Impact of concurrent medications on clinical outcomes of cancer patients treated with immune checkpoint inhibitors: analysis of Health Insurance Review and Assessment data.

PURPOSE: Medications regulating immune homeostasis and gut microbiota could affect the efficacy of immune checkpoint inhibitors (ICIs). This study aimed to investigate the impact of concurrent medications on the clinical outcomes of patients with cancer receiving ICI therapy in South Korea. METHODS: We identified patients newly treated with ICI for non-small cell lung cancer (NSCLC), urothelial carcinoma (UC), and malignant melanoma (MM) between August 2017 and June 2020 from a nationwide database in Korea. The effect of concurrent antibiotics (ATBs), corticosteroids (CSs), proton-pump inhibitors (PPIs), and opioids prescribed within 30 days before ICI initiation on the treatment duration and survival was assessed. RESULTS: In all, 8870 patients were included in the ICI cohort (NSCLC, 7,128; UC, 960; MM, 782). The patients were prescribed ATBs (33.8%), CSs (47.8%), PPIs (28.5%), and opioids (53.1%) at the baseline. The median overall survival durations were 11.1, 12.2, and 22.1 months in NSCLC, UC, and MM subgroups, respectively, since starting the ICI mostly as second-line (NSCLC and UC) and first-line (MM) therapy. Early progression was observed in 34.2% of the patients. Opioids and CS were strongly associated with poor survival across all cancer types. A high number of concurrent medications was associated with early progression and short survival. Opioid and CS use was associated with poor prognosis in all patients treated with ICIs. However, ATBs and PPIs had a cancer-specific effect on survival. CONCLUSION: A high number of concurrent medications was associated with poor clinical outcomes.

Augmenting external control arms using Bayesian borrowing: a case study in first-line non-small cell lung cancer.

Aim: This study aimed to improve comparative effectiveness estimates and discuss challenges encountered through the application of Bayesian borrowing (BB) methods to augment an external control arm (ECA) constructed from real-world data (RWD) using historical clinical trial data in first-line non-small-cell lung cancer (NSCLC). Materials & methods: An ECA for a randomized controlled trial (RCT) in first-line NSCLC was constructed using ConcertAI Patient360™ to assess chemotherapy with or without cetuximab, in the bevacizumab-inappropriate subpopulation. Cardinality matching was used to match patient characteristics between the treatment arm (cetuximab + chemotherapy) and ECA. Overall survival (OS) was assessed as the primary outcome using Cox proportional hazards (PH). BB was conducted using a static power prior under a Weibull PH parameterization with borrowing weights from 0.0 to 1.0 and augmentation of the ECA from a historical control trial. Results: The constructed ECA yielded a higher overall survival (OS) hazard ratio (HR) (HR = 1.53; 95% CI: 1.21-1.93) than observed in the matched population of the RCT (HR = 0.91; 95% CI: 0.73-1.13). The OS HR decreased through the incorporation of BB (HR = 1.30; 95% CI: 1.08-1.54, borrowing weight = 1.0). BB was applied to augment the RCT control arm via a historical control which improved the precision of the observed HR estimate (1.03; 95% CI: 0.86-1.22, borrowing weight = 1.0), in comparison to the matched population of the RCT alone. Conclusion: In this study, the RWD ECA was unable to successfully replicate the OS estimates from the matched population of the selected RCT. The inability to replicate could be due to unmeasured confounding and variations in time-periods, follow-up and subsequent therapy. Despite these findings, we demonstrate how BB can improve precision of comparative effectiveness estimates, potentially aid as a bias assessment tool and mitigate challenges of traditional methods when appropriate external data sources are available.

Unmet Needs, Quality of Life, and Financial Toxicity Among Survivors of Lung Cancer.

Importance: Despite a growing population of survivors of lung cancer, there is limited understanding of the survivorship journey. Survivors of lung cancer experience unmet physical, social, emotional, and medical needs regardless of stage at diagnosis or treatment modalities. Objective: To investigate the association of unmet needs with quality of life (QOL) and financial toxicity (FT) among survivors of lung cancer. Design, Setting, and Participants: This survey study was conducted at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center thoracic oncology clinics between December 1, 2020, and September 30, 2021, to assess needs (physical, social, emotional, and medical), QOL, and FT among survivors of lung cancer. Patients had non-small cell lung cancer of any stage and were alive longer than 1 year from diagnosis. A cross-sectional survey was administered, which consisted of an adapted needs survey developed by the Mayo Survey Research Center, the Comprehensive Score for Financial Toxicity measure, and the European Organization for Research and Treatment of Cancer QLQ-C30 QOL scale. Demographic and clinical information was obtained through retrospective medical record review. Data analysis was performed between May 9 and December 8, 2022. Main Outcomes and Measures: Separate multiple linear regression models, treating QOL and FT as dependent variables, were performed to assess the adjusted association of total number of unmet needs and type of unmet need (physical, emotional, social, or medical) with QOL and FT. Results: Of the 360 survivors of lung cancer approached, 232 completed the survey and were included in this study. These 232 respondents had a median age of 69 (IQR, 60.5-75.0) years. Most respondents were women (144 [62.1%]), were married (165 [71.1%]), and had stage III or IV lung cancer (140 [60.3%]). Race and ethnicity was reported as Black (33 [14.2%]), White (172 [74.1%]), or other race or ethnicity (27 [11.6%]). A higher number of total unmet needs was associated with lower QOL (ß [SE], -1.37 [0.18]; P < .001) and higher FT (ß [SE], -0.33 [0.45]; P < .001). In the context of needs domains, greater unmet physical needs (ß [SE], -1.24 [0.54]; P = .02), social needs (ß [SE], -3.60 [1.34]; P = .01), and medical needs (ß [SE], -2.66 [0.98]; P = .01) were associated with lower QOL, whereas only greater social needs was associated with higher FT (ß [SE], -3.40 [0.53]; P < .001). Conclusions and Relevance: The findings of this survey study suggest that among survivors of lung cancer, unmet needs were associated with lower QOL and higher FT. Future studies evaluating targeted interventions to address these unmet needs may improve QOL and FT among survivors of lung cancer.

The value of lung function assessment and Testin expression detection in clinicopathological features and prognosis of NSCLC patients.

OBJECTIVE: The aim of this study is to investigate the clinical value and potential prognostic significance of lung function assessment and Testin expression in non-small cell lung cancer (NSCLC) patients. METHODS: The NSCLC patients were classified into three groups according to lung function: group of normal lung function, group of PRISm (preserved ratio impaired spirometry) (FEV1, forced expiratory volume during the first second < 80% predicted and FEV1/FVC (forced vital capacity) ≥ 70%) and group of COPD (chronic obstructive pulmonary disease) (FEV1/FVC < 70%). The pre-operational clinicopathological characteristics of these patients were recorded and the markers of systemic inflammatory response, including neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR) and eosinophils (EOS), were compared between three groups. The expression of Testin in NSCLC samples was detected by IHC and we further explored the correlation between Testin expression and clinicopathological characteristics and prognosis of NSCLC patients. Finally, Cox regression analysis was conducted to study the prognostic factors of NSCLC patients. RESULTS: Of the 158 NSCLC patients, percentages of normal lung function, PRISm and COPD were 41.4%, 22.8% and 36.1%, respectively. Patients with tumor in the left lung were more likely to have pulmonary dysfunction (PRISm and COPD) than the right lung. The markers of systemic inflammatory response showed differences to various degree in the three groups and NSCLC patients with PRISm or COPD presented more unfavorable prognosis than patients with normal function. The expression of Testin correlated with lymph node metastasis, TNM stage and tumor invasion of NSCLC patients. Moreover, patients with low Testin expression exhibited poorer disease-free survival and overall survival than those with high Testin expression. In Cox regression analysis, we found that PRISm, COPD and Testin expression served as prognostic factors in NSCLC patients. CONCLUSIONS: The presence of COPD or PRISm influenced systemic inflammatory response and prognosis of NSCLC patients. Testin expression correlated with clinicopathological features and could be potentially used as a prognostic marker in NSCLC.

Combination tumor-treating fields treatment for patients with metastatic non-small cell lung cancer: A cost-effectiveness analysis.

BACKGROUND: Tumor-treating field (TTFields) was a novel antitumor therapy that provided significant survival for previously treated metastatic non-small cell lung cancer (mNSCLC). The consistency of the cost of the new treatment regimen with its efficacy was the main objective of the study. METHODS: The primary parameters, derived from the Phase 3 LUNAR study, were collected to evaluate the cost and efficacy of TTFields plus standard-of-care (SOC) (immune checkpoint inhibitors [ICIs] and docetaxel [DTX]) or SOC in patients with mNSCLC by establishing a three-state Markov model over a 15-year time horizon. Primary outcome measures for this study included costs, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs). Sensitivity analyses were performed. RESULTS: The total costs of TTFields plus SOC, TTFields plus ICI, and TTFields plus DTX were $319,358, $338,688, and $298,477, generating 1.23 QALYs, 1.58 QALYs, and 0.89 QALYs, respectively. The ICERs of TTFields plus SOC versus SOC, TTFields plus ICI versus ICI, and TTFields plus DTX versus DTX were $613,379/QALY, $387,542/QALY, and $1,359,559/QALY, respectively. At willingness-to-pay (WTP) thresholds of $150,000/QALY, the probability of combination TTFields being cost-effective was 0%. In addition, TTFields plus SOC exhibited similar efficacy (1.12 QALYs and 1.14 QALYs) and costs ($309,822 and $312,531) in the treatment of squamous cell carcinoma (SCC) and non-squamous cell carcinoma (NSCC) populations. CONCLUSIONS: In the United States, TTFields plus SOC as second-line treatment was not a more cost-effective strategy for patients with mNSCLC. Of the analyzed regimens, TTFields plus ICI was associated with most significant health benefits.

Critical Examination of Modeling Approaches Used in Economic Evaluations of First-Line Treatments for Locally Advanced or Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations: A Systematic Literature Review.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with up to 32% of patients with NSCLC harboring an epidermal growth factor receptor (EGFR) mutation. NSCLC harboring an EGFR mutation has a dedicated treatment pathway, with EGFR tyrosine kinase inhibitors and platinum-based chemotherapy often being the therapy of choice. OBJECTIVE: The aim of this study was to systemically review and summarize economic models of first-line treatments used for locally advanced or metastatic NSCLC harboring EGFR mutations, as well as to identify areas for improvement for future models. METHODS: Literature searches were conducted via Ovid in PubMed, MEDLINE, MEDLINE In-Process, Embase, Evidence-Based Medicine Reviews: Health Technology Assessment, Evidence-Based Medicine Reviews: National Health Service Economic Evaluation Database, and EconLit. An initial search was conducted on 19 December 2022 and updated on 11 April 2023. Studies were selected according to predefined criteria using the Population, Intervention, Comparator, Outcome and Study design (PICOS) framework. RESULTS: Sixty-seven articles were included in the review, representing 59 unique studies. The majority of included models were cost-utility analyses (n = 52), with the remaining studies being cost-effectiveness analyses (n = 4) and a cost-minimization analysis (n = 1). Two studies incorporated both a cost-utility and cost-minimization analysis. Although the model structure across studies was consistently reported, justification for this choice was often lacking. CONCLUSIONS: Although the reporting of economic models in NSCLC harboring EGFR mutations is generally good, many of these studies lacked sufficient reporting of justification for structural choices, performing extensive sensitivity analyses and validation in economic evaluations. In resolving such gaps, the validity of future models can be increased to guide healthcare decision making in rare indications.

Cost-effectiveness of first-line versus second-line use of brigatinib followed by lorlatinib in patients with ALK-positive non-small cell lung cancer.

Background: The ALTA-1 L trial and EXP-3B arm of NCT01970865 trial found that both brigatinib and lorlatinib showed durable and robust responses in treating ALK-positive non-small cell lung cancer (NSCLC) patients. However, brigatinib and lorlatinib treatments are costly and need indefinite administration until the disease progression. Thus, it remains uncertain whether using brigatinib followed by lorlatinib before chemotherapy is cost-effective compared to reserving these two drugs until progression after chemotherapy. Methods: We used a Markov model to assess clinical outcomes and healthcare costs of treating ALK-positive NSCLC individuals with brigatinib followed by lorlatinib before chemotherapy versus a strategy of reserving these drugs until progression after chemotherapy. Transition probabilities were estimated using parametric survival modeling based on multiple clinical trials. The drug acquisition costs, adverse events costs, administration costs were extracted from published studies before and publicly available data. We calculated lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from the perspective of a United States payer. Results: Our base-case analysis indicated that the incremental cost-effectiveness ratios of using first-line brigatinib followed by lorlatinib compared with second-line brigatinib followed by lorlatinib is $-400,722.09/QALY which meant that second-line brigatinib followed by lorlatinib had less costs and better outcomes. Univariate sensitivity analysis indicated the results were most sensitive to the cost of brigatinib. Probability sensitivity analysis revealed that using brigatinib followed by lorlatinib before chemotherapy had a 0% probability of cost-effectiveness versus delaying these two drugs until progression after chemotherapy at a willingness-to-pay threshold of $150,000 per QALY. Sensitivity analyses conducted revealed the robustness of this result, as incremental cost-effectiveness ratios never exceeded the willingness-to-pay threshold. Conclusion: Using brigatinib as first-line treatment followed by lorlatinib for ALK-positive NSCLC may not be cost-effective given current pricing from the perspective of a United States payer. Delaying brigatinib followed by lorlatinib until subsequent lines of treatment may be a reasonable strategy that could limit healthcare costs without affecting clinical outcomes. More mature data are needed to better estimate cost-effectiveness in this setting.

Cost-effectiveness of immunotherapies for advanced squamous non-small cell lung cancer: a systematic review.

BACKGROUND: There are differences in the pharmacoeconomics of Immune checkpoint blocking (ICB) therapies for the treatment of lung squamous cell carcinoma (LSCC). However, no corresponding review studies have fully discussed the cost-effectiveness of ICBs in treating LSCC. The aim of this paper is to systematically review and evaluate all available pharmacoeconomic studies of ICBs for LSCC. METHOD: The inclusion criteria were based on the population, intervention, comparator, outcomes, and study designs. An electronic search was conducted by June 2023, and the following databases were used: PubMed, EMBASE, Cochrane Library, and Web of Science. Search keywords included 'Carcinoma', Non-Small-Cell Lung', 'Immunotherapy', and 'Economics, Medical'. The primary outcome was the cost-effectiveness analysis of ICB therapy in LSCC patients. Drummond Checklist was used to assess quality problems and possible bias in the study design of included pharmacoeconomic studies. RESULTS: This review searched 15 articles on the economic evaluation of ICB treatment for LSCC. After a qualitative review of 15 studies, we concluded that nivolumab is more cost-effective as a monotherapy than chemotherapy alone. In the combination regimen, pembrolizumab combined with chemotherapy appears to be the most cost-effective option at present, but for Chinese payers with LSCC, locally developed treatments such as sintilimab or toripalimab in combination with chemotherapy are more cost-effective. DISCUSSION: The inclusion of economic evaluation has heterogeneity in research design and outcomes, which can only support qualitative synthesis. Therefore, The results of this paper need to be treated with caution. For the Chinese market, instead of imported drugs, the possible cost-effectiveness of locally developed ICB therapies should be the focus of future research.

Outcomes and costs with the introduction of robotic-assisted thoracic surgery in public hospitals.

Robotic-assisted thoracic surgery (RATS) is an effective treatment of non-small cell lung cancer (NSCLC) but the effects of its implementation in university hospital networks has not been described. We analyzed the early clinical outcomes, estimated costs, and revenues associated with three robotic systems implemented in the Paris Public Hospital network. A retrospective study included patients who underwent RATS for NSCLC in 2019 and 2020. Ninety-day morbidity, mortality, hospital costs, and hospital revenues were described. Economic analyses were conducted either from the hospital center or from the French health insurance system perspectives. Cost drivers were tested using univariate and multivariable analyses. Sensitivity analyses were performed to assess uncertainty over in-hospital length of stay (LOS), number of robotic surgeries per year, investment cost, operating room occupancy time, maintenance cost, and commercial discount. The study included 188 patients (65.8 ± 9.3 years; Charlson 4.1 ± 1.4; stage I 76.6%). Median in-hospital LOS was 6 days [5-9.5], 90-day mortality was 1.6%. Mean hospital expenses and revenues were €12,732 ± 4914 and €11,983 ± 5708 per patient, respectively. In multivariable analysis, factors associated with hospital costs were body mass index, DLCO, major complications, and transfer to intensive care unit. Sensitivity analyses showed that in-hospital LOS (€11,802-€15,010) and commercial discounts on the list price (€11,458-€12,732) had an important impact on costs. During the first 2 years following the installation of three robotic systems in Paris Public Hospitals, the clinical outcomes of RATS for NSCLC have been satisfactory. Without commercial discount, hospital expenses would have exceeded hospital revenues.Clinical registration number CNIL, N°2221601, CERC-SFCTCV-2021-07-20-Num17_MOPI_robolution.

Prognostic Impact of Preoperative Assessment of Muscle Mass and Strength in Surgically Resected Lung Cancer.

BACKGROUND/AIM: The association between resected non-small cell lung cancer (NSCLC) and long-term outcomes of muscle mass depletion and muscle weakness has also not been well documented. This study evaluated whether muscle mass depletion assessed by bioelectrical impedance analysis (BIA) and low muscle strength assessed by the peak expiratory flow rate as a percentage of predicted value (%PEFR) were associated with surgical outcomes in patients with resected NSCLC. PATIENTS AND METHODS: This retrospective study included 219 patients with resected NSCLC between 2016 and 2021. The cutoff value for muscle mass depletion was according to guidelines, for low muscle strength, we defined by receiver operating characteristics analysis for recurrence-free survival (RFS). Survival analysis was performed, and postoperative outcomes were compared. RESULTS: A total of 76 patients (34.7%) had muscle mass depletion, and 114 patients (52.1%) had low muscle strength. Muscle mass depletion and low muscle strength were independent poor prognostic factors for overall survival [hazard ratio (HR)=2.631, p=0.003; HR=1.983, p=0.044] and RFS (HR=3.120, p<0.001; HR=1.857, p=0.028) in multivariate analysis. Postoperative complication was associated with low muscle strength (p=0.009). Postoperative recurrence was associated with muscle mass depletion (p=0.03). CONCLUSION: Preoperative muscle mass depletion assessed by BIA and low muscle strength determined by %PEFR are worse prognostic factors after surgical resection for NSCLC. Our results may provide some important information for preoperative management.

Comparison of partitioned survival modeling with state transition modeling approaches with or without consideration of brain metastasis: a case study of Osimertinib versus pemetrexed-platinum.

BACKGROUND: The partitioned survival model (PSM) and the state transition model (STM) are widely used in cost-effectiveness analyses of anticancer drugs. Using different modeling approaches with or without consideration of brain metastasis, we compared the quality-adjusted life-year (QALY) estimates of Osimertinib and pemetrexed-platinum in advanced non-small cell lung cancer with epidermal growth factor receptor mutations. METHODS: We constructed three economic models using parametric curves fitted to patient-level data from the National Health Insurance Review and Assessment claims database from 2009 to 2020. PSM and 3-health state transition model (3-STM) consist of three health states: progression-free, post-progression, and death. The 5-health state transition model (5-STM) has two additional health states (brain metastasis with continuing initial therapy, and with subsequent therapy). Time-dependent transition probabilities were calculated in the state transition models. The incremental life-year (LY) and QALY between the Osimertinib and pemetrexed-platinum cohorts for each modeling approach were estimated over seven years. RESULTS: The PSM and 3-STM produced similar incremental LY (0.889 and 0.899, respectively) and QALY (0.827 and 0.840, respectively). However, 5-STM, which considered brain metastasis as separate health states, yielded a slightly higher incremental LY (0.910) but lower incremental QALY (0.695) than PSM and 3-STM. CONCLUSIONS: Our findings indicate that incorporating additional health states such as brain metastases into economic models can have a considerable impact on incremental QALY estimates. To ensure appropriate health technology assessment decisions, comparison and justification of different modeling approaches are recommended in the economic evaluation of anticancer drugs.

Tumor microenvironment(TME) and single-source dual-energy CT(ssDECT) on assessment of inconformity between RECIST1.1 and pathological remission in neoadjuvant immunotherapy of NSCLC.

BACKGROUND: The inconformity (IC) between pathological and imaging remissions after neoadjuvant immunotherapy in patients with NSCLC can affect the evaluation of curative effect of neoadjuvant therapy and the decision regarding the chance of surgery. MATERIALS AND METHODS: Patients who achieved disease control(CR/PR/SD) after neoadjuvant chemoimmunotherapy from a clinical trial (NCT04326153) and after neoadjuvant chemotherapy during the same period were enrolled in this study. All patients underwent radical resection and systematic mediastinal lymphadenectomy after neoadjuvant treatments. The pathological remission, immunohistochemistry (CD4, CD8, CD20, CD56, FoxP3, CD68, CD163, CD11b tumor-infiltrating lymphocytes, or macrophages), and single-source dual-energy computed tomography (ssDECT) scans were assessed. The IC between imaging remission by CT and pathological remission was investigated. The underlying cause of IC, the correlation between IC and DFS, and prognostic biomarkers were explored. RESULTS: After neoadjuvant immunotherapy, enhanced immune killing and reduced immunosuppressive performance were observed. 70 % of neoadjuvant chemoimmunotherapy patients were in high/medium IC level. Massive necrosis and repair around and inside the cancer nest were the main pathological changes observed 30-45 days post-treatment with PD1/PD-L1 antibody and were the main causes of IC between the pathology and imaging responses after neoadjuvant immunotherapy. High IC and preoperative CD8 expression (H score ≥ 3) indicate a high pathological response rate and prolonged DFS. Iodine material density ssDECT images showed that the iodine content in the lesion causes hyperattenuation in post-neoadjuvant lesion in PCR patient. CONCLUSIONS: Compared to chemotherapy and targeted therapy, the efficacy of neoadjuvant immunotherapy was underestimated based on the RECIST criteria due to the unique antitumor therapeutic mechanism. Preoperative CD8+ expression and ssDECT predict this IC and evaluate the residual tumor cells. This is of great significance for screening immune beneficiaries and making more accurate judgments about the timing of surgery.

Cost-Effectiveness Analysis of Sintilimab Plus Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer: A Societal Perspective.

INTRODUCTION: The updated ORIENT-11 study demonstrated that sintilimab, when combined with chemotherapy, had promising survival advantage compared to standard chemotherapy alone in the first-line treatment for previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer (nsNSCLC). This study aims to evaluate the cost-effectiveness of sintilimab plus chemotherapy for advanced nsNSCLC from a Chinese societal perspective. METHODS: A partitioned survival model with a embedded decision tree was developed to assess the economic value of sintilimab plus chemotherapy over a lifetime horizon. Clinical data was captured from the updated ORIENT-11 study, while costs, health productivity losses, and utility values were collected from a nationwide cross-sectional survey in tertiary hospitals across multiple provinces in China. The primary outcomes were measured using the metrics of quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICER). Costs and health outcomes were discounted at an annual rate of 5% per annum. Sensitivity analyses, including one-way and probabilistic sensitivity analyses, subgroup analyses, and scenario analyses, were performed. RESULTS: Compared to standard chemotherapy, treatment with sintilimab plus chemotherapy incurred a mean total cost of $23,979 and gained 0.98 QALYs over the lifetime horizon, resulting in an ICER of $24,568 per QALY gained. The use of sintilimab accumulated direct non-medical costs of $9262 and indirect costs of $6780 over 16 years. Probabilistic sensitivity analyses showed an 84.2% probability of sintilimab plus chemotherapy being cost-effective at a threshold of three times China's per capita gross domestic product in 2022 ($38,201). The model was most sensitive to the discount rate of QALYs and costs, as well as the costs of pemetrexed, sintilimab, and subsequent therapy in progressive disease state. Subgroup analyses indicated favorable incremental net monetary benefits in all subgroups. CONCLUSION: Sintilimab plus chemotherapy is a cost-effective first-line treatment therapy for advanced nsNSCLC in China when compared to standard chemotherapy. These findings, along with the improved progression-free survival and overall survival (OS) observed in ORIENT-11, support the use of this regimen in eligible candidates for advanced nsNSCLC.

RT-PCR para identificação de mutação do receptor do fator de crescimento epidérmico (EGFR) em pacientes com câncer de pulmão de células não pequenas / RT-PCR for identification of epidermal growth factor receptor (EGFR) mutation in patients with non-small cell lung cancer

INTRODUÇÃO: O câncer de pulmão foi o segundo tipo de câncer mais diagnosticado (11,4%) no mundo e 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. Considera-se para fins terapêuticos e prognósticos a divisão em dois principais tipos histológicos: câncer de pulmão células não pequenas células (CPCNP), que representa cerca de 85% de todos os casos de câncer de pulmão, e câncer de pulmão pequenas células (CPPC), associado a aproximadamente 15% dos casos. O comportamento biológico dos tumores malignos pode estar relacionado à expressão molecular, principalmente de proteínas envolvidas no crescimento e sobrevivência celulares, de modo que a segurança e a eficácia do tratamento guardam relação não só com o subtipo histopatológico como também com as características moleculares do tumor. Assim, para melhor direcionamento da terapia (por exemplo, erlotinibe e gefinitibe), torna-se importante diferenciar os subtipos histológicos, e identificar a presença de mutações específicas, como, por exemplo formas alteradas no gene do EGFR, como se recomenda nas Diretrizes Diagnósticas e Terapêuticas do Câncer de Pulmão do Ministério da Saúde. Entretanto, o Ministério da Saúde não recomenda nenhuma técnica específica para identificação de mutação no gene do EGFR, sendo que o rt-PCR é considerado o teste de referência em muitos contextos clínicos e estudos, seguido pelo sequenciamento de nova geração (NGS). PERGUNTA: Em pacientes diagnosticados com CPCNP, qual a acurácia diagnóstica, custoefetividade e impacto orçamentário do diagnóstico molecular por meio da técnica de rtPCR para identificação de mutação do EGFR em comparação ao NGS ou a não realização de rt-PCR? EVIDÊNCIAS CIENTÍFICAS: A revisão sistemática identificou 19 estudos observacionais de acurácia diagnóstica (teste de referência: NGS). A sensibilidade e especificidade do rt-PCR em comparação ao NGS foi de 92,0% e 97,0%, respectivamente. Apenas um estudo reportou dados de sobrevida global para a comparação de rt-PCR positivo e negativo para mutação de EGFR, apresentando uma diferença não significativa estatisticamente, de 19,2 versus 11,6 meses (Log rank p=0,143). Todos os estudos apresentaram ao menos um domínio com alto risco de viés e nenhuma preocupação quanto à aplicabilidade. AVALIAÇÃO ECONÔMICA: Na análise de custo-efetividade/utilidade comparou-se a realização de rt-PCR com a não realização do teste para um horizonte temporal por toda vida. A análise sugere que a realização do rt-PCR de mutação do EGFR para auxiliar na padronização do melhor tratamento de pacientes com CPCNP e sem tratamento prévio na fase metastática, em comparação a não realização do teste, sugere um modesto benefício clínico de 0,043 ano de vida ajustado pela qualidade (QALY) e 0,040 ano de vida (AV) ganho e uma economia de R$ 3.138,25. Portanto, rt-PCR dominou a não realização do teste (razão de custo-efetividade incremental, RCEI, não representada em casos de dominância). Ademais, as análises de sensibilidade determinística revelaram que para QALY e AV, as proporções de pacientes que usam o erlotinibe e gefitinibe são as variáveis que mais impactam na RCEI, seguida pela proporção de resultados positivos obtidos pela rt-PCR de mutação do EGFR. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: Considerando um horizonte temporal de cinco anos, utilizando demanda aferida (dados de APAC de 2015 a 2021) foi estimado o quantitativo de pacientes com carcinoma pulmonar de células não pequenas avançado. Ademais, foi estimada uma taxa de difusão conservadora, tendo um aumento de 10% ao ano para a tecnologia em análise. Desta forma, observou-se que a incorporação do rt-PCR para identificação de mutação do EGFR em pacientes com CPCNP, sem tratamento prévio na fase metastática, pode gerar um incremento de R$ 1.553.250,00 no primeiro ano, chegando a um incremento de R$ 8.193.750,00 no quinto ano de análise (total acumulado de cerca de R$ 24 milhões em cinco anos) em análise que não considera as potenciais economias com a incorporação do teste. Em análise de sensibilidade considerando preço 20% menor, coerente com preço informado por um dos fabricantes contatados, o impacto orçamentário acumulado em cinco anos seria de cerca de R$ 20 milhões. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: No Monitoramento do Horizonte Tecnológico foi encontrada 1 tecnologia, a Allele-Discriminating Priming System (kit - ADPS), da empresa Genecast, sem identificação de licenças sanitárias Anvisa e FDA. CONSIDERAÇÕES FINAIS: A evidência disponível sobre o uso de rt-PCR para identificação de mutação EGFR em comparação ao NGS sugere elevada acurácia do rt-PCR, com sensibilidade e especificidade de 92,0% e 97,0%, respectivamente. A análise de custoefetividade sugere que a realização da rt-PCR de mutação do EGFR em pacientes com CPCNP, em comparação a não realização do teste, é dominante para QALY e AV. A análise de impacto orçamentário da incorporação da rt-PCR de mutação do EGFR em pacientes com CPCNP, no SUS, sugere um incremento de cerca de R$ 21 a 40 milhões em cinco anos de análise, a depender do preço do kit e market share considerado, em análise que não considera a potencial economia com a incorporação do teste. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Comitê de Procedimentos e Produtos, presentes na 123ª Reunião Ordinária da Conitec realizada no dia 05 de outubro de 2023, deliberaram por unanimidade que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à incorporação do diagnóstico molecular por meio da técnica de rt-PCR para identificação de mutação do EGFR em pacientes com câncer de pulmão de células não pequenas. CONSULTA PÚBLICA: A consulta pública nº 51 foi realizada entre os dias 12 de dezembro de 2023 e 02 de janeiro de 2024. Foram recebidas 50 contribuições, sendo 6 classificadas como técnico-científicas e 44 como de experiência ou opinião. Todas as contribuições foram favoráveis à incorporação de rt-PCR para identificação de mutação do EGFR em pacientes com CPCNP. Referente às contribuições técnico-científicas, os estudos sugeridos para inclusão no PTC não contemplavam os critérios de elegibilidade da pergunta PIROS e todas as demais contribuições corroboram os resultados apresentados no relatório de recomendação. Quanto às contribuições de experiência e opinião, das 44 recebidas, uma foi desconsiderada por tratar de outra consulta pública. Também foram recebidos dois anexos. As contribuições recebidas e anexos foram submetidos à análise de conteúdo temática. Das 43 contribuições consideradas, todas expressaram concordância em relação à recomendação preliminar da Conitec, portanto, mostraramse favoráveis à incorporação do procedimento em avaliação. Os participantes que tiveram experiência com o rt-PCR relataram como efeitos positivos a importância do uso e acesso ao teste para os pacientes usuários do SUS terem um melhor direcionamento no tratamento do câncer de pulmão de células não pequenas. Enquanto efeitos negativos e dificuldades no uso do rt-PCR, foram apontados a dificuldade no acesso e o custo. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Comitê de Produtos e Procedimentos presentes na 126ª Reunião Ordinária da Conitec deliberaram, por unanimidade, recomendar a incorporação de rt-PCR para identificação da mutação do receptor do fator de crescimento epidérmico (EGFR) em pacientes com câncer de pulmão de células não pequenas. Foi assinado o Registro de Deliberação nº 876/2024. DECISÃO: e incorporar, no âmbito do Sistema Único de Saúde - SUS, o RT-PCR para identificação de mutação do receptor do fator de crescimento epidérmico (EGFR) em pacientes com câncer de pulmão de células não pequenas, publicada no Diário Oficial da União nº 46, seção 1, página 54, em 07 de março de 2024.

Cost of genetic testing, delayed care, and suboptimal treatment associated with polymerase chain reaction versus next-generation sequencing biomarker testing for genomic alterations in metastatic non-small cell lung cancer.

AIMS: To assess US payers' per-patient cost of testing associated with next-generation sequencing (NGS) versus polymerase chain reaction (PCR) biomarker testing strategies among patients with metastatic non-small cell lung cancer (mNSCLC), including costs of testing, delayed care, and suboptimal treatment initiation. METHODS: A decision tree model considered biomarker testing for genomic alterations using either NGS, sequential PCR testing, or hotspot panel PCR testing. Literature-based model inputs included time-to-test results, costs for testing/medical care, costs of delaying care, costs of immunotherapy [IO]/chemotherapy [CTX] initiation prior to receiving test results, and costs of suboptimal treatment initiation after test results (i.e. costs of first-line IO/CTX in patients with actionable mutations that were undetected by PCR that would have been identified with NGS). The proportion of patients testing positive for a targetable alteration, time to appropriate therapy initiation, and per-patient costs were estimated for NGS and PCR strategies combined. RESULTS: In a modeled cohort of 1,000,000 members (25% Medicare, 75% commercial), an estimated 1,119 had mNSCLC and received testing. The proportion of patients testing positive for a targetable alteration was 45.9% for NGS and 40.0% for PCR testing. Mean per-patient costs were lowest for NGS ($8,866) compared to PCR ($18,246), with lower delayed care costs of $1,301 for NGS compared to $3,228 for PCR, and lower costs of IO/CTX initiation prior to receiving test results (NGS: $2,298; PCR:$5,991). Cost savings, reaching $10,496,220 at the 1,000,000-member plan level, were driven by more rapid treatment with appropriate therapy for patients tested with NGS (2.1 weeks) compared to PCR strategies (5.2 weeks). LIMITATIONS: Model inputs/assumptions were based on published literature or expert opinion. CONCLUSIONS: NGS testing was associated with greater cost savings versus PCR, driven by more rapid results, shorter time to appropriate therapy initiation, and minimized use of inappropriate therapies while awaiting and after test results.

Rapid automated extracellular vesicle isolation and miRNA preparation on a cost-effective digital microfluidic platform.

As a prerequisite for extracellular vesicle (EV) -based studies and diagnosis, effective isolation, enrichment and retrieval of EV biomarkers are crucial to subsequent analyses, such as miRNA-based liquid biopsy for non-small-cell lung cancer (NSCLC). However, most conventional approaches for EV isolation suffer from lengthy procedure, high cost, and intense labor. Herein, we introduce the digital microfluidic (DMF) technology to EV pretreatment protocols and demonstrate a rapid and fully automated sample preparation platform for clinical tumor liquid biopsy. Combining a reusable DMF chip technique with a low-cost EV isolation and miRNA preparation protocol, the platform completes automated sample processing in 20-30 min, supporting immediate RT-qPCR analyses on EV-derived miRNAs (EV-miRNAs). The utility and reliability of the platform was validated via clinical sample processing for EV-miRNA detection. With 23 tumor and 20 non-tumor clinical plasma samples, we concluded that EV-miR-486-5p and miR-21-5p are effective biomarkers for NSCLC with a small sample volumn (20-40 µL). The result was consistent to that of a commercial exosome miRNA extraction kit. These results demonstrate the effectiveness of DMF in EV pretreatment for miRNA detection, providing a facile solution to EV isolation for liquid biopsy.

Environment-Sensitive Fluorescent Probe Enables Assessment of Anaplastic Lymphoma Kinase Activity in Nonsmall Cell Lung Cancer.

Anaplastic lymphoma kinase (ALK) rearrangements have been identified as key oncogenic drivers of a subset of nonsmall cell lung cancer (NSCLC). The final chimeric protein of the fusion gene can be constitutively activated, which accounts for the growth and proliferation of ALK-rearranged tumors and thus strongly associates with cancer invasion and metastasis. Diagnostic tools enabling the visualization of ALK activity in a structure-function-based approach are highly desirable to determine ALK status and guide ALK tyrosine kinase inhibitor (ALK-TKI) treatment making. Here, we describe the design, synthesis, and application of a new environment-sensitive fluorescent probe HX16 by introducing an environment-sensitive fluorophore 4-sulfonamidebenzoxadiazole to visualize ALK activity in living cancer cells and tumor tissue slices (mouse model and human biopsy sample). HX16 is a multifunctional chemical tool based on the pharmacophore of ALK-TKI (ceritinib) and can specifically target the kinase domain of ALK with a high sensitivity. Using flow cytometry and confocal microscopy, HX16 enables visualization of ALK activity in various cancer cells with distinct ALK fusion genes, as well as xenograft mouse models. Importantly, HX16 was also applied to visualize ALK activity in a tumor biopsy from a NSCLC patient with ALK-echinoderm microtubule-associated protein-like-4 fusion gene for prediction of ALK-TKI sensitivity. These results demonstrate that strategically designed ALK-TKI-based probe allows the assessment of ALK activity in tumor tissues and hold promise as a useful diagnostic tool in predicting ALK-TKI therapy response.

Economic evaluation of cemiplimab plus chemotherapy regimen for advanced non-small-cell lung cancer.

OBJECTIVE: Cemiplimab, a novel PD-1 inhibitor, exhibits significant antitumor activity against advanced non-small cell lung cancer (NSCLC). However, the cost-effectiveness of this drug for the treatment remains unclear. This study aimed to assess the cost-effectiveness of cemiplimab plus chemotherapy compared to chemotherapy for the treatment of advanced NSCLC, from the perspective of the United States payer. METHODS: A partitioned survival approach was developed to project the disease progression of NSCLC. Overall survival (OS) and progression-free survival (PFS) data were obtained from the EMPOWER lung 3 trial and extrapolated to estimate long-term survival outcomes. Direct medical costs and utility data were collected. The primary outcome measure, the incremental cost-utility ratio (ICUR), was used to evaluate the cost-effectiveness of cemiplimab plus chemotherapy regimen. One-way sensitivity analyses (OWSA) and probabilistic sensitivity analyses (PSA) were conducted to assess the robustness of the results. RESULTS: In the base-case analysis, the ICUR for cemiplimab plus chemotherapy versus chemotherapy alone was estimated to be $395,593.8 per quality-adjusted life year (QALY). OWSA revealed that the results were sensitive to Hazard ratio value, utility of PFS, and cost of cemiplimab. PSA demonstrated that cemiplimab plus chemotherapy exhibited 0% probability of cost-effectiveness.In hypothetical scenario analysis, the ICUR of two regimens was $188.803.3/QALY. OWSA revealed that the results were sensitive to the discount rate, utility, and cost of cemiplimab. PSA indicated that cemiplimab plus chemotherapy achieved at least an 11.5% probability of cost-effectiveness. CONCLUSION: Our cost-effectiveness analysis suggests that, at its current price, cemiplimab plus chemotherapy regimen is unlikely to be a cost-effective option compared with chemotherapy alone for advanced NSCLC patients, based on a threshold of $150,000 per QALY, from the perspective of the US payer.

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.

Medicaid Expansion Under the Affordable Care Act and Early Mortality Following Lung Cancer Surgery.

Importance: Medicaid expansion under the Patient Protection and Affordable Care Act is associated with gains in health insurance coverage, earlier stage diagnosis, and improved survival among patients with cancer. Objective: To examine the association of Medicaid expansion with changes in early mortality among adults undergoing surgical resection of non-small cell lung cancer (NSCLC), a setting in which access to care is a major determinant of survival. Design, Setting, and Participants: This cohort study used the National Cancer Database to identify 14 984 adults 45 to 64 years of age who underwent surgical resection of NSCLC between 2008 and 2019. Analysis was conducted between March 28, 2021, and September 1, 2023. Exposure: State of residence Medicaid expansion status. Main Outcomes and Measures: Descriptive statistics were used to compare study population characteristics by Medicaid expansion status of patients' state of residence. Difference-in-differences analyses were used to evaluate the association between Medicaid expansion and postoperative mortality before implementation of the ACA (2008-2013) vs after (2014-2019). Results: Among 14 984 adults included, the mean (SD) age was 56.3 (5.1) years, 54.6% were women, and 62.1% lived in Medicaid expansion states. Both 30-day (from 0.97% to 0.26%) and 90-day (from 2.63% to 1.32%) postoperative mortality decreased from before the ACA to after among patients residing in Medicaid expansion states (both P < .001) but not in nonexpansion states (30-day mortality before the ACA, 0.75% vs after the ACA, 0.68%; P = .74; and 90-day mortality before the ACA, 2.43% vs after the ACA, 2.20%; P = .57), leading to a difference-in-differences of -0.64 percentage points (95% CI, -1.19 to -0.08; P = .03) for 30-day mortality and -1.08 percentage points (95% CI, -2.08 to -0.08; P = .03) for 90-day mortality. The difference-in-differences for in-hospital mortality was not significant (P = .34) between expansion states (1.41% before the ACA to 0.77% after the ACA; 0.63 percentage point decrease; P = .004) and nonexpansion states (1.49% before the ACA to 1.20% after the ACA; 0.30 percentage point decrease; P = .29). Conclusions and Relevance: In this cohort study of patients with NSCLC, Medicaid expansion was associated with declines in 30- and 90-day postoperative mortality following hospital discharge. These findings suggest that Medicaid expansion may be an effective strategy for improving access to care and cancer outcomes in this population.