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

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

Aspirin use and head and neck cancer survival and recurrence.

BACKGROUND: Head and neck cancer (HNC) has low 5-year survival, and evidence-based recommendations for tertiary prevention are lacking. Aspirin improves outcomes for cancers at other sites, but its role in HNC tertiary prevention remains understudied. METHODS: HNC patients were recruited in the University of Michigan Head and Neck Cancer Specialized Program of Research Excellence (SPORE) from 2003 to 2014. Aspirin data were collected through medical record review; outcomes (overall mortality, HNC-specific mortality, and recurrence) were collected through medical record review, Social Security Death Index, or LexisNexis. Cox proportional hazards models were used to evaluate the associations between aspirin use at diagnosis (yes/no) and HNC outcomes. RESULTS: We observed no statistically significant associations between aspirin and cancer outcome in our HNC patient cohort (n = 1161) (HNC-specific mortality: HR = 0.91, 95% CI = 0.68-1.21; recurrence: HR = 0.94, 95% CI = 0.73-1.19). In analyses stratified by anatomic site, HPV status, and disease stage, we observed no association in any strata examined with the possible exception of a lower risk of recurrence in oropharynx patients (HR = 0.60, 95% CI 0.35-1.04). CONCLUSIONS: Our findings do not support a protective association between aspirin use and cancer-specific death or recurrence in HNC patients, with the possible exception of a lower risk of recurrence in oropharynx patients.

Assessment of Swallowing Function in Patients with Head and Neck Squamous Cell Carcinoma in High vs. Low Dose Cisplatin.

Cisplatin-based therapies are standard-of-care for advanced-stage head and neck squamous cell carcinoma (HNSCC). Treatment regimens include 3 weeks of high-dose bolus cisplatin or 6-7 weeks of low-dose weekly cisplatin, both with concurrent radiation. The effects of cisplatin dosage on swallowing function warrant further study. A 237-patient cohort treated for HNSCC at a single center were studied retrospectively. Gastrostomy tube dependence served as the primary endpoint. Secondary endpoints included weight changes, esophageal stricture, and lymphedema. The primary/secondary outcomes were not statistically significant; however, ototoxicity and renal toxicity were significantly higher in the high-dose group. These findings add insight into cisplatin dose-based functional outcomes.

Impact of monoclonal antibody therapy for head and neck cancer on end-of-life care utilization and costs.

BACKGROUND: The impact of monoclonal antibody therapy (mAB) for advanced head and neck cancer on end-of-life health care utilization and costs has yet to be adequately studied. METHODS: Retrospective cohort study of patients aged 65 and over with a diagnosis of head and neck cancer between 2007 and 2017 within the SEER-Medicare registry assessing the impact of mAB therapy (i.e., cetuximab, nivolumab, or pembrolizumab) on end-of-life health care utilization (ED visits, inpatient admissions, ICU admissions, and hospice claims) and costs. RESULTS: Of 12 544 patients with HNC, 270 (2.2%) utilized mAB therapy at the end-of-life period. On multivariable analyses adjusting for demographic and clinicopathologic characteristics, there was a significant association between mAB therapy and emergency department visits (OR: 1.38, 95% CI: 1.1-1.8, p = 0.01) and healthcare costs (ß: $9760, 95% CI: 5062-14 458, p < 0.01). CONCLUSIONS: mAB use is associated with higher emergency department utilization and health care costs potentially due to infusion-related and drug toxicity expenses.

Assessment of neoadjuvant chemotherapy with docetaxel, cisplatin, and fluorouracil in patients with oral cavity cancer.

BACKGROUND: Chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) has been studied in patients with head and neck cancer. Its impact on patients with oral cavity cancer was not specified. METHODS: We consecutively reviewed medical files of patients with untreated oral cavity cancer who received neoadjuvant TPF chemotherapy in our department from January 2017 to April 2020. Outcomes included the objective response to TPF chemotherapy, factors associated with the response, and progression and survival in different response groups. RESULTS: A total of 167 patients were included, with half of stage IV disease. Complete or partial response was observed in 51 patients. A total of 91 patients had stable disease, and 25 patients had progressive disease. The response was not associated with age, sex, anatomic subsite, and the tumor's T stage. It was related with N stage (p < 0.001) and clinical stage (p = 0.004). Most patients with bulky nodes or nodes with obvious necrosis showed low response or even progressed after neoadjuvant TPF chemotherapy. The planned surgery was conducted in 159 patients. Disease relapse mostly occurred in 2 years after treatment. The 2-year overall survival and the progression-free survival were 89.0% and 85.2% for patients with complete or partial response, 62.4% and 55.6% for patients with stable disease, and 12.5% and 4.2% for patients with progressive disease, respectively. CONCLUSIONS: The response of neoadjuvant TPF chemotherapy in patients with oral cavity cancer is related to disease stage, especially the nodal stage. Patients with complete or partial response developed less progression events and better survival.

Assessment of the methylene blue mediated photodynamic therapy on BCL2 and BAX genes expression at mRNA level and apoptosis of head and neck squamous cell carcinoma cell line.

AIM: This study aimed to assess the effect of photodynamic therapy (PDT) on apoptosis of head and neck squamous cell carcinoma (HNSCC) cells by flow cytometry and evaluating BAX and BCL2 genes expression.

Cost-effectiveness of pembrolizumab for the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma in the United States.

AIMS: Pembrolizumab, as monotherapy in first-line recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) with a combined positive score (CPS) ≥1 and in combination with platinum and 5-fluorouracil (5-FU) in the overall R/M HNSCC population, received US FDA approval based on the KEYNOTE-048 trial. Using public drug prices, from a US payer perspective, we evaluated the cost-effectiveness of each pembrolizumab regimen vs. cetuximab + platinum+5-FU (EXTREME regimen, trial comparator), cisplatin + docetaxel + cetuximab (TPEx regimen), cisplatin + paclitaxel, and platinum+5-FU. METHODS: A three-state partitioned-survival model was used to project costs and outcomes over 20 years with 3% annual discounting. Progression-free and overall survival were modeled using long-term extrapolation of KEYNOTE-048 data and, for alternative comparators, data from a network meta-analysis was used. Time-on-treatment was derived from KEYNOTE-048 or approximated using network meta-analysis progression-free survival estimates. Costs included first-line and subsequent treatments, disease management, adverse events, and terminal care costs. Utilities were derived from the KEYNOTE-048 Euro-QoL five-dimension data and using a US algorithm. RESULTS: In the CPS ≥1 R/M HNSCC population, pembrolizumab monotherapy was dominant vs. EXTREME and TPEx regimens, and cost-effective (at $100,000/QALY threshold) vs. platinum+5-FU ($86,827/QALY) and cisplatin + paclitaxel ($81,473/QALY). Pembrolizumab combination therapy in the overall R/M HNSCC population was dominant vs. TPEx regimen, and cost-effective vs. EXTREME regimen ($1769/QALY), platinum+5-FU ($81,989/QALY), and cisplatin + paclitaxel ($89,505/QALY). Sensitivity analyses showed a high cost-effectiveness probability for pembrolizumab at the $100,000/QALY threshold. CONCLUSIONS: First-line pembrolizumab monotherapy in patients with CPS ≥1, and pembrolizumab combination therapy in the overall R/M HNSCC population is cost-effective from the perspective of the US payers.

Cetuximab como tratamiento de primera línea para pacientes con cáncer de cabeza y cuello no nasofaríngeo metastásico o recurrente en combinación con quimioterapia por 6 cursos seguidos como agente único de mantenimiento semanal hasta la progresión o toxicidad inaceptable / Cetuximab as first-line treatment for patients with metastatic or recurrent non-nasopharyngeal head and neck cancer in combination with chemotherapy for 6 consecutive courses as a single agent for weekly maintenance until progression or unacceptable toxicity

INTRODUCCIÓN: Según GLOBOCAN, durante el año 2020 aproximadamente 1,428 casos nuevos de cáncer de cabeza y cuello fueron diagnosticados en el Perú. Con respecto a la mortalidad, el cáncer de cabeza y cuello ha sido el responsable de más de 600 muertes en nuestro país. El cáncer de cabeza y cuello se asocia con la infección por PVH, siendo los subtipos 16 y 18 los más frecuentemente detectados, por lo cual esta neoplasia se asocia con mayor frecuencia a poblaciones jóvenes y económicamente activa. El cáncer de cabeza y cuello presenta una alta tasa de recurrencia (30-50%) y se asocia con pobre respuesta a la quimioterapia y una corta sobrevida. TECNOLOGÍA: Cetuximab es un anticuerpo monoclonal dirigido contra el receptor del factor de crecimiento epidermoide (EGFR), cuyo mecanismo de acción permitiría el bloqueo de vías moleculares que inhibirían el desarrollo y progresión del cáncer. Por lo cual, se estableció la siguiente pregunta PICO: "¿En los pacientes con diagnóstico de carcinoma escamoso de cabeza y cuello, no nasofaríngeo, estadio clínico IV o irresecable, ¿Cuál es la eficacia y seguridad de cetuximab asociado a quimioterapia en comparación con quimioterapia?" MÉTODOS: La estrategia de búsqueda sistemática de información científica para el desarrollo del presente informe se realizó siguiendo las recomendaciones de la Pirámide jerárquica de la evidencia propuesta por Haynes y se consideró los siguientes estudios: Sumarios y guías de práctica clínica. Revisiones sistemáticas y/o metanálisis. Ensayos Controlados Aleatorizados (ECA) . Estudios Observacionales (cohortes, caso y control, descriptivos). DISCUSIÓN: Según GLOGOCAN, durante el año 2020 aproximadamente 1,428 casos nuevos de cáncer de cabeza y cuello fueron diagnosticados en el Perú. Con respecto a la mortalidad, el cáncer de cabeza y cuello ha sido el responsable de más de 600 muertes en nuestro país. En Estados Unidos, más de la mitad de neoplasias de cabeza y cuello se originan por el virus del papiloma humano (PVH), siendo los subtipos 16 y 18 los más frecuentemente detectados. El cáncer bucofaríngeo relacionado con PVH se presenta en poblaciones más jóvenes, económicamente activa. El 5-10% de pacientes presentan enfermedad metastásica durante el diagnóstico. Sin embargo, el 30-50% de pacientes con enfermedad regional o localmente avanzada que fueron operadas y/o tratadas localmente presentarán recurrencia de enfermedad durante su evolución. Este grupo de pacientes presenta una duración corta de respuesta a tratamientos citotóxicos, y una pobre supervivencia (6-8 meses). Cetuximab es un anticuerpo monoclonal dirigido contra el receptor del factor de crecimiento epidermoide (EGFR), cuyo mecanismo de acción permitiría el bloqueo de vías moleculares que inhibirían el desarrollo del cáncer. CONCLUSIONES: Los pacientes con cáncer de cabeza y cuello metastásico/recurrente, no nasofaríngeo, corresponden a una población principalmente joven, económicamente activa, con pobre pronóstico y respuesta a quimioterapia convencional. 2. Las guías de práctica clínica internacional (NCCN, ESMO, NICE) recomiendan el uso de Cetuximab-Quimioterapia en esta población de interés. 3. RS/MA reporta mejoría estadísticamente significativa en TRO y SLP, y una tendencia a mejorar significativamente la SG con Cetuximab-Quimioterapia en la población de interés. 4. ECAs fase III reporta mejoría estadísticamente significativa en TRO, SLP y SG con Cetuximab-Platino-5FU en la población de interés. 5. Estudio de Calidad de Vida reporta que añadir Cetuximab no deteriora la calidad de vida de los pacientes tratados. 6. Dos estudios fármaco-económicos catalogan Cetuximab-Quimioterapia como una combinación "no costo-efectiva" en la población de interés. 7. Se estima que el costo de añadir cetuximab al régimen de tratamiento de los pacientes con cáncer de cabeza y cuello metastásico/recurrente es de aproximadamente S/. 19,925.04 por cada paciente. 8. Se discutió la presente evaluación de tecnología sanitaria en reunión de la Unidad Funcional de Tecnología Sanitaria (UFETS), recomendando su uso en los regímenes de quimioterapia estandarizada por 6 cursos en los pacientes con cáncer de cabeza y cuello avanzado, no nasofaríngeo, seguido de terapia como agente único de mantenimiento semanal.

Pembrolizumab en primera línea de tratamiento para el cáncer de cabeza y cuello metastásico o recurrente / Pembrolizumab in first-line treatment for metastatic or recurrent head and neck cancer

INTRODUCCIÓN: Se denomina cáncer de cabeza y cuello (CCyC) a un grupo de patologías oncológicas con origen predominante en células escamosas que se desarrollan en el tracto aerodigestivo superior (labios, lengua, cavidad oral, cavidad nasal, faringe y laringe). Los factores de riesgo identificados son el consumo de tabaco, el alcoholismo, la infección por el virus del papiloma humano y el virus Epstein-Barr.1 El tratamiento del CCyC es multimodal, dependiendo la elección del mismo principalmente del estadio y la localización del tumor primario.2 En estadios avanzados, como los estadios III/IV, se suelen asociar terapias (cirugía, radioterapia y/o quimioterapia), siendo la secuencia del tratamiento una decisión a tomar por un equipo multidisciplinario considerando el tamaño del tumor primario, la localización y numero de sitios de metástasis, accesibilidad y posible toxicidad de órganos cercanos. En los casos de progresión al tratamiento y enfermedad irresecable no existe un tratamiento estándar. Entre las opciones se cuentan la combinación de re-irradiación con o sin terapia sistémica, terapia sistémica únicamente o el mejor cuidado de soporte. Pembrolizumab se propone en primera línea de tratamiento como monoterapia, o combinado con quimioterapia (5-fluorouracilo más platinos) por lo que el presente informe evalúa si su utilización en pacientes con CCyC metastásico o recurrente no pasible de tratamiento local con intención curativa se asocia a beneficios en términos de sobrevida, calidad de vida y costos, en comparación con el tratamiento habitual, en primera línea de tratamiento. OBJETIVO: El objetivo del presente informe será evaluar la eficacia y seguridad comparativa del pembrolizumab en pacientes con cáncer escamoso de cabeza y cuello (orofaringe, cavidad oral, hipofaringe o laringe) metastásico o recurrente no pasible de tratamiento local con intención curativa, en primera línea de tratamiento. METODOLOGÍA: Se buscó en los sitios públicos de Pubmed, LILACS, BRISA/REDETSA-, CRD (del inglés, Centre for Reviews and Dissemination- University of York), Cochrane; en "buscadores genéricos de internet" y sociedades científicas. En lo que respecta a agencias de ETS, se buscó en: Base de datos internacional para las ETS de INHATA (su sigla del inglés, International Network of Agencies for Health Technology Assessment), Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), y en agencias como NICE (del inglés, National Institute for Health and Clinical Excellence) del Reino Unido; PBAC (del inglés, The Pharmaceutical Benefits Advisory Committee) de Australia; CADTH (del inglés, Canadian Agency for Drugs and Technologies in Health) de Canadá y CONITEC (del portugués, Comissão Nacional de Incorporação de Tecnologías no SUS) de Brasil. RESULTADOS: Como resultado se incluyeron un estudio aleatorizado, cuatro guías de práctica clínica, tres evaluaciones de tecnologías sanitarias, nueve políticas de cobertura, un estudio económico y se realizó un análisis de impacto presupuestario. CONCLUSIONES: Evidencia de alta calidad muestra que el pembrolizumab en monoterapia o asociado a quimioterapia, comparado con cetuximab más quimioterapia, produce una mejoría en la sobrevida global. La misma es más marcada cuanto mayor sea el porcentaje de expresión del receptor del PDL1, medido a través del índice CPS. Evidencia de alta calidad muestra que el pembrolizumab en monoterapia o asociado a quimioterapia, comparado con cetuximab más quimioterapia, no se asocia a un mayor tiempo de sobrevida libre de progresión. En el caso del uso de pembrolizumab en combinación con quimioterapia, respecto a cetuximab con quimioterapia, evidencia de moderada calidad sugiere que los eventos adversos entre ambos tratamientos son similares. En el caso de pembrolizumab en monoterapia respecto a cetuximab más quimioterapia, la ocurrencia de eventos adversos graves fue menor. Las principales guías de práctica clínica acerca del tratamiento del cáncer de cabeza y cuello recomiendan el uso de pembrolizumab en monoterapia o combinado con quimioterapia para esta indicación. En cuanto a las políticas de cobertura, ninguno de los países de la región relevados hace referencia explícita a la cobertura de pembrolizumab para esta indicación, mientras que, entre los países de altos ingresos relevados, Australia y España no brindan cobertura mientras que Canadá, Escocia, Alemania, el Reino Unido y aseguradoras privadas de Estados Unidos sí lo hacen para esta indicación. Un estudio económico realizado en la Argentina desde la perspectiva de la seguridad social estimó índices de costo efectividad del pembrolizumab versus cetuximab más quimioterapia. Los mismos resultaron mayormente costo-efectivos para un umbral de pago de tres productos brutos internos per cápita. La estimación del impacto presupuestario de la incorporación del pembrolizumab en esta indicación resultó ser superior al límite establecido en el país.

Pembrolizumab with or without chemotherapy versus cetuximab plus chemotherapy to treat recurrent or metastatic head and neck squamous cell carcinoma: An updated KEYNOTE-048 based cost-effectiveness analysis.

OBJECTIVES: Recently, updated data from KEYNOTE-048 revealed that pembrolizumab with or without chemotherapy could improve progression-free survival (PFS)2 compared with cetuximab plus chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: A Markov structure was conducted to evaluate the cost and effectiveness of pembrolizumab monotherapy or pembrolizumab plus chemotherapy vs. cetuximab plus chemotherapy in the first-line treatment of recurrent or metastatic HNSCC from the United States payer's perspective. Total cost, health outcomes, and incremental cost-effective ratios (ICERs) were estimated. Additional analyses were conducted in the total population and in two different programmed cell death 1 ligand 1 (PD-L1) combined positive scores (CPSs) (≥1 and ≥ 20) population. Sensitivity analysis were used to test the stability of the model. RESULTS: When compared with cetuximab plus chemotherapy, the pembrolizumab monotherapy strategy was dominated by lower cost and better efficacy in all three populations. The incremental costs and quality adjusted life years (QALYs) yielded by pembrolizumab plus chemotherapy compared with cetuximab plus chemotherapy were $16016.88 and 0.11 in the total population, and $24467.47 and 0.18 and $30448.46 and 0.20 in the populations with a PD-L1 CPS ≥ 1 and CPS ≥ 20, respectively, leading to ICERs of $147876.14, $134237.84, and $153660.78 per QALY, respectively. CONCLUSION: First-line treatment with pembrolizumab or pembrolizumab plus chemotherapy are cost-effective strategies compared with cetuximab plus chemotherapy when the value of willingness-to-pay (WTP) was $150000 per QALY for the total and PD-L1 CPS ≥ 1 populations with recurrent or metastatic HNSCC.

Assessment of Renal Function in Head and Neck Cancer Patients Treated with Cisplatin: Different Biomarkers and Acute Kidney Injury Classifications.

Cisplatin is associated with dose-limiting nephrotoxicity, and the timely detection of acute kidney injury (AKI) can affect morbimortality. Therefore, this study aimed to investigate the tools for monitoring renal function in AKI. This was a retrospective, cohort study. Cisplatin-treated patients with head and neck cancer were included. Nephrotoxicity was assessed using serum creatinine, estimated creatinine clearance, serum electrolytic alterations, and plasma kidney injury molecule-1 (KIM-1). The toxicity severity was classified according to Common Terminology Criteria for Adverse Events (CTCAE), and AKI was classified by Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN). A total of 81 participants were included, of whom only 32 did not have AKI. Almost 90% of participants had a decreased estimated glomerular filtration rate five (D5) days after chemotherapy. The AKI estimate differs between AKIN and RIFLE; more participants were diagnosed by the RIFLE at D5, 19.5% versus 2.4% by AKIN, and fifteen had a discordance between these classifications. All laboratory markers showed significant changes on D5. KIM-1 appeared a possible biomarker when considering CTCAE or AKIN classifications (p < 0.05 on D5), but not when RIFLE classification was used (p = 0.0780). Further studies may seek to understand the profiles of different biomarkers together.

Survival impact of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in head and neck cancer.

BACKGROUND: Preclinical evidence suggests a link between the renin-angiotensin system and oncogenesis. We aimed to explore the impact of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) in head and neck cancer (HNC). METHODS: Over 5000 patients were identified from the Surveillance, Epidemiology, and End Results-Medicare linked dataset and categorized according to ACEi and ARB and diagnoses of chronic kidney disease (CKD) or hypertension (HTN). Overall survival (OS) and cancer-specific survival (CSS) were compared using Cox multivariable regression (MVA), expressed as hazard ratios (HR) with 95% confidence intervals (95%CI). RESULTS: No significant MVA associations for OS or CSS were found for ACEi. Compared to patients with CKD/HTN taking ARB, those with CKD/HTN not taking ARB experienced worse OS (HR 1.28, 95%CI 1.09-1.51, p = 0.003) and CSS (HR 1.23, 95%CI 1.00-1.50, p = 0.050). CONCLUSIONS: ARB usage is associated with improved OS and CSS among HNC patients with CKD or HTN.

Nivolumab vs Pembrolizumab for Treatment of US Patients With Platinum-Refractory Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Network Meta-analysis and Cost-effectiveness Analysis.

Importance: Nivolumab and pembrolizumab are approved for treating platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Physicians and patients are uncertain which drug is preferable, rendering a cost-effectiveness comparison between them necessary. Objective: To evaluate the cost-effectiveness of nivolumab vs pembrolizumab in treating platinum-refractory R/M HNSCC. Design, Setting, and Participants: Both the network meta-analysis and cost-effectiveness analysis included patients from the CheckMate 141 and the KEYNOTE 040 phase 3 randomized clinical trials. The Checkmate 141 trial started on May 1, 2014, with the present analysis based on a September 2017 data cutoff. The KEYNOTE 040 trial started on November 17, 2014, with the present analysis based on a May 15, 2017, data cutoff. A bayesian network meta-analysis that included 856 patients was carried out, and a cost-effectiveness analysis that included 487 patients was conducted by developing a partitioned survival model, both between February and November 2020. The robustness of the model was assessed via 1-way, 2-way, and probabilistic sensitivity analyses; subgroup analyses were included; and scenario analyses were conducted to investigate the associations of dosage adjustment of nivolumab with cost-effectiveness. Main Outcomes and Measures: Life-years, quality-adjusted life-years (QALYs), overall costs, and incremental cost-effectiveness ratios (ICERs) were measured. Results: In the cost-effectiveness analysis that included 487 patients, for US health care payers, when nivolumab was administered based on patient weight (3 mg/kg biweekly), at a willingness-to-pay (WTP) threshold of $100 000 per QALY, the probability of nivolumab being cost-effective compared with pembrolizumab was 56%; at a WTP threshold of $150 000 per QALY, the probability was 62%. When nivolumab was administered at a fixed dose of 240 mg biweekly or 480 mg monthly, at a WTP threshold of $100 000 per QALY, the probability of nivolumab being cost-effective was 42% to 45%; at a WTP threshold of $150 000 per QALY, the probability was 52% to 55%. Conclusions and Relevance: Findings from this network meta-analysis and cost-effectiveness analysis suggest considering both WTP threshold and patient body weight when choosing between nivolumab and pembrolizumab for the treatment of patients with platinum-refractory R/M HNSCC. When the WTP threshold was $100 000 per QALY, for patients weighing less than 72 kg, nivolumab (3 mg/kg, biweekly) was considered cost-effective; otherwise, pembrolizumab was preferable. When the WTP threshold was $150 000 per QALY, nivolumab (3 mg/kg biweekly) was considered cost-effective for patients weighing less than 75 kg; otherwise, fixed-dose nivolumab (240 mg biweekly or 480 mg monthly) provided more cost savings.

Cost-Effectiveness of Pembrolizumab Regimens for the First-Line Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma in Argentina.

INTRODUCTION: The phase III KEYNOTE-048 trial showed that the programmed death receptor 1 (PD-1) inhibitor pembrolizumab, in the combined positive score (CPS) ≥ 1 population and combined with platinum + 5-fluorouracil in the total population, improves survival over cetuximab + platinum + 5-fluorouracil in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). We evaluated the cost-effectiveness of pembrolizumab as monotherapy in the CPS ≥ 1 population or combined with platinum + 5-fluorouracil in the total population versus cetuximab + platinum + 5-fluorouracil from the social security perspective in Argentina. METHODS: A partitioned survival model projected costs and outcomes over 20 years with 3% annual discounting. Health state occupancy was modeled using KEYNOTE-048 Kaplan-Meier curves until the final analysis data cutoff, followed by parametric extrapolations guided by statistical criteria. Costs for initial and subsequent treatments, disease and adverse events management, and terminal care were included (AR $74.00 = 1 USD). Time-on-treatment and EuroQol five-dimension scores were taken from KEYNOTE-048. Utilities were derived using an Argentina-specific algorithm. RESULTS: With pembrolizumab monotherapy, patients accrued 1.1040 additional life-years and 0.8768 additional quality-adjusted life-years (QALYs), for incremental cost-effectiveness ratios (ICERs) of AR $135,801/life-year and AR $170,985/QALY gained over cetuximab + platinum + 5-fluorouracil. Additional life-years and QALYs gained with pembrolizumab combination therapy versus cetuximab + platinum + 5-fluorouracil were 1.3296 and 1.0536, respectively (ICERs of AR $680,143/life-year and AR $858,306/QALY). Considering a threshold of AR $1,676,122/QALY gained, pembrolizumab monotherapy and combination therapy had an 88.0% and a 77.1% probability of being cost-effective, respectively. CONCLUSION: Pembrolizumab either as monotherapy or in combination with chemotherapy offers substantial survival gains for patients with R/M HNSCC at small additional costs, making it a cost-effective treatment versus cetuximab + platinum + 5-FU in Argentina.

Assessment of exposure-response relationship for cetuximab in patients with metastatic colorectal cancer and head and neck cancer.

OBJECTIVE: There is limited scientific evidence on the cetuximab exposure-response relationship and no concentration threshold has been associated with optimal disease control. The aims were to assess, in a real-life setting, the  relationship between steady state cetuximab concentrations (Ctrough, SS) and  disease control. METHOD: A prospective observational study in patients with metastatic colorectal cancer or head and neck cancer treated with cetuximab.  Steady state trough concentrations were compared with the results of  radiological assessment of response (progression or clinical benefit).  Generalized estimating equations analysis was performed. To test the  association between steady state concentrations and overall survival and  progression-free survival, Cox proportional hazard models were developed. An  optimal cut-off point was searched using the area under the receiver operating  characteristic curve. RESULTS: A total of 30 steady state cetuximab concentrations from 16 patients  were analysed. Median Ctrough, SS was 26.86 mg/L and there was marked  inter- and intraindividual variability (standard deviation 32.4 mg/L and 16.9 mg/L, respectively). A positive association was found between cetuximab  Ctrough, SS and clinical benefit (odds ratio 1.24, 95% confidence interval:  0.95-1.63, p = 0.113), although without reaching statistical significance. The  area under the receiver operating characteristic curve (n = 30) had moderate  discrimination power (0.71; 95% confidence interval 0.49­0.93), and the  empirical optimal cutoff point was 19.12 mg/L. However, no association was  observed between cetuximab Ctrough, SS and survival in metastatic colorectal  cancer or neck cancer patients. CONCLUSIONS: We cannot confirm a relationship between cetuximab Ctrough,  SS and disease control despite a positive association. This study was  conducted with a small sample, which reduces the power analysis. Further  controlled randomised studies with a sufficient number of patients are needed.

OBJETIVO: Evaluar, en condiciones de vida real, la relación entre las concentraciones valle en estado estacionario de cetuximab y el control de  la enfermedad, así como buscar la relación entre estas concentraciones y la supervivencia. Además, estudiar si existe una concentración límite que se  pueda asociar con la probabilidad de beneficio clínico.Método: Estudio observacional prospectivo llevado a cabo en pacientes con  cáncer colorrectal metastásico o cáncer de cabeza y cuello en tratamiento con  cetuximab. Se realizó un análisis de regresión de ecuaciones de estimación  generalizadas para evaluar la asociación entre la concentración valle en estado  estacionario de cetuximab y la respuesta al tratamiento (progresión o beneficio  clínico). Mediante modelos de riesgos proporcionales de Cox, se  evaluó la asociación entre la mediana de concentraciones valle en estado  estacionario de cetuximab en cada paciente o la última medida con la  supervivencia global y la supervivencia libre de progresión, en cada una de las  patologías. Asimismo, se buscó un punto de corte óptimo a través del área  bajo la curva de características operativas del receptor. RESULTADOS: Se analizaron 30 muestras de 16 pacientes. La concentración valle en estado estacionario mediana fue 26,86 mg/l y se  encontró una gran variabilidad inter e intraindividual (desviación estándar de  32,4 y 16,9 mg/l, respectivamente). Se observó una asociación positiva entre  la concentración valle en estado estacionario y el beneficio clínico (odds ratio  1,24; intervalo de confianza del 95%: 0,95-1,63; p = 0,113), aunque no alcanzó significación estadística debido a la baja potencia. El área bajo la  curva de características operativas del receptor de las concentraciones (n =  30) tuvo una moderada capacidad discriminatoria (área bajo la curva de  características operativas del receptor 0,710; intervalo de confianza del 95%:  0,49-0,93) y el punto de corte estimado fue de 19,12 mg/l. Sin embargo, no  se observó relación entre la supervivencia y las concentraciones valle en  estado estacionario en ninguna de las patologías. CONCLUSIONES: No se ha podido confirmar una relación entre exposición a  cetuximab y eficacia, a pesar de encontrar una tendencia positiva en el control  de la enfermedad con el aumento de la concentración valle en estado  estacionario. El nivel de evidencia se vio reducido por la pequeña muestra de  pacientes en cada grupo, por lo que se necesitan estudios aleatorizados y  controlados, con un número suficiente de pacientes, para evaluar  adecuadamente esta relación.

Cost-effectiveness of pembrolizumab for treatment of platinum-resistant recurrent or metastatic head and neck squamous cell carcinoma in China: an economic analysis based on a randomised, open-label, phase III trial.

BACKGROUND: Pembrolizumab was recently demonstrated to have survival benefit in patients with recurrent or metastatic head and neck squamous cell carcinoma (r/mHNSCC). However, the cost-effectiveness of pembrolizumab versus chemotherapy in China remains uncertain. OBJECTIVE: This analysis aimed to describe the cost-effectiveness of pembrolizumab versus standard-of-care (SOC) therapy in r/mHNSCC in China. DESIGN: A Markov model consisting of three health states (stable, progressive and dead) was developed to compare the cost and effectiveness of pembrolizumab with SOC in platinum-resistant r/mHNSCC. Model inputs for transition probabilities and toxicity were collected from the KEYNOTE-040 trial, while health utilities were estimated from a literature review. Cost data were acquired for the payer's perspective in China. Costs and outcomes were discounted at an annual rate of 3.0%. Sensitivity analyses were conducted to test the uncertainties surrounding model parameters. OUTCOME MEASURES: The primary outcome was incremental cost-effectiveness ratios (ICERs), which were calculated as the cost per quality-adjusted life years (QALYs). RESULTS: The total mean cost of pembrolizumab and SOC was US$45 861 and US$41 950, respectively. As for effectiveness, pembrolizumab yielded 0.31 QALYs compared with 0.25 QALYs for SOC therapy. The ICER for pembrolizumab versus SOC was US$65 186/QALY, which was higher than the willingness-to-pay threshold (WTP) of US$28 130/QALY in China. The univariate sensitivity analysis indicated that utility values for progressive state, probability from stable to progressive in the SOC group, as well as cost of pembrolizumab were the three most influential variables on ICER. The probabilistic sensitivity analysis demonstrated that standard therapy was more likely to be cost-effective compared with pembrolizumab at a WTP value of US$28 130/QALY. Results were robust across both univariate analysis and probabilistic sensitivity analysis. CONCLUSIONS: Pembrolizumab is not likely to be a cost-effective strategy compared with SOC therapy in patients with platinum-resistant r/mHNSCC in China. TRIAL REGISTRATION NUMBER: NCT02252042; Post-results.

Pembrolizumab vs the EXTREME Regimen in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Cost-Effectiveness Analysis.

BACKGROUND AND OBJECTIVE: The KEYNOTE-048 clinical trial revealed that pembrolizumab improved the overall survival time of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) vs cetuximab plus chemotherapy (EXTREME regimen). The current study examined the cost effectiveness of pembrolizumab monotherapy and pembrolizumab plus chemotherapy compared with the EXTREME regimen in patients with HNSCC from the perspectives of USA and China. METHODS: A partitioned survival model was implemented for patients with R/M HNSCC, and the cost effectiveness of pembrolizumab monotherapy and pembrolizumab plus chemotherapy compared with the EXTREME regimen was compared. Survival information was derived from the KEYNOTE-048 trial. The model was designed as a 20-year time horizon, a 3-week cycle, and a 3% discount rate for costs and utilities. An incremental cost-effectiveness ratio (ICER) value less than $100,000/quality-adjusted life-year (QALY) was considered cost effective in the USA and $27,538/QALY in China. We analyzed the uncertainty by performing one-way and probabilistic sensitivity analyses. RESULTS: From the base-case analysis, we found that the pembrolizumab monotherapy scheme had a lower cost and better efficacy compared with the EXTREME regimen in the USA. In China, the ICER of the comparison was $62,401/QALY. The ICER of pembrolizumab plus chemotherapy vs the EXTREME regimen was $66,630/QALY in the USA and $90,538/QALY in China. CONCLUSIONS: The observations suggested that treatment with pembrolizumab monotherapy or pembrolizumab plus chemotherapy is a cost-effective strategy for patients with R/M HNSCC in the USA. However, the conclusion is the opposite for China: the EXTREME regimen is still a cost-effective choice.