Osimertinib in Patients With Treatment-Naive EGFR-Mutant Non-small Cell Lung Cancer: Overall Survival, Post-progression Management and Budget Impact Analysis in Real-World.

INTRODUCTION: The observational multicenter prospective FLOWER study (NCT04965701) confirmed effectiveness and safety of osimertinib in the real-world (RW) management of untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) patients. METHODS: Herein, we report updated survival data, post-progression management, cost/effectiveness and budget impact (BI) of osimertinib compared with a RW population receiving gefitinib or erlotinib. RESULTS: Overall, 189 Caucasian patients receiving first-line osimertinib were included. After a follow-up of 20.7 months, 74(39.2%) patients discontinued osimertinib, median time-to-treatment discontinuation (mTTD) was 27.9 months, overall survival 36.8 months. At progression, tissue biopsy was performed in 29 (56.9%), liquid biopsy in 15 (29.4%) and both in 7 (13.7%) cases. The most frequent resistant mechanism was MET amplification (N = 14, 29.8%). At data cutoff, 13 (6.9%) patients were continuing osimertinib beyond progression; 52 (67.5%) received second-line treatment; no further treatments were administered in 25 (32.5%) cases. Thirty-three (63.4%) patients received chemotherapy, 12(23.1%) TKIs combination. Cost-effectiveness analysis showed a total cost per patient based on RW mTTD of 98,957.34€, 21,726.28€ and 19,637.83€ for osimertinib, erlotinib and gefitinib, respectively. The incremental cost-effectiveness ratio (ICER)/month for osimertinib was 359,806.0€/life-year-gained (LYG) and 197,789.77€/LYG compared to erlotinib and gefitinib. For osimertinib, the BI-gap between RW-TTD and theoretical-TTD was 16,501.0€ per patient. CONCLUSIONS: This updated analysis confirms the effectiveness of osimertinib in RW. Although the ICER of osimertinib seems not cost-effective, additional costs for the management of disease progression to old generation TKIs were not considered in this study. The BI-gap suggests RW mTTD as a more reliable measure for expense estimation.

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.

Distribution and ecological risk assessment of priority water pollutants in surface river sediments with emphasis on industrially affected areas.

Priority water pollutants comprising six plasticizers, 18 volatile organic compounds (VOCs), total petroleum hydrocarbon (TPH), 1,4-dioxane, epichlorohydrin, formaldehyde, acrylamide, and cyanides were determined in surface river sediments to assess their distribution patterns and ecological risks. Among these, di (2-ethylhexyl) phthalate (DEHP), toluene, TPH, and acrylamide were frequently found in sediments. The industrial sites had higher concentrations of ∑plasticizers (median 628 ng/g dry weight (dw)), ∑VOCs (median 3.35 ng/g dw), acrylamide (median 0.966 ng/g dw), and TPH (median 152 µg/g dw) in sediments than the mixed and non-industrial areas. The other pollutants did not show the significant differences in levels according to site types because of their relatively low detection frequencies. Volatile and soluble substances as well as hydrophobic pollutants were predominantly detected in surface sediments from industrial areas. Sediment contamination patterns were affected by the size and composition of the industrial zones around the sampling sites. The ecological risks determined using the sediment quality guidelines (DEHP, VOCs, and TPH) and the mean probable effect level quotients (DEHP) were mostly acceptable. However, the two most representative industrial regions (the largest industrial area and the first industrial city) showed risks of concern for DEHP and TPH.

Data-Driven Global Assessment of Protein Kinase Inhibitors with Emphasis on Covalent Compounds.

Large-scale analysis of public human and mouse protein kinase inhibitor (PKI) data identified more than 155,000 human PKIs (and ∼3000 murine PKIs), for which reliable activity measurements were available. Human PKIs were active against 440 kinases (85% coverage of the kinome). Over the past years, there has been substantial growth of human PKIs, dominated by inhibitors with single-kinase annotations and high core structure diversity. Human PKIs included an unexpectedly large number of nearly 14,000 covalent PKIs (CPKIs), ∼87% of which contained acrylamide or heterocyclic urea warheads. These CPKIs were active against a large number of 369 human kinases. The promiscuity of PKIs and CPKIs was overall comparable. However, there was a notable enrichment of acrylamide- but not heterocyclic urea-containing CPKIs among most promiscuous inhibitors. Furthermore, CPKIs with both warheads had significantly higher potency than structurally analogous PKIs. Taken together, these findings have several implications for medicinal chemistry that are discussed.

Assessment of verdinexor as a canine P-glycoprotein substrate.

The P-glycoprotein (P-gp) substrate status of antineoplastic drugs intended for veterinary patients is an important characteristic to define for two reasons. First, neoplastic cells expressing P-gp can actively efflux drugs that are P-gp substrates curtailing their efficacy. Second, antineoplastic drugs tend to have a narrow therapeutic index. Antineoplastic drugs that are P-gp substrates can cause severe adverse reactions in animals with P-gp dysfunction such as dogs with ABCB1-1Δ and cats with ABCB11930_1931del TC. Animals with P-gp dysfunction experience greater overall exposure to P-gp substrate drugs due to mechanisms such as increased intestinal absorption, decreased biliary clearance and greater central nervous system penetration compared with animals with normal P-gp function. Accordingly, knowing the P-gp substrate status of antineoplastic drugs is an important safety consideration prior to use in canine or feline cancer patients. This study used a cell line overexpressing canine P-gp to assess the P-gp substrate status of verdinexor. Based on both a cytotoxicity assay and a competitive flow cytometry assay verdinexor is not a substrate for canine P-gp.

Associations between residential volatile organic compound exposures and liver injury markers: The role of biological sex and race.

While occupational exposures to volatile organic compounds (VOCs) have been linked to steatohepatitis and liver cancer in industrial workers, recent findings have also positively correlated low-dose, residential VOC exposures with liver injury markers. VOC sources are numerous; factors including biological make up (sex), socio-cultural constructs (gender, race) and lifestyle (smoking) can influence both VOC exposure levels and disease outcomes. Therefore, the current study's objective is to investigate how sex and race influence associations between residential VOC exposures and liver injury markers particularly in smokers vs. nonsmokers. Subjects (n = 663) were recruited from residential neighborhoods; informed consent was obtained. Exposure biomarkers included 16 urinary VOC metabolites. Serological disease biomarkers included liver enzymes, direct bilirubin, and hepatocyte death markers (cytokeratin K18). Pearson correlations and generalized linear models were conducted. Models were adjusted for common liver-related confounders and interaction terms. The study population constituted approximately 60% females (n = 401) and 40% males (n = 262), and a higher percent of males were smokers and/or frequent drinkers. Both sexes had a higher percent of White (75% females, 82% males) vs. Black individuals. Positive associations were identified for metabolites of acrolein, acrylamide, acrylonitrile, butadiene, crotonaldehyde, and styrene with alkaline phosphatase (ALP), a biomarker for cholestatic injury; and for the benzene metabolite with bilirubin; only in females. These associations were retained in female smokers. Similar associations were also observed between these metabolites and ALP only in White individuals (n = 514). In Black individuals (n = 114), the styrene metabolite was positively associated with aspartate transaminase. Interaction models indicated that positive associations for acrylamide/crotonaldehyde metabolites with ALP in females were dose-dependent. Most VOC associations with K18 markers were negative in this residential population. Overall, the findings demonstrated that biological sex, race, and smoking status influence VOC effects on liver injury and underscored the role of biological-social-lifestyle factor(s) interactions when addressing air pollution-related health disparities.

Interspecific protoplast fusion of atmospheric and room-temperature plasma mutants of Aspergillus generates an L-asparaginase hyper-producing hybrid with techno-economic benefits.

The axenic culture of Aspergillus candidus (Asp-C) produced an anti-leukemic L-asparaginase while Aspergillus sydowii (Asp-S) produced the acrylamide-reduction type. Upon mutagenesis by atmospheric and room-temperature plasma (ARTP), their individual L-asparaginase activities improved 2.3-folds in each of Ile-Thr-Asp-C-180-K and Val-Asp-S-180-E stable mutants. Protoplast fusion of selected stable mutants generated fusant-09 with improved anti-leukemic activity, acrylamide reduction, higher temperature optimum and superior kinetic parameters. Submerged (SmF) and solid-state fermentation (SSF) types were compared; likewise batch, fed-batch and continuous fermentation modes; and fed-batch submerged fermentation was selected on the basis of impressive techno-economics. Fusant L-asparaginase was purified by PEG/Na+ citrate aqueous two-phase system and molecular exclusion chromatography to 69.96 and 146.21-fold, respectively, and characterized by molecular weight, specificity, activity and stability to chemical and physical agents. Michaelis-Menten kinetics, evaluated under optimum conditions gave Km, Vmax, Kcat, and Kcat/Km as 1.667 × 10-3 M, 1666.67 µmol min-1 mg-1 protein, 645.99 s-1 and 3.88 × 105 M-1 s-1 respectively. In-vitro cytotoxicity of HL-60 cell lines by fusant-09 L-asparaginase improved 3.00 and 18.71-folds from mutants Ile-Thr-Asp-C-180-K and Val-Asp-S-180-E, and from 5.73 and 32.55 from respective original strains. Free-radical scavenging and acrylamide reduction improvements were intermediate. Fusant-09 L-asparaginase is strongly recommended for sustainable economic anti-leukemic and food industry applications.

Assessment of exposure to volatile organic compounds through urinary concentrations of their metabolites in pet dogs and cats from the United States.

Volatile organic compounds (VOCs) are ubiquitous environmental pollutants, exposure to which is associated with birth defects, neurocognitive and reproductive impairments, and cancer. Little is known, however, about VOC exposure in pet dogs and cats, which represent sentinels for human exposure as well as having value as companion animals. In this study, we determined 38 VOC metabolites (VOCMs) in urine samples collected from 47 dogs and 42 cats from the Albany area of New York State. Seventeen (in cats) to twenty (in dogs) VOCMs were found at detection frequencies (DFs) above 60%. The creatinine-adjusted geometric mean (GM) concentrations of individual VOCMs ranged from 5.43 (EMA) to 761 µg/g (3HPMA) in dog urine and 0.824 (SBMA) to 278 µg/g (ATCA) in cat urine. The ∑20 VOCM concentration in dog urine was 2280 µg/g (geometric mean) and the ∑17 VOCM concentration in cat urine was 847 µg/g. Eight individual VOCMs were significantly more abundant in dog than in cat urine, and the urinary concentrations of several VOCMs in dogs were comparable to those reported for human tobacco smokers. Metabolites of acrolein accounted for 43% of ∑20 VOCM concentration in dogs, whereas those of cyanide and benzene accounted for 60% of ∑17 VOCM concentration in cats. Based on acrylamide exposure doses, calculated hazard quotients were above 1 in 77% of dogs and 50% of cats studied, and cancer risk values (using a benchmark of 10-6) from exposure to acrylamide exceeded 1 for all dogs and cats. This is the first study to report VOCM concentrations in urine collected from pet dogs and cats and highlights the need to identify sources and health implications of VOCs exposure in these animals.

Cost-Effectiveness of Pyrotinib Plus Capecitabine versus Lapatinib Plus Capecitabine for the Treatment of HER2-Positive Metastatic Breast Cancer in China: A Scenario Analysis of Health Insurance Coverage.

BACKGROUND: The overexpression of the human epidermal growth factor receptor-2 (HER2) gene is present in 20~25% of breast cancer (BC) patients, contributing to an inferior prognosis. Recent clinical trials showed that pyrotinib has promising antitumor activities and acceptable tolerability for those patients (ClinicalTrials.gov, NCT03080805 and NCT02422199). Therefore, this study aims to assess the cost-effectiveness of pyrotinib plus capecitabine versus lapatinib plus capecitabine for patients with HER2-positive metastatic BC after prior trastuzumab. METHODS: A lifetime-partitioned survival model was established to evaluate health and economic outcomes with different treatment strategies. The primary outcome was the incremental cost-effectiveness ratio (ICER). Data were derived from the published literature, clinical trials, expert opinions, and other local charges. Sensitivity analyses were performed to assess the robustness of the findings. Scenario analyses were developed to make further evaluations. RESULTS: The pyrotinib regimen had significant advantages over the lapatinib regimen after enrolling in the National Reimbursement Drug List (NRDL), with cost savings of USD 15,599.27 and a gain of 0.53 QALYs. Meanwhile, before enrolling in NRDL, the pyrotinib regimen afforded the same QALYs at a higher incremental cost of USD 45,400.64 versus the lapatinib regimen, producing an ICER of USD 85,944.79 per QALY. Scenario analyses yielded similar results. Sensitivity analyses suggested stability in the cost-effectiveness findings. CONCLUSIONS: Compared to lapatinib plus capecitabine, the pyrotinib plus capecitabine enrolled in NRDL is a cost-effective alternative second-line treatment for patients with HER2-positive metastatic BC in China.

Modeling the Cost-Effectiveness of Adjuvant Osimertinib for Patients with Resected EGFR-mutant Non-Small Cell Lung Cancer.

INTRODUCTION: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib was recently approved for resected EGFR-mutant stages IB-IIIA non-small cell lung cancer due to improved disease-free survival (DFS) in this population compared with placebo. This study aimed to evaluate the cost-effectiveness (CE) of this strategy. MATERIALS AND METHODS: We constructed a Markov model using post-resection health state transitions with digitized DFS data from the ADAURA trial to compare cost and quality-adjusted life years (QALYs) of 3 years of adjuvant osimertinib versus placebo over a 10-year time horizon. An overall survival (OS) benefit of 5% was assumed. Costs and utility values were derived from Medicare reimbursement data and literature. A CE threshold of 3 times the gross domestic product per capita was used. Sensitivity analyses were performed. RESULTS: The incremental cost-effectiveness ratio for adjuvant osimertinib was $317 119 per QALY-gained versus placebo. Initial costs of osimertinib are higher in years 1-3. Costs due to progressive disease (PD) are higher in the placebo group through the first 6.5 years. Average pre-PD, post-PD, and total costs were $2388, $379 047, and $502 937, respectively, in the placebo group, and $505 775, $255 638, and $800 697, respectively, in the osimertinib group. Sensitivity analysis of OS gains reaches CE with an hazard ratio (HR) of 0.70-0.75 benefit of osimertinib over placebo. A 50% discount to osimertinib drug cost yielded an ICER of $115 419. CONCLUSIONS: Three-years of adjuvant osimertinib is CE if one is willing to pay $317 119 more per QALY-gained. Considerable OS benefit over placebo or other economic interventions will be needed to reach CE.

Incidence and management of pyrotinib-associated diarrhea in HER2-positive advanced breast cancer patients.

BACKGROUND: The PHOEBE study showed that pyrotinib is an alternative treatment option for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer after trastuzumab and chemotherapy. Diarrhea was a common adverse event that could compromise or modify treatment administration. METHODS: We conducted a retrospective cohort study of HER2-positive advanced breast cancer patients receiving a pyrotinib-based regimen between August 2018 and January 2021. The risk of diarrhea with 95% confidence limits (CLs) was calculated and management was analyzed. RESULTS: A total of 46 HER2-positive advanced breast cancer patients were enrolled. Diarrhea of any grade occurred in 100% of patients, and grade 3 diarrhea was observed in 52.2% (n=24) of patients. Treatment dose modification was implemented in 39.1% (n=18) of advanced breast cancer patients. Compared with other treatment regimens, patients receiving pyrotinib plus vinorelbine suffered the highest risk of diarrhea (60%), though no significant difference was confirmed (P=0.77). Antidiarrheal agents were commonly used and loperamide-based regimens achieved an ideal antidiarrheal effect (95.3-100%), while non-loperamide-based regimens (such as montmorillonite powder) had a lower control rate (78.6%). CONCLUSIONS: Diarrhea was a common adverse event of pyrotinib-based treatment, and approximately 50% of patients suffered high grade diarrhea. Loperamide-based antidiarrheal agents could commendably manage most episodes.

Assessment of Anti-tumor Efficacy of Osimertinib in Non-Small Cell Lung Cancer Patients by Liquid Biopsy Using Bronchoalveolar Lavage Fluid, Plasma, or Pleural Effusion.

PURPOSE: This study was to evaluate anti-tumor efficacy of osimertinib in patients positive for acquired epidermal growth factor receptor (EGFR) T790M mutation in liquid biopsy using plasma, bronchoalveolar lavage fluid (BALF) or bronchial washing fluid (BWF), and pleural effusion. MATERIALS AND METHODS: Among patients benefited from previous EGFR‒tyrosine kinase inhibitor treatment followed by treatment failure, patients in whom T790M mutations are detected in at least one of the samples including tumor tissues, BALF/BWF, plasma, and pleural effusion were enrolled. T790M mutation was detected by extracting cell free DNA from liquid biopsy samples, using PANA Mutyper. Objective response rate (ORR) and progression-free survival (PFS) with osimertinib treatment were evaluated. RESULTS: Between January 2018 and December 2019, 63 patients were enrolled and received osimertinib. Mean age was 63 years, and 38 (60.3%) were female. Twenty-six patients had T790M mutation in both liquid and tissue samples (group A), 19 patients had only in tissue biopsy samples (group B), and 18 patients had T790M mutation only in liquid biopsy samples (group C). ORR in overall population was 63.5%, and was 61.5% in group A, 68.4% in group B, and 61.1% in group C, respectively. Median PFS in overall patients was 15.6 months (95% confidence interval, 10.7 to 24.2). There was no significant difference in ORR or PFS between groups. CONCLUSION: Osimertinib showed favorable efficacy in lung cancer patients with acquired resistance to prior EGFR-TKI therapies, who screened positive for harboring T790M mutation detected from cell free DNA extracted from plasma, BALF/BWF, and pleural effusion.

Evaluation of osimertinib for advanced non-small cell lung cancer with leptomeningeal metastases: a cost-effectiveness and budget impact analysis.

Background Few regimens for non-small cell lung cancer (NSCLC) with leptomeningeal metastases (LM) patients exist up to date, most with low efficacy. A retrospective analysis showed that osimertinib significantly improved the overall survival of LM patients by 11.5 months (17.0 vs. 5.5) as compared to no osimertinib treatment. Until now, no pharmacoeconomic evaluation of osimertinib has been performed to determine its feasibility for widespread use in LM patients. Aim This study analyzed the cost-effectiveness of osimertinib in LM of NSCLC from the perspective of the Chinese health care system. Methods Based on a retrospective analysis from the Samsung Medical Center, a Markov model was constructed to estimate the lifetime benefits and costs for LM patients who were treated with osimertinib. The main outcomes were cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed to verify the robustness of model. A budget impact analysis was conducted to estimate the annual incremental cost of osimertinib treatment. Results Compared with patients who were not treated with osimertinib, the survival time of patients treated with osimertinib was higher by 0.69 (1.24 vs. 0.55) QALYs. The incremental cost was $11,877 ($29,232 vs. $17,355) and the ICER was $17,214/QALY, which was below the willingness-to-pay threshold of $30,867/QALY. Osimertinib treatment will increase national cancer spending by $220 million in the first year and increase to $474 million in the fifth year. Conclusions Osimertinib treatment is deemed to be cost-effective for NSCLC with LM patients, however, its use would significantly increase annual cancer spending.

Cost-effectiveness of osimertinib in the treatment of advanced EGFR-mutated non-small cell lung cancer: a systematic review.

BACKGROUND: The most common type of lung cancer is advanced and mutant non-small cell lung cancer (NSCLC). Although targeted tyrosine kinase inhibitors (TKIs) have reconstructed the care of these patients, the resistance of TKIs to the secondary EGFR-T790M mutation in advanced or metastatic NSCLC led to the introduction of the third generation of them, like osimertinib. Osimertinib has represented a remarkable increase in progression-free survival (PFS) and a decrease in death and hazard ratios in patients with required T790 mutation and sensitizing EGFR mutation without T790M. We aimed to evaluate the cost-effectiveness of osimertinib for the treatment of these patients compared to chemotherapy or immunotherapy with the last generations of EGFR-TKIs. AREAS COVERED: Electronic searches were conducted on PubMed, Embase, Science Direct, Scopus, , Web of Knowledge, NHSEED, NHS Health Technology assessment (CRD), and Cost-Effectiveness Analysis Registry databases. Related articles were reviewed from January 2015 to the end of August 2020. Out of 2708 initial studies, 10 articles had the inclusion criteria. EXPERT OPINION: Although osimertinib improves the quality of life and PFS for the mentioned patients based on its greater efficacy compared to standard EGFR-TKIs and chemotherapy, its high cost prevents considering it a cost-effective option. And, since most entered studies have been done in developed countries, it certainly does not true to extend these results to low-income and developing countries. Therefore, further studies in those countries are needed to evaluate the cost-effectiveness of osimertinib for sensitizing EGFR mutation without T790M and required T790M in advanced or metastatic NSCLC.

Cost-effectiveness analysis of first-line treatments for advanced epidermal growth factor receptor-mutant non-small cell lung cancer patients.

OBJECTIVES: Recent studies showed prolonged survival for advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients treated with both monotherapies and combined therapies. However, high costs limit clinical applications. Thus, we conducted this cost-effectiveness analysis to explore an optimal first-line treatment for advanced EGFR-mutant NSCLC patients. MATERIALS AND METHODS: Survival data were extracted from six clinical trials, including ARCHER1050 (dacomitinib vs. gefitinib); FLAURA (osimertinib vs. gefitinib/erlotinib); JO25567 and NEJ026 (bevacizumab +erlotinib vs. erlotinib); NEJ009 (gefitinib +chemotherapy vs. gefitinib); and NCT02148380 (gefitinib +chemotherapy vs. gefitinib vs. chemotherapy) trials. Cost-related data were obtained from hospitals and published literature. The effect parameter (quality-adjusted life year [QALY]) was the reflection of both survival and utility. Incremental cost-effectiveness ratio (ICER), average cost-effectiveness ratio (ACER), and net benefit were calculated, and the willingness-to-pay (WTP) threshold was set at $30828/QALY from the perspective of the Chinese healthcare system. Sensitivity analysis was performed to explore the stability of results. RESULTS: We compared treatment groups with control groups in each trial. ICERs were $1897750.74/QALY (ARCHER1050), $416560.02/QALY (FLAURA), -$477607.48/QALY (JO25567), -$464326.66/QALY (NEJ026), -$277121.22/QALY (NEJ009), -$399360.94/QALY (gefitinib as comparison, NCT02148380), and -$170733.05/QALY (chemotherapy as comparison, NCT02148380). Moreover, ACER and net benefit showed that the combination of EGFR-TKI with chemotherapy and osimertinib was of more economic benefit following first-generation EGFR-TKIs. Sensitivity analyses showed that the impact of utilities and monotherapy could be cost-effective with a 50% cost reduction. CONCLUSION: First-generation EGFR-TKI therapy remained the most cost-effective treatment option for advanced EGFR-mutant NSCLC patients. Our results could serve as both a reference for both clinical practice and the formulation of medical insurance reimbursement.

Incremental cost-effectiveness analysis of tyrosine kinase inhibitors in advanced non-small cell lung cancer with mutations of the epidermal growth factor receptor in Colombia.

OBJECTIVE: To estimate the cost-effectiveness of sequences starting with tyrosine kinase inhibitors (TKI), afatinib and osimertinib, for the treatment of epidermal growth factor receptor (EGFR) mutation-positive (Exon 19 deletion or L858R) non-small cell lung cancer (NSCLC), stages IIIB - IV in Colombia. METHODS: A partitioned survival model was designed, using information from global and progression-free survival curves. For first and second-generation TKI, second line treatment was assumed according to the presence of T790M mutation to define the use of osimertinib or chemotherapy. The cost of the states without progression and post-progression was estimated using the base case approach, identified through consultation with clinical experts. RESULTS: The cost of treatment starting with afatinib in the first line was of 222,247 USD (1 USD = 3171.99 COP) and produced 1.36 QALYs. The strategy with afatinib was dominant with respect to that of first line TKI (227,289 USD and 1.34 QALY). The strategy with osimertinib resulted in more QALYs and higher costs, with ICERs of 35,062 USD, exceeding the current willingness to pay threshold for Colombia. CONCLUSIONS: Treatment starting with afatinib in the first line is dominant with respect to the strategy with first line TKI. The ICER of osimertinib sequence exceeds the threshold when compared with afatinib one.

Cost-effectiveness of osimertinib versus standard EGFR-TKI as first-line treatment for locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer in Australia.

Objectives: To assess the cost-effectiveness of osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib, as first-line treatment for patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer in Australia from a healthcare system perspective.Methods: A partitioned survival model comprising three mutually exclusive health states with a five-year time horizon was developed. Model inputs were sourced from the pivotal trial (FLAURA) and published literature. Incremental cost-effectiveness ratios (ICERs), in terms of cost per quality-adjusted life-year (QALY) gained and cost per life-year (LY) gained, were calculated. Uncertainty of the results was assessed using deterministic and probabilistic sensitivity analyses.Results: Compared with standard EGFR-TKIs, osimertinib was associated with a higher incremental cost of A$118,502, and an incremental benefit of 0.274 QALYs and 0.313 LYs. The ICER was estimated to be A$432,197/QALY gained and A$378,157/LY gained. The base-case ICER was most sensitive to changes in cost of first-line osimertinib, time horizon, and choice of overall survival data (interim versus final analysis).Conclusions: At a willingness-to-pay threshold of A$50,000/QALY, first-line osimertinib is not cost-effective compared with standard EGFR-TKIs in Australia based on the current published price. To achieve acceptable cost-effectiveness, the cost of first-line osimertinib needs to be reduced by at least 68.4%.

EGFR tyrosine kinase inhibitors in non-small cell lung cancer: treatment paradigm, current evidence, and challenges.

Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for patients with EGFR-mutated non-small cell lung cancer (NSCLC) has been shown to have superior outcomes when compared to chemotherapy. First-generation EGFR TKI, including gefitinib and erlotinib, and second-generation EGFR TKI, including afatinib and dacomitinib, proved to be effective in patients with NSCLC harboring EGFR-sensitizing mutation. Later, resistance mutations were identified. Consequently, osimertinib, a third-generation EGFR TKI, was studied and demonstrated activity against EGFR-sensitizing and resistant mutations. Osimertinib moved recently to the first-line setting with the positive results of the FLAURA (AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer) trial. The use of these drugs is limited by their cost and availability mainly in middle- to low-income countries.