Bayesian survival extrapolation for cost-effectiveness analysis: a case study of RELAY for ramucirumab in combination with erlotinib in the treatment of non-small-cell lung cancer.

AIM: Increasing trend for progression-free survival (PFS)-based primary endpoint in oncology has led to lack of mature overall survival (OS) data at the time of approval. To address this evidence gap in economic evaluations, we used a joint Bayesian approach to predict survival outcomes using immature OS data from the RELAY trial. METHODS: Patient data from RELAY and systematic literature review (SLR) of phase 3 randomized clinical trials with hazard ratio (HR) estimates of mature PFS and immature OS were considered. OS and PFS were analyzed individually using a univariate model; bivariate analysis was performed using a joint model based on modified Bayesian normal induced copula estimation model. First, a Bayesian univariate model incorporated informative priors based on predicted HR and acceleration factor for OS and PFS. Second, a Bayesian-based joint model of RELAY PFS and OS data was based on the correlation between PFS and OS established in trials of similar populations. Marginal distribution of PFS was used to estimate the same for OS. RESULTS: Publications (N = 122) of first-line treatments in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer were identified in the SLR, of which 36 trials were linked to RELAY. Twenty-six trials with HR data were used. The univariate model could predict OS with reduced uncertainty compared with the frequentist approach. In the joint model, the marginal OS distribution borrowed strength from the marginal PFS distribution through the established correlation coefficient. LIMITATIONS: Bayesian approach was successfully used in RELAY analysis but may not be universally applied to oncology trials due to the different associations of OS and PFS and different trial patient populations. CONCLUSIONS: We demonstrated that both the univariate and joint Bayesian models reduced uncertainty in predicting OS compared to frequentist method. The methodology introduced here will have potential applications in clinical decision-making for other oncology trials.

First-line systemic treatment strategies for unresectable hepatocellular carcinoma: A cost-effectiveness analysis.

BACKGROUND: Oral multikinase inhibitors and immune checkpoint inhibitors (ICIs) are effective for treating advanced hepatocellular carcinoma (aHCC) but may increase cost. This study compared the cost-effectiveness of oral multikinase inhibitors and ICIs in the first-line treatment of patients with aHCC. METHODS: A three-state Markov model was established to study the cost-effectiveness of drug treatment from the perspective of Chinese payers. The key outcomes in this study were total cost, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER). RESULTS: The total costs and QALYs of sorafenib, sunitinib, donafenib, lenvatinib, sorafenib plus erlotinib, linifanib, brivanib, sintilimab plus IBI305, and atezolizumab plus bevacizumab were $9070 and 0.25, $9362 and 0.78, $33,814 and 0.45, $49,120 and 0.83, $63,064 and 0.81, $74,814 and 0.82, $81,995 and 0.82, $74083 and 0.85, and $104,188 and 0.84, respectively. The drug regimen with the lowest ICER was sunitinib ($551 per QALY), followed by lenvatinib ($68,869 per QALY). For oral multikinase inhibitors, the ICER of lenvatinib, sorafenib plus erlotinib, linifanib and brivanib compared with sunitinib was $779576, $1534,347, $1768,971, and $1963,064, respectively. For ICIs, sintilimab plus IBI305 is more cost effective than atezolizumab plus bevacizumab. The model was most sensitive to the price of sorafenib, the utility of PD, and the price of second-line drugs. CONCLUSION: For oral multikinase inhibitors, the order of possible treatment options is sunitinib > lenvatinib > sorafenib plus erlotinib > linifanib > brivanib > donafenib. For ICIs, the order of possible treatment options is sintilimab plus IBI305 > atezolizumab plus bevacizumab.

Inequalities in survival and care across social determinants of health in a cohort of advanced lung cancer patients in Quebec (Canada): A high-resolution population-level analysis.

BACKGROUND: Advanced lung cancer patients exposed to breakthrough therapies like EGFR tyrosine kinase inhibitors (EGFR-TKI) may experience social inequalities in survival, partly from differences in care. This study examined survival by neighborhood-level socioeconomic and sociodemographic status, and geographical location of advanced lung cancer patients who received gefitinib, an EGFR-TKI, as first-line palliative treatment. Differences in the use and delay of EGFR-TKI treatment were also examined. METHODS: Lung cancer patients receiving gefitinib from 2001 to 2019 were identified from Quebec's health administrative databases. Accounting for age and sex, estimates were obtained for the median survival time from treatment to death, the probability of receiving osimertinib as a second EGFR-TKI, and the median time from biopsy to receiving first-line gefitinib. RESULTS: Among 457 patients who received first-line treatment with gefitinib, those living in the most materially deprived areas had the shortest median survival time (ratio, high vs. low deprivation: 0.69; 95% CI: 0.47-1.04). The probability of receiving osimertinib as a second EGFR-TKI was highest for patients from immigrant-dense areas (ratio, high vs. lowdensity: 1.95; 95% CI: 1.26-3.36) or from Montreal (ratio, other urban areas vs. Montreal: 0.39; 95% CI: 0.16-0.71). The median wait time for gefitinib was 1.27 times longer in regions with health centers peripheral to large centers in Quebec or Montreal in comparison to regions with university-affiliated centers (95% CI: 1.09-1.54; n = 353). CONCLUSION: This study shows that real-world variations in survival and treatment exist among advanced lung cancer patients in the era of breakthrough therapies and that future research on inequalities should also focus on this population.

Novel 2-(5-Aryl-4,5-Dihydropyrazol-1-yl)thiazol-4-One as EGFR Inhibitors: Synthesis, Biological Assessment and Molecular Docking Insights.

Introduction: Epidermal growth factor receptor (EGFR) regulates several cell functions which include cell growth, survival, multiplication, differentiation, and apoptosis. Currently, EGFR kinase inhibitors are of increasing interest as promising targeted antitumor therapeutic agents. Methods: Different thiazolyl-pyrazoline derivatives (7a-o) were synthesized and were first tested for anti-proliferative effect towards the A549 lung cancer cell line and the T-47D breast cancer cell line in MTT assay. Thereafter, thiazolyl-pyrazolines (7b, 7g, 7l, and 7m) were subsequently evaluated for their PK inhibition for EGFR. Moreover, representative promising derivatives (7g and 7m) in cytotoxic and PK inhibition assays were tested to investigate their impact on the apoptosis and cell cycle phases in T-47D cells in order to explore more insights into the antitumor actions of the target thiazolyl-pyrazolines. Furthermore, docking studies were accomplished to evaluate the patterns of binding of thiazolyl-pyrazolines 7b, 7g, 7l, and 7m in the EGFR active pocket (PDB ID: 1M17). Results: Testing the thiazolyl pyrazoline compounds 7a-o on A549 and T-47D cell lines showed IC50 arrays between 3.92 and 89.03 µM, and between 0.75 and 77.10 µM, respectively. Also, the tested thiazolyl-pyrazolines (7b, 7g, 7l, and 7m) demonstrated significant sub-micromolar EGFR inhibitory actions with IC50 values 83, 262, 171 and 305 nM, respectively, in comparison to erlotinib (IC50 =57 nM). Discussion: Generally, it was observed that the tested thiazolyl pyrazolines showed more potent antiproliferative activity toward breast cancer cells T-47D than toward lung cancer cell lines A549. In particular, thiazolyl pyrazolines 7g and 7m showed the best activity against A549 cells (IC50 = 3.92 and 6.53 µM) and T-47D cells (IC50 = 0.88 and 0.75 µM). Compounds 7g and 7m provoked a sub-G1 phase arrest and cell apoptosis which are in agreement with the expected outcome of EGFR inhibition. Finally, the molecular docking of 7g and 7m in the active site of EGFR revealed a common binding pattern similar to that of erlotinib which involves the accommodation of the 1,3 thiazol-4-one ring and pyrazoline ring of target compounds in the binding region of erlotinib's quinazoline ring and anilino moiety.

Utilization and costs of epidermal growth factor receptor mutation testing and targeted therapy in Medicare patients with metastatic lung adenocarcinoma.

BACKGROUND: Guidelines in 2013 and 2014 recommended Epidermal Growth Factor Receptor (EGFR) testing for metastatic lung adenocarcinoma patients as the efficacy of targeted therapies depends on the mutations. However, adherence to these guidelines and the corresponding costs have not been well-studied. METHODS: We identified 2362 patients at least 65 years old newly diagnosed with metastatic lung adenocarcinoma from January 2013 to December 2015 using the SEER-Medicare database. We examined the utilization patterns of EGFR testing and targeted therapies including erlotinib and afatinib. We further examined the costs of both EGFR testing and targeted therapy in terms of Medicare costs and patient out-of-pocket (OOP) costs. RESULTS: The EGFR testing rate increased from 38% in 2013 to 51% and 49% in 2014 and 2015 respectively. The testing rate was 54% among the 394 patients who received erlotinib, and 52% among the 42 patients who received afatinib. The median Medicare and OOP costs for testing were $1483 and $293. In contrast, the costs for targeted therapy were substantially higher with median 30-day costs at $6114 and $240 for erlotinib and $6239 and $471 for afatinib. CONCLUSION: This population-based study suggests that testing guidelines improved the use of EGFR testing, although there was still a large proportion of patients receiving targeted therapy without testing. The costs of targeted therapy were substantially higher than the testing costs, highlighting the need to improve adherence to testing guidelines in order to improve clinical outcomes while reducing the economic burden for both Medicare and patients.

Cost-effectiveness analysis of the first-line EGFR-TKIs in patients with advanced EGFR-mutated non-small-cell lung cancer.

AIM: To evaluate the cost-effectiveness of first-line treatments, such as erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib, for patients diagnosed with stage IIIB/IV NSCLC harboring EGFR mutations. MATERIALS & METHODS: A partitioned survival model was developed to estimate quality-adjusted life-year (QALY) and incremental cost-effectiveness ratio (ICER) from the perspective of the Spanish National Health System. Two Bayesian NMAs were performed independently, by using the polynomial fraction method to fit Kaplan-Meier curves for overall survival and progression-free survival. Deterministic and probabilistic sensitivity analyses were performed to evaluate the uncertainty. RESULTS: The ICER was calculated for the four first-line treatments by comparing them with gefitinib, and the ratios obtained were as follows: €166,416/QALY for osimertinib, €183,682/QALY for dacomitinib, €167,554/QALY for afatinib, €36,196/QALY for erlotinib. It was seen that patients who received osimertinib presented higher QALYs (0.49), followed by dacomitinib (0.33), afatinib (0.32), erlotinib (0.31), and gefitinib (0.28). CONCLUSIONS: Gefitinib is the most cost-effective treatment. In terms of QALYs gained, Osimertinib was more effective than all other TKIs. Nevertheless, with a Spanish threshold of €24,000/QALY, the reduction in the acquisition cost of osimertinib will have to be greater than 70%, to obtain a cost-effectiveness alternative.

The Influence of Intervening on the Pharmaceutical Consultation Targeting Outpatients with Advanced Non-small Cell Lung Cancer Receiving Erlotinib Treatment.

Erlotinib is used to treat advanced non-small-cell lung cancer (NSCLC), the common serious adverse events are skin disorders. The dose intensity of erlotinib should be maintained as much as possible by an appropriate control of adverse events in order to maintain its efficacy. Therefore, the management of these adverse events related to skin disorders would enable a continuous erlotinib treatment without interruption and dose reduction. This study assessed the effect of pharmaceutical consultation in outpatients who received erlotinib. Participants included patients with NSCLC who received erlotinib therapy for more than 6 months between December 2007 and March 2019. The participants were divided into two groups: the intervention group that included patients who received pharmaceutical consultation targeting outpatients by a pharmacist and the nonintervention group that included patients who did not. We retrospectively investigated patient characteristics, treatment regimens, and treatment efficacy. We included a total of 33 patients (18 and 15 patients in the nonintervention and intervention groups, respectively) in this study. The intervention group had a significantly higher median relative dose intensity (RDI) of erlotinib than the nonintervention group (p = 0.0437). In addition, the pharmaceutical consultation targeting outpatients was identified as a factor contributing to the maintenance of RDI ≥90% (p = 0.0269). The present study indicated that there was improvement in RDI with pharmaceutical consultation targeting outpatients with advanced NSCLC.

Pharmacoeconomic Evaluation of Erlotinib for the Treatment of Pancreatic Cancer.

PURPOSE: To evaluate the cost-effectiveness of gemcitabine and gemcitabine plus erlotinib as first-line treatments for advanced pancreatic cancer. METHODS: On the basis of the Gemcitabine With/Out Erlotinib in Unresectable Locally Advanced/Metastatic Pancreatic Cancer (PA.3) trial, the Markov model was constructed to simulate the development of advanced pancreatic cancer. Cost-effectiveness analysis was used to determine the economic level of the treatments, according to the willingness-to-pay (WTP) threshold. The sensitivity analysis was conducted for cost-effectiveness and other indexes. FINDINGS: The results of the cost-effectiveness analysis revealed that the cost-effectiveness ratios for the first-line treatment of advanced pancreatic cancer were ¥60,492.78 (US$8892.44/€7568.88) per 6.34 quality-adjusted life-months (QALMs) for gemcitabine and ¥99,595.39 (US$14,640.52/€12,461.42) per 7.02 QALMs for gemcitabine plus erlotinib. The incremental cost-effectiveness of the 2 regimens was ¥57,503.84 ($8453.06/€7194.90) per QALM, which was higher than the WTP set in this study (¥16,161 [$2375.66/€2022.07] per QALM). The results of the sensitivity analysis indicate that the analysis results were stable. Gemcitabine was more cost-effective than gemcitabine plus erlotinib. IMPLICATIONS: Compared with gemcitabine, gemcitabine plus erlotinib was not cost-effective at the level of the WTP. Gemcitabine plus erlotinib therapy has no economic significance as a first-line medical treatment for pancreatic cancer.

Design and Synthesis of Non-Covalent Imidazo[1,2-a]quinoxaline-Based Inhibitors of EGFR and Their Anti-Cancer Assessment.

A series of 30 non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized. EGFR inhibitory assessment (against wild type) data of compounds revealed 6b, 7h, 7j, 9a and 9c as potent EGFRWT inhibitors with IC50 values of 211.22, 222.21, 193.18, 223.32 and 221.53 nM, respectively, which were comparable to erlotinib (221.03 nM), a positive control. Furthermore, compounds exhibited excellent antiproliferative activity when tested against cancer cell lines harboring EGFRWT; A549, a non-small cell lung cancer (NSCLC), HCT-116 (colon), MDA-MB-231 (breast) and gefitinib-resistant NSCLC cell line H1975 harboring EGFRL858R/T790M. In particular, compound 6b demonstrated significant inhibitory potential against gefitinib-resistant H1975 cells (IC50 = 3.65 µM) as compared to gefitinib (IC50 > 20 µM). Moreover, molecular docking disclosed the binding mode of the 6b to the domain of EGFR (wild type and mutant type), indicating the basis of inhibition. Furthermore, its effects on redox modulation, mitochondrial membrane potential, cell cycle analysis and cell death mode in A549 lung cancer cells were also reported.

Cost-Effectiveness Analysis of Afatinib, Erlotinib, and Gefitinib as First-Line Treatments for EGFR Mutation-Positive Non-Small-Cell Lung Cancer in Ontario, Canada.

OBJECTIVE: The objective of this study was to compare the cost effectiveness of first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for the treatment of non-small-cell lung cancer. METHODS: This study used Ontario Cancer Registry-linked administrative data to identify patients with a primary diagnosis of lung cancer who received EGFR-TKIs as first-line treatment between 1 January, 2014 and 31 August, 2019. A net benefit regression approach accounting for baseline covariates and propensity scores was used to estimate incremental net benefits and incremental cost-effectiveness ratios. Outcome measures were calculated over a 68-month period and were discounted with an annual rate of 1.5%. Sensitivity analyses were conducted to assess and characterize the uncertainties. RESULTS: A total of 547 patients were included in the study, of whom 20.1%, 23.6%, and 56.3% received afatinib, erlotinib, and gefitinib, respectively. Erlotinib was dominated by afatinib and gefitinib. Compared to gefitinib, afatinib was associated with higher effectiveness (adjusted incremental quality-adjusted life-year: 0.21), higher total costs (adjusted incremental costs: $9745), and an incremental cost-effectiveness ratio of $46,506 per quality-adjusted life-year gained. Results from the sensitivity analyses indicated the findings of the base-case analysis were robust. CONCLUSIONS: Contrary to previously published studies, our study established head-to-head comparisons of effectiveness and treatment-related costs of first-line EGFR-TKIs. Our findings suggest afatinib was the most cost-effective option among the three EGFR-TKIs.

EGFR mutation-guided use of afatinib, erlotinib and gefitinib for advanced non-small-cell lung cancer in Hong Kong - A cost-effectiveness analysis.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) therapy targets at epidermal growth factor receptor (EGFR) gene mutations in non-small-cell lung cancer (NSCLC). We aimed to compare the EGFR mutation-guided target therapy versus empirical chemotherapy for first-line treatment of advanced NSCLC in the public healthcare setting of Hong Kong. METHODS: A Markov model was designed to simulate outcomes of a hypothetical cohort of advanced (stage IIIB/IV) NSCLC adult patients with un-tested EGFR-sensitizing mutation status. Four treatment strategies were evaluated: Empirical first-line chemotherapy with cisplatin-pemetrexed (empirical chemotherapy group), and EGFR mutation-guided use of a TKI (afatinib, erlotinib, and gefitinib). Model outcome measures were direct medical cost, progression-free survival, overall survival, and quality-adjusted life-years (QALYs). Incremental cost per QALY gained (ICER) was estimated. Sensitivity analyses were performed to examine robustness of model results. RESULTS: Empirical chemotherapy and EGFR mutation-guided gefitinib gained lower QALYs at higher costs than the erlotinib group. Comparing with EGFR mutation-guided erlotinib, the afatinib strategy gained additional QALYs with ICER (540,633 USD/QALY). In 10,000 Monte Carlo simulations for probabilistic sensitivity analysis, EGFR mutation-guided afatinib, erlotinib, gefitinib and empirical chemotherapy were preferred strategy in 0%, 98%, 0% and 2% of time at willingness-to-pay (WTP) 47,812 USD/QALY (1x gross domestic product (GDP) per capita), and in 30%, 68%, 2% and 0% of time at WTP 143,436 USD/QALY (3x GDP per capita), respectively. CONCLUSIONS: EGFR mutation-guided erlotinib appears to be the cost-effective strategy from the perspective of Hong Kong public healthcare provider over a broad range of WTP.

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.

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.

Cost-effectiveness analysis of adding ramucirumab to the first-line erlotinib treatment for untreated EGFR-mutated metastatic non-small cell lung cancer in China.

OBJECTIVE: To investigate the cost-effectiveness of ramucirumab plus erlotinib compared with placebo plus erlotinib in the first-line setting for patients with EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) from the Chinese healthcare system perspective. DESIGN: A Markov model consisting of three health states using clinical survival data from the RELAY phase III randomised clinical trial, a lifetime horizon for costs and quality-adjusted life-years (QALYs) was constructed to analyse the cost-effectiveness of ramucirumab plus erlotinib. One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of the model. Additional price reduction scenario analyses were performed. SETTING: The Chinese healthcare system perspective. PARTICIPANTS: A hypothetical Chinese cohort of patients with confirmed previously documented ex19del or Leu858Arg mutation stage IV NSCLC, and without known epidermal growth factor receptor (EGFR) Thr790Met mutation and central nervous system metastases. INTERVENTIONS: Ramucirumab plus erlotinib versus placebo plus erlotinib. PRIMARY OUTCOME MEASURE: Costs, QALYs, incremental cost-effectiveness ratio (ICER). RESULTS: In base-case analysis, ramucirumab plus erlotinib yield an additional 4.21 QALYs at a cost of $540 590, resulting in an ICER of $128 302/QALY. In price reduction scenario analysis, the ICER ($65 227/QALY) was decreased significantly when the National Reimbursement Drug List (NRDL) negotiation was available for ramucirumab, and the ICER ($131 554/QALY) was increased slightly when the NRDL negotiation was unavailable for erlotinib. Sensitivity analyses demonstrated our results to be most sensitive to the unit cost of ramucirumab (10 mg/kg), and more than 52.1% reduction in the price of ramucirumab resulted in the ICER under the willingness-to-pay threshold set for affluent regions ($70 353/QALY). CONCLUSIONS: Ramucirumab plus erlotinib is unlikely to be cost-effective for patients with untreated EGFR-mutated mNSCLC in China. Reducing the price of ramucirumab through the National Healthcare Security Administration negotiation was found to be the most realistic action to improve cost-effectiveness.

Cost-effectiveness analysis of first and second-generation EGFR tyrosine kinase inhibitors as first line of treatment for patients with NSCLC harboring EGFR mutations.

BACKGROUND: Tyrosine-kinase inhibitors (TKIs) have become the cornerstone treatment of patients with non-small cell lung cancer that harbor oncogenic EGFR mutations. The counterpart of these drugs is the financial burden that they impose, which often creates a barrier for accessing treatment in developing countries. The aim if the present study was to compare the cost-effectiveness of three different first and second generation TKIs. METHODS: We designed a retrospective cost-effectiveness analysis of three different TKIs (afatinib, erlotinib, and gefitinib) administered as first-line therapy for patients with NSCLC that harbor EGFR mutations. RESULTS: We included 99 patients with the following TKI treatment; 40 treated with afatinib, 33 with gefitinib, and 26 with erlotinib. Median PFS was not significantly different between treatment groups; 15.4 months (95% CI 9.3-19.5) for afatinib; 9.0 months (95% CI 6.3- NA) for erlotinib; and 10.0 months (95% CI 7.46-14.6) for gefitinib. Overall survival was also similar between groups: 29.1 months (95% CI 25.4-NA) for afatinib; 27.1 months (95% CI 17.1- NA) for erlotinib; and 23.7 months (95% CI 18.6-NA) for gefitinib. There was a statistically significant difference between the mean TKIs costs; being afatinib the most expensive treatment. This difference was observed in the daily cost of treatment (p < 0.01), as well as the total cost of treatment (p = 0.00095). Cost-effectiveness analysis determined that afatinib was a better cost-effective option when compared with first-generation TKIs (erlotinib and gefitinib). CONCLUSION: In our population, erlotinib, afatinib, and gefitinib were statistically equally effective in terms of OS and PFS for the treatment of patients with advanced EGFR-mutated NSCLC population. Owing to its marginally increased PFS and OS, the cost-effectiveness analysis determined that afatinib was a slightly better cost-effective option when compared with first-generation TKIs (erlotinib and gefitinib).

EGFR testing and erlotinib use in non-small cell lung cancer patients in Kentucky.

This study determined the frequency and factors associated with EGFR testing rates and erlotinib treatment as well as associated survival outcomes in patients with non small cell lung cancer in Kentucky. Data from the Kentucky Cancer Registry (KCR) linked with health claims from Medicaid, Medicare and private insurance groups were evaluated. EGFR testing and erlotinib prescribing were identified using ICD-9 procedure codes and national drug codes in claims, respectively. Logistic regression analysis was performed to determine factors associated with EGFR testing and erlotinib prescribing. Cox-regression analysis was performed to determine factors associated with survival. EGFR mutation testing rates rose from 0.1% to 10.6% over the evaluated period while erlotinib use ranged from 3.4% to 5.4%. Factors associated with no EGFR testing were older age, male gender, enrollment in Medicaid or Medicare, smoking, and geographic region. Factors associated with not receiving erlotinib included older age, male gender, enrollment in Medicare or Medicaid, and living in moderate to high poverty. Survival analysis demonstrated EGFR testing or erlotinib use was associated with a higher likelihood of survival. EGFR testing and erlotinib prescribing were slow to be implemented in our predominantly rural state. While population-level factors likely contributed, patient factors, including geographic location (areas with high poverty rates and rural regions) and insurance type, were associated with lack of use, highlighting rural disparities in the implementation of cancer precision medicine.

Treatment sequence of first and second generation tyrosine kinase inhibitor followed by osimertinib in EGFR-mutated non-small-cell lung cancer: a real life study.

Background: We aimed to assess the effectiveness and cost of patients with first line tyrosine kinase inhibitors (TKIs) sequence of first (1G) and second generation (2G) followed by osimertinib. Materials & methods: Using the French nationwide claims and hospitalization database, we analyzed non-small-cell lung cancer patients who had been treated with osimertinib between April 2015 and December 2017, after a first line treatment with a TKI-1G/2G. Results: The median time on treatment for sequential TKI-1G/2G followed by osimertinib was 34 months (95% CI: 31-46); 13 and 12months, respectively for TKI 1G or 2G and TKI 3G, respectively. The median overall survival for sequential TKI 1G or 2G followed by osimertinib was 37 months (95% CI: 34-42). The mean monthly costs per patient was €5162. Conclusion: These results, in line with those observed during clinical trials, confirm the effectiveness of the sequence TKI-1G/2G followed by osimertinib in EGFR-mutated non-small-cell lung cancer.

Comparative effectiveness and cost-effectiveness of three first-line EGFR-tyrosine kinase inhibitors: Analysis of real-world data in a tertiary hospital in Taiwan.

INTRODUCTION: Comparison of the effectiveness and cost-effectiveness of three first-line EGFR-tyrosine kinase inhibitors (TKIs) would improve patients' clinical benefits and save costs. Using real-world data, this study attempted to directly compare the effectiveness and cost-effectiveness of first-line afatinib, erlotinib, and gefitinib. METHODS: During May 2011-December 2017, all patients with non-small cell lung cancer (NSCLC) visiting a tertiary center were invited to fill out the EuroQol five-dimension (EQ-5D) questionnaires and World Health Organization Quality of Life, brief version (WHOQOL-BREF), and received follow-ups for survival and direct medical costs. A total of 379 patients with EGFR mutation-positive advanced NSCLC under first-line TKIs were enrolled for analysis. After propensity score matching for the patients receiving afatinib (n = 48), erlotinib (n = 48), and gefitinib (n = 96), we conducted the study from the payers' perspective with a lifelong time horizon. RESULTS: Patients receiving afatinib had the worst lifetime psychometric scores, whereas the differences in quality-adjusted life expectancy (QALE) were modest. Considering 3 treatments together, afatinib was dominated by erlotinib. Erlotinib had an incremental cost-effectiveness of US$17,960/life year and US$12,782/QALY compared with gefitinib. Acceptability curves showed that erlotinib had 58.6% and 78.9% probabilities of being cost-effective given a threshold of 1 Taiwanese per capita GDP per life year and QALY, respectively. CONCLUSION: Erlotinib appeared to be cost-effective. Lifetime psychometric scores may provide additional information for effectiveness evaluation.

Assessment of modelling strategies for drug response prediction in cell lines and xenografts.

Data from several large high-throughput drug response screens have become available to the scientific community recently. Although many efforts have been made to use this information to predict drug sensitivity, our ability to accurately predict drug response based on genetic data remains limited. In order to systematically examine how different aspects of modelling affect the resulting prediction accuracy, we built a range of models for seven drugs (erlotinib, pacliatxel, lapatinib, PLX4720, sorafenib, nutlin-3 and nilotinib) using data from the largest available cell line and xenograft drug sensitivity screens. We found that the drug response metric, the choice of the molecular data type and the number of training samples have a substantial impact on prediction accuracy. We also compared the tasks of drug response prediction with tissue type prediction and found that, unlike for drug response, tissue type can be predicted with high accuracy. Furthermore, we assessed our ability to predict drug response in four xenograft cohorts (treated either with erlotinib, gemcitabine or paclitaxel) using models trained on cell line data. We could predict response in an erlotinib-treated cohort with a moderate accuracy (correlation ≈ 0.5), but were unable to correctly predict responses in cohorts treated with gemcitabine or paclitaxel.