Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L).

PURPOSE: Patients with non-small-cell lung cancer (NSCLC) have been shown to benefit from maintenance therapy. COMPASS evaluated the efficacy and safety of bevacizumab with or without pemetrexed as continuation maintenance therapy after carboplatin, pemetrexed, and bevacizumab induction therapy. PATIENTS AND METHODS: Patients with untreated advanced nonsquamous NSCLC without confirmed EGFR 19 deletion or L858R mutation received first-line therapy with carboplatin area under the curve 6, pemetrexed 500 mg/m2, and bevacizumab 15 mg/kg once every 3 weeks for 4 cycles. Patients without disease progression during the induction therapy were randomly assigned 1:1 for maintenance therapy with pemetrexed 500 mg/m2 plus bevacizumab 15 mg/kg or bevacizumab 15 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) after random assignment. RESULTS: Between September 2010 and September 2015, 907 patients received induction therapy. Of those, 599 were randomly assigned: 298 received pemetrexed plus bevacizumab, and 301 received bevacizumab. The median OS was 23.3 v 19.6 months (hazard ratio [HR], 0.87; 95% CI, 0.73 to 1.05; 1-sided stratified log-rank P = .069). In the wild-type EGFR subset, the OS HR was 0.82 (95% CI, 0.68 to 0.99; 1-sided unstratified log-rank P = .020). The median progression-free survival (PFS) was 5.7 v 4.0 months (HR, 0.67; 95% CI, 0.57 to 0.79; 2-sided log-rank P < .001). The safety data were consistent with previous reports of treatment regimens. CONCLUSION: In terms of the primary end point of OS, no statistically significant benefit was observed; however, PFS in the total patient population and OS in patients with wild-type EGFR was prolonged with the addition of pemetrexed to bevacizumab maintenance therapy.

Cost-Utility Analysis of First-Line Pemetrexed Plus Cisplatin in Non-Small Cell Lung Cancer in Thailand.

OBJECTIVE: To assess the cost-effectiveness of first-line chemotherapy regimens for non-small cell lung cancer patients in Thailand. METHODS: A Markov model comprising 3 health states (progression-free survival, progression, death) was used to estimate the long-term costs and health outcomes under a societal perspective with a lifetime horizon. Intervention was the combination of pemetrexed and cisplatin, AND the comparators were gemcitabine plus cisplatin and carboplatin plus paclitaxel. The efficacy and toxicity were obtained from landmark clinical trials, and the costs were based on a local Thai database. All costs and outcomes were discounted at 3%. The findings were reported as incremental cost-effectiveness ratios (ICERs) in both Thai baht (THB) and USD per quality-adjusted life year (QALY) gained. A series of sensitivity analyses, including 1-way and probabilistic sensitivity analyses, were performed. A cost-effectiveness acceptability curve was generated with a threshold of 160 000 THB/QALY or 4987 USD/QALY. RESULTS: Under the base-case analysis, pemetrexed plus cisplatin had the greatest total cost among 3 regimens, yielding an ICER of 64 369.97 USD/QALY (2 064 989 THB/QALY) compared with gemcitabine plus cisplatin, and ICER of 8649.16 USD/QALY (277 465 THB/QALY) compared with carboplatin plus paclitaxel. The probabilistic sensitivity analysis results indicated that at the local Thai threshold, gemcitabine plus cisplatin was likely to be the most cost-effective regimen. CONCLUSIONS: At the current price of pemetrexed, the combination of pemetrexed plus cisplatin was not found to be a cost-effective first-line regimen for patients with non-small cell lung cancer at the local Thai threshold compared with the gemcitabine plus cisplatin and carboplatin plus paclitaxel regimens.

Cost-effectiveness of Osimertinib as a Second-line Treatment in Patients With EGFR-mutated Advanced Non-Small Cell Lung Cancer in China.

PURPOSE: To assess the cost-effectiveness of osimertinib used as a second-line treatment after failure of epidermal growth factor receptor tyrosine kinase inhibitor therapy for advanced non-small cell lung cancer (NSCLC) in China. METHODS: From the perspective of China's health care system, a Markov model was used for estimating the costs and health outcomes of osimertinib and 4 platinum-based chemotherapies, including pemetrexed + platinum (PP), gemcitabine + platinum (GP), docetaxel + platinum (DP), and paclitaxel + platinum (TP). Two scenarios were considered, one in all confirmed patients with T790M-positive disease (scenario 1) and the other in all patients whose disease progressed after epidermal growth factor receptor tyrosine kinase inhibitor therapy, which consisted of patients with T790M-positive or T790M-negative NSCLC (scenario 2). Clinical data for transition probabilities and treatment effects were obtained from published clinical trials. Health care resource utilization and costs were derived from local administrative databases and published literature. Deterministic and probabilistic sensitivity analyses were conducted to assess the uncertainty of the results. FINDINGS: In the base-case analysis, compared with the 4 platinum-based chemotherapies, osimertinib yielded an additional 0.671 to 0.846 quality-adjusted life-year (QALY), with incremental costs of 15,943 to 20,299 USD in scenario 1, and an additional 0.376 to 0.808 QALY with incremental costs of 9710 to 15,407 USD in scenario 2. In the probabilistic sensitivity analysis, the probabilities that osimertinib would be cost-effective were 57.7% in scenario 1 and 58.4% in scenario 2 if the willingness-to-pay threshold were 30,000 USD/QALY, and probabilities would be more than 75 % in both scenarios if the willingness-to-pay threshold were 50,000 USD/QALY. IMPLICATIONS: Osimertinib is likely to be cost-effective when used as a second-line treatment of advanced NSCLC in China based on the latest reimbursement price of osimertinib through National Reimbursement Drug List negotiation.

Determining the Comparative Value of Pharmaceutical Risk-Sharing Policies in Non-Small Cell Lung Cancer Using Real-World Data.

BACKGROUND: Risk-sharing arrangements (RSAs) can be used to mitigate uncertainty about the value of a drug by sharing the financial risk between payer and pharmaceutical company. We evaluated the projected impact of alternative RSAs for non-small cell lung cancer (NSCLC) therapies based on real-world data. METHODS: Data on treatment patterns of Dutch NSCLC patients from four different hospitals were used to perform "what-if" analyses, evaluating the costs and benefits likely associated with various RSAs. In the scenarios, drug costs or refunds were based on response evaluation criteria in solid tumors (RECIST) response, survival compared to the pivotal trial, treatment duration, or a fixed cost per patient. Analyses were done for erlotinib, gemcitabine/cisplatin, and pemetrexed/platinum for metastatic NSCLC, and gemcitabine/cisplatin, pemetrexed/cisplatin, and vinorelbine/cisplatin for nonmetastatic NSCLC. RESULTS: Money-back guarantees led to moderate cost reductions to the payer. For conditional treatment continuation schemes, costs and outcomes associated with the different treatments were dispersed. When price was linked to the outcome, the payer's drug costs reduced by 2.5% to 26.7%. Discounted treatment initiation schemes yielded large cost reductions. Utilization caps mainly reduced the costs of erlotinib treatment (by 16%). Given a fixed cost per patient based on projected average use of the drug, risk sharing was unfavorable to the payer because of the lower than projected use. The impact of RSAs on a national scale was dispersed. CONCLUSIONS: For erlotinib and pemetrexed/platinum, large cost reductions were observed with risk sharing. RSAs can mitigate uncertainty around the incremental cost-effectiveness or budget impact of drugs, but only when the type of arrangement matches the setting and type of uncertainty.

Cost-effectiveness of pembrolizumab in combination with chemotherapy in the 1st line treatment of non-squamous NSCLC in the US.

AIMS: To describe cost-effectiveness of pembrolizumab plus platinum and pemetrexed chemotherapy in metastatic, non-squamous, NSCLC patients in the US. MATERIALS AND METHODS: A model is developed utilizing partitioned survival analysis to estimate the cost-effectiveness of KEYNOTE-189 trial comparators pembrolizumab + chemotherapy (carboplatin/cisplatin + pemetrexed) vs chemotherapy alone. Clinical efficacy, treatment utilization, health utility, and safety data are derived from the trial and projected over 20 years. For extrapolating survival beyond the trial, a novel SEER population-data approach is applied (primary analysis), with separate estimation via traditional parametric extrapolation methods. Costs for drugs and non-drug disease management are also incorporated. Based on an indirect treatment comparison, cost-effectiveness of pembrolizumab + chemotherapy vs pembrolizumab monotherapy is evaluated for patients with programmed death-ligand 1 (PD-L1) ≥ 50%. RESULTS: In the full non-squamous population, pembrolizumab + chemotherapy is projected to increase life expectancy by 2.04 years vs chemotherapy (3.96 vs 1.92), for an approximate doubling of life years. Resultant incremental cost-effectiveness ratios (ICERs) are $104,823/QALY and $87,242/life year. In patients with PD-L1 ≥ 50% and 1-49%, life expectancy is more than doubled (4.53 vs 1.88 years) and (4.87 vs 2.01 years), with a 32% (2.60 vs 1.97 years) increase in PD-L1 < 1% patients. Corresponding incremental costs/quality-adjusted life year (QALY) are $103,402, $66,837, and $183,529 for PD-L1 ≥ 50%, 1-49%, and <1% groups, respectively. Versus pembrolizumab monotherapy in PD-L1 ≥ 50% patients, representing current standard of care, pembrolizumab + chemotherapy increases life expectancy by 65% (4.53 vs 2.74 years) at an ICER of $147,365/QALY. LIMITATIONS AND CONCLUSIONS: The addition of pembrolizumab to chemotherapy is projected to extend life expectancy to a point not previously seen in previously untreated metastatic non-squamous NSCLC. Although ICERs vary by sub-group and comparator, results suggest pembrolizumab + chemotherapy yields ICERs near, or in most cases, well below a 3-times US per capita GDP threshold of $180,000/QALY, and may be a cost-effective first-line treatment for metastatic non-squamous NSCLC patients.

A cost-effectiveness analysis of consolidative local therapy in oligometastatic non-squamous non-small cell lung cancer (NSCLC).

BACKGROUND: Novel systemic therapies have improved the prognosis of metastatic non-small cell lung cancer (NSCLC), but costs of some of these drugs are a matter of ongoing debate. More recently, local therapies (LT) such as radiotherapy and surgery have been suggested as additional treatment in oligometastatic NSCLC demonstrating an improved progression-free survival (PFS) in a phase II trial compared to maintenance chemotherapy (MC) alone. The aim of this analysis was to assess the cost-effectiveness of local therapies in oligometastatic NSCLC. METHODS: We constructed a Markov model comparing the cost-effectiveness of LT versus MC for oligometastatic NSCLC from the Swiss healthcare payer's perspective. Treatment specifications and PFS were based on the phase II trial (NCT01725165). Overall survival (OS) was inferred from a recent phase III trial. Utilities were taken from published data. Primary outcome was the incremental cost-effectiveness-ratio (ICER, costs in Swiss Francs (CHF) per quality-adjusted life-year (QALY) gained). RESULTS: PFS in the model was 3.8 months for MC and 11.4 months for LT (compared to 3.9 months and 11.9 months in the trial). OS in the model was 15.5 months in both arms. LT was cost-effective with a gain of 0.24 QALYs at an additional cost of CHF 9641, resulting in an ICER of CHF 40,972/QALY gained. Probabilistic sensitivity analyses demonstrated that LT was dominant or cost-effective at a willingness-to-pay threshold of CHF 100,000 per QALY in 61.7% of the simulations. CONCLUSIONS: LT may be cost-effective for selected patients with oligometastatic NSCLC responding to first-line systemic therapy.

Pharmacoeconomic analysis for pemetrexed as a maintenance therapy for NSCLC patients with patient assistance program in China.

OBJECTIVE: This study is to evaluate the costs, clinical efficacy, and social benefits of a patient assistance program (PAP) implemented by the China Primary Healthcare Foundation for the use of pemetrexed as a first-line non-squamous non-small cell lung cancer (NSCLC) maintenance therapy in China. METHODS: A survival analysis was conducted on the clinical data of 1,366 patients who participated in the PAP. The progression-free survival (PFS) and median maintenance treatment cycle of pemetrexed were analyzed. A 36-month Markov model from a payer's perspective was constructed to analyze the cost and effectiveness associated with the PAP for pemetrexed. The inputs of the model were sourced from the PAP clinical database and published literature. The study estimated the incremental quality adjusted life-years (QALYs) (pemetrexed plus best supportive care [BSC] vs BSC only), the cost saving of the PAP, the impact on the percentage of catastrophic health expenditures (CHE), and poverty headcount ratio (HCR). RESULTS: The median of PFS and maintenance treatment cycles were 187 days and five cycles (total nine cycles, which included four cycles of induction therapy), respectively. The pemetrexed plus BSC treatment with PAP resulted in an additional 0.12 QALYs over BSC only. The total cost was $48,034.46 and $96,191.57 for the patients who had or had not joined the PAP in 3 years, respectively. Compared to the patients without PAP, the percentage of CHE and HCR with PAP was reduced from 98.39% to 19.91% and 66.98% to 4.89%, respectively, indicating that the PAP substantially decreased the number of patients who had CHE and fallen into poverty. CONCLUSION: The study concluded that the pemetrexed PAP generated noticeable clinical and economic benefits to society and to patients. The program also increased patients' compliance with chemotherapy by allowing patients, for whom the pemetrexed treatment was unaffordable, to continue to receive it.

Cost-effectiveness of pemetrexed in combination with cisplatin as first line treatment for patients with advanced non-squamous non-small-cell lung cancer in Spain.

INTRODUCTION: Lung cancer is the third most frequent neoplastic tumour in Spain, with around 27 000 new cases diagnosed per year; 80-95% of these are non-small-cell cancer (NSCLC), and the majority of cases are diagnosed in advanced stages of the disease, and for this reason it is one of the oncologic conditions with higher mortality rates (21.4% mean survival at 5 years). The main treatment regimens used for first-line treatment of NSCLC are: cisplatin/pemetrexed (cis/pem), cisplatin/gemcitabine/ bevacizumab (cis/gem/bev), and carboplatin/paclitaxel/ bevacizumab (carb/pac/bev). The objective of this study was to evaluate the cost-effectiveness ratio of antineoplastic 1st line NSCLC treatment regimens, from the point of view of hospital management. METHODOLOGY: A cost-efficacy mathematical model was prepared, based on a decision tree. The efficacy variable was Progression Free Survival, obtained from the PARAMOUNT, AVAIL and SAIL Phase III clinical trials. The study was conducted from the perspective of the hospital management, considering only the direct costs of drug acquisition. A deterministic sensitivity analysis was conducted to confirm the robustness of outcomes. RESULTS: The PFS obtained in clinical trials with cis/pem, cis/ gem/bev and carb/pac/bev was: 6.9, 6.7 and 6.2 months, respectively. Based on our model, the mean cost of treatment per patient for these regimens was: 19 942 €, 15 594 € and 36 095 €, respectively. The incremental cost-effectiveness ratio per month of additional PFS between cis/pem and cis/gem/bev was 19 303 €. Estimating a 30% reduction in acquisition costs for pemetrexed (Alimta®Eli Lilly Nederland B.V.), due to the forthcoming launch of generic medications, the cis/pem treatment would become the predominant alternative for 1st line treatment of NSCLC patients, by offering the best health results at a lower cost.

Introducción: El cáncer de pulmón es la tercera neoplasia tumoral más frecuente en España, con unos 27.000 nuevos casos/ año, de los que el 80-85% son de etiología no microcítica (NSCLC) y en la mayoría de los casos diagnosticados en estadíos avanzados de la enfermedad, razón por la que es uno de los procesos oncológicos con mayores tasas de mortalidad (supervivencia media a los 5 años del 21,4%). Los principales esquemas de primera línea utilizados en el tratamiento del NSCLC son: cisplatino/pemetrexed (cis/pem), cisplatino/gemcitabina/ bevacizumab (cis/gem/bev), y carboplatino/paclitaxel/bevacizumab (carbo/pac/Bev). El objetivo del presente trabajo consistirá en realizar un análisis para estimar el ratio coste-eficacia de los esquemas antineoplásicos de primera línea en el tratamiento del NSCLC, desde la perspectiva de la gerencia hospitalaria. Metodos: Se elaboró un modelo matemático de coste-eficacia basado en un árbol de decisiones. Como variable de eficacia se utilizó la supervivencia libre de progresión, obtenida de los ensayos clínicos fase III PARAMOUNT, AVAIL y SAIL. El estudio se efectuó desde la perspectiva de la gerencia hospitalaria considerando únicamente los costes directos de adquisición de los fármacos. Se realizó un análisis de sensibilidad determinístico para comprobar la robustez de los resultados. Resultados: La SLP obtenida en los ensayos clínicos de los tratamientos cis/pem, cis/gem/bev y carb/pac/bev fue de: 6,9, 6,7 y 6,2 meses, respectivamente. En base a nuestro modelo, el coste medio del tratamiento por paciente para estos esquemas fue de 19.942 €, 15.594 € y 36.095 €, respectivamente. La razón coste-eficacia incremenal por mes de SLP adicional entre cis/pem y cis/gem/bev fue de 19.303 €. Estimando una reducción del 30% de los costes de adquisición de pemetrexed (Alimta®Eli Lilly Nederland B.V) ante su próxima incorporación al mercado de medicamentos genéricos, el tratamiento cis/pem se convertiría en la alternativa dominante en el tratamiento de primera línea de los pacientes con NSCLC, al ofrecer los mejores resultados en salud a un menor coste.

Cost-effectiveness of gefitinib, icotinib, and pemetrexed-based chemotherapy as first-line treatments for advanced non-small cell lung cancer in China.

Tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) are becoming the standard treatment option for patients with advanced non-small cell lung cancer (NSCLC) harboring an EGFR mutation, but the economic impact of this practice is unclear, especially in a health resource-limited setting. A decision-analytic model was developed to simulate 21-day patient transitions in a 10-year time horizon. The health and economic outcomes of four first-line strategies (pemetrexed plus cisplatin [PC] alone, PC followed by maintenance with pemetrexed, or initial treatment with gefitinib or icotinib) among patients harboring EGFR mutations were estimated and assessed via indirect comparisons. Costs in the Chinese setting were estimated. The primary outcome was the incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed. The icotinib strategy resulted in greater health benefits than the other three strategies in NSCLC patients harboring EGFR mutations. Relative to PC alone, PC followed by pemetrexed maintenance, gefitinib and icotinib resulted in ICERs of $104,657, $28,485 and $19,809 per quality-adjusted life-year gained, respectively. The cost of pemetrexed, the EGFR mutation prevalence and the utility of progression-free survival were factors that had a considerable impact on the model outcomes. When the icotinib Patient Assistance Program was available, the economic outcome of icotinib was more favorable. These results indicate that gene-guided therapy with icotinib might be a more cost-effective treatment option than traditional chemotherapy.

[Oral vinorelbine therapy for non-small cell lung cancer: clinical and pharmacoeconomic aspects].

AIM: To evaluate clinical and pharmacoeconomic aspects of treatment for non-small cell lung cancer (NSCLC) by oral vinorelbine. MATERIAL AND METHODS: The evaluation was conducted based on randomized trials that compared NSCLC therapy by oral vinorebline with injectable form of vinorelbine and peme- trexed. Treatment costs were calculated on the basis of prices registered in 2016 including VAT and 10% of trade allow- ances. Medical services costs were calculated based on tariffs of obligatory health insurance for St. Petersburg in 2016. RESULTS: Clinical trials showed that with comparable effi- cacy and tolerability 3 of 4 patients preferred oral vinorelbine to its injectable form, although therapy costs of oral form in- creased 1,9 times. Compared with pemetrexed, therapy of pa- tients with NSCLC by oral vinorelbine allowed reducing costs 1,74 times and the savings occurred 310.0 thousand rubles per 1 patient. CONCLUSION: Currently oral vinorelbine therapy can be regarded as a mode that is comparable by efficacy and tol- erability both with intravenous injections of vinorelbine and pemetrexed therapy. As compared with intravenous vinorelbine its oral form requires additional costs but, being compared with pemetrexed, oral vinorelbine can significantly reduce the burden on the health budget.

Cost Analyses in the US and Japan: A Cross-Country Comparative Analysis Applied to the PRONOUNCE Trial in Non-Squamous Non-Small Cell Lung Cancer.

INTRODUCTION: Health technology assessment is not required for regulatory submission or approval in either the United States (US) or Japan. This study was designed as a cross-country evaluation of cost analyses conducted in the US and Japan based on the PRONOUNCE phase III lung cancer trial, which compared pemetrexed plus carboplatin followed by pemetrexed (PemC) versus paclitaxel plus carboplatin plus bevacizumab followed by bevacizumab (PCB). METHODS: Two cost analyses were conducted in accordance with International Society For Pharmacoeconomics and Outcomes Research good research practice standards. Costs were obtained based on local pricing structures; outcomes were considered equivalent based on the PRONOUNCE trial results. Other inputs were included from the trial data (e.g., toxicity rates) or from local practice sources (e.g., toxicity management). The models were compared across key input and transferability factors. RESULTS: Despite differences in local input data, both models demonstrated a similar direction, with the cost of PemC being consistently lower than the cost of PCB. The variation in individual input parameters did affect some of the specific categories, such as toxicity, and impacted sensitivity analyses, with the cost differential between comparators being greater in Japan than in the US. CONCLUSION: When economic models are based on clinical trial data, many inputs and outcomes are held consistent. The alterable inputs were not in and of themselves large enough to significantly impact the results between countries, which were directionally consistent with greater variation seen in sensitivity analyses. The factors that vary across jurisdictions, even when minor, can have an impact on trial-based economic analyses. FUNDING: Eli Lilly and Company.

Cost-Effectiveness and Value of Information of Erlotinib, Afatinib, and Cisplatin-Pemetrexed for First-Line Treatment of Advanced EGFR Mutation-Positive Non-Small-Cell Lung Cancer in the United States.

OBJECTIVES: To determine the cost-effectiveness of tyrosine kinase inhibitors erlotinib or afatinib, or chemotherapy cisplatin-pemetrexed, for first-line treatment of advanced epithelial growth factor receptor mutation-positive non-small-cell lung cancer in the United States. We also assessed the expected benefit of further research to reduce uncertainty regarding which treatment is optimal. METHODS: We developed a Markov model to compare the cost-effectiveness of erlotinib, afatinib, and cisplatin-pemetrexed. Model transition and adverse-effect probabilities were from two published phase III trials: EURTAC (Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer) and LUX-Lung (Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma) 3. EURTAC survival estimates were corrected for patients entering the trial with more severe disease, compared with LUX-Lung 3. Health utilities and costs were from national estimates or the published literature. Inputs were modeled as distributions for probabilistic sensitivity analysis and expected value of perfect information (EVPI) analysis to estimate the expected benefit of reducing uncertainty regarding the decision of optimal treatment. RESULTS: In the base case, both tyrosine kinase inhibitors were more cost-effective than cisplatin-pemetrexed. Erlotinib had an incremental cost-effectiveness ratio of $61,809/quality-adjusted life-year (QALY) compared with afatinib. The acceptability curve showed that erlotinib was the optimal treatment at a willingness-to-pay threshold of $100,000/QALY (10-year population EVPI = $85.9 million). At a willingness-to-pay threshold of $50,000/QALY to $70,000/QALY (EVPI = $211.5 million-$261.8 million), however, there was considerable uncertainty whether erlotinib or afatinib was the optimal treatment. CONCLUSIONS: Our analysis suggests that erlotinib is the preferred first-line treatment for advanced epithelial growth factor receptor mutation-positive non-small-cell lung cancer. Further research comparing erlotinib and afatinib is potentially justified, although accurate data are needed on the required cost and sample size of the trial.