The cost-effectiveness of iruplinalkib versus alectinib in anaplastic lymphoma kinase-positive crizotinib-resistant advanced non-small-cell lung cancer patients in China.

Background: Iruplinalkib is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with efficacy in patients with ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC), which is independently developed by a Chinese pharmaceutical company. This study examined the cost-effectiveness of iruplinalkib versus alectinib in the Chinese healthcare setting. Methods: A partitioned survival model was developed to project the economic and health outcomes. Efficacy was derived using unanchored matching-adjusted indirect comparison (MAIC). Cost and utility values were obtained from the literature and experts' opinions. Deterministic and probabilistic sensitivity analyses (PSA) were carried out to evaluate the model's robustness. Results: Treatment with iruplinalkib versus alectinib resulted in a gain of 0.843 quality-adjusted life years (QALYs) with incremental costs of $20,493.27, resulting in an incremental cost-effectiveness ratio (ICER) of $24,313.95/QALY. Parameters related to relative efficacy and drug costs were the main drivers of the model outcomes. From the PSA, iruplinalkib had a 90% probability of being cost-effective at a willingness-to-pay threshold of $37,863.56/QALY. Conclusion: Compared to alectinib, iruplinalkib is a cost-effective therapy for patients with ALK-positive crizotinib-resistant advanced NSCLC.

Economic Evaluation of Targeted Therapies for Anaplastic Lymphoma Kinase- and ROS1 Fusion-Positive Non-Small Cell Lung Cancer in India.

PURPOSE: Targeted therapies, such as crizotinib and ceritinib, have shown promising results in treating non-small cell lung cancer (NSCLC) with specific oncogenic drivers like anaplastic lymphoma kinase (ALK), c-ros (ROS1) oncogene, etc. This study aims to assess the cost-effectiveness of these therapies for patients with NSCLC in India. METHODS: The Markov model consisted of three health states: progression-free survival, progressive disease, and death. Lifetime costs and consequences were estimated for three treatment arms: crizotinib, ceritinib, and chemotherapy for patients with ALK- and ROS1-positive NSCLC. Incremental cost per quality-adjusted life-year (QALY) gained with crizotinib and ceritinib was compared to chemotherapy and assessed using a willingness-to-pay threshold of one-time per capita gross domestic product in India. RESULTS: The total lifetime cost per patient for ALK-positive NSCLC was ₹332,456 ($4,054 US dollars [USD]), ₹1,284,100 ($15,659 USD), and ₹2,337,779 ($28,509 USD) in the chemotherapy, crizotinib, and ceritinib arms, respectively. The mean QALYs lived per patient were 1.20, 2.21, and 3.34, respectively. For patients with ROS1-positive NSCLC, the total cost was ₹323,011 ($3,939 USD) and ₹1,763,541 ($21,507 USD) for chemotherapy and crizotinib, with mean QALYs lived per patient of 1.16 and 2.73, respectively. Nearly 92% and 81% reduction in the price of ceritinib and crizotinib is required to make it a cost-effective treatment option for ALK- and ROS1-positive NSCLC, respectively. CONCLUSION: Our study findings suggest that the prices of ceritinib and crizotinib need to be reduced significantly to justify their value for inclusion in India's publicly financed health insurance scheme for treatment of patients with locally advanced/metastatic ALK- and ROS1-positive NSCLC, respectively.

Lorlatinib as a first-line treatment of adult patients with anaplastic lymphoma kinase-positive advanced non-small cell lung cancer: Α cost-effectiveness analysis in Greece.

OBJECTIVES: To evaluate the cost-effectiveness of lorlatinib compared to 1st generation anaplastic lymphoma kinase (ALK) TKI crizotinib, and 2nd generation TKIs alectinib and brigatinib, for previously untreated patients with ALK+ advanced Non-Small Cell Lung Cancer (aNSCLC). METHODS: A partitioned survival model was locally adapted from a Greek payer perspective over a lifetime horizon. Clinical, safety and utility data were extracted from literature. Direct medical costs reflecting the year 2023 were included in the analysis (€). Model outcomes were patients' life years (LYs), quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs). RESULTS: Total cost per patient with lorlatinib, alectinib, crizotinib, and brigatinib was estimated to be €188,205, €183,343, €75,028, and €145,454 respectively. Lorlatinib appeared to yield more LYs and QALYs gained versus alectinib, crizotinib, and brigatinib. Hence, lorlatinib resulted in ICERs of €4,315 per LY gained and €4,422 per QALY gained compared to alectinib, €34,032 per LY gained and €48,256 per QALY gained versus crizotinib and €16,587 per LY gained and €26,271 per QALY gained compared to brigatinib. CONCLUSION: Lorlatinib provides substantial clinical benefit and appears to be a cost - effective treatment option compared to 1st and 2nd generation TKIs for previously untreated patients with ALK+ aNCSLC in Greece.

Alectinibe para o tratamento do câncer de pulmão de células não pequenas localmente avançado ou metastático cujos tumores expressam rearranjo no gene ALK em pacientes não tratados previamente ou após falha com crizotinibe / Alectinib for the treatment of locally advanced or metastatic non-small cell lung cancer whose tumors express regrowth of the ALK gene in patients not previously treated or after failure with crizotinib

INTRODUÇÃO: O câncer de pulmão pode ser divido em dois grandes grupos, carcinoma de células não pequenas (CPCNP) e o carcinoma de pequenas células. O primeiro compreende aproximadamente 85% dos cânceres de pulmão e pode ser dividido em quatro subtipos histológicos principais: adenocarcinoma, carcinoma de células escamosas, carcinoma adenoescamoso e carcinoma de células grandes. Normalmente, o CPCNP é diagnosticado em estágio avançado para o qual a sobrevida em cinco anos estimada está entre 3% e 6%. A quinase do linfoma anaplásico (ALK) é uma tirosina quinase cuja expressão pode ocorrer de forma aberrante em vários tipos de câncer. No CPCNP os rearranjos cromossômicos nos loci do gene ALK são encontrados em 3 a 5% dos casos. Nesse caso o rearranjo cromossômico mais comum resulta no gene de fusão ELM-ALK, cuja atividade está relacionada a tumores com caraterísticas clinicopatológicas distintas e tem importância na correta programação do tratamento. Tumores positivos para os genes de fusão ALK estão associados a características clínicas específicas, tais como ausência de histórico de tabagismo e incidência em indivíduos mais jovens. Os tumores ALK positivos são altamente sensíveis ao tratamento com medicamentos inibidores da ALK (terapia-alvo). No SUS est

A Systematic Review of the Cost-Effectiveness Analyses of Anaplastic Lymphoma Kinase (ALK) Inhibitors in Patients with Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC).

BACKGROUND: The anaplastic lymphoma kinase (ALK) inhibitor treatment landscape is rapidly evolving, providing patients with ALK-positive (+) non-small cell lung cancer (NSCLC) with multiple therapy options, multiple lines of treatments, and prolonged survival. However, these recent treatment advances have resulted in additional increases in treatment costs. The objective of this article is to review the economic evidence of ALK inhibitors in patients with ALK+ NSCLC. METHODS: The systematic review was conducted in accordance with the Joanna Briggs Institute (JBI) systematic reviews of economic evaluation. The population included adult patients with locally advanced (stage IIIb/c) or metastatic (stage IV) NSCLC cancer with confirmed ALK fusions. The interventions included the ALK inhibitors alectinib, brigatinib, ceritinib, crizotinib, ensartinib, or lorlatinib. The comparators included the listed ALK inhibitors, chemotherapy, or best supportive care. The review considered cost-effectiveness analysis studies (CEAs) that reported incremental cost-effectiveness ratio in quality-adjusted life years and/or in life years gained. Published literature was searched in Medline (via Ovid) by 4 January 2023, in Embase (via Ovid) by 4 January 2023, in International Pharmaceutical Abstracts (via Ovid) by 4 January 2023, and in Cochrane library (via Wiley) by 11 January 2023. Preliminary screening of titles and abstracts was conducted against the inclusion criteria by two independent researchers followed by a full text of selected citations. Search results are presented in a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram. Critical appraisal was conducted using the validated Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS) tool as well as the Phillips et al. 2004 appraisal tool to assess the reporting and quality of the economic evaluations. Data were extracted from the final set of articles and presented in a table of characteristics of included studies, an overview of study methods of included studies, and a summarization of outcomes of included studies. RESULTS: A total of 19 studies met all inclusion criteria. The majority of the studies were in the first-line treatment setting (n = 15). Included CEAs varied in the interventions and comparators being evaluated and were conducted from different country perspectives, limiting their comparability. Outcomes from the included CEAs showed that ALK inhibitors may be considered a cost-effective treatment option for patients with ALK+ NSCLC in the first-line and subsequent lines of treatment setting. However, the probability of cost effectiveness of ALK inhibitors ranged from 46 to 100% and were mostly achieved at willingness-to-pay thresholds of $100,000 USD or higher (> $30,000 or higher in China) in the first-line treatment setting and at thresholds of $50,000 USD or higher in subsequent lines of treatment setting. The number of published full-text CEAs is low and the studies represent a handful of country perspectives. The source of survival data was dependent on data from randomized controlled trials (RCTs). Where RCT data were not available, indirect treatment comparisons or matched adjusted indirect comparisons were performed using efficacy data from different clinical studies. Real world evidence was rarely used for efficacy and costing data inputs. CONCLUSION: The findings summarized available evidence on cost effectiveness of ALK inhibitors for the treatment of patients with locally advanced or metastatic ALK+ NSCLC across lines of treatment settings and generated a valuable overview of analytical approaches utilized to support future economic analyses. To help further inform treatment and policy decisions, this review emphasizes the need for comparative cost effectiveness of multiple ALK inhibitors simultaneously using real-world data sources with broad representation of settings.

Cost­Effectiveness of Lorlatinib in First-Line Treatment of Adult Patients with Anaplastic Lymphoma Kinase (ALK)­Positive Non­Small­Cell Lung Cancer in Sweden.

BACKGROUND: We aimed to investigate the cost effectiveness of lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), used first-line in Sweden to treat patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC). In January 2022, the European Medicines Agency (EMA) extended its approval of lorlatinib to include adult patients with ALK+ NSCLC not previously treated with an ALK inhibitor. Extended first-line approval was based on results from CROWN, a phase III randomized trial that enlisted 296 patients randomized 1:1 to receive lorlatinib or crizotinib. Our analysis compared lorlatinib against the first-generation ALK-TKI crizotinib, and second-generation ALK TKIs alectinib and brigatinib. METHODS: A partitioned survival model with four health states [pre-progression, non-intracranial (non-central nervous system [CNS]) progression, CNS progression, and death] was constructed. The progressed disease state (which is typically modelled in cost-effectiveness analyses of oncology treatments) was explicitly separated into non-CNS and CNS progression as brain metastases, which are common in NSCLC, and can have a large impact on patient prognosis and health-related quality of life. Treatment effectiveness estimates in the lorlatinib and crizotinib arms of the model were derived from CROWN data, while indirect relative effectiveness estimates for alectinib and brigatinib were informed using network meta-analysis (NMA). Utility data were derived from the CROWN study in the base case, and cost-effectiveness results were compared when applying UK and Swedish value sets. Costs were obtained from Swedish national data. Deterministic and probabilistic sensitivity analyses were conducted to test model robustness. RESULTS: Fully incremental analysis identified crizotinib as the least costly and least effective treatment. Brigatinib was extendedly dominated by alectinib and, subsequently, alectinib was extendedly dominated by lorlatinib. Lorlatinib was associated with an incremental cost-effectiveness ratio (ICER) of Swedish Krona (SEK) 613,032 per quality-adjusted life-year (QALY) gained compared with crizotinib. Probabilistic results were generally consistent with deterministic results, and one-way sensitivity identified NMA HRs, alectinib and brigatinib treatment duration, and the CNS-progressed utility multiplier as key model drivers. CONCLUSIONS: The ICER of SEK613,032 for lorlatinib versus crizotinib falls below the typical willingness-to-pay threshold per QALY gained for high-severity diseases in Sweden (approximately SEK1,000,000). Furthermore, as brigatinib and alectinib were extendedly dominated in the incremental analysis, the results of our study indicate that lorlatinib may be considered a cost-effective treatment option for first-line patients with ALK+ NSCLC in Sweden when compared with crizotinib, alectinib, and brigatinib. Longer-term follow-up data for endpoints informing treatment effectiveness for all first-line treatments would help to reduce uncertainty in the findings.

Crizotinibe para o tratamento, em primeira linha, de pacientes adultos com câncer de pulmão não pequenas células (CPNPC) avançado ALK+ / Crizotinib for the first-line treatment of adult patients with advanced ALK+ non-small cell lung cancer (NSCLC)

INTRODUÇÃO: O câncer de pulmão (CP) é um dos cânceres mais prevalentes (em homens e mulheres) e que apresenta a maior taxa de mortalidade entre todos os tipos de cânceres (exceto câncer de pele não melanoma). De acordo com a literatura, 85% dos casos são do tipo câncer de pulmão não pequenas células (CPNPC) e, desses, aproximadamente, 3% apresentam a translocação ALK+, esta entidade clínica é responsiva ao tratamento direcionado ao evento molecular indutor deste câncer. Nos casos de pacientes com CPNPC, a Diretriz Diagnóstica e Terapêutica (DDT) publicada em 2014 pelo MS, recomenda o tratamento com radioterapia associada ou não com quimioterapia ou cirurgia. O crizotinibe, um antineoplásico da classe dos inibidores de tirosina quinase, está indicado para o tratamento do CPNPC avançado ALK+. Considerando o exposto, o presente relatório tem por objetivo avaliar o pedido de incorporação de crizotinibe para o tratamento, em primeira linha, do CPNPC avançado ALK+ de pacientes adultos, no SUS. PERGUNTA DE PESQUISA: Crizotinibe é eficaz, seguro, custo-efetivo e economicamente viável no tratamento, em primeira linha, do câncer de pulmão não pequenas células, avançado ALK+ na perspectiva do SUS? EVIDÊNCIAS CLÍNICAS: O demandante apresentou resultados de sete estudos, entretanto, os pareceristas julgaram adequado considerar apenas 5 ECR. Os resultados para mediana de SLP entre os pacientes que receberam crizotinibe foram de 10,9 meses (IC 95%: 8,3 a 13,9) e 7,0 meses (IC 95%: 6,8 a 8,2) para os que receberam quimioterapia, com uma estimativa menor risco de progressão da doença e morte para o crizotinibe (HR: 0,45; IC 95%: 0,35 a 0,60; P <0,001). Os resultados apresentados por outro estudo foram de 11,1 meses (IC 95%: 8,3 a 12,6) para o grupo crizotinibe, enquanto no grupo quimioterapia a SLP mediana foi de 6,8 meses (IC 95%: 5,7 a 7,0), com um risco significativamente menor de progressão da doença ou morte para os pacientes tratados com crizotinibe (HR: 0,402 [IC 95%: 0,286 a 0,565]; p-valor <0,001). Para a SG não foi verificada diferença significativa entre os pacientes tratados com crizotinibe e os que receberam quimioterapia (HR: 0,82; IC 95%: 0,54 a 1,26; P= 0,36) na análise do ECR pivotal. Na análise com maior tempo de seguimento, a SG média para quimioterapia foi de 47,5 meses e não foi alcançada para crizotinibe, com um HR de 0,760 (IC 95%: 0,548 a 1,053; P= 0,0978). Após ajuste, a SG foi significativamente favorável ao uso de crizotinibe (HR: 0,346; IC95% de 0,081 a 0,718), com mediana de 59,8 meses (IC95%, 46,6 a não alcançado) para crizotinibe e 19,2 meses (IC 95%, 13,6 a não alcançado) para quimioterapia. AVALIAÇÃO ECONÔMICA: Foi realizada uma avaliação de custo-utilidade utilizando um modelo de sobrevida particionado considerando-se a transição por três estados de saúde (sobrevida livre de progressão, progressão e morte), comparando o crizotinibe com a quimioterapia. Foi utilizada a perspectiva do SUS com um horizonte temporal de 30 anos. Os desfechos avaliados, mensalmente, foram anos de vida ganhos (AVG) e anos de vida ganhos ajustados por qualidade (AVAQ). Entre os custos envolvidos, considerou-se, no estado de progressão da doença, os custos da progressão da doença com linhas posteriores de quimioterapia. Dados de qualidade de vida foram extraídos pelo método standard gamble e os custos foram obtidos por microcusteio e do SIGTAP. A razão de custo-efetividade incremental (RCEI) calculada foi de R$83.573,70/AVAQ que representa 2,4 vezes o PIB per capita (R$ 35.172,00). Na análise de sensibilidade probabilística, 99% das iterações estão no limiar de até 3 vezes o PIB per capita brasileiro. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Foi realizada uma análise de impacto orçamentário da incorporação do crizotinibe no SUS, num horizonte de 5 anos, e em quatro cenários diferentes. Estimou-se a população com CPNPC avançado ALK+ a partir do histórico da produção do procedimento para quimioterapia do carcinoma pulmonar de células não pequenas avançado. O tempo em tratamento considerou a SLP obtida da literatura para crizotinibe e quimioterapia. Considerando o valor de aquisição proposto pelo proponente, a incorporação do crizotinibe demandará, no primeiro ano, um recurso incremental de R$ 6,6 milhões, sendo que no acumulado em cinco anos, esse recurso incremental é de R$ 48,3 milhões. Portanto, no cenário de maior impacto, a média anual do recurso incremental é de, aproximadamente, R$ 9,5 milhões. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram identificadas três tecnologias potenciais para o tratamento em primeira linha do câncer de pulmão não pequenas células avançado ALK positivo: iruplinalkib, lorlatinibe e XZP-3621. Todos inibidores de tirosina quinase ALK. CONSIDERAÇÕES FINAIS: Na síntese de evidências, dois estudos principais foram identificados entre os 7 artigos incluídos, o PROFILE 1014 e o PROFILE 1029. A estruturação das estratégias de busca foi adequada e nenhum estudo adicional foi encontrado na atualização das buscas para a data atual. Entretanto, foi considerada inadequada a inclusão de uma revisão sistemática (Cameron et al, 2022) por não acrescentar nenhum estudo adicional aos já incluídos e a meta-análise realizada agrupou os resultados de ensaios que avaliaram diferentes inibidores de tirosina quinase ALK. A qualidade metodológica dos estudos foi avaliada entre moderada e baixa considerando o risco de viés encontrado em um dos domínios do instrumento utilizado e a qualidade da evidência moderada. Um estudo de custo-utilidade utilizando a técnica de sobrevida particionada foi construído baseado na sobrevida livre de progressão e sobrevida global extraída dos ensaios clínicos. Os resultados mostraram uma RCEI de aproximadamente R$ 83.000/AVAQ, valor que não variou significativamente na análise de sensibilidade (até R$100.000/AVAQ), mesmo construindo cenários mais amplos (±50%) nas variáveis com maior grau de incerteza. Os valores de RCEI ficaram entre 2 e 3 vezes o PIB per capita (R$80.000/AVAQ e R$100.000/AVAQ). O impacto orçamentário incremental total em cinco anos resultante da incorporação do crizotinibe para tratamento de pacientes com CPNPC ALK+ foi estimado em R$ R$ 54.509.755,98. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Pelo exposto, os membros do Plenário, presentes na 111ª Reunião Ordinária da Conitec, no dia 04 de agosto de 2022, recomendaram que a matéria fosse disponibilizada em consulta pública com parecer desfavorável à incorporação do crizotinibe para o tratamento, em primeira linha, de pacientes adultos com câncer de pulmão não pequenas células (CPNPC) avançado ALK+. A recomendação foi justificada pela reduzida qualidade da evidência apresentada, com alto risco de viés pela falta de cegamento e altas taxas de crossover entre os grupos intervenção (crizotinibe) e comparador (quimioterapia). Os estudos demonstraram benefício modesto para o desfecho de sobrevida livre de progressão (SLP) e não foi verificada diferença para sobrevida global entre crizotinibe e quimioterapia para pacientes adultos com câncer de pulmão não pequenas células (CPNPC) avançado ALK+. CONSULTA PÚBLICA: A Consulta Pública Nº 61/2022 foi realizada no período de 13/09/2022 a 03/10/2022. Fo.ram recebidas 61 contribuições, sendo 32 pelo formulário técnico-científico e 29 pelo formulário sobre experiência ou opinião de pacientes, familiares, amigos, cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Após apreciação das contribuições recebidas na Consulta Pública, o Plenário da Conitec entendeu que houve argumentação suficiente para mudança de entendimento acerca de sua recomendação preliminar. Desse modo, a Comissão concluiu que as novas evidências apresentadas pelo demandante contribuíram para diminuir a incerteza inicial quanto ao desfecho da SLP. Adicionalmente, a avaliação de custo-efetividade, considerando a desoneração do medicamento a partir do próximo ano, diminuiu a razão de custo incremental por QALY que foi mantida dentro do limite estabelecido para doenças graves, e diminui também o impacto orçamentário. RECOMENDAÇÃO FINAL: : Pelo exposto, o Plenário da Conitec, em sua 114ª Reunião Ordinária, no dia 10 de novembro de 2022, deliberou por unanimidade recomendar a incorporação de crizotinibe para o tratamento, em primeira linha, de pacientes adultos com câncer de pulmão não pequenas células (CPNPC) avançado ALK+ no SUS. Os membros da Conitec consideraram que as novas evidências apresentadas durante a consulta pública contribuíram para diminuir as incertezas inicialmente discutidas quanto ao desfecho de sobrevida livre de progressão. Além disso, levaram em conta a redução da razão de custo incremental por QALY e do impacto orçamentário. Por fim, foi assinado o Registro de Deliberação nº 783/2022. DECISÃO: Incorporar, no âmbito do Sistema Único de Saúde - SUS, o crizotinibe para o tratamento, em primeira linha, de pacientes adultos com câncer de pulmão não pequenas células (CPNPC) avançado ALK+, conforme protocolo estabelecido pelo Ministério da Saúde, conforme a Portaria nº 168, publicada no Diário Oficial da União nº 230, seção 1, página 295, em 8 de dezembro de 2022.

Cost-effectiveness of ensartinib, crizotinib, ceritinib, alectinib, brigatinib and lorlatinib in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer in China.

Objective: Six anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), including one domestic (ensartinib) and five imported ALK-TKIs (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib), have been recommended as first-line treatments for advanced ALK-positive NSCLC in China. This study sought to examine the cost-effectiveness of these six novel therapies in Chinese patients. Material and methods: We constructed a Markov model to compare the cost-effectiveness of the six ALK-TKIs as a first-line treatment for patients with advanced ALK-positive NSCLC from the perspective of the Chinese healthcare system. Transition probabilities were estimated by synthesizing data from the PROFILE 1,029 trial and a network meta-analysis. Health state utilities and costs were sourced from published literature, publicly available national databases, and local general hospitals. The robustness of model was assessed via deterministic sensitivity analyses and probabilistic sensitivity analyses. Results: Compared with crizotinib, ensartinib achieved additional 0.12 quality-adjusted life-year (QALY) with marginal costs of $3,249, resulting in an incremental cost-effectiveness ratio (ICER) of $27,553/ QALY. When compared with ceritinib and brigatinib, ensartinib achieved additional 0.06 and 0.03 QALYs with substantially reduced costs. When compared with lorlatinib and alectinib, ensartinib was associated with a lower QALY and decreased total costs; the ICERs for lorlatinib and alectinib were $934,101/ QALY and $164,888/ QALY, respectively. Conclusion: For Chinese patients with advanced ALK-positive NSCLC, ensartinib was a cost-effective option compared with crizotinib, and was a dominant alternative to ceritinib and brigatinib. Although lorlatinib and alectinib were associated with prolonged survival compared with ensartinib, they were less cost-effective than ensartinib due to the overwhelming total costs.

The cost-effectiveness of brigatinib in adult patients with ALK inhibitor-naive ALK-positive non-small cell lung cancer from a US perspective.

BACKGROUND: The discovery of specific oncogenic drivers in non-small cell lung cancer (NSCLC) has led to the development of highly targeted anaplastic lymphoma kinase tyrosine kinase inhibitors (ALKis). Brigatinib is a next-generation ALKi associated with prolonged progression-free survival in patients with ALKi-naive ALK+ NSCLC. OBJECTIVE: To estimate the cost-effectiveness of brigatinib compared with crizotinib and alectinib in patients with ALKi-naive ALK+ NSCLC, from a US payer perspective. METHODS: A lifetime area under the curve-partitioned survival model with 4 health states was used to evaluate the relative cost-effectiveness of brigatinib in the ALKi-naive ALK+ NSCLC setting. Brigatinib was compared with crizotinib within a cost-effectiveness framework and compared with alectinib in a cost-comparison framework, where all efficacy outcomes were assumed equal. The efficacy of brigatinib and crizotinib was informed by the ALTA-1L trial, and an indirect treatment comparison was performed to inform the efficacy of brigatinib vs alectinib owing to a lack of head-to-head data. Costs were derived from public sources. The main outcomes of the model were total costs, quality-adjusted life-years (QALYs), life-years, and incremental cost-effectiveness ratios. Univariate and probabilistic sensitivity analyses, in addition to multiple scenario analyses, were conducted to assess the robustness of the model outcomes. RESULTS: The improved outcomes observed in ALTA-1L translated into QALY gains (+0.97) in the comparison of brigatinib vs crizotinib. The superior efficacy profile was associated with increased time on treatment with brigatinib, which drove the increase in costs vs crizotinib (+$210,519). The resulting base-case incremental cost-effectiveness ratio was $217,607/QALY gained. Compared with alectinib, brigatinib was associated with a cost difference of -$8,546. Sensitivity analysis suggested that extrapolation of overall survival, the assumptions relating to time on treatment, and subsequent therapy costs were the most influential determinants of results. Probabilistic sensitivity analysis suggested brigatinib had the highest probability of being cost-effective beyond willingness-to-pay thresholds of $236,000 per QALY vs crizotinib and alectinib. CONCLUSIONS: At list prices and under base-case assumptions in the current analysis, brigatinib was associated with cost-savings vs alectinib, and QALY gains but at higher costs vs crizotinib. Additional research into the real-world efficacy of ALKis is warranted to further understand the comparative cost-effectiveness of these therapies. DISCLOSURES: Ms Cranmer and Ms Kearns are employees of Takeda UK Ltd. Dr Young is a former employee of Takeda Pharmaceuticals America, Inc. Dr Humphries is an employee of Takeda Pharmaceuticals U.S.A., Inc. Mr Trueman is an employee of Source Health Economics, the consultancy company that provided health economic and writing services. This work was funded by ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Work by Source Health Economics was funded by ARIAD Pharmaceuticals, Inc. Professional medical writing assistance was provided by Phillipa White, of Source Health Economics, and funded by ARIAD Pharmaceuticals, Inc.

Crizotinib como tratamiento de primera línea para cáncer de pulmón de células no pequeñas con mutación ROS1 / Crizotinib as first-line treatment for non-small cell lung cancer with ROS1 mutation

ANTECECENTES: El cáncer de pulmón es una de las neoplasias con mayor incidencia y mortalidad a nivel mundial. En nuestro país, el cáncer de pulmón es el causante de aproximadamente 2,595 defunciones durante el año 2020, siendo la segunda neoplasia con mayor mortalidad en ambos sexos. Por general, el cáncer de pulmón es diagnosticado en etapas avanzadas de la enfermedad y la sobrevida a los 5 años es menor al 10%. • Los pacientes con CPCNP avanzado con rearreglo del ROS-1 representan el 0.9-2.6% del total de casos. La mutación del ROS-1 es más frecuente en pacientes jóvenes, de sexo femenino y sin antecedente de tabaquismo. Además, se asocia con una mayor frecuencia de metástasis al SNC durante el diagnóstico y evolución del cáncer. Crizotinib es un inhibidor tirosina quinasa que inhibe la activación de las vías de señalización que permiten el desarrollo del cáncer, obteniendo potencial beneficio en supervivencia en esta subpoblación. METOLOGÍA: Se realizó búsqueda sistemática en MEDLINE, COCHRANE, BRISA, TRIPDATABASE y INAHTA. DISCUSIÓN: El cáncer de pulmón es una de las principales neoplasias a nivel mundial y causante de una alta mortalidad. Aproximadamente 2,595 defunciones fueron reportadas en el Perú durante el año 2020, lo que lo vuelve la segunda neoplasia con la mortalidad más alta en ambos sexos en Perú. Por general, el cáncer de pulmón es diagnosticado en etapas avanzadas de la enfermedad y la sobrevida a los 5 años es menor al 10%. Los pacientes con CPCNP avanzado con rearreglo del ROS-1 representan el 0.9-2.6% del total de casos. La mutación del ROS-1 es más frecuente en pacientes jóvenes, de sexo femenino y sin antecedente de tabaquismo. Además, se asocia con una mayor frecuencia de metástasis al SNC durante el diagnóstico y evolución del cáncer. Crizotinib es un inhibidor tirosina quinasa que bloquea la proteína transmembrana, inhibiendo la activación de las vías de señalización que permiten el desarrollo del câncer. Se realizó búsqueda sistemática en MEDLINE, COCHRANE, BRISA, TRIPDATABASE e INAHTA. Sin embargo, la evidencia encontrada es limitada, debido principalmente a la infrecuencia de esta población de pacientes. A pesar de esto, las guías de práctica clínica internacionales (NCCN, ASCO, NICE y ESMO) recomiendan el empleo de Crizotinib en pacientes con CPCNP EC IV con mutación del ROS1. Una revisión sistemática publicada recientemente, reportó que Crizotinib fue seguro y eficaz en pacientes con ROS1 mutado. Con una TRO de 77.4% (IC 95%, 72.8-82.1%), una mSLP de 14.5 meses (5.5-22.8 meses) y una mSG de 32.6 meses (17.2-51.4 meses) obtenidas, apunta a que Crizotinib es un agente con eficacia importante en esta población de pobre pronóstico. Además, la toxicidad severa fue infrecuente y manejable. Los EA ≥ 3 registrados con mayor frecuencia fueron: neutropenia (5.7%), elevación de transaminasas (4.2%), anemia (2.4%), nauseas (1.8%) y vómitos (1.6%). Los ensayos clínicos prospectivos encontrados, reportan beneficio en TRO, SLP y SG; y frecuencia baja de EA grado 3-4 con Crizotinib en las poblaciones de estudio con mutación del ROS1. De forma similar, los estudios retrospectivos encontrados, reportan beneficio en supervivencia con el uso de Crizotinib en la población ROS1 mutado procedente de Asia. Con respecto al costo de la aplicación de Crizotinib, el costo de tratamiento de un paciente durante un año es de aproximadamente S/. 111,930.9. Se estima que aproximadamente 02 pacientes recibirían Crizotinib anualmente, por lo cual el costo estimado sería aproximadamente S/. 223,861.80. Se presentó la evidencia encontrada en la reunión de la Unidad Funcional de Tecnología Sanitaria (UFETS). Luego de discusión y analizar la evidencia, el panel concluye que Crizotinib debe adoptarse como opción de tratamiento como primera línea en CPCNP EC IV con mutación del ROS1. CONCLUSIONES: Los pacientes con CPCNP EC IV ROS-1 mutado son una población muy infrecuente, caracterizada por una edad menos longeva, con mayor frecuencia de metástasis cerebral. Se realizó búsqueda sistemática en MEDLINE, COCHRANE, BRISA, TRIPDATABASE y INAHTA. Las Guías de Práctica Clínica internacionales recomiendan el uso de Crizotinib en CPCNP EC IV ROS-1 mutado Una RS/MA concluye que el tratamiento con Crizotinib es eficaz y seguro en CPCNP EC IV ROS-1 mutado. Si bien la evidencia es limitada, estudios prospectivos fase I, II y estudios retrospectivos reportan que el uso de Crizotinib en CPCNP EC IV ROS-1 mutado es eficaz y segura. FDA y EMA validan el uso de Crizotinib en CPCNP EC IV ROS-1 mutado. Aproximadamente 02 pacientes recibirían terapia con crizotinib anualmente en el INEN. El costo de tratamiento con Crizotinib en cada paciente es de aproximadamente S/. 111,930.9. Se discutió la evidencia de seguridad y eficacia de Crizotinib, concluyéndose que Crizotinib debe adoptarse como opción de tratamiento como primera línea en CPCNP EC IV con mutación del ROS1.

Cost-effectiveness of ensartinib for patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer in China.

Background: Crizotinib and ensartinib improved survival in patients with ALK arrangement non-small-cell lung cancer (NSCLC); however, the economic outcomes of using ensartinib versus crizotinib are still unclear. Aim: The objective of this study was to assess the cost-effectiveness of ensartinib versus crizotinib for ALK-positive NSCLC patients from the perspective of China's healthcare system. Methods: A partitioned survival model with three health states (stable, progressive and death) was developed. Survival data were obtained from published eXalt3 clinical trials of ensartinib verses crizotinib for patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer. Parametric models were used to extrapolate outcomes beyond the trial period. The drug cost comes from the local drug procurement platform. Other costs and utility values were obtained from published literature, and one-way and probabilistic sensitivity analyses were carried out to determine the robustness of the model outcomes. Results: In the whole life cycle, the average annual cost of ensatinib was US$77,636.63, and utility value was 5.5 quality adjusted life years (QALYs). Patients receiving crizotinib had 3.315QALYs and US$32,935.88 costs over the same time horizon. The incremental cost utility ratio is US$19,810.55/QALYs. In 2021, the per capita GDP of China is US$12,721.33, and the incremental cost utility is lower than the threshold of willingness to pay US$38,163.99. Conclusion: Compared with crizotinib, ensatinib is economical in the treatment of ALK-positive NSCLC and should be promoted.

Monitoramento do horizonte tecnológico: Medicamentos para o tratamento de câncer de pulmão de células não pequenas / Monitoring the technology horizon: Drugs for the treatment of non-small cell lung cancer

A DOENÇA: O câncer de pulmão é uma das principais causas de morte evitável em todo o mundo, uma vez que em 90% dos casos diagnosticados está associado ao tabagismo. A mais recente estimativa mundial apontou que o câncer de pulmão foi a principal causa de morte por câncer (18%) durante o ano de 2020, totalizando 2,2 milhões de novos casos e 1,8 milhões de mortes no ano (2). No Brasil, em 2016, a estimativa do número de novos casos de câncer em geral foi de 596.000, sendo 28.220 (4,7%) os casos de neoplasia maligna primária de pulmão. Além disso, a estimativa nacional de novos casos de câncer de pulmão para o triênio 2020-2022 é de 17.760 em homens e 12.440 em mulheres, com cerca de 30 mil mortes no país. Em homens, o câncer de pulmão é o tipo de câncer mais incidente e a principal causa de morbimortalidade. Em mulheres, é o terceiro câncer com maior incidência e o segundo em mortalidade. Existem dois principais tipos histológicos de câncer de pulmão: câncer de pulmão de células não pequenas - CPCNP, que representa cerca de 85% de todos os casos de câncer de pulmão, e câncer de pulmão pequenas células, responsável por aproximadamente 15% dos casos (5,6). Este tem evolução clínica mais agressiva, enquanto o primeiro grupo agrega outros tipos histopatológicos. Assim, o CPCNP pode ser classificado em: i) carcinoma de células escamosas (epidermoide) e ii) carcinoma de células não escamosas, que compreende o adenocarcinoma (atualmente responsável pela maior parte dos casos, cerca de 40% a 60%) entre outras histologias menos comuns, como carcinoma de grandes células. Os tumores podem ser classificados segundo a extensão anatômica aparente da doença pelo sistema TNM, que considera três componentes: T - a extensão/características do tumor primário; N - a ausência ou presença e a extensão de metástase em linfonodos regionais (isto é, as características dos linfonodos

Eficacia y seguridad de crizotinib en pacientes adultos con cáncer de pulmón de células no pequeñas, ALK positivo, metastásico, con ecog 0-2 y que progresa a quimioterapia / Efficacy and safety of crizotinib in adult patients with metastatic ALK-positive non-small cell lung cancer with echog 0-2 and progressing to chemotherapy

INTRODUCCIÓN: Siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, la Dra. Sally Corrales Sequeiros, médica oncóloga del Hospital Nacional Edgardo Rebagliati Martins, envía al Instituto de Evaluación de Tecnologías en Salud e Investigación ­ IETSI, la solicitud de uso fuera del petitorio del producto alectinib (un inhibidor de ALK de segunda generación) para pacientes adultos con cáncer de pulmón de células no pequeñas (CPCNP), metastásico, ALK positivo que progresa a quimioterapia y crizotinib. El paciente, que motivo dicha solicitud, recibió crizotinib en forma particular. Dado que crizotinib no forma parte del Petitorio Farmacológico de EsSalud (EsSalud 2021), se vio la necesidad de evaluar su uso como opción de tratamiento en pacientes adultos con CPCNP, metastásico, ALK positivo que progresa a quimioterapia. De esta forma, se llevó a cabo una reunión técnica con la Dra. Sally Corrales Sequeiros, médica oncóloga del Hospital Nacional Edgardo Rebagliati Martins y los representantes del equipo técnico del IETSI. METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad de crizotinib, comparado con la quimioterapia basada en platino, para el tratamiento de pacientes adultos con CPCNP, metastásico, ALK positivo, con ECOG 0-2 y que progresa a quimioterapia. RESULTADOS: La presente sinopsis describe la evidencia científica sobre el uso de crizotinib como tratamiento de pacientes con adultos con CPCNP, metastásico, ALK positivo, con ECOG 0-2 y que progresa a quimioterapia, según el tipo de publicación. RECOMENDACIONES: El IETSI-EsSalud recomienda el uso de las terapias disponibles en EsSalud para el tratamiento de pacientes adultos pacientes adultos con CPCNP, metastásico, ALK positivo, con ECOG 0-2 y que progresa a quimioterapia. Adicionalmente, se recomienda a los especialistas que, en caso de identificar nueva evidencia que responda a la pregunta PICO de interés, envíen sus propuestas para ser evaluadas en el marco de la Directiva N° 003-ETSI-ESSALUD-2016. CONCLUSIONES: - El objetivo del presente dictamen fue evaluar la mejor evidencia disponible sobre la eficacia y seguridad de crizotinib comparado con la quimioterapia basada en platino para el tratamiento de pacientes adultos con CPCNP, metastásico, ALK positivo, con ECOG 0-2 y que progresa a quimioterapia. Luego de la búsqueda de la literatura se identificó una GPC desarrollada por la NCCN; tres ETS desarrolladas por SMC, NICE e IQWiG; un ECA de fase I/II denominado PROFILE 1007 publicado por Shaw et al. La guía de la NCCN no presenta recomendaciones para la población específica del presente dictamen; no obstante, ha sido incluida por ser considerada una guía de referencia para los médicos especialistas en oncología de EsSalud. Las ETS de NICE y SMC evaluaron el uso de crizotinib en pacientes con CPCNP, metastásico, ALK positivo, tratados previamente, basados en los resultados del ECA PROFILE 1007. Ambas ETS recomendaron el uso de crizotinib; pero, condicionando su uso a un descuento confidencial en el precio del medicamento. En una evaluación previa, IQWiG concluyó que no se ha probado el beneficio adicional de crizotinib en pacientes con CPCNP, metastásico, ALK positivo, tratados previamente. En una siguiente evaluación, basándose en los resultados con los resultados maduros del estudio PROFILE 1007, concluyó que estos no fueron informativos y que su decisión inicial no cambiaba. El ECA PROFILE 1007 de fase III y etiqueta abierta, evaluó crizotinib frente a quimioterapia en pacientes adultos con CPCNP, avanzado o metastásico, ALK positivo, que progresaron a un régimen de quimioterapia basada en platino. Sus resultados no mostraron diferencia en la SG entre los grupos de intervención y una mayor incidencia de EA serios con crizotinib. Además, las limitaciones del estudio afectan la validez interna del estudio y no permite determinar con certeza el efecto del tratamiento con crizotinib sobre los desenlaces evaluados. Por lo expuesto, el IETSI no aprueba el uso de crizotinib para el tratamiento de pacientes adultos con CPCNP, metastásico, ALK positivo, con ECOG 0-2 y que progresa a quimioterapia.

Cost-effectiveness analysis of first-line treatment with crizotinib in ROS1-rearranged advanced non-small cell lung cancer (NSCLC) in Canada.

INTRODUCTION: While no direct comparative data exist for crizotinib in ROS1+ non-small cell lung cancer (NSCLC), studies have suggested clinical benefit with this targeted agent. The objective of this study was to assess the cost-effectiveness of crizotinib compared to standard platinum-doublet chemotherapy for first-line treatment of ROS1+ advanced NSCLC. METHODS: A Markov model was developed with a 10-year time horizon from the perspective of the Canadian publicly-funded health care system. Health states included progression-free survival (PFS), up to two further lines of therapy post-progression, palliation and death. Given a lack of comparative data and small study samples, crizotinib or chemotherapy studies with advanced ROS1+ NSCLC patients were identified and time-to-event data from digitized Kaplan-Meier curves were collected to pool PFS data. Costs of drugs, treatment administration, monitoring, adverse events and palliative care were included in 2018 Canadian dollars, with 1.5% discounting. An incremental cost-effectiveness ratio (ICER) was estimated probabilistically using 5000 simulations. RESULTS: In the base-case probabilistic analysis, crizotinib produced additional 0.885 life-years and 0.772 quality-adjusted life-years (QALYs) at an incremental cost of $238,077, producing an ICER of $273,286/QALY gained. No simulations were found to be cost-effective at a willingness-to-pay threshold of $100,000/QALY gained. A scenario analysis assuming efficacy equivalent to the ALK+ NSCLC population showed a slightly more favorable cost-effectiveness profile for crizotinib. CONCLUSIONS: Available data appear to support superior activity of crizotinib compared to chemotherapy in ROS1+ advanced NSCLC. At the list price, crizotinib was not cost-effective at commonly accepted willingness-to-pay thresholds across a wide range of sensitivity analyses.

Potential of German claims data to characterize utilization of new cancer drugs: the example of crizotinib.

Aims: Premarketing clinical trials are typically conducted under controlled conditions and in selected study populations, so real-world information on the utilization of new cancer drugs is limited. We aimed to explore the potential of German claims data in this regard, exemplified by the ALK inhibitor crizotinib, used in non-small-cell lung cancer therapy. Materials & methods: We identified patients treated with crizotinib in the German Pharmacoepidemiological Research Database (2004-2017; 20% of the German population) and assessed patient characteristics, treatment and survival. Results: We identified 348 crizotinib-treated patients (56% female; 25% first-line users). After 2 years, overall survival was 48%, with higher survival in men than in women (58 vs 40%). Overall, 76% of patients discontinued crizotinib treatment. Of those, 41% received another ALK inhibitor afterward. Conclusion: The results underline the potential of German claims data for real-world monitoring of oncological drug utilization.

Pharmacoenhancement of Low Crizotinib Plasma Concentrations in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer using the CYP3A Inhibitor Cobicistat.

The inhibitor of anaplastic lymphoma kinase (ALK) crizotinib significantly increases survival in patients with ALK-positive non-small cell lung cancer (NSCLC). When evaluating crizotinib pharmacokinetics (PKs) in patients taking the standard flat oral dose of 250 mg b.i.d., interindividual PK variability is substantial and patient survival is lower in the quartile with the lowest steady-state trough plasma concentrations (Cmin,ss ), suggesting that concentrations should be monitored and doses individualized. We investigated whether the CYP3A inhibitor cobicistat increases Cmin,ss of the CYP3A substrate crizotinib in patients with low exposure. Patients with ALK-positive NSCLC of our outpatient clinic treated with crizotinib were enrolled in a phase I trial (EudraCT 2016-002187-14, DRKS00012360) if crizotinib Cmin,ss was below 310 ng/mL and treated with cobicistat for 14 days. Crizotinib plasma concentration profiles were established before and after a 14-day co-administration of cobicistat to construct the area under the plasma concentration-time curve in the dosing interval from zero to 12 hours (AUC0-12 ). Patients were also monitored for adverse events by physical examination, laboratory tests, and 12-lead echocardiogram. Enrolment was prematurely stopped because of the approval of alectinib, a next-generation ALK-inhibitor with superior efficacy. In the only patient enrolled, cobicistat increased Cmin,ss from 158 ng/mL (before cobicistat) to 308 ng/mL (day 8) and 417 ng/mL (day 14 on cobicistat), concurrently the AUC0-12 increased by 78% from 2,210 ng/mL*h to 3,925 ng/mL*h. Neither safety signals nor serious adverse events occurred. Pharmacoenhancement with cobicistat as an alternative for dose individualisation for patients with NSCLC with low crizotinib exposure appears to be safe and is cost-effective and feasible.

Assessment of a Highly Curated Somatic Oncology Database to Aid in the Interpretation of Clinically Important Variants in Next-Generation Sequencing Results.

This study evaluated the accuracy of NAVIFY Mutation Profiler, a cloud-based CE-IVD software that aids in interpreting clinically relevant variants detected in somatic oncology next-generation sequencing tests. This tool reports tiered classifications based on different levels of clinical evidence from a highly curated, regularly updated database derived from medical guidelines, drug approvals, and peer-reviewed literature. A retrospective analysis was performed on next-generation sequencing results from 37 lung cancer cases treated with chemotherapy (n = 10), EGFR tyrosine kinase inhibitor (TKI) (n = 5), or ALK TKI (n = 22). Several aspects were assessed, including accuracy of interpretation compared with manual curation, validity of curation content updates over time, and agreement with public databases. For chemotherapy cases with no targetable biomarkers, NAVIFY Mutation Profiler did not identify any targeted therapies. In EGFR and ALK TKI cases, the software associated appropriate targeted therapies and accurately interpreted variant combinations containing drug-resistance variants. Of the nine unique ALK mutations conferring resistance to crizotinib, NAVIFY Mutation Profiler provided correct annotation for all mutations, whereas OncoKB and Catalogue of Somatic Mutations in Cancer indicated crizotinib resistance for eight of nine mutations. For 145 variants analyzed, NAVIFY Mutation Profiler and OncoKB showed substantial agreement (Cohen κ = 0.62) for classifying actionable mutations. Furthermore, NAVIFY Mutation Profiler presented accurate targeted therapies across different regions and remained up-to-date with evolving regional approvals and medical guidelines.

Ophthalmological assessment of crizotinib in advanced non-small-cell lung cancer.

OBJECTIVES: During crizotinib clinical evaluation, visual disturbances, generally of grade 1 severity, were frequently reported adverse events (AE). Consequently, ophthalmologic assessments were included in a patient subgroup enrolled in PROFILE 1001 (NCT00585195), a phase 1, open-label, single-arm trial of crizotinib in patients with advanced non-small-cell lung cancer and are reported here. MATERIALS AND METHODS: At least 30 patients were required to undergo ophthalmologic assessments, including: best-corrected visual acuity (BCVA), refractive error, pupil size, slit-lamp anterior segment biomicroscopy, intraocular inflammation, intraocular pressure, retinal fundoscopic exams, fundus photography, ocular characteristics, and optical coherence tomography (OCT). Scheduled assessments included those at baseline, Cycle 1 Day 15, Cycle 3 Day 1 (C3D1), annually during treatment, and end of treatment (28 days after last crizotinib dose). RESULTS: Thirty-three patients completed all required ophthalmologic assessments through C3D1, and 22 (66.7 %) had abnormal findings on ≥1 ophthalmologic test. Clinically important changes were ≥2-line loss in BCVA in 10 patients (30.3 %), >±1.25-diopter change in refractive error in 3 patients (9.1 %), >±2-mm change pupillary diameter change in 3 patients (9.1 %), and >50 µm increase in OCT center point thickness in 7 patients (21.2 %). Three patients (15 %) reported clinically significant abnormalities in anterior segment biomicroscopy (grade 1 cataract [n = 2], grade 1 Visual Impairment [n = 1]). No permanent treatment discontinuations were associated with ophthalmologic findings changes. Twenty-four patients (72.7 %) reported ≥1 ocular all-causality treatment-emergent AE (TEAE); none required dose reduction or permanent discontinuation, but 2 required temporary dosing interruption. Although TEAEs and ophthalmologic findings may not have occurred concurrently, of 24 patients with ≥1 all-causality ocular TEAE, 18/24 (75.0 %) had ≥1 abnormal ophthalmologic finding and 6/24 (25 %) had none; and of 9 patients without an all-causality ocular TEAE, 4/9 (44.4 %) had ≥1 abnormal ophthalmologic finding and 5/9 (55.6 %) had none. Of the 18 patients with ≥1 abnormal ophthalmologic finding, 9 (50 %) had preexisting ocular conditions. CONCLUSION: During crizotinib treatment, ophthalmologic changes from baseline did not appear to be associated with patient-reported ocular TEAEs. Abnormal ophthalmologic findings occurred in the context of preexisting conditions for a number of patients. No ophthalmologic changes from baseline or ocular all-causality TEAEs required permanent treatment discontinuation.

Economic burden in patients with ALK + non-small cell lung cancer, with or without brain metastases, receiving second-line anaplastic lymphoma kinase (ALK) inhibitors.

Aims: To describe the real-world economic burden of patients with anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) treated with post-crizotinib, second-line ALK inhibitor therapy.Materials and methods: Retrospective analysis using data from US Optum: Clinformatics Data Mart administrative claims database. Adult patients with ALK + NSCLC treated with ceritinib or alectinib as second-line ALK inhibitors between 1 January 2011 and 30 September 2017 were included. Healthcare costs and resource utilization for up to 1 year of therapy were calculated on a per-patient-per-month (PPPM) basis and stratified by presence or absence of brain metastases (BM). Multivariate regression analysis was performed to identify factors associated with costs. Top ten cost drivers of non-inpatient procedure costs were recorded.Results: One hundred and twelve patients received second-line ALK inhibitors. Total mean PPPM healthcare costs were $23,984 for all patients receiving up to 1 year of post-crizotinib, second-line ALK inhibitor therapy. Total mean PPPM costs for patients with BM on or prior to post-crizotinib, second-line ALK inhibitor therapy were 1.37-times as high as those for patients without BM (p = 0.0406). Mean PPPM outpatient visits and inpatient hospitalization stays were higher for patients with BM versus no BM. The main cost drivers for non-inpatient procedures were radiation therapy, medications, and diagnostic radiology.Limitations: Analyses did not include newer ALK-directed therapies. BM development after the index date (defined as the date of the first claim for a second-line ALK inhibitor) may have been misclassified as non-BM. Findings may not be generalizable to patients with no health insurance coverage.Conclusions: Treatment of patients with ALK + NSCLC with ceritinib or alectinib as post-crizotinib, second-line ALK inhibitor therapy represents a high economic burden. Healthcare costs and resource utilization were significantly higher for patients with ALK + NSCLC with BM versus no BM.

Cost-effectiveness of alectinib compared to crizotinib for the treatment of first-line ALK+ advanced non-small-cell lung cancer in France.

The aim of the study is to evaluate the cost-effectiveness of alectinib for first-line treatment of ALK+ advanced non-small-cell lung cancer compared to crizotinib in the French setting. This study used a partitioned survival model, with three discrete health states (progression-free survival, post-progression survival and death). Survival probabilities were derived from a randomised Phase III clinical trial comparing alectinib to crizotinib (ALEX). Beyond the length of the trial (18 months), the efficacy of both treatments was considered equivalent. Occurrence of adverse events or brain metastases were considered as inter-current events. Utilities (and disutilities for intercurrent adverse events) derived from the EQ-5D were applied. Costs were attributed using standard French national public health tariffs. Projected mean overall survival was 4.62 years for alectinib and 4.18 years for crizotinib. Projected mean progression-free survival was 30.30 months for alectinib and 16.13 months for crizotinib. The total number of quality-adjusted life years projected was 3.40 for alectinib and 2.84 for crizotinib. The projected total cost of treatment over the lifetime of the model was € 246,022 for alectinib and € 195,486 for crizotinib. This extra cost was principally attributable to treatment acquisition costs and management before progression. Alectinib was associated with lower costs related to brain metastases and to management post-progression. The incremental cost per life year gained was 115,334 €/year and the incremental cost-effectiveness ratio was 90,232 €/QALY. First-line treatment of ALK+ NSCLC with alectinib provides superior clinical outcomes to crizotinib and is cost-effective in the French context.