles County Department of Health Services (LAC-DHS), a safety-net healthcare system, and the City of Hope Comprehensive Cancer Center (COH), a tertiary oncology center, between January 1, 2015 and December 31, 2021. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method and covariates were adjusted using multivariate Cox proportional hazards regression. RESULTS: Of 94 patients, 40 patients (43%) were Latinx while the remainder were non-Latinx (44 pts [46%] White, 7 pts [7%] Asian, and 3 pts [3%] Other). Fifty (53%) and 44 (47%) patients received their care at COH and LAC-DHS, respectively. Most Latinx patients (95%) were treated at LAC-DHS, and most non-Latinx patients (89%) were treated at COH. Pooled analysis by ethnicity demonstrated significantly shorter PFS in Latinx versus non-Latinx patients (10.1 vs. 25.2 months, hazard ratios [HR] 3.61, 95% CI 1.96-6.66, P ≤ .01). Multivariate analysis revealed a HR of 3.41 (95% CI 1.31-8.84; P = .01). At a median follow-up of 11.0 months, the median OS was not reached in either arm at the time of data cutoff. CONCLUSION: Latinx patients with mRCC had a shorter PFS treated with frontline nivolumab/ipilimumab compared to their non-Latinx counterparts. No difference was observed in OS although these data were immature. Larger studies are needed to further interrogate the social and economic determinants of ethnicity on clinical outcomes in mRCC.

Health Technology Reassessment: Addressing Uncertainty in Economic Evaluations of Oncology Drugs at Time of Reimbursement Using Long-Term Clinical Trial Data.

The evidence base to support reimbursement decision making for oncology drugs is often based on short-term follow-up trial data, and attempts to address this uncertainty are not typically undertaken once a reimbursement decision is made. To address this gap, we sought to conduct a reassessment of an oncology drug (pembrolizumab) for patients with advanced melanoma which was approved based on interim data with a median 7.9 months of follow-up and for which long-term data have since been published. We developed a three-health-state partitioned survival model based on the phase 3 KEYNOTE-006 clinical trial data using patient-level data reconstruction techniques based on an interim analysis. We used a standard survival analysis and parametric curve fitting techniques to extrapolate beyond the trial follow-up time, and the model structure and inputs were derived from the literature. Five-year long-term follow-up data from the trial were then used to re-evaluate the cost-effectiveness of pembrolizumab versus ipilimumab for treatment of advanced melanoma. The best fitting parametric curves and corresponding survival extrapolations for reconstructed interim data and long-term data reconstructed from KEYNOTE-006 were different. An analysis of the 5 year long-term follow-up data generated a base case incremental cost-effectiveness ratio (ICER) that was 28% higher than the ICER based on interim trial data. Our findings suggest that there may be a trade-off between certainty and the ICER. Conducting health technology re-assessments of certain oncology products on the basis of longer-term data availability, especially for those health technology adoption decisions made based on immature clinical data, may be of value to decision makers.

Brief Communication on Pathologic Assessment of Persistent Stable Metastatic Lesions in Patients Treated With Anti-CTLA-4 or Anti-CTLA-4 + Anti-PD-1 Therapy.

Despite the wide use of immune checkpoint inhibition for the treatment of melanoma, the mechanisms leading to long-term stable disease are incompletely understood. Patients with metastatic melanoma who had received ipilimumab alone or ipilimumab plus nivolumab 2+years prior and attained at least 6 months of stable disease were identified. Positron emission tomography/computed tomography (PET/CT) was performed. Pretreatment and posttreatment biopsies of areas of stable disease were assessed for tumor, fibrosis, and inflammation. Seven patients underwent PET/CT and tissue biopsy. Fluorodeoxyglucose avid lesions on PET/CT ranged from no activity to an SUV of 22. In 6 patients, the residual stable lesions were composed of necrosis and fibrosis with a prominent pigment containing macrophages and no residual melanoma. In 1 patient, a nodal lesion demonstrated melanoma with active inflammation. In most patients with durable stable disease after treatment with ipilimumab or ipilimumab/nivolumab, residual lesions demonstrated predominantly necrosis and fibrosis consistent with resolving lesions. The presence of melanophages in these samples may suggest ongoing immune surveillance. One patient did demonstrate residual melanoma, indicating the need for ongoing monitoring of this patient population.

Cost-effectiveness of second-line ipilimumab for metastatic melanoma: A real-world population-based cohort study of resource utilization.

BACKGROUND: The efficacy-effectiveness gap between randomized trial and real-world evidence regarding the clinical benefit of ipilimumab for metastatic melanoma (MM) has been well characterized by previous literature, consistent with initial concerns raised by health technology assessment agencies (HTAs). As these differences can significantly impact cost-effectiveness, it is critical to assess the real-world cost-effectiveness of second-line ipilimumab versus non-ipilimumab treatments for MM. METHODS: This was a population-based retrospective cohort study of patients who received second-line non-ipilimumab therapies between 2008 and 2012 versus ipilimumab treatment between 2012 and 2015 (after public reimbursement) for MM in Ontario. Using a 5-year time horizon, censor-adjusted and discounted (1.5%) costs (from the public payer's perspective in Canadian dollars) and effectiveness were used to calculate incremental cost-effectiveness ratios (ICERs) in life-years gained (LYGs) and quality-adjusted life years (QALYs), with bootstrapping to capture uncertainty. Varying the discount rate and reducing the price of ipilimumab were done as sensitivity analyses. RESULTS: In total, 329 MM were identified (Treated: 189; Controls: 140). Ipilimumab was associated with an incremental effectiveness of 0.59 LYG, incremental cost of $91,233, and ICER of $153,778/LYG. ICERs were not sensitive to discounting rate. Adjusting for quality of life using utility weights resulted in an ICER of $225,885/QALY, confirming the original HTA estimate prior to public reimbursement. Reducing the price of ipilimumab by 100% resulted in an ICER of $111,728/QALY. CONCLUSION: Despite its clinical benefit, ipilimumab as second-line monotherapy for MM patients is not cost-effective in the real world as projected by HTA under conventional willingness-to-pay thresholds.

Cost-Effectiveness of the First Line Treatment Options For Metastatic Renal Cell Carcinoma in India.

PURPOSE: Tyrosine kinase inhibitors such as sunitinib and pazopanib are the mainstay of treatment of metastatic renal cell carcinoma (mRCC) in India. However, pembrolizumab and nivolumab have shown significant improvement in the median progression-free survival and overall survival among patients with mRCC. In this study, we aimed to determine the cost-effectiveness of the first-line treatment options for the patients with mRCC in India. METHODS: A Markov state-transition model was used to measure the lifetime costs and health outcomes associated with sunitinib, pazopanib, pembrolizumab/lenvatinib, and nivolumab/ipilimumab among patients with first-line mRCC. Incremental cost per quality-adjusted life-year (QALY) gained with a given treatment option was compared against the next best alternative and assessed for cost-effectiveness using a willingness to pay threshold of one-time per capita gross-domestic product of India. The parameter uncertainty was analyzed using the probabilistic sensitivity analysis. RESULTS: We estimated the total lifetime cost per patient of ₹ 0.27 million ($3,706 US dollars [USD]), ₹ 0.35 million ($4,716 USD), ₹ 9.7 million ($131,858 USD), and ₹ 6.7 million ($90,481 USD) for the sunitinib, pazopanib, pembrolizumab/lenvatinib, and nivolumab/ipilimumab arms, respectively. Similarly, the mean QALYs lived per patient were 1.91, 1.86, 2.75, and 1.97, respectively. Sunitinib incurs an average cost of ₹ 143,269 ($1,939 USD) per QALY lived. Therefore, sunitinib at current reimbursement rates (₹ 10,000 per cycle) has a 94.6% probability of being cost-effective at a willingness to pay threshold of 1-time per capita gross-domestic product (₹ 168,300) in the Indian context. CONCLUSION: Our findings support the current inclusion of sunitinib under India's publicly financed health insurance scheme.

Cost Effectiveness of Treatment Sequences in Advanced Renal Cell Carcinoma.

BACKGROUND: The treatment landscape for metastatic renal cell carcinoma (mRCC) has significantly evolved in recent years. Without direct comparator trials, factors such as cost effectiveness (CE) are important to guide decision-making. OBJECTIVE: To assess the CE of guideline-recommended approved first- and second-line treatment regimens. DESIGN, SETTING, AND PARTICIPANTS: A comprehensive Markov model was developed to analyze the CE of the five current National Comprehensive Cancer Network-recommended first-line therapies with appropriate second-line therapy for patient cohorts with International Metastatic RCC Database Consortium favorable and intermediate/poor risk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Life years, quality-adjusted life years (QALYs), and total accumulated costs were estimated using a willingness-to-pay threshold of $150 000 per QALY. One-way and probabilistic sensitivity analyses were performed. RESULTS AND LIMITATIONS: In patients with favorable risk, pembrolizumab + lenvatinib followed by cabozantinib added $32 935 in costs and yielded 0.28 QALYs, resulting in an incremental CE ratio (ICER) of $117 625 per QALY in comparison to pembrolizumab + axitinib followed by cabozantinib. In patients with intermediate/poor risk, nivolumab + ipilimumab followed by cabozantinib added $2252 in costs and yielded 0.60 QALYs compared to cabozantinib followed by nivolumab, yielding an ICER of $4184. Limitations include differences in median follow-up duration between treatments. CONCLUSIONS: Pembrolizumab + lenvatinib followed by cabozantinib, and pembrolizumab + axitinib followed by cabozantinib were cost-effective treatment sequences for patients with favorable-risk mRCC. Nivolumab +ipilimumab followed by cabozantinib was the most cost-effective treatment sequence for patients with intermediate-/poor-risk mRCC, dominating all preferred treatments. PATIENT SUMMARY: Because new treatments for kidney cancer have not been compared head to head, comparison of their cost and efficacy can help in making decisions about the best treatments to use first. Our model showed that patients with a favorable risk profile are most likely to benefit from pembrolizumab and lenvatinib or axitinib followed by cabozantinib, while patients with an intermediate or poor risk profile will probably benefit most from nivolumab and ipilimumab followed by cabozantinib.

Cost-effectiveness of first-line immunotherapies for advanced non-small cell lung cancer.

BACKGROUND: Researchers have not simultaneously compared the cost-effectiveness of six immunotherapies with chemotherapy for advanced non-small cell lung cancer. This study evaluated the cost-effectiveness across different programmed death-ligand 1 (PD-L1) levels. METHODS: A Markov model with lifetime horizon was created for seven regimens: pembrolizumab plus chemotherapy (pembro-chemo), nivolumab plus ipilimumab (nivo-ipi), nivolumab, ipilimumab plus chemotherapy (nivo-ipi-chemo), atezolizumab plus chemotherapy (atezo-chemo), atezolizumab, bevacizumab plus chemotherapy (atezo-beva-chemo), single-agent pembrolizumab, and chemotherapy alone. Input parameters were derived from trial data, a network meta-analysis, and other literature. We conducted the analysis from the perspective of US health care sector. RESULTS: For all patients without considering PD-L1 expression, the incremental cost-effectiveness ratio (ICER) of pembro-chemo versus chemotherapy was $183,299 per quality-adjusted life year (QALY). The preferred regimens based on ICERs differed by PD-L1 levels. For patients with PD-L1 ≥50%, pembrolizumab versus chemotherapy and pembro-chemo versus pembrolizumab resulted in ICERs of $96,189 and $198,913 per QALY, respectively. The other strategies were dominated. For patients with PD-L1 of 1%-49%, the ICER of pembro-chemo comparing to chemotherapy was $218,159 per QALY. The other regimens were dominated by pembro-chemo. For patients with PD-L1 <1%, nivo-ipi versus chemotherapy and nivo-ipi-chemo versus nivo-ipi resulted in ICERs of $161,277 and $881,975 per QALY, and the other regimens were dominated strategies. At the willingness-to-pay threshold of $150,000 per QALY, pembrolizumab had 87% and pembro-chemo had 1% probabilities being cost-effective in patients with PD-L1 ≥50% and 1%-49%, respectively. Nivo-ipi had a 34% probability being cost-effective in patients with PD-L1 <1%. CONCLUSIONS: The PD-L1 level should be incorporated into treatment decision-making. Our findings suggest that first-line pembrolizumab, pembro-chemo, and nivo-ipi are the preferred strategies for patients with PD-L1 ≥50%, 1%-49%, and <1%, respectively.

Cost-effectiveness of nivolumab plus ipilimumab versus chemotherapy as first-line therapy in advanced non-small cell lung cancer.

OBJECTIVES: First-line treatment with nivolumab plus ipilimumab has been shown to improve overall survival (OS) and progression-free survival (PFS) for patients with advanced non-small cell lung cancer (NSCLC). The current study evaluated the cost-effectiveness of nivolumab plus ipilimumab versus chemotherapy in advanced NSCLC from the perspective of Chinese healthcare system. METHODS: A three state-transition Markov model was employed to evaluate the cost and effectiveness of nivolumab plus ipilimumab versus chemotherapy in the first-line treatment of advanced NSCLC. Key clinical data in the model were derived from Part 1 of the phase 3 CheckMate 227 trial (NCT02477826). Costs and utilities were obtained from published literatures. The main endpoints of the model were costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were performed to assess the model uncertainty. RESULTS: Nivolumab plus ipilimumab was associated with an increase in overall cost of $95,867.82 and improved effectiveness of 0.98 QALYs compared with chemotherapy, yielding an ICER of $97,676.24 per QALY. In one-way sensitivity analysis, the variables that had the greatest influence on the ICER were hazard ratio for OS and body weight. In probabilistic analysis, nivolumab plus ipilimumab had a 0% probability of being cost-effective at a willingness-to-pay (WTP) threshold of $37,663.26/QALY in China. However, the combination therapy would become cost-effective when the cost of nivolumab and ipilimumab were discounted by 65%. CONCLUSION: First-line nivolumab plus ipilimumab treatment for advanced NSCLC was found to be not cost-effective compared with chemotherapy at a WTP threshold of $37,663.26/QALY in China.

Grade 3/4 Adverse Event Costs of Immuno-oncology Combination Therapies for Previously Untreated Advanced Renal Cell Carcinoma.

BACKGROUND: Despite 4 approved combination regimens in the first-line setting for advanced renal cell carcinoma (aRCC), adverse event (AE) costs data are lacking. MATERIALS AND METHODS: A descriptive analysis on 2 AE cost comparisons was conducted using patient-level data for the nivolumab-based therapies and published data for the pembrolizumab-based therapies. First, grade 3/4 AE costs were compared between nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + axitinib using data from the CheckMate 214 (median follow-up [mFU]: 13.1 months), CheckMate 9ER (mFU: 12.8 months), and KEYNOTE-426 (mFU: 12.8 months) trials, respectively. Second, grade 3/4 AE costs were compared between nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + lenvatinib using data from the CheckMate 214 (mFU: 26.7 months), CheckMate 9ER (mFU: 23.5 months), and KEYNOTE-581 (mFU: 26.6 months) trials, respectively. Per-patient costs for all-cause and treatment-related grade 3/4 AEs with corresponding any-grade AE rates ≥ 20% were calculated based on the Healthcare Cost and Utilization Project database and inflated to 2020 US dollars. RESULTS: Per-patient all-cause grade 3/4 AE costs for nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + axitinib were $2703 vs. $4508 vs. $5772, and treatment-related grade 3/4 AE costs were $741 vs. $2722 vs. $4440 over ~12.8 months of FU. For nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + lenvatinib, per-patient all-cause grade 3/4 AE costs were $3120 vs. $5800 vs. $9285, while treatment-related grade 3/4 AE costs were $863 vs. $3162 vs. $5030 over ~26.6 months of FU. CONCLUSION: Patients with aRCC treated with first-line nivolumab-based therapies had lower grade 3/4 all-cause and treatment-related AE costs than pembrolizumab-based therapies, suggesting a more favorable cost-benefit profile.