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OBJECTIVE To evaluate the cost-effectiveness of nivolumab combined with ipilimumab in the first-line treatment of unresectable malignant pleural mesothelioma （MPM）. METHODS From the perspective of healthcare system ，a partitioned survival model were developed ，the cost-effectiveness of nivolumab combined with ipilimumab （dual-immunotherapy plan ）versus chemotherapy in the first-line treatment of unresectable MPM by cost-utility analysis. Clinical trial data were collected from CheckMate 743 study. Direct medical cost included drug costs ，disease management cost and cost of treatment of adverse reactions. Costs and utilities were discounted at an annual rate of 5％. The willingness to pay threshold was 3 times of gross domestic product （GDP）per capita in 2021 [242 928 yuan/QALY（quality-adjusted life year ）]. Scenario analysis was used to analyze and compare the two regimens under the scenario of complimentary drug for patients in dual-immunotherapy group. The robustness of the findings was evaluated by one-way sensitivity analysis and probabilistic sensitivity analysis. RESULTS Baseline analysis results showed that total cost of dual-immunotherapy regimen was higher than that of chemotherapy regimen ，and the utility was also better than that of chemotherapy plan ；the incremental cost-effectiveness ratio （ICER）was 417 122.2 yuan/QALY，which was higher than the willingness to pay threshold ；the dual-immunotherapy regimen was not cost-effective compared to the chemotherapy regimen. Under the scenario of complimentary drug ，the cost of dual-immunotherapy was 327 454.5 yuan，ICER was 75 664.1 yuan/QALY，which was lower than the willingness to pay threshold and resulted in a reversal of the baseline analysis. One-way sensitivity analysis showed that under the health states of progression free survival and progressive disease ，utility value and the price of nivolumab had a greater impact on the ICER value. Probabilistic sensitivity analysis showed that the results of baseline analysis were robust. CONCLUSIONS At a 163.com willingness to pay threshold of 3 times of GDP per capita in nivolumab combined with ipilimumab is not cost-effective compared with chemotherapy regimen in the first-line treatment of unresectable MPM. However ，if patients receive complimentary drugs ，the dual-immunotherapy regimen is cost-effective.
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Objective: To perform an analysis over time of the number needed to treat (NNT) and the cost of preventing an event (COPE) for nivolumab + ipilimumab (NIVO+IPI) and pembrolizumab + axitinib (PEMBRO+AXI) as first-line treatments for advanced renal cell carcinoma patients with intermediate or poor-risk, under the Brazilian private healthcare system perspective. Methods: The NNT for overall survival (OS) and progression-free survival (PFS) from 12-month to maximum available follow-up from CheckMate 214 and KEYNOTE-426 studies were used to estimate the COPE. Treatment costs were estimated considering the labeled dosing and median PFS as a proxy for treatment duration. Results: The OS NNT for NIVO+IPI decreased from 12 to 8 and for PEMBRO+AXI increased slightly from 7 to 8 at 12 and 42 months, respectively. For PFS, NNT for NIVO+IPI decreased from 15 to 6, and for PEMBRO+AXI increased from 7 to 10 at 12 and 30 months. The estimated treatment cost is R$ 638,620 for an estimated median of 11.2 months of NIVO+IPI treatment and R$ 966,818 for 13.8 months of PEMBRO+AXI treatment. COPE for OS at 12 and 42 months was R$ 7,663,440 and R$ 5,108,960 with NIVO+IPI and R$ 6,047,417 and R$ 7,734,547 with PEMBRO+AXI. For PFS, COPE at 12 and 30 months was R$ 9,579,300 and R$ 3,831,720 with NIVO+IPI and R$ 6,047,417 and R$ 9,668,184 with PEMBRO+AXI. Conclusions: Treatment with NIVO+IPI results in lower COPE than PEMBRO+AXI from month 18 onwards, driven by lower treatment costs and improved NNT over time with NIVO+IPI
Objetivo: Analisar ao longo do tempo o número necessário a tratar (NNT) e o custo para prevenir um evento (COPE) para nivolumabe + ipilimumabe (NIVO+IPI) e pembrolizumabe + axitinibe (PEMBRO+AXI) na primeira linha de tratamento do carcinoma de células renais avançado com risco intermediário ou alto na perspectiva do sistema suplementar de saúde brasileiro. Métodos: O NNT para sobrevida global (SG) e sobrevida livre de progressão (SLP) para 12 meses até o máximo de tempo de seguimento disponível dos estudos CheckMate 214 e KEYNOTE-426 foi usado para estimar o COPE. Custos de tratamento foram estimados considerando a dosagem em bula e a mediana de SLP como aproximação para duração de tratamento. Resultados: O NNT de SG para NIVO+IPI reduziu de 12 para 8 e para PEMBRO+AXI subiu de 7 para 8 em 12 e 42 meses, respectivamente. Para SLP, NIVO+IPI teve redução de 15 para 6 e para PEMBRO+AXI aumentou de 7 para 10 em 12 e 30 meses. O custo estimado é de R$ 638.620 para mediana de 11,2 meses de tratamento com NIVO+IPI e de R$ 966.818 para 13,8 meses com PEMBRO+AXI. O COPE para SG foi de R$ 7.663.440 e R$ 5.108.960 com NIVO+IPI e de R$ 6.047.417 e R$ 7.734.547 com PEMBRO+AXI para 12 e 42 meses. Para SLP, foi de R$ 9.579.300 e R$ 3.831.720 com NIVO+IPI e de R$ 6.047.417 e R$ 9.668.184 com PEMBRO+AXI em 12 e 30 meses. Conclusões: O tratamento com NIVO+IPI resulta em menor COPE, em comparação com PEMBRO+AXI, a partir de 18 meses de seguimento, justificado por menor custo de tratamento e melhora do NNT ao longo do tempo com NIVO+IPI
Subject(s)
Carcinoma, Renal Cell , Health Care Costs , Costs and Cost Analysis , Nivolumab , AxitinibABSTRACT
@#We report a rare case of isolated giant cell arteritis caused by combined immunotherapy with nivolumab and ipilimumab in metastatic pleural mesothelioma. Whilst combination immunotherapy is thought to provide synergistic anti-tumor effects in metastatic malignancies, it has also been associated with an increased frequency of severe immune-related adverse effects. To our knowledge, giant cell arteritis has been described in only four previous cases in relation to single agent immunotherapy, and our patient is the first reported case of isolated giant cell arteritis from combination immunotherapy. This report adds to the literature a rare case of an important adverse effect that clinicians should be aware of, especially with increasing use of combination immunotherapy
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@# Objective: To study the effect of ipilimumab on T lymphocytes and Bcl-2 mRNA expression in lung cancer-bearing mice by inhibiting TGF-β1/ERK signaling pathway. Methods: Forty-five C57 mices inoculated with Lewis lung cancer cells were randomly divided into control group, low dose ipilimumab group and high dose ipilimumab group with 15 mice in each. The low and high dose groups were given 3 mg/kg and 5 mg/kg ipilimumab respectively, while the control group was given 0.9% sodium chloride solution with the same volume. The effects of ipilimumab on TGF-β1/ERK signaling pathway, Bcl-2 mRNA expression, immune function improvement and tumor inhibition in three groups were detected by WB and qPCR. Results: After administration of ipilimumab, the tumor weight and volume of mice in low-dose and high-dose groups were significantly lower than that of the control group, and the tumor inhibition rate increased in a dose-dependent manner (P<0.05). The thymus index and spleen index of mice were significantly higher than that of control group, which also increased in a dose-dependent manner (P<0.05). The levels of CD3+, CD4+, CD4+/CD8+ cells in the high and low dose groups were significantly higher than those in the control group, with significantly higher levels in high dose group compared with the low dose group (P<0.05). The levels of serum inflammatory factors were significantly lower than those in control group, and the levels of serum TNF-α, IL-6 and IL-3 in the high dose group were significantly lower than those in the low dose group (P<0.05). The expressions of TGF-β1, ERK1/2, p-ERK1/2 and MEK in tumor tissues of both high and low dose groups significantly decreased, with more lower levels in high dose group than in low dose groups (all P<0.05), and the positive rate of TGF-β1 expression in high dose group was the lowest. The mRNAexpression of Bcl-2 in tumor tissues of high and low dose groups decreased significantly after drug administration, with a significantly lower level in high does group than that in low dose group (P<0.05). Conclusion: Ipilimumab can effectively inhibit TGF-β1/ERK signaling pathway, improve immune function and down-regulate the expression of Bcl-2, thus inhibit the growth of Lewis lung cancer cells and play an antitumor role in mice.
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PURPOSE: Ipilimumab improves survival in advanced melanoma patients. However, the efficacy and safety of ipilimumab has not been evaluated in Asian melanoma patients with a high frequency of mucosal and acral melanoma subtypes. MATERIALS AND METHODS: Advanced melanoma patients treated with 3 mg/kg ipilimumab in a Korean multicenter named-patient program (NPP) were evaluated between September 2014 and July 2015. Baseline characteristics and blood parameters including neutrophil to lymphocyte ratio (NLR) were assessed, and outcome and adverse events were evaluated according to subtypes. RESULTS: A total of 104 advanced melanoma patients were treated. The primary sites were acral (31.7%), mucosal (26%), cutaneous (26%), uveal (9.6%), and unknown (6.7%). Sixty-eight patients (65.4%) experienced adverse events, and the most common toxicity was skin rash (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher. The median progression-free survival (PFS) was 2.73 months (95% confidence interval, 2.67 to 2.85), and there was no difference in PFS according to subtypes. Poor performance status, liver metastasis, and NLR (≥ 5) were independent poor prognostic factors by multivariate analysis. CONCLUSION: In the Korean NPP cohort, ipilimumab showed similar efficacy and tolerability compared to Western patients, regardless of subtypes. All subtypes should benefit from ipilimumab with consideration of performance status, liver metastasis, and NLR.
Subject(s)
Humans , Asian People , Biomarkers , Cohort Studies , Disease-Free Survival , Exanthema , Immunotherapy , Liver , Lymphocytes , Melanoma , Multivariate Analysis , Neoplasm Metastasis , NeutrophilsABSTRACT
Background and purpose:Checkpiont targeted immunotherapy in the field of solid tumor therapy has huge potential, triggering a boom in the study of immune targeted drugs. A study has provided a basis for the follow-up study of ipilimumab combined with chemotherapy in the treatment of non-small cell lung cancer(NSCLC) patients. This study counted the adverse event statistics that ipilimumab or placebo combined with paclitaxel and carboplatin as first-line therapy for the treatment of stage Ⅳ or recurrent squamous cell carcinoma to evaluate the safety of ipilimumab combined with chemotherapy in the treatment of advanced squamous cell carcinoma.Methods:This study selected 13 patients with ECOG scores≤1 and stage ⅣA or ⅣB squamous cell carcinoma in the Shanghai Chest Hospital, Shanghai Jiao Tong Uni-versity. Randomized controlled double blind trial was used in this study. The patients of experimental group were treated with ipilimumab combined with paclitaxel and carboplatin, while the patients of control group were treated with the placebo combined with paclitaxel and carboplatin. Adverse events (AEs) were counted in the process of treatment.Results:The most common AEs were the 1/2 grade AEs. Immune-related AEs (irAEs) reported in the ipilimumab group included level Ⅰ of diarrhea and pruritus, level Ⅱ of rash and pruritus and level Ⅲ of hypophysitis.Conclusion:The side effects of ipilimumab were mild, tolerable and manageable.
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Ion-pairing high-performance liquid chromatography–ultraviolet (HPLC–UV) methods were developed to determine two commonly used chelating agents, ethylenediaminetetraacetic acid (EDTA) in Abilifys (a small molecule drug with aripiprazole as the active pharmaceutical ingredient) oral solution and die-thylenetriaminepentaacetic acid (DTPA) in Yervoys (a monoclonal antibody drug with ipilimumab as the active pharmaceutical ingredient) intravenous formulation. Since the analytes, EDTA and DTPA, do not contain chromophores, transition metal ions (Cu2 t , Fe3 t ) which generate highly stable metallocom-plexes with the chelating agents were added into the sample preparation to enhance UV detection. The use of metallocomplexes with ion-pairing chromatography provides the ability to achieve the desired sensitivity and selectivity in the development of the method. Specifically, the sample preparation in-volving metallocomplex formation allowed sensitive UV detection. Copper was utilized for the de-termination of EDTA and iron was utilized for the determination of DTPA. In the case of EDTA, a gradient mobile phase separated the components of the formulation from the analyte. In the method for DTPA, the active drug substance, ipilimumab, was eluted in the void. In addition, the optimization of the concentration of the ion-pairing reagent was discussed as a means of enhancing the retention of the aminopolycarboxylic acids (APCAs) including EDTA and DTPA and the specificity of the method. The analytical method development was designed based on the chromatographic properties of the analytes, the nature of the sample matrix and the intended purpose of the method. Validation data were presented for the two methods. Finally, both methods were successfully utilized in determining the fate of the chelates.
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Although early stage melanoma can be cured by complete resection, the prognosis of the patients with unresectable or metastatic disease is dismal with the overall survival less than 1 year based on resistance to chemotherapeutic agents. Dacarbazine as either a single agent or in combination regimens with other cytotoxic agents has still remained as a standard in Korea for more than three decades although it has not been associated with any survival benefit for metastatic melanoma. Recently, according to advances in molecular science and immunology, the mechanisms responsible for biology of melanoma have been elucidated and then new agents targeting these mechanisms have been introduced leading survival benefit in patients with metastatic melanoma. Unfortunately, however, it is still difficult to give those new drugs to these patients in Korea because of the health insurance guidelines still defining dacarbazine as a front line regimen and moreover high cost and unavailability in the practice. Therefore, amendment of current guidelines and an in-depth discussion with the government for the earlier use of the novel drugs are strongly needed for the patients' sake.
Subject(s)
Humans , Antibodies, Monoclonal , Biology , Cytotoxins , Dacarbazine , Indoles , Insurance, Health , Korea , Melanoma , Prognosis , SulfonamidesABSTRACT
Although early stage melanoma can be cured by complete resection, the prognosis of the patients with unresectable or metastatic disease is dismal with the overall survival less than 1 year based on resistance to chemotherapeutic agents. Dacarbazine as either a single agent or in combination regimens with other cytotoxic agents has still remained as a standard in Korea for more than three decades although it has not been associated with any survival benefit for metastatic melanoma. Recently, according to advances in molecular science and immunology, the mechanisms responsible for biology of melanoma have been elucidated and then new agents targeting these mechanisms have been introduced leading survival benefit in patients with metastatic melanoma. Unfortunately, however, it is still difficult to give those new drugs to these patients in Korea because of the health insurance guidelines still defining dacarbazine as a front line regimen and moreover high cost and unavailability in the practice. Therefore, amendment of current guidelines and an in-depth discussion with the government for the earlier use of the novel drugs are strongly needed for the patients' sake.