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.

Assessment of the safety of nivolumab in people living with HIV with advanced cancer on antiretroviral therapy: the AIDS Malignancy Consortium 095 Study.

BACKGROUND: Although immunotherapy has emerged as a therapeutic strategy for many cancers, there are limited studies establishing the safety and efficacy in people living with HIV (PLWH) and cancer. METHODS: PLWH and solid tumors or Kaposi sarcoma (KS) receiving antiretroviral therapy and a suppressed HIV viral load received nivolumab at 3 mg/kg every 2 weeks, in two dose deescalation cohorts stratified by CD4 count (stratum 1: CD4 count > 200/µL and stratum 2: CD4 count 100-199/µL). An expansion cohort of 24 participants with a CD4 count > 200/µL was then enrolled. RESULTS: A total of 36 PLWH received nivolumab, including 15 with KS and 21 with a variety of other solid tumors. None of the first 12 participants had dose-limiting toxicity in both CD4 strata, and five patients (14%) overall had grade 3 or higher immune related adverse events. Objective partial response occurred in nine PLWH and cancer (25%), including in six of 15 with KS (40%; 95% CI, 16.3-64.7). The median duration of response was 9.0 months overall and 12.5 months in KS. Responses were observed regardless of PDL1 expression. There were no significant changes in CD4 count or HIV viral load. CONCLUSIONS: Nivolumab has a safety profile in PLWH similar to HIV-negative subjects with cancer, and also efficacy in KS. Plasma HIV remained suppressed and CD4 counts remained stable during treatment and antiretroviral therapy, indicating no adverse impact on immune function. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02408861.

Cost-effectiveness analysis of nivolumab-chemotherapy as first-line therapy for locally advanced/metastatic gastric cancer: a United States payer perspective.

OBJECTIVES: Nivolumab, an immune checkpoint inhibitor, was approved by the United States (US) Food and Drug administration as a first-line systemic therapy for locally advanced/metastatic gastric cancer patients. The current study aimed to investigate the cost-effectiveness of nivolumab-chemotherapy combination versus chemotherapy alone as a first-line therapy from a US payer perspective. METHODS: An economic evaluation was conducted using a partitioned survival model in Microsoft Excel® using data from the CheckMate 649 trial. Three discrete mutually exclusive health states (progression-free, post-progression, and death) were included in the model. The health state occupancy was calculated using the overall survival and progression-free survival curves derived from the CheckMate 649 trial. Cost, resource use, and health utility estimates were estimated from a US payer perspective. Deterministic and probabilistic sensitivity analyses assessed the uncertainty of the model parameters. RESULTS: Nivolumab-chemotherapy provided additional 0.25 life years compared to chemotherapy alone and the quality-adjusted life years (QALYs) were 0.701 and 0.561, respectively, producing a gain of 0.140 QALYs and an incremental cost-effectiveness ratio of $574,072/QALY. CONCLUSION: From the US payer perspective, at a willingness to pay threshold of $US150,000/QALY, nivolumab-chemotherapy was not found to be cost-effective as a first-line therapy for locally advanced/metastatic gastric cancer.

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.

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.

Early Response Assessment in Advanced Stage Melanoma Treated with Combination Ipilimumab/Nivolumab.

Background: Standard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma followed by nivolumab single-agent maintenance therapy. While many patients receive less than 4 doses due to immune-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and assess if fewer doses of I/N can lead to similar survival outcomes. Methods: We performed a retrospective analysis on a cohort of patients with advanced melanoma who w0ere treated with standard I/N. Cox regression of progression-free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 1 or 2 vs 3 or 4 doses of I/N adjusted by known prognostic variables in advanced melanoma. Results: 199 patients were evaluated. Patients with CBR after 1 dose of I/N had improved PFS (HR: 0.16, 95% CI 0.08-0.33; p<0.001) and OS (HR: 0.12, 0.05-0.32; p<0.001) compared to progressive disease (PD). Patients with CBR (vs PD) after 2 doses of I/N also had improved PFS (HR: 0.09, 0.05-0.16; p<0.001) and OS (HR: 0.07, 0.03-0.14; p<0.001). There was no survival risk difference comparing 1 or 2 vs 3 or 4 doses of I/N for PFS (HR: 0.95, 0.37-2.48; p=0.921) and OS (HR: 1.04, 0.22-4.78; p=0.965). Conclusions: Early interval imaging with response during induction with I/N may be predictive of long-term survival in advanced stage melanoma. CBR after 1 or 2 doses of I/N is associated with favorable survival outcomes, even in the setting of fewer I/N doses received. Further studies are warranted to evaluate if electively administering fewer combination I/N doses despite tolerance in select patients may balance the benefits of therapy while decreasing toxicities.

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.

Assessment of hyperprogression versus the natural course of disease development with nivolumab with or without ipilimumab versus placebo in phase III, randomized, controlled trials.

BACKGROUND: Retrospective studies have suggested a potential risk of hyperprogressive disease (HPD) in patients receiving immune checkpoint inhibitors (ICIs). We compared the incidence of HPD during treatment with nivolumab±ipilimumab versus natural tumor progression with placebo in post hoc analyses of two randomized, double-blind clinical trials. METHODS: ATTRACTION-2 randomized patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC) and progression on ≥2 prior regimens to nivolumab 3 mg/kg Q2W or placebo. CheckMate 451 randomized patients with extensive-disease small cell lung cancer (ED SCLC) and ongoing complete/partial response or stable disease after first-line chemotherapy to nivolumab 240 mg Q2W, nivolumab 1 mg/kg+ipilimumab 3 mg/kg Q3W for four doses then nivolumab 240 mg Q2W, or placebo. Patients receiving ≥1 dose of study drug and with tumor scans at baseline and the first on-treatment evaluation were included in the HPD analyses. HPD definitions were ≥20%, ≥50%, and ≥100% increase in target lesion sum of the longest diameters (SLD) at the first on-treatment assessment. RESULTS: In the ATTRACTION-2 HPD-evaluable population, 243 patients received nivolumab and 115 placebo. Fewer patients receiving nivolumab versus placebo had increases in SLD ≥20% (33.7% vs 46.1%) and ≥50% (6.2% vs 11.3%); similar proportions had increases in SLD ≥100% (1.6% vs 1.7%). In the CheckMate 451 HPD-evaluable population, 177 patients received nivolumab, 179 nivolumab+ipilimumab, and 175 placebo. Fewer patients receiving nivolumab or nivolumab+ipilimumab versus placebo had increases in SLD ≥20% (27.1%, 27.4% vs 45.7%), ≥50% (10.2%, 11.2% vs 22.3%), and ≥100% (2.8%, 2.8% vs 6.3%). CONCLUSIONS: Nivolumab±ipilimumab was not associated with an increased rate of progression versus placebo in patients with GC, GEJC, or ED SCLC, suggesting that previous reports of HPD may reflect the natural disease course in some patients rather than ICI-mediated progression. TRIAL REGISTRATION NUMBER: NCT02538666; NCT02267343.

Efficacy of a Flat Low Dose of Nivolumab in Advanced Cancer: A Retrospective Case Series.

BACKGROUND/AIM: Immunotherapy with PD-1/PDL1 blocking monoclonal antibodies has improved survival compared to the standard-of-care chemotherapy for several malignancies at different stages of these malignancies. Due to several reasons, many cancer patients in medical need have no access to these drugs. In this study, we aimed to investigate whether a low dose of nivolumab could also lead to a therapeutic response. PATIENTS AND METHODS: Patients with advanced cancer were treated with a flat low dose of 10 mg of nivolumab IV every two weeks at no drug cost. RESULTS: Disease control was noted in nine of the 18 patients. Two patients achieved complete remission, two had prolonged partial remission, and five had stable disease, of these only two experienced adverse events. CONCLUSION: A flat low dose of nivolumab may have clinical activity and is a cheap therapeutic option in patients in medical need for whom standard-dose immune checkpoint inhibitors are not accessible for any reason.

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.

Adverse events during immunotherapy in Slovenian patients with metastatic melanoma reveal a positive correlation with better treatment outcomes.

BACKGROUND: Immunotherapy with CTLA-4 inhibitors and PD1 checkpoint inhibitors has initiated a breakthrough in the treatment and prognosis of patients with metastatic melanoma. The survival of these patients has increased from the expected survival time of less than 12 months to at least forty months. However, immunotherapy with either anti-CTLA-4 antibodies or PD1 inhibitors alone or in combination has a broad palette of significant immune-related adverse events. The aim of the study was to assess the correlation of immune-related adverse events with treatment outcomes defined as significant differences in the overall response rate (ORR) and progression-free survival (PFS) of patients, who developed immune-related adverse events during immunotherapy. PATIENTS AND METHODS: A retrospective analysis of patients with metastatic melanoma treated with immunotherapy in 2020 at the Oncology Institute of Ljubljana was performed. Only patients with radiological evaluation of the immunotherapy response were included. The patients were divided into two cohorts: a cohort of patients with immune-related adverse events (irAE group) and a cohort of patients with no immune-related adverse events (NirAE group). Significantly better overall response and progression-free survival in the irAE cohort defined the primary aim of our study. To investigate the differences in progression-free survival between the irAE cohort and NirAE cohort, we used survival analysis. In particular, a Cox proportional hazards model with covariates of time to progression and adverse events was used for survival analysis. The Kruskal-Wallis H-test was applied, and a p-value of p <= 0.05 was considered the cut-off point for a statistically significant difference between the groups. RESULTS: Among the 120 patients treated with immunotherapy, radiological response evaluation was performed for 99 patients: 38 patients in the irAE cohort and 61 patients in the NirAE cohort. The ORRs for the irAE and NirAE cohorts were 57% and 37%, respectively. The PFS was significantly better for the irAE cohort (301.6 days) than for the NirAE cohort (247.29 days). The results of the survival regression analysis showed a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort. CONCLUSIONS: Patients with metastatic melanoma treated with immunotherapy who developed immune-related adverse events showed better treatment outcomes with longer times to disease progression and better overall response rates than patients treated with immunotherapy who did not develop immune-related adverse events, with a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.

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

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

Clinical Benefit-Risk Assessment of Nivolumab 240 mg Every 2 Weeks in Chinese Patients With Advanced and Metastatic Solid Tumors.

Nivolumab 240 mg every 2 weeks is approved in China by the National Medical Product Agency for squamous cell carcinoma of the head and neck and gastric cancer, based on population pharmacokinetic (PPK) analyses and benefit-risk assessment of safety/efficacy in solid tumors, including Chinese and global populations. The aim of this assessment was to investigate exposure and risk for adverse events (AEs) with flat dosing compared with weight-based dosing. Nivolumab 240-mg and 3-mg/kg every-2-week exposures in Chinese patients were simulated using PPK modeling, and AEs in Chinese and pooled global populations were compared by dosing regimen, exposure, and weight. The 10-mg/kg every-2-week regimen was included because it is known to be well tolerated. Predicted nivolumab exposure in Chinese patients receiving 240 mg every 2 weeks was ∼25% higher versus 3 mg/kg every 2 weeks, but ∼60% lower versus 10 mg/kg every 2 weeks. Grade 3/4 AE incidence in Chinese patients receiving nivolumab 3 mg/kg every 2 weeks was similar with 240-mg every-2-week dosing and with patients from global populations treated with 3 or 10 mg/kg every 2 weeks. There was no trend toward increased AE incidence with high versus low nivolumab exposure or in global patients of varying body weight receiving 3 or 10 mg/kg every 2 weeks. Objective response rates were similar in Chinese and global patients with squamous and nonsquamous NSCLC. Results showed that benefit-risk profiles with nivolumab 240 mg every 2 weeks were similar to those of the 3-mg/kg every-2-week regimen in Chinese patients and global populations, providing an alternative treatment option to Chinese patients.

Eficacia y seguridad de cobimetinib más vemurafenib para el tratamiento de pacientes adultos con melanoma metastásico no resecable con progresión a nivolumab y quimioterapia con mutación BRAF V600E / Efficacy and safety of cobimetinib plus vemurafenib for the treatment of adult patients with unresectable metastatic melanoma with progression to nivolumab and chemotherapy with BRAF V600E mutation

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad del cobimetinib más vemurafenib, comparado con quimioterapia, para el tratamiento de pacientes adultos con melanoma metastásico no resecable con progresión a nivolumab y quimioterapia con mutación BRAF V600E. El melanoma es un tumor maligno que afecta a los melanocitos y es característicamente agresivo. La mayoría de los melanomas se localizan en la piel (95 %) y con menos frecuencia (5 %) en mucosas (oral, tubo digestivo, genital), retina o meninges. Alrededor de 50 % de los casos recién diagnosticados se presentan en pacientes de 35 a 65 años de edad. En el 2018, a nivel mundial se estimó que la tasa de incidencia estandarizada por edad fue de 3.1 casos por cada 100,000 habitantes en tanto que para el Perú la tasa de incidencia estandarizada por edad estimada fue de 2.7 casos por cada 100,000 habitantes, reportándose 321 casos nuevos en hombres y 317 casos nuevos en mujeres. Los estadios clínicos de la enfermedad describen cuatro etapas en el desarrollo de melanoma, siendo la última etapa, IV, que describe la presencia de metástasis a distancia "M1". La clasificación genómica, de acuerdo a las mutaciones más frecuentes definen cuatro grupos según la presencia o ausencia de mutaciones en los genes principales BRAF, RAS y NF1. Por su parte, la mutación BRAF es la más frecuentemente encontrada reportándose en cerca del 50 % de los melanomas cutáneos. El esquema de tratamiento empleado dependerá de la etapa en la que se encuentre el paciente al momento del diagnóstico según la clasificación clínica y genómica. El melanoma es un tumor maligno que afecta a los melanocitos y es característicamente agresivo. La mayoría de los melanomas se localizan en la piel (95 %) y con menos frecuencia (5 %) en mucosas (oral, tubo digestivo, genital), retina o meninges. Alrededor de 50 % de los casos recién diagnosticados se presentan en pacientes de 35 a 65 años de edad. En el 2018, a nivel mundial se estimó que la tasa de incidencia estandarizada por edad fue de 3.1 casos por cada 100,000 habitantes en tanto que para el Perú la tasa de incidencia estandarizada por edad estimada fue de 2.7 casos por cada 100,000 habitantes, reportándose 321 casos nuevos en hombres y 317 casos nuevos en mujeres. Los estadios clínicos de la enfermedad describen cuatro etapas en el desarrollo de melanoma, siendo la última etapa, IV, que describe la presencia de metástasis a distancia "M1". La clasificación genómica, de acuerdo a las mutaciones más frecuentes definen cuatro grupos según la presencia o ausencia de mutaciones en los genes principales BRAF, RAS y NF1. Por su parte, la mutación BRAF es la más frecuentemente encontrada reportándose en cerca del 50 % de los melanomas cutáneos. El esquema de tratamiento empleado dependerá de la etapa en la que se encuentre el paciente al momento del diagnóstico según la clasificación clínica y genómica. En el contexto de EsSalud, los pacientes diagnosticados con melanoma metastásico disponen de opciones terapéuticas como nivolumab o quimioterapia (dacarbazina, entre otros agentes citotóxicos). No obstante, en algunos pacientes, la neoplasia persiste y crece (a pesar de recibir el tratamiento correspondiente) y presentan además la mutación BRAF V600E, para los cuales no habría un tratamiento específico disponible más allá de la quimioterapia o mejor terapia de soporte. Es por ello, que los médicos especialistas de la institución sugieren el uso de cobimetinib más vemurafenib para el tratamiento dirigido a este tipo de mutación en pacientes con melanoma metastásico que progresan a quimioterapia y nivolumab. METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con el objetivo de identificar la mejor evidencia sobre eficacia y seguridad del cobimetinib más vemurafenib, comparado con quimioterapia, para el tratamiento de pacientes adultos con melanoma metastásico no resecable con progresión a nivolumab y quimioterapia con mutación BRAF V600E. Se utilizaron las bases de datos The Cochrane Library, PubMed, LILACS y el metabuscador TRIP Database. Priorizando evidencia proveniente de ensayos clínicos controlados aleatorizados (ECA). 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 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 melanoma. 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 reportados en las publicaciones y de este modo disminuir el sesgo de publicación. La búsqueda sistemática se basó en una metodología escalonada, la cual consistió en la búsqueda inicial de estudios secundarios (del tipo revisiones sistemáticas de ensayos clínicos) que respondan a la pregunta PICO, seguido de la búsqueda de estudios primarios (del tipo ensayos clínicos aleatorizados). RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de cobimetinib más vemurafenib comparado con quimioterapia como tratamiento de pacientes adultos con melanoma metastásico no resecable con progresión a nivolumab y quimioterapia con mutación BRAF V600E. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). CONCLUSIONES: El presente dictamen preliminar tuvo como objetivo evaluar la evidencia disponible en relación a la eficacia y seguridad del cobimetinib más vemurafenib, comparado con quimioterapia, para el tratamiento de pacientes adultos con melanoma metastásico no resecable con progresión a nivolumab y quimioterapia con mutación BRAF V600E. Luego de la búsqueda sistemática de la literatura no se encontraron estudios de tipo ensayo clínicos aleatorizados, o revisiones sistemáticas que respondieran a la pregunta PICO de interés. Sin embargo, se identificaron tres GPC y tres ETS. La GPC de NCCN recomienda de manera explícita el uso de cobimetinib más vemurafenib para los pacientes con melanoma metastásico no resecable con mutación BRAF que progresaron a nivolumab. No obstante emplea evidencia que no corresponde con la población para dicha recomendación, debido a que el estudio de respaldo evalúa a pacientes que no han recibido tratamiento previo, es decir, lo utilizaron como primera línea de tratamiento. Por su parte, la guía de ESMO, si bien recomienda de manera general el uso de medicamentos anti-BRAF/MEK para pacientes que progresen a inmunoterapia, la bibliografía empleada para dicha recomendación no hace referencia al uso de cobimetinib más vemurafenib, sino a otros medicamentos. Por otro lado, la guía de SIGN no recomienda el uso de esta tecnología dentro de las opciones terapéuticas, no obstante, recomienda fuertemente la terapia paliativa para estos pacientes. En relación a la ETS de NICE, esta no recomendó el uso de cobimetinib más vemurafenib para nuestra población de interés, para ello utilizó evidencia procedente del estudio CoBRIM (resultados obtenidos de una población distinta y que se generalizaron para esta población) así como el análisis de costo efectividad que mostró que la intervención no era costo-efectiva para el sistema sanitario de Inglaterra. La ETS de CADTH, que correspondió a una revisión rápida para responder a una pregunta de investigación similar a la planteada en la pregunta PICO del presente dictamen, encontró solo tres estudios del tipo análisis retrospectivo, de baja calidad, que no brindaron información referente a uso de cobimetinib más vemurafenib, sino a otros inhibidores de BRAF. La ETS de pCODR, no recomienda el uso de cobimetinib más vemurafenib debido a que no existe evidencia suficiente que respalde el uso de esta tecnología en nuestra población de interés. En resumen, no se encontró evidencia que responda a la pregunta PICO para el presente dictamen, en ese sentido existe incertidumbre sobre el balance riesgo beneficio de cobimetinib más vemurafenib comparado con quimioterapia en la población de interés. En consecuencia, se necesitan estudios comparativos para poder determinar si el esquema cobimetinib más vemurafenib es más eficaz y seguro que la quimioterapia disponible actualmente en EsSalud. Por lo expuesto, el IETSI no aprueba el uso de cobimetinib más vemurafenib para el tratamiento de pacientes con melanoma metastásico no resecable con progresión a nivolumab y quimioterapia.

Cost-effectiveness analysis of nivolumab in the second-line treatment for advanced esophageal squamous cell carcinoma.

Background: To investigate the cost-effectiveness of nivolumab versus chemotherapy in the second-line treatment for advanced esophageal squamous cell carcinoma. Materials & methods: A Markov model reflecting the patients in the ATTRACTION-3 trial was established. Weibull survival model was employed to fit the Kaplan-Meier progression-free survival and overall survival probabilities of the nivolumab and chemotherapy strategy, respectively. Meanwhile, one-way and PSA were performed to test the uncertainty in the model. Results: Overall, the incremental effectiveness and cost of nivolumab versus chemotherapy were 0.107 quality-adjusted life-years and $14,627.90, resulting in an incremental cost-effectiveness ratio of $136,709.35/quality-adjusted life-year. Conclusion: Nivolumab is not a cost-effective treatment option compared with chemotherapy from the perspective of Chinese society.

Immune checkpoint inhibitors of the PD-1/PD-L1-axis in non-small cell lung cancer: promise, controversies and ambiguities in the novel treatment paradigm.

Immune checkpoint inhibitors (ICIs) have received much attention not least for melanoma since the award of the Nobel prize in 2018. Here, we review the current state of knowledge about the use of these monoclonal antibodies (mAbs) in non-small cell lung cancer (NSCLC). These drugs have generally been conditionally approved on limited early data and there are few long-term follow-up data from randomized clinical trials. The effect observed for NSCLC thus far is, on average, moderately better than that obtained with chemotherapy. Severe side-effects are more common than might have been expected. The drugs themselves are expensive and are associated with time-consuming histopathologic testing even though the predictive value of these tests can be discussed. In addition, monitoring for side-effects involves increased workload and budgetary expense for clinical chemistry laboratories. Here, we review and summarize the current knowledge, controversies and ambiguities of ICIs for the treatment of NSCLC.

Cost-effectiveness analysis of nivolumab for the treatment of squamous cell carcinoma of the head and neck in the United States.

Aim: To assess the cost-effectiveness of nivolumab monotherapy for recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) in the US.Methods: We constructed a cohort-based partitioned survival model for three health states (progression-free, progressed disease, and death). Using overall survival and progression-free survival data from the nivolumab and investigator's choice (IC) arms of the CheckMate 141 study, the proportion of patients in each health state was estimated by parametric modeling over a 25-year period. Cost, utility, adverse event, and disease management data inputs were obtained from relevant literature and applied to patients in each health state. A scenario analysis was conducted assuming increased uptake of subsequent immunotherapies. A one-way deterministic sensitivity analysis assessed the impact of variation in multiple parameters. A probabilistic sensitivity analysis in which probabilistic distributions were applied to each input during 1,000 model iterations was also conducted.Results: Total costs incurred were higher with nivolumab ($101,552) than with IC ($38,067). Nivolumab was associated with a higher number of life-years (LY; 1.21) and quality-adjusted life-years (QALYs; 0.89), compared with IC (0.68 and 0.42, respectively). The incremental cost-effectiveness ratio for nivolumab compared with IC was $134,438 per QALY, and this remained qualitatively similar when increased uptake of subsequent immunotherapies was assumed ($129,603 per QALY). Sensitivity analyses supported these findings.Conclusions: These results suggest that, at a willingness-to-pay threshold of $150,000 per QALY, nivolumab is a cost-effective option for therapy of SCCHN in the US.

Benefit-risk assessment of nivolumab 240 mg flat dose relative to 3 mg/kg Q2W regimen in Japanese patients with advanced cancers.

Nivolumab 3 mg/kg every 2 weeks (Q2W) has been approved in Japan for various cancers; however, use of a flat dose is expected to simplify dosing and administration. A quantitative clinical pharmacology approach was used to assess the benefit-risk profile of nivolumab 240 mg Q2W relative to the approved dose of nivolumab 3 mg/kg Q2W in Japanese patients. Three exposure-response safety analyses were performed for adverse events that led to discontinuation/death, were grade 3 or higher, and were immune-mediated and grade 2 or higher for Japanese patients diagnosed with one of multiple tumor types. Exposure-response analyses of efficacy were evaluated for overall survival and objective response rate. Exposures of nivolumab 240 mg Q2W were 37% higher than those of nivolumab 3 mg/kg Q2W in Japanese patients across the tumor types analyzed. Predicted safety profiles at the two doses differed by less than 2% across tumor types for adverse events leading to discontinuation/death, adverse events of grade 3 or higher, or immune-mediated adverse events of grade 2 or higher. In addition, the predicted 1-year and 2-year overall survival rates, the mean overall survival and the objective response rates were comparable between the doses regardless of the tumor type analyzed. Overall, these results demonstrated that the benefit-risk of nivolumab 240 mg Q2W was comparable to that of the previously approved 3 mg/kg Q2W dosing regimen, and was the basis for the approval of the 240 mg Q2W as an alternative dosing regimen for treatment in Japanese patients across multiple tumor types.

Assessment of Combined Nivolumab and Bevacizumab in Relapsed Ovarian Cancer: A Phase 2 Clinical Trial.

Importance: To date, single-agent programmed cell death 1 protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint blockade has shown limited activity in recurrent epithelial ovarian cancer. Combination strategies of PD-1/PD-L1 inhibition with antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment and represent a potential therapeutic opportunity in this disease. Objective: To evaluate the activity of combined nivolumab and bevacizumab in women with relapsed ovarian cancer. Design, Setting, and Participants: A single-arm, phase 2 study enrolled patients between February 8, 2017, and December 29, 2017, at 2 sites in the United States; the primary data analysis was completed July 27, 2018. Thirty-eight women with relapsed epithelial ovarian cancer were enrolled in this study. Participants had disease recurrence within 12 months of their last platinum-based therapy and had received between 1 and 3 lines of prior therapy. Interventions: Participants received intravenous nivolumab and intravenous bevacizumab once every 2 weeks. Main Outcome and Measures: The primary end point was objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors 1.1. Secondary end points included evaluation of the ORR by platinum sensitivity, assessment of progression-free survival, assessment of safety data, and investigation of the association of tumor PD-L1 with response to therapy. Results: Of the 38 women enrolled, 18 had platinum-resistant and 20 had platinum-sensitive disease; mean (SD) age was 63.0 (9.1) years. Eleven patients experienced a confirmed response to nivolumab with bevacizumab (ORR, 28.9%; 95% exact binomial CI, 15.4%-45.9%), with 1 additional unconfirmed response. The ORR was 40.0% (19.1%-64.0%) in platinum-sensitive and 16.7% (95% CI 3.6%-41.4%) in platinum-resistant participants. Thirty-four participants (89.5%) experienced at least 1 treatment-related adverse event; 9 participants (23.7%) experienced a grade 3 or higher treatment-related adverse event. Median progression-free survival was 8.1 months (95% CI, 6.3-14.7 months). In 36 histologic samples for which PD-L1 testing could be performed, 22 samples (61.1%) had a PD-L1 tumoral percentage less than 1, and 14 samples (38.9%) had a PD-L1 tumoral percentage of 1 or greater. Ten responses occurred in patients with PD-L1 tumor percentage less than 1, and 2 in patients with PD-L1 tumor percentages of 1 or greater. Conclusions and Relevance: The nivolumab with bevacizumab combination appeared to show activity in patients with relapsed ovarian cancer, with greater activity in the platinum-sensitive setting. Alternative combinational strategies may be necessary in the platinum-resistant setting.