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 (progressionfree 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 costeffectiveness 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. OPEN ACCESS Citation: Sivignon M, Monnier R, Tehard B, Roze S (2020) Cost-effectiveness of alectinib compared to crizotinib for the treatment of first-line ALK+ advanced non-small-cell lung cancer in France. PLoS ONE 15(1): e0226196. https://doi.org/ 10.patients who develop cancers bearing these fingerprints [3]. In particular, inhibitors of the epidermal growth factor receptor (EGFR), such as gefitinib and erlotinib, or anaplastic lymphoma kinase (ALK), such as crizotinib and alectinib, have been developed. Mutations in the Erb-1 gene encoding EGFR are present in 10-20% of patients developing squamous cell lung cancer and rearrangements of the ALK gene are present in around 3.2% of patients developing nonsmall cell lung cancer (NSCLC) [3,4].Crizotinib, the first ALK inhibitor to be introduced for the treatment of lung cancer in 2011, has rapidly become the gold standard for this type of cancer [5,6]. However, its longterm effectiveness is compromised by the development of resistance and progression of central nervous system (CNS) disease [7]. Alectinib is an orally-administered inhibitor of ALK which has been demonstrated to be effective in the treatment of ALK+ NSCLC [8]. Since this molecule is lipophilic and is not a substrate for p-glycoprotein, it penetrates the CNS effectively and can prevent the growth o...

Objectives: To assess the publicly available French health-economic opinions, an exhaustive retrospective analysis was conducted on Incremental Cost-Effectiveness Ratios (ICERs) and methodological objections delivered by the HAS. MethOds: An electronic database was built to extract and analyze all health-economic relevant information from the publicly available opinions published by the HAS/CEESP (Comité d'Evaluation Economique et Santé Publique) on their website. This database was structured based on the following items: structural choices, results, sensitivity analysis, cost-effectiveness ratio and methodological objections. Our analysis was performed from December, 2014 (published date of the first economic opinion) until June 8th, 2016. A hypothetical threshold of 50,000 euros per Quality Adjusted Life Year gained (€ /QALY) was used for the ICER analysis cut-off. Results: Currently, 18 health-economic opinions have been published in which: 16 studies express results in cost per QALY. Among these studies, 4 were completely invalidated, leading to the exclusion of the corresponding ICERs. These exclusions were due to various reasons such as: lack of uncertainty investigation, wrong comparator and weakness of input data. From a collective perspective, the ICERs ranged from 5,866€ /QALY up to 191,661€ /QALY. Half of them (6/12) were below the hypothetical threshold of 50,000 € /QALY. cOnclusiOns: From this wide spread of ICERs, it clearly indicates that at this stage, no threshold could be deducted for France. 6 drugs reported an ICER superior to 50,000€ /QALY, and finally access to the reimbursement system. Two products did not obtain the reimbursement in France with ICERs inferior to 30,000€ /QALY (respectively 24,413€ /QALY and 29,797€ /QALY), due to unsatisfactory safety data. To conclude, the willingness to pay of the French Health Care system is not limited by any threshold. The health-economic appraisal on the methodology plays an important role in the pricing negotiations.

Aim: To estimate the cost-effectiveness of atezolizumab compared with docetaxel and nivolumab for the treatment of advanced non-small cell lung cancer (NSCLC), as a second-line treatment, in a French setting. Materials and methods: A three-state partitioned-survival model was developed (progression-free survival, post-progression survival, death) based on the phase IIIOAK trial on a 10-year time horizon. The comparison between nivolumab and atezolizumab came from a network meta-analysis. Utilities were estimated from the OAK trial EQ-5D applying the French utility tariffs. Overall survival (OS), progression-free survival (PFS), and treatment duration were estimated using parametric models selected using Akaike and Bayesian information criterion. Extrapolation beyond the trial duration followed NICE DSU TSD 14. Economic perspective was the one of all payers, discount rate fixed at 4% on benefits and costs. This analysis was aligned with French Haute Autorit e de Sant e recommendations. Results were expressed in total cost (2019) and e/QALY (Quality Adjusted Life Year). Model robustness was checked through sensitivity analyses, and a probabilistic sensitivity analysis was conducted. Results: In comparison to docetaxel, atezolizumab costs 49,429e more and increased life expectancy by 8 months, generating 0.47 QALY. Incremental cost-effectiveness ratio was estimated at 104,835e/ QALY. When comparing nivolumab to atezolizumab, a cost minimization analysis was conducted since no clear evidence supporting a difference in terms of survival benefit was reported. Using list price, and the Market Access Authorization regimens, atezolizumab saved approximately 6,000e, 9.5% of its total costs. Sensitivity analyses confirmed the robustness of our findings. Conclusion: Atezolizumab is more efficient and more costly than docetaxel in the second-line treatment of NSCLC of stage IIIB or IV, in France, with results consistent to previous French authorities' evaluation of immunotherapies in similar indication. Lastly, atezolizumab is a cost saving alternative to nivolumab, based on list price. ARTICLE HISTORY

suggests that stigmatization around schizophrenia and major depression is present in France; the public willing to help mental disease patients as demonstrated by our study, stress on the relevance of investing in mental health to reduce the enormous associated costs that burden individuals, families and societies. This stigmatization contributes to marginalize patients, exclude them from health care management and affects their disease severity. Impact of stigma on willingness to pay is being assessed.

Publicly available information on EUnetHTA JAs for individual drugs were identified along with the associated appraisal by NICE, SMC, TLV, HAS, AIFA, SMC, NCPE, ZIN, Medicinradet, AOTM and NOMA (to 12/06/2019). HTA recommendation rates and time to positive appraisal were compared between comparative clinical efficacy (CCE) markets (HAS and Medicinradet) and other (non-CCE) markets (costeffectiveness or budget impact payer archetypes) Results: Eight EUnetHTA JAs were identified, 5/8 were for oncology indications and 2/8 were orphan drugs. Forty-one corresponding national HTA appraisals were identified, ten of which were produced by a CCE market (HAS: seven; Medicinradet: three). Of these 7/10 (70%) received a positive appraisal, which did not significantly differ from non-CCE markets 20/31 (65%). CCE-appraised products had a significantly lower mean delay from ECapproval to national HTA publication in comparison to non-CCE markets (223 days and 324 days respectively; p=0.025) Conclusions: To date, drugs appraised under EUnetHTA JAs have been assessed in a shorter time by CCE markets in comparison to those appraised by non-CCE markets with a similar rate of positive appraisal. This may reflect a greater alignment between the JA clinical framework to CCE market HTA decision-drivers than the non-CCE markets or, may rather reflect natural assessment timelines of the HTA bodies involved. If the pan-clinical HTA proposals come to fruition, their impact may be limited by economic evaluations representing the primary focus of many payer bodies.