Economic value of toripalimab plus axitinib as first-line treatment for advanced renal cell carcinoma in China: a model-based cost-effectiveness analysis.

OBJECTIVE: The current analysis aimed to evaluate the economic benefit of toripalimab plus axitinib for previously untreated RCC patients from the Chinese healthcare system perspective. METHODS: The partitioned survival model was developed to simulate 3-week patients' transition in 20-year time horizon to evaluate the cost-effectiveness of toripalimab plus axitinib compared with sunitinib for advanced RCC. Survival data were gathered from the RENOTORCH trial, and cost and utility inputs were obtained from the database and published literature. Total cost, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were the model outputs. Subgroup analyses and sensitivity analyses were conducted to increase the comprehensiveness and estimate the robustness of the model results. RESULTS: In the base-case analysis, compared with sunitinib, toripalimab plus axitinib could bring additional 1.19 LYs and 0.65 QALYs, with the marginal cost of $41,499.23, resulting in the ICER of $64,337.49/QALY, which is higher than the WTP threshold. And ICERs were always beyond the WTP threshold of all subgroups. Sensitivity analyses demonstrated the model results were robust. CONCLUSIONS: Toripalimab plus axitinib was unlikely to be the cost-effective first-line therapy for patients with previously untreated advanced RCC compared with sunitinib from the Chinese healthcare system perspective.

Cost-Effectiveness Analysis of Pembrolizumab as an Adjuvant Treatment of Renal Cell Carcinoma Post-nephrectomy in the United States.

INTRODUCTION: Pembrolizumab was recently approved as an adjuvant treatment of renal cell carcinoma (RCC), based on prolonged disease-free survival compared to placebo in the phase III KEYNOTE-564 trial. The objective of this study was to evaluate the cost-effectiveness of pembrolizumab as monotherapy in the adjuvant treatment of RCC post-nephrectomy, from a US health sector perspective. PATIENTS AND METHODS: A Markov model with 4 health states (disease-free, locoregional recurrence, distant metastases, and death) was developed to compare the cost and effectiveness of pembrolizumab versus routine surveillance or sunitinib. Transition probabilities were estimated using patient-level KEYNOTE-564 data (cutoff: June 14, 2021), a retrospective study, and published literature. Costs of adjuvant and subsequent treatments, adverse events, disease management, and terminal care were estimated in 2022 US$. Utilities were based on EQ-5D-5L data collected in KEYNOTE-564. Outcomes included costs, life-years (LYs), and quality-adjusted LYs (QALYs). Robustness was assessed through one-way and probabilistic sensitivity analyses. RESULTS: Total cost per patient was $549,353 for pembrolizumab, $505,094 for routine surveillance, and $602,065 for sunitinib. Over a lifetime, pembrolizumab provided gains of 0.96 QALYs (1.00 LYs) compared to routine surveillance, yielding an incremental cost-effectiveness ratio of $46,327/QALY. Pembrolizumab dominated sunitinib with 0.89 QALYs (0.91 LYs) gained while saving costs. At a $150,000/QALY threshold, pembrolizumab was cost-effective versus both routine surveillance and sunitinib in 84.2% of probabilistic simulations. CONCLUSION: Pembrolizumab is projected to be cost-effective as an adjuvant RCC treatment versus routine surveillance or sunitinib based on a typical willingness-to-pay threshold.

First-line systemic treatment strategies for unresectable hepatocellular carcinoma: A cost-effectiveness analysis.

BACKGROUND: Oral multikinase inhibitors and immune checkpoint inhibitors (ICIs) are effective for treating advanced hepatocellular carcinoma (aHCC) but may increase cost. This study compared the cost-effectiveness of oral multikinase inhibitors and ICIs in the first-line treatment of patients with aHCC. METHODS: A three-state Markov model was established to study the cost-effectiveness of drug treatment from the perspective of Chinese payers. The key outcomes in this study were total cost, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER). RESULTS: The total costs and QALYs of sorafenib, sunitinib, donafenib, lenvatinib, sorafenib plus erlotinib, linifanib, brivanib, sintilimab plus IBI305, and atezolizumab plus bevacizumab were $9070 and 0.25, $9362 and 0.78, $33,814 and 0.45, $49,120 and 0.83, $63,064 and 0.81, $74,814 and 0.82, $81,995 and 0.82, $74083 and 0.85, and $104,188 and 0.84, respectively. The drug regimen with the lowest ICER was sunitinib ($551 per QALY), followed by lenvatinib ($68,869 per QALY). For oral multikinase inhibitors, the ICER of lenvatinib, sorafenib plus erlotinib, linifanib and brivanib compared with sunitinib was $779576, $1534,347, $1768,971, and $1963,064, respectively. For ICIs, sintilimab plus IBI305 is more cost effective than atezolizumab plus bevacizumab. The model was most sensitive to the price of sorafenib, the utility of PD, and the price of second-line drugs. CONCLUSION: For oral multikinase inhibitors, the order of possible treatment options is sunitinib > lenvatinib > sorafenib plus erlotinib > linifanib > brivanib > donafenib. For ICIs, the order of possible treatment options is sintilimab plus IBI305 > atezolizumab plus bevacizumab.

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 analysis of anlotinib versus sunitinib as first-line treatment for metastatic renal cell carcinoma in China.

BACKGROUND: Sunitinib was approved several years ago as a first-line drug for treating metastatic renal cell carcinoma (mRCC); however, its high price and broad side effects when administered at the standard dose have limited its clinical use. A clinical trial (NCT02072031) confirmed that anlotinib could be used as the first-line treatment for mRCC. This study was conducted to evaluate the cost-effectiveness of anlotinib as a first-line treatment for mRCC compared to that of sunitinib in China. METHODS: A Markov model was established to compare the cost-effectiveness of anlotinib with that of sunitinib. Clinical data were obtained from a multi-center phase II trial (clinical trial information: NCT02072031). Utility values were obtained from the literature. Total costs were calculated from a Chinese societal perspective. A sensitivity analysis was conducted to assess the model uncertainty. The life-year (LY), quality-adjusted life-year (QALY), and incremental cost-effectiveness ratio were calculated. RESULTS: The base-case analysis over a lifetime horizon of 10 years showed that the anlotinib group had 2.196 LYs and 1.487 QALYs at a total cost of $68,597.84. The sunitinib group had 2.194 LYs and 1.432 QALYs at a total cost of $88,060.02. This resulted in incremental cost-effectiveness ratios (ICER) of anlotinib versus sunitinib of $-9,210,858.93 per LYs and $-354,117.07 per QALYs, suggesting that anlotinib is a more effective and less costly strategy than sunitinib. CONCLUSION: Anlotinib may be a more cost-effective first-line treatment strategy for mRCC than sunitinib in China.

Cost-Effectiveness Analysis of Six Immunotherapy-Based Regimens and Sunitinib in Metastatic Renal Cell Carcinoma: A Public Payer Perspective.

PURPOSE: Several new treatment combinations have been approved in metastatic renal cell carcinoma (mRCC). To determine the optimal therapy on the basis of cost and health outcomes, we performed a cost-effectiveness analysis of approved immunotherapy-tyrosine kinase inhibitor/immunotherapy drug combinations and sunitinib using public payer acquisition costs in the United States. METHODS: We constructed a decision model with a 10-year time horizon. The seven treatment drug strategies included atezolizumab + bevacizumab, avelumab + axitinib, pembrolizumab + axitinib, nivolumab + ipilimumab (NI), nivolumab + cabozantinib, lenvatinib + pembrolizumab, and sunitinib. The effectiveness outcome in our model was quality-adjusted life-years (QALYs) with utility values on the basis of the published literature. Costs included drug acquisition costs and costs for management of grade 3-4 drug-related adverse events. We used a partitioned survival model in which patients with mRCC transitioned between three health states (progression-free, progressive disease, and death) at monthly intervals on the basis of parametric survival function estimated from published survival curves. To determine cost-effectiveness, we constructed incremental cost-effectiveness ratios (ICERs) by dividing the difference in cost by the difference in effectiveness between nondominated treatments. RESULTS: The least expensive treatment was sunitinib ($357,948 US dollars [USD]-$656,100 USD), whereas the most expensive was either lenvatinib + pembrolizumab or pembrolizumab + axitinib ($959,302 USD-$1,403,671 USD). NI yielded the most QALYs (3.6), whereas avelumab + axitinib yielded the least (2.5). NI had an incremental ICER of $297,465 USD-$348,516 USD compared with sunitinib. In sensitivity analyses, this ICER fell below $150,000 USD/QALY if the initial 4-month cost of NI decreased by 22%-38%. CONCLUSION: NI was the most effective combination for mRCC, but at a willingness-to-pay threshold of $150,000 USD/QALY, sunitinib was the most cost-effective approach.

First-Line Lenvatinib Plus Pembrolizumab or Everolimus versus Sunitinib for Advanced Renal Cell Carcinoma: A United States-Based Cost-Effectiveness Analysis.

INTRODUCTION: The CLEAR trial indicated that survival benefits were generated with lenvatinib plus pembrolizumab (LP) or everolimus (LE) than with sunitinib for advanced renal cell carcinoma (aRCC). However, the high cost of immuno-target and dual-targeted treatment, we assessed the cost-effectiveness of lenvatinib plus pembrolizumab or everolimus in the first-line setting for treatment of patients with aRCC from the United States (US) payers' perspective. MATERIALS AND METHODS: A comprehensive Markov model was developed to evaluate the cost and effectiveness of LP or LE in first-line therapy for aRCC. We estimated life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Utility values and direct costs related to the treatments were gathered from the published studies. Then, one-way and probabilistic sensitivity analyses were performed. Additional subgroup analyses were considered. RESULTS: Treatment with LP and LE provided an additional 0.67 QALYs (0.62 LYs) and 0.66 QALYs (0.90 LYs) compared with sunitinib, resulting in ICER of $131,656 per QALY and 201,928 per QALY, respectively. The most influential factor in this model was the cost of pembrolizumab with LP. Probabilistic sensitivity analysis showed there was a 58.97% and 28.91% probability that LP and LE were cost-effective at WTP values of $150,000 per QALY in the US. Subgroup analyses demonstrated that LP was more cost-effective for patients from Western Europe and North America, intermediate risk of the International risk group of Metastatic Renal Cell Carcinoma Database Consortium (IMDC), favorable and intermediate risk group of Memorial Sloan Kettering Cancer Center (MSKCC) and PD-L1 combined positive score greater than or equal to 1%. CONCLUSION: From the perspective of the US payer, LP is a cost-effective option as first-line treatment for patients with aRCC at a WTP threshold of $150,000 per QALY, but LE is the opposite.

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.

Economic evaluation of first-line nivolumab plus cabozantinib for advanced renal cell carcinoma in China.

Background: In the Checkmate9ER trial, first-line treatment with nivolumab combined with cabozantinib (NI + CA) has shown efficacy for advanced renal cell carcinoma. This study aims to evaluate the impact of the health and economic outcomes of NI + CA in China. Methods: Clinical efficacy data were derived from pivotal phase III CheckMate 9ER trial. A three-state partitioned survival model was established based on disease progression. Progression-free survival and overall survival of NI + CA vs. sunitinib were fitted with log-logistic and log-normal distributions, respectively. Mixture cure, non-mixture cure, and Royston/Parmar spline models were used to evaluate model robustness. The results derived the computational cost from the Chinese healthcare system perspective. The primary outcomes were quality-adjusted life-years (QALYs), total cost in US dollars, as well as incremental cost-effectiveness ratios (ICERs) at the willingness-to-pay threshold in China. One-way and probabilistic sensitivity analysis were also used to assess the robustness of the model. Results: In the base-case analysis result, 0.86 additional QALYs could be obtained in the NI+CA (3.84 QALYs) versus the sunitinib strategy (2.97 QALYs). The ICER of NI+CA compared with the sunitinib strategy was US$292,945 per QALY. The ICER value in the NI+CA strategy was higher than the Chinese willingness-to-pay threshold of US$38,024 per QALY. Although NI+CA can improve long-term patient survival significantly over sunitinib in the treatment of advanced renal cell carcinoma, it is unlikely to be cost-effective due to high cost. The results of the one-way sensitivity analysis showed that drug cost, health utility value at the stage of disease progression, and subsequent treatment proportion had a greater impact on the stability of ICER values. Conclusions: Nivolumab combined with cabozantinib can prolong the life of patients with advanced renal cell carcinoma and improve their quality of life, but there is a corresponding increase in medical cost. The NI + CA strategy is unlikely to be considered cost-effective in the treatment of advanced RCC from the perspective of Chinese healthcare system.

Functional Evaluation and Nephrotoxicity Assessment of Human Renal Proximal Tubule Cells on a Chip.

An in vitro human renal proximal tubule model that represents the proper transporter expression and pronounced epithelial polarization is necessary for the accurate prediction of nephrotoxicity. Here, we constructed a high-throughput human renal proximal tubule model based on an integrated biomimetic array chip (iBAC). Primary human renal proximal tubule epithelial cells (hRPTECs) cultured on this microfluidic platform were able to form a tighter barrier, better transporter function and more sensitive nephrotoxicity prediction than those on the static Transwell. Compared with the human immortalized HK2 model, the hRPTECs model on the chip gained improved apical-basolateral polarization, barrier function and transporter expression. Polymyxin B could induce nephrotoxicity not only from the apical of the hRPTECs, but also from the basolateral side on the iBAC. However, other chemotherapeutic agents, such as doxorubicin and sunitinib, only induced nephrotoxicity from the apical surface of the hRPTECs on the iBAC. In summary, our renal proximal tubule model on the chip exhibits improved epithelial polarization and membrane transporter activity, and can be implemented as an effective nephrotoxicity-screening toolkit.

Temporal Trends in Grade 3/4 Adverse Events and Associated Costs of Nivolumab Plus Cabozantinib Versus Sunitinib for Previously Untreated Advanced Renal Cell Carcinoma.

BACKGROUND AND OBJECTIVES: Novel immunotherapy-based combination treatments have drastically improved clinical outcomes for previously untreated patients with advanced/metastatic renal cell carcinoma (aRCC). This study aimed to assess the temporal trends in grade 3/4 adverse event (AE) rates and associated costs of nivolumab plus cabozantinib combination therapy versus sunitinib monotherapy in previously untreated patients with aRCC. METHODS: Individual patient data from the CheckMate 9ER trial (nivolumab plus cabozantinib: N = 320; sunitinib: N = 320) were used to calculate the proportion of patients experiencing grade 3/4 AEs. AE unit costs were obtained from the United States (US) 2017 Healthcare Cost and Utilization Project (HCUP) and inflated to 2020 US dollars. Per-patient-per-month (PPPM) all-cause and treatment-related grade 3/4 AE costs over 18-months, temporal trends, and top drivers of AE costs were evaluated in both treatment arms. RESULTS: Overall, the proportion of patients experiencing grade 3/4 AEs decreased over time, with the highest rates observed in the first 3 months for the nivolumab plus cabozantinib and sunitinib arms. Compared with sunitinib, nivolumab plus cabozantinib was associated with consistently lower average all-cause AE costs PPPM [month 3: $2021 vs. $3097 (p < 0.05); month 6: $1653 vs. $2418 (p < 0.05); month 12: $1450 vs. $1935 (p > 0.05); month 18: $1337 vs. $1755 (p > 0.05)]. Over 18 months, metabolism and nutrition disorders ($244), laboratory abnormalities ($182), and general disorders and administration site conditions ($122) were the costliest all-cause PPPM AE categories in the nivolumab plus cabozantinib arm, and laboratory abnormalities ($443), blood and lymphatic system disorders ($254), and metabolism and nutrition disorders ($177) were the costliest in the sunitinib arm. Trends of treatment-related AE costs were consistent with all-cause AE costs. CONCLUSIONS: Nivolumab plus cabozantinib was associated with lower costs of grade 3/4 AE management PPPM than sunitinib, which accumulated over the 18-month study period.

Cost-effectiveness analysis of nivolumab plus cabozantinib versus sunitinib as first-line therapy in advanced renal cell carcinoma.

Aim: To evaluate the cost-effectiveness of first-line treatment for advanced renal cell carcinoma with nivolumab plus cabozantinib versus sunitinib from a US payer perspective. Methods: Economic outcomes were estimated with Markov and partitioned survival models. Efficacy, safety and other data were taken from the CheckMate 9ER trial. Costs and utilities were gathered from published sources. Sensitivity analyses addressed model uncertainties. Results: The incremental cost-effectiveness ratio of nivolumab plus cabozantinib versus sunitinib was US$555,663 and $531,748 per quality-adjusted life year in the Markov and partitioned survival models, respectively, exceeding the willingness-to-pay threshold (US$150,000 per quality-adjusted life-year). Sensitivity analyses showed robust outcomes. Conclusion: From a US payer perspective, first-line nivolumab plus cabozantinib for advanced renal cell carcinoma is not cost effective.

Renal cell carcinoma (RCC) is a common cancer in the USA. Up to 30% of patients with RCC are in an advanced stage of disease at diagnosis. RCC is difficult to cure, with an 11% chance of survival after 5 years for patients with advanced RCC. A recent clinical study showed that nivolumab plus cabozantinib (NC) had a greater benefit in patients with advanced RCC than sunitinib. The US FDA approved NC for advanced RCC, but NC is relatively expensive. This study explored the cost­effectiveness of NC for advanced RCC versus sunitinib for a US payer using two cost­effectiveness models developed based on the results of the aforementioned clinical study. The results showed that to gain an additional year in perfect health, NC costs an average of US$555,663 or $531,748 more versus sunitinib, which is more than a US payer is willing to pay for an additional year in perfect health ($150,000). Therefore, NC for advanced RCC is not cost-effective versus sunitinib for a US payer at current prices.

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.

[177Lu]Lu-DOTA-TATE versus standard of care in adult patients with gastro-enteropancreatic neuroendocrine tumours (GEP-NETs): a cost-consequence analysis from an Italian hospital perspective.

PURPOSE: To assess and compare clinical outcomes and costs, to the Italian healthcare system, of three therapeutic options approved in the management of adult patients with gastro-enteropancreatic neuroendocrine tumours (GEP-NETs). METHODS: We compared the efficacy, safety, and costs of [177Lu]Lu-DOTA-TATE, everolimus (both originator and generic products), and sunitinib in patients with advanced GEP-NETs (NET G1 and G2) that had progressed following treatment with somatostatin analogs (SSAs). A cost-consequence model was developed and validated by a panel of clinical experts from three NET reference centres in Italy. The clinical outcomes included in the model were median progression-free survival and the incidence of grade 3 or 4 adverse events (AEs), as reported in pivotal clinical trials. The costs for acquisition and administration of each treatment, and of managing AEs, were calculated from the perspective of the Italian national health service. Treatment costs per progression-free month were calculated separately for patients with NETs of pancreatic (PanNETs; all three treatments) and gastrointestinal (GI-NETs; [177Lu]Lu-DOTA-TATE and everolimus only) origin. RESULTS: In patients with PanNETs, total costs per progression-free month were €2989 for [177Lu]Lu-DOTA-TATE, €4975 for originator everolimus, €3472 for generic everolimus, and €5337 for sunitinib. In patients with GI-NETs, total costs per progression-free month were €3189 for [177Lu]Lu-DOTA-TATE, €4990 for originator everolimus, and €3483 for generic everolimus. CONCLUSIONS: [177Lu]Lu-DOTA-TATE was associated with lower costs per progression-free month versus relevant treatment options in patients with GI-NETs or PanNETs (NET G1-G2; progressed following SSA treatment), although acquisition and administration costs are higher. These findings provide further economic arguments in the overall context of treatment decision-making.

Temporal trends of adverse events and costs of nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma.

Aims: To assess grade 3/4 adverse events (AEs) and costs of first-line nivolumab plus ipilimumab versus sunitinib in advanced or metastatic renal cell carcinoma. Methods: Individual patient data from the all treated population in the CheckMate 214 trial (nivolumab plus ipilimumab, n = 547; sunitinib, n = 535) were used to calculate the number of AEs. AE unit costs were obtained from US 2017 Healthcare Cost and Utilization Project and inflated to 2020 values. Results: The proportion of patients experiencing grade 3/4 AEs decreased over time. Patients who received nivolumab plus ipilimumab had lower average per-patient all-cause grade 3/4 AE costs versus sunitinib (12-month: US$15,170 vs US$20,342; 42-month: US$19,096 vs US$27,473). Conclusion: Treatment with nivolumab plus ipilimumab was associated with lower grade 3/4 AE costs than sunitinib.

Immunotherapy combinations are now accepted as safe and effective first-line treatment options for advanced or metastatic renal cell carcinoma. This study used patient data from the CheckMate 214 clinical trial to evaluate the temporal trends and costs related to grade 3/4 adverse events (AEs) among patients treated with nivolumab plus ipilimumab versus sunitinib. We found that the proportion of patients experiencing grade 3/4 AEs decreased over time and that patients treated with nivolumab plus ipilimumab had lower AE costs compared with those treated with sunitinib (at 42 months: US$19,096 vs US$27,473 per patient). As such, nivolumab plus ipilimumab may represent a treatment option that may reduce both the clinical and economic burden among patients with advanced or metastatic renal cell carcinoma.

Multiparametric MRI for assessment of early response to neoadjuvant sunitinib in renal cell carcinoma.

PURPOSE: To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI. METHOD: Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival. RESULTS: 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001). CONCLUSIONS: Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS. TRIAL REGISTRATION: EudraCtNo: 2005-004502-82.

Pembrolizumab plus axitinib and nivolumab plus ipilimumab as first-line treatments of advanced intermediate- or poor-risk renal-cell carcinoma: a number needed to treat analysis from the Brazilian private perspective.

BACKGROUND: Considering clinical benefits of new combination therapies for metastatic renal-cell carcinoma (mRCC), this study aims to calculate the number needed to treat (NTT) and the cost of preventing an event (COPE) for pembrolizumab plus axitinib (P + A), and nivolumab plus ipilimumab (N + I) as first-line treatments, from the Brazilian private perspective. METHODS: Overall survival (OS) and progression-free survival (PFS) data for intermediate- and poor-risk groups were obtained from KEYNOTE-426 and CHECKMATE-214 trials for P + A and N + I, respectively, versus sunitinib as mRCC first-line treatment. RESULTS: Considering a 12-month time horizon, 6 patients should be treated with P + A to prevent one death with sunitinib use, resulting in a COPE of 3,773,865 BRL. Using N + I, NNT for 12-month OS rate was 13 compared to sunitinib, with a COPE of 6,357,965 BRL. Regarding PFS data, NNT was also 6 when comparing P + A versus sunitinib, with an estimated COPE of 3,773,865 BRL. Estimated NNT was 20 comparing N + I and sunitinib, resulting in a COPE of 10,172,744 BRL. Cost differences between two treatment options, reached more than 6 million BRL for PFS, and 2 million BRL for OS. CONCLUSION: At the 12-month landmark, P + A suggests better economic scenario versus N + I as first-line mRCC treatment option for intermediate- and poor-risk groups, through an indirect comparison using sunitinib as a common comparator.

Eficacia y seguridad de pazopanib para el tratamiento de pacientes adultos con carcinoma renal de células claras recurrente/metastásico con intolerancia a sunitinib como tratamiento de primera línea / Efficacy and safety of pazopanib for the treatment of adult patients with recurrent/metastatic clear cell renal cell carcinoma intolerant to sunitinib as first-line treatment

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de pazopanib comparado con interferón alfa 2a (IFNα 2a) para el tratamiento de pacientes adultos con carcinoma renal de células claras recurrente/metastásico con intolerancia a sunitinib como tratamiento de primera línea. El carcinoma de células renales (CCR) es el tipo más frecuente de cáncer renal y se origina en el revestimiento de los túbulos del riñón dentro de la corteza renal. Representa un 80-85 % de todos los tumores malignos renales. El CCR de células claras (CCRCC) es el subtipo histológico más frecuente (80 %), generalmente tiene una deleción del cromosoma 3p y surgen del túbulo proximal. Los pacientes con CCRCC metastásico, se encuentran en la etapa más avanzada de la enfermedad y la sobrevida a 5 años es menor al 10 %. Por otro lado, en los pacientes con CCRCC recurrente, la neoplasia puede reaparecer en el riñón o en otras partes del cuerpo incluso años después del tratamiento inicial. Aproximadamente, en el 20-30 % de los pacientes con tumores localizados se produce recurrencia/metástasis luego del tratamiento quirúrgico. El tratamiento de los pacientes con CCRCC recurrente/metastásico es principalmente la terapia sistémica; cuya finalidad es conseguir remisión o impedir la progresión de la enfermedad. La terapia sistémica incluye el tratamiento con medicamentos biológicos (inmunoterapia) y/o inhibidores de puntos de control (IPC) específicos. Los IPC específicos son el IPC del ligando 1 de muerte celular (PD-L1) y el inhibidor del factor de crecimiento endotelial vascular (VEGF, por sus siglas en inglés). Actualmente, la terapia sistémica con interleucina 2 (IL-2) e interferón alfa 2a (IFNα2a) se usa con menos frecuencia. En el contexto de EsSalud, a la fecha, los pacientes con CCRCC recurrente/metastásico tienen a su disposición medicamentos para terapia sistémica tales como sunitinib e IFNα2a. Sunitinib es un inhibidor de los receptores de VEGF y del factor de crecimiento derivado de plaquetas en las células cancerígenas, células endoteliales vasculares y pericitos, inhibiendo la proliferación de células tumorales y el desarrollo de vasos sanguíneos tumorales. Sunitinib tiene autorización de uso en el Perú desde el 2008 y ha sido aprobado por Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) - EsSalud en el 2015 como tratamiento de primera línea en pacientes con CCR metastásico. Sin embargo, algunos pacientes con CCRCC recurrente/metastásico presentan intolerancia a la terapia con sunitinib, por lo que los especialistas de la institución sugieren el uso de pazopanib como opción de tratamiento a fin de lograr el control de la enfermedad. Los especialistas sugieren que pazopanib sería la opción de tratamiento más adecuada en términos de eficacia y seguridad, comparado con IFNα2a (la otra alternativa de tratamiento disponible en EsSalud). METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con el objetivo de identificar la mejor evidencia sobre eficacia y seguridad de pazopanib comparado con IFNα 2a para el tratamiento de pacientes adultos con CCRCC recurrente/metastásico con intolerancia a sunitinib como tratamiento de primera línea. Se utilizaron las bases de datos The Cochrane Library, PubMed, LILACS y el metabuscador TRIP Database, priorizando evidencia proveniente de ensayos clínicos controlados aleatorizados. La búsqueda sistemática se basó en una metodología escalonada, la cual consistió en la búsqueda inicial de estudios secundarios (de tipo revisiones sistemáticas de ensayos clínicos) que respondan a la pregunta PICO, seguido de la búsqueda de estudios primarios (de tipo ensayos clínicos aleatorizados). Asimismo, se realizó una búsqueda manual dentro de las bases de datos pertenecientes a grupos que realizan evaluación de tecnologías sanitarias y guías de práctica clínica (GPC) incluyendo la National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Institute for Clinical and Economic Review (ICER), The Institute for Quality and Efficiency in Healthcare (IQWiG por sus siglas en alemán), Base regional de informes de evaluación de tecnologías en salud de las Américas (BRISA) y páginas web de organizaciones especializadas en el manejo de CCR. Se realizó una búsqueda adicional en la página web de clinicaltrial.gov para poder identificar ensayos clínicos en curso, corroborar los resultados y eventos adversos (EA) reportados en las publicaciones. RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de pazopanib como tratamiento de pacientes adultos con CCRCC recurrente/metastásico con intolerancia a sunitinib como tratamiento de primera línea. La presente sinopsis describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS con o sin metaanálisis o metaanálisis en red y estudios primarios). CONCLUSIONES: Previamente, IETSI aprobó el uso de sunitinib como tratamiento de primera línea para pacientes con CCRCC recurrente/metastásico, concluyendo que sunitinib presenta mayor eficacia y similar perfil seguridad que IFNα2a. Asimismo, evaluó pazopanib vs sunitinib, concluyendo que ambos medicamentos tendrían similar eficacia y seguridad, por lo que teniendo aprobado a sunitinib como medicamento fuera de petitorio, no se aprobó el uso de pazopanib. Actualmente, en el contexto de EsSalud, se tiene la necesidad de una alternativa de tratamiento para aquellos pacientes con intolerancia a sunitinib. Así, considerando que sunitinib es superior a IFNα2a y que pazopanib sería similar a sunitinib, los especialistas consideran a pazopanib como una alternativa de tratamiento para aquellos pacientes con intolerancia a sunitinib. El presente dictamen evaluó la mejor evidencia disponible en torno a la eficacia y seguridad de pazopanib, comparado con IFNα2a, para el tratamiento de pacientes adultos con CCRCC recurrente/metastásico con intolerancia a sunitinib como tratamiento de primera línea. Se identificaron tres GPC elaboradas por NCCN, EUA y ESMO que formularon recomendaciones sobre el tratamiento de pacientes con CCRCC recurrente/metastásico en el contexto de primera línea de tratamiento; una ETS, desarrollada por CADTH, que comparó pazopanib con sunitinib en pacientes CCRCC metastásico en el contexto de primera línea y una RSNWMA. Así, considerando: i) todas las GPC recomiendan el uso de pazopanib, especialmente para aquellos con mejor nivel pronóstico, pero no presentan a IFNα2a como parte de las alternativas de tratamiento, ii) la evidencia procedente de una RSNWMA sugiere que pazopanib tiene mayor eficacia y similar perfil de seguridad que IFNα2a, iii) todas las GPC recomendaron pazopanib y sunitinib (actual primera línea tratamiento disponible en EsSalud) en el mismo grado de recomendación, iv) el antecedente de evaluación de medicamentos para el tratamiento de CCRCC recurrente/metastásico realizados por el IETSI refiere que pazopanib es no inferior a sunitinib en términos de eficacia y seguridad; v) la necesidad de tratamiento para los pacientes con CCRCC recurrente/metastásico e intolerantes a sunitinib y vi) los costos del tratamiento a un año con pazopanib serían similares o incluso menores al costo de la terapia con sunitinib (actual primera línea tratamiento disponible en EsSalud), podemos concluir que pazopanib podría considerarse como una alternativa de tratamiento para el control de los pacientes con CCRCC recurrente/metastásico intolerante a sunitinib. Por lo expuesto, el IETSI aprueba el uso de pazopanib en pacientes con CCRCC recurrente/metastásico con intolerancia a sunitinib, según lo establecido en el Anexo N° 1. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo.

Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.

BACKGROUND: The data from the phase III clinical trial KEYNOTE-426 indicated that pembrolizumab plus axitinib compared with sunitinib could generate clinical benefits in patients with previously untreated advanced renal cell carcinoma (RCC). Given the incremental clinical benefits, we examined the potential cost-effectiveness of pembrolizumab plus axitinib versus sunitinib in the first-line setting for patients with advanced RCC from the U.S. payers' perspective. MATERIALS AND METHODS: Cost and health outcomes were estimated at a willingness-to-pay (WTP) threshold of $100,000 to $150,000 per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were performed by varying potentially modifiable parameters, and additional subgroup analyses were performed as well. RESULTS: Upon our analyses, the total treatment costs in the pembrolizumab plus axitinib and sunitinib groups were $522,796 and $348,424 and the QALYs gained 2.90 and 1.72, respectively. In the base-case analysis, compared with receiving sunitinib, patients with advanced RCC receiving pembrolizumab plus axitinib gained 1.18 more QALYs at an incremental cost-effectiveness ratio of $148,676/QALY. The results of subgroup analyses demonstrated that pembrolizumab plus axitinib was most cost-effective for patients who had one organ with metastasis. CONCLUSION: First-line treatment with pembrolizumab plus axitinib, compared with sunitinib, is a cost-effective strategy when the value of WTP is from $100,000 to $150,000 per QALY in patients with advanced RCC. For patients with one-organ metastasis and those in International Metastatic Renal Cell Carcinoma Database Consortium poor risk group, first-line treatment with pembrolizumab plus axitinib is more cost-effective than others. IMPLICATIONS FOR PRACTICE: This was the first study to examine the cost-effectiveness of pembrolizumab plus axitinib versus sunitinib in advanced renal cell carcinoma (RCC). This study found that first-line treatment with pembrolizumab plus axitinib is a cost-effective strategy when the value of willingness-to-pay is from $100,000 to $150,000 per quality-adjusted life-year in patients with advanced RCC from the U.S. payers' perspective.

Comprehensive geriatric assessment is an independent prognostic factor in older patients with metastatic renal cell cancer treated with first-line Sunitinib or Pazopanib: a single center experience.

BACKGROUND: There is poor data on the prognostic role of Comprehensive Geriatric Assessment (CGA) in older patients with metastatic renal cell carcinoma (mRCC) treated with first line Tyrosine Kinase Inhibitors (TKIs). MATERIALS AND METHODS: We retrospectively reviewed the clinical charts of mRCC patients older than 70 years treated at our Institute with first-line Sunitinib or Pazopanib for at least 6 months. Every patient received a CGA at baseline and was identified as fit, vulnerable or frail according to Balducci's Criteria. We then assessed the impact of CGA category on survival, disease control and tolerability of TKIs. RESULTS: We identified 86 eligible patients. Median age: 74.5 years, 56% males; 45.4% were fit, 37.2% vulnerable and 17.4% frail at CGA. There were no significant differences in the rate of Grade (G)1-2 and G3-4 toxicities, dose reduction rates, PFS and OS between Sunitinib and Pazopanib. Fit, vulnerable and frail patients achieved significantly different median PFS (18.9 vs 11.2 vs 5.1 months; p < 0.001) and OS (35.5 vs 14.6 vs 10.9 months; p < 0.001). Patients categorized as fit had higher chance of receiving a second-line treatment (66.6% vs 28.9% in vulnerable/frail; p = 0.002). The incidence of G3/4 events was significantly lower in the fit subgroup (19% vs 45% in vulnerable/frail; p = 0.0025). CONCLUSIONS: In our retrospective single-center experience, CGA could accurately discriminate patients with higher risk of experiencing G3/4 toxicities, shorter PFS, and lower chance of receiving a second line treatment. CGA strongly impacted on OS, independently from International mRCC Database Consortium (IMDC) classification.