Estimating Taiwan's QALY league table for catastrophic illnesses: Providing real-world evidence to integrate prevention with treatment for resources allocation.

BACKGROUND/PURPOSE: Curative technologies improve patient's survival and/or quality of life but increase financial burdens. Effective prevention benefits all three. We summarize estimation methods and provide examples of how much money is spent per quality-adjusted life year (QALY) or life year (LY) on treating a catastrophic illness under a lifetime horizon and how many QALYs/LYs and lifetime medical costs (LMC) could be potentially saved by prevention. METHODS: We established cohorts by interlinkages of Taiwan's nation-wide databases including National Health Insurance. We developed methods to estimate lifetime survival functions, which were multiplied with the medical costs and/or quality of life and summed up to estimate LMC, quality-adjusted life expectancy (QALE) and lifetime average cost per QALY/LY for catastrophic illnesses. By comparing with the age-, sex-, and calendar year-matched referents simulated from vital statistics, we obtained the loss-of-QALE and loss-of-life expectancy (LE). RESULTS: The lifetime cost-effectiveness ratios of ventilator-dependent comatose patients, dialysis, spinal cord injury, major trauma, and cancers were US$ 96,800, 16,200-20,000, 5500-5,900, 3400-3,600, and 2900-11,900 per QALY or LY, respectively. The successful prevention of lung, liver, oral, esophagus, stomach, nasopharynx, or ovary cancer would potentially save US$ 28,000-97,000 and > 10 QALYs; whereas those for end-stage kidney disease, stroke, spinal injury, or major trauma would be US$ 55,000-300,000 and 10-14 QALYs. Loss-of-QALE and loss-of-LE were less confounded indicators for comparing the lifetime health benefits of different technologies estimated from real-world data. CONCLUSIONS: Integration of prevention with treatment for resources allocation seems feasible and would improve equity and efficiency.

Possible overdiagnosis of early-stage lung adenocarcinoma among never-smokers in Taiwan.

10-year survival for never-smokers with >1 cm but ≤3 cm AIS/BAC/MIA was not inferior to that of the matched referents, pointing to possible overdiagnosis. Clinicians might consider adhering to Lung-RADS and watchful waiting for these non-solid nodules. https://bit.ly/41U6kxs.

Distinct Features of Plasma Ultrashort Single-Stranded Cell-Free DNA as Biomarkers for Lung Cancer Detection.

BACKGROUND: Using broad range cell-free DNA sequencing (BRcfDNA-Seq), a nontargeted next-generation sequencing (NGS) methodology, we previously identified a novel class of approximately 50 nt ultrashort single-stranded cell-free DNA (uscfDNA) in plasma that is distinctly different from 167 bp mononucleosomal cell-free DNA (mncfDNA). We hypothesize that uscfDNA possesses characteristics that are useful for disease detection. METHODS: Using BRcfDNA-Seq, we examined both cfDNA populations in the plasma of 18 noncancer controls and 14 patients with late-stage nonsmall cell lung carcinoma (NSCLC). In comparison to mncfDNA, we assessed whether functional element (FE) peaks, fragmentomics, end-motifs, and G-Quadruplex (G-Quad) signatures could be useful features of uscfDNA for NSCLC determination. RESULTS: In noncancer participants, compared to mncfDNA, uscfDNA fragments showed a 45.2-fold increased tendency to form FE peaks (enriched in promoter, intronic, and exonic regions), demonstrated a distinct end-motif-frequency profile, and presented with a 4.9-fold increase in G-Quad signatures. Within NSCLC participants, only the uscfDNA population had discoverable FE peak candidates. Additionally, uscfDNA showcased different end-motif-frequency candidates distinct from mncfDNA. Although both cfDNA populations showed increased fragmentation in NSCLC, the G-Quad signatures were more discriminatory in uscfDNA. Compilation of cfDNA features using principal component analysis revealed that the first 5 principal components of both cfDNA subtypes had a cumulative explained variance of >80%. CONCLUSIONS: These observations indicate that the distinct biological processes of uscfDNA and that FE peaks, fragmentomics, end-motifs, and G-Quad signatures are uscfDNA features with promising biomarker potential. These findings further justify its exploration as a distinct class of biomarker to augment pre-existing liquid biopsy approaches.

Estimation of disability free life expectancy in non small cell lung cancer based on real world data.

To quantify the societal impact of disability in patients with non-small cell lung cancer (NSCLC), this study estimated the disability-free life expectancy (DFLE), loss-of-DFLE and explored their associations with quality-adjusted life expectancy (QALE) and loss-of-QALE. We interlinked national databases and applied a rolling-over algorithm to estimate the lifetime survival function for patients with NSCLC. Using the EuroQOL-5 Dimension (EQ-5D) and Barthel index (BI), we repeatedly measured the quality-of-life and disability functions of NSCLC patients who visited our hospital from 2011 to 2020. Age-, sex-matched referents were simulated from lifetables of the same calendar year of diagnosis. We categorized BI scores ≤ 70 as in need of long-term care and constructed linear mixed models to estimate the utility values and disability scores. We collected 960 cases and 3088 measurements. The proportions of measurements without disability at age 50-64 and in stage I-IIIa, 50-64 and stage IIIb-IV, 65-89 and stage I-IIIa and 65-89 and stage IIIb-IV were 97.3%, 89.3%, 94.8%,78.3%, corresponding to DFLEs of 15.3, 2.4, 6.8, 1.2 years and losses-of-DFLE of 8.1, 20.7, 4.0, 8.6 years, respectively, indicating that advanced stage had a stronger effect than old age. Survivors in advanced stages showed increased demands for assistance in almost all subitems. The DFLEs seemed to be approximate to the QALEs and the latter were shorter than the former due to discomfort and depression. From a societal perspective, future health technology assessment should consider the impact of lifetime duration of functional disability. Early diagnosis of NSCLC may decrease the burden of long-term care.

Losses of lifetime employment duration and productivity for patients with different subtypes and stages of lung cancer.

BACKGROUND: How different subtypes and stages of lung cancer affect morbidity- and mortality-associated productivity have not been investigated. This study quantified the losses of lifetime employment duration and productivity among patients with various subtypes and stages of lung cancer. METHODS: We identified nationwide lung cancer patients diagnosed at the ages of 50-64 between 2011 and 2019. Monthly survival probabilities were weighted by monthly employed-to-population ratios and working salaries to estimate lifetime employment duration and productivity. We compared lifetime employment duration and productivity of patients with those of the age-, sex-, calendar year-matched general population for losses of lifetime employment duration and productivity, which were multiplied by pathology and stage shifts based on the first-round screening of Taiwan Lung Cancer Screening in Never Smoker Trial (TALENT) to calculate the savings of lifetime employment duration and productivity. RESULTS: Lung cancer patients had shorter survival and employment duration than the referents. Patients with lung cancers other than adenocarcinoma experienced greater losses of lifetime employment duration and productivity as compared to adenocarcinoma patients. Applying the estimations of never-smoking patients to 100 lung cancer patients with pathology and stage shifts based on the TALENT, the savings of lifetime employment duration and productivity were 132.2 (95% prediction interval: 116.2-147.4) years and 3353 (95% prediction interval: 2914-3802) thousand US dollars, respectively. CONCLUSIONS: Early diagnosis of lung cancer would save the losses of employment duration and lifetime productivity. Future evaluation of the cost-effectiveness of lung cancer screening could consider incorporating these societal impacts.

Effect of BIM expression on the prognostic value of PD-L1 in advanced non-small cell lung cancer patients treated with EGFR-TKIs.

The role of Programmed Cell Death Ligand 1 (PD-L1) expression in predicting epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) efficacy remains controversial. Recent studies have highlighted that tumor-intrinsic PD-L1 signaling can be modulated by STAT3, AKT, MET oncogenic pathway, epithelial-mesenchymal transition, or BIM expression. This study aimed to investigate whether these underlying mechanisms affect the prognostic role of PD-L1. We retrospectively enrolled patients with EGFR mutant advanced stage NSCLC who received first-line EGFR-TKI between January 2017 and June 2019, the treatment efficacy of EGFR-TKI was assessed. Kaplan-Meier analysis of progression-free survival (PFS) revealed that patients with high BIM expression had shorter PFS, regardless of PD-L1 expression. This result was also supported by the COX proportional hazard regression analysis. In vitro, we further proved that the knockdown of BIM, instead of PDL1, induced more cell apoptosis following gefitinib treatment. Our data suggest that among the pathways affecting tumor-intrinsic PD-L1 signaling, BIM is potentially the underlying mechanism that affects the role of PD-L1 expression in predicting response to EGFR TKI and mediates cell apoptosis under treatment with gefitinib in EGFR-mutant NSCLC. Further prospective studies are required to validate these results.

Estimating time and transportation costs associated with lung cancer screening and diagnostic lung procedures in Taiwan: a cross-sectional survey in a medical centre.

OBJECTIVES: Earlier research has evaluated the non-medical costs after lung cancer diagnosis. This study estimated the time costs and transportation costs associated with low-dose CT (LDCT) screening and diagnostic lung procedures in Taiwan. DESIGN: Cross-sectional study. SETTING: A tertiary referral medical centre. PARTICIPANTS AND INTERVENTIONS: The study participants were individuals aged 50-80 years who underwent LDCT screening or diagnostic lung procedures between 2021 and 2022. Participants completed a questionnaire including items on time spent on receiving care, time spent on travel and its cost and time taken off from work by the participant and any accompanying caregiver. OUTCOME MEASURES: Time costs were valued using the age- and sex-specific average daily wage for employed participants/caregivers. Costs of informal healthcare sector consisted of time cost of the participant, transportation cost and time cost of the caregiver. RESULTS: A total of 209 participants who underwent LDCT screening (n=84) or non-surgical (n=12) or surgical (n=113) diagnostic lung procedures for the first time were enrolled. Considering the purchasing power parity, the average costs of informal healthcare sector were US$126.4 (95% CI 101.6 to 151.2), US$290.7 (95% CI 106.9 to 474.5) and US$749.8 (95% CI 567.3 to 932.4), respectively, for LDCT screening, non-surgical procedures and surgical procedures. CONCLUSIONS: This study estimated time and transportation costs associated with LDCT screening and diagnostic lung procedures, which could be used for future analysis of cost-effectiveness of lung cancer screening in Taiwan.

Cost-effectiveness of first-line immunotherapies for advanced non-small cell lung cancer.

BACKGROUND: Researchers have not simultaneously compared the cost-effectiveness of six immunotherapies with chemotherapy for advanced non-small cell lung cancer. This study evaluated the cost-effectiveness across different programmed death-ligand 1 (PD-L1) levels. METHODS: A Markov model with lifetime horizon was created for seven regimens: pembrolizumab plus chemotherapy (pembro-chemo), nivolumab plus ipilimumab (nivo-ipi), nivolumab, ipilimumab plus chemotherapy (nivo-ipi-chemo), atezolizumab plus chemotherapy (atezo-chemo), atezolizumab, bevacizumab plus chemotherapy (atezo-beva-chemo), single-agent pembrolizumab, and chemotherapy alone. Input parameters were derived from trial data, a network meta-analysis, and other literature. We conducted the analysis from the perspective of US health care sector. RESULTS: For all patients without considering PD-L1 expression, the incremental cost-effectiveness ratio (ICER) of pembro-chemo versus chemotherapy was $183,299 per quality-adjusted life year (QALY). The preferred regimens based on ICERs differed by PD-L1 levels. For patients with PD-L1 ≥50%, pembrolizumab versus chemotherapy and pembro-chemo versus pembrolizumab resulted in ICERs of $96,189 and $198,913 per QALY, respectively. The other strategies were dominated. For patients with PD-L1 of 1%-49%, the ICER of pembro-chemo comparing to chemotherapy was $218,159 per QALY. The other regimens were dominated by pembro-chemo. For patients with PD-L1 <1%, nivo-ipi versus chemotherapy and nivo-ipi-chemo versus nivo-ipi resulted in ICERs of $161,277 and $881,975 per QALY, and the other regimens were dominated strategies. At the willingness-to-pay threshold of $150,000 per QALY, pembrolizumab had 87% and pembro-chemo had 1% probabilities being cost-effective in patients with PD-L1 ≥50% and 1%-49%, respectively. Nivo-ipi had a 34% probability being cost-effective in patients with PD-L1 <1%. CONCLUSIONS: The PD-L1 level should be incorporated into treatment decision-making. Our findings suggest that first-line pembrolizumab, pembro-chemo, and nivo-ipi are the preferred strategies for patients with PD-L1 ≥50%, 1%-49%, and <1%, respectively.

Pembrolizumab and Chemotherapy Combination Prolonged Progression-Free Survival in Patients with NSCLC with High PD-L1 Expression and Low Neutrophil-to-Lymphocyte Ratio.

The use of immune checkpoint inhibitors (ICIs) has provided overall survival (OS) benefits in patients with treatment-naïve advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. However, studies comparing ICIs monotherapy with combination therapy either with chemotherapy or radiotherapy in programmed death-ligand 1 high expressors remain limited. This study aimed to retrospectively compare the treatment efficacy of the therapies by studying 47 patients with treatment-naïve advanced NSCLC who received ICI monotherapy (n = 28) or combination therapy either with chemotherapy or radiotherapy (n = 19). Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method and compared using log-rank tests. It was observed that patients who received combination therapy had a better PFS than monotherapy, but no such significant benefit was observed in OS. The difference in PFS was higher in the subgroup of patients with low neutrophil-to-lymphocyte ratio (NLR) than in the high-NLR patient subgroup. This study suggests that pembrolizumab in combination with chemotherapy or radiotherapy could provide a significant benefit in PFS, especially in patients with treatment-naïve advanced NSCLC with low NLR. Furthermore, our study also demonstrates the potential use of NLR as a biomarker for prediction of treatment outcomes in patients with advanced NSCLC receiving combination therapy.

PM2.5 exposure and risk of lung adenocarcinoma in women of Taiwan: A case-control study with density sampling.

BACKGROUND AND OBJECTIVE: The prevalence of smoking among women in Taiwan is <5%, but the incidence of lung cancer remains high. This study determined the association between PM2.5 (fine particulate matter with an aerodynamic diameter of ≤2.5 µm) exposure and lung cancer among women in Taiwan. METHODS: In total, 21,301 female lung cancer cases nationwide were newly diagnosed between 2012 and 2017. Each case was age-, sex- and calendar year-matched with four controls randomly selected from the general population. Allowing a latent period of 5 years, we estimated the PM2.5 and nitrogen dioxide (NO2 ) exposures for each individual according to the residential changes from 2000. We adopted self-reported smoking statuses for the cases, while those of controls were estimated using annual surveys in each residential county. We performed multiple logistic regression analyses to examine the associations between PM2.5 and NO2 exposures and incident lung cancer cases. RESULTS: The ORs of lung adenocarcinoma for the third (30.5-35.1 µg/m3 ), fourth (35.1-39.3 µg/m3 ) and fifth PM2.5 exposure quintiles (39.3-48.1 µg/m3 ) relative to the first quintile were 1.10 (95% CI: 1.04-1.16), 1.12 (95% CI: 1.06-1.19) and 1.10 (95% CI: 1.04-1.16), respectively, after adjusting for smoking, residence and comorbidities. A dose-response relationship (p = 0.004) was found. The associations persisted with a 10-year latency and were not detected for small-cell and squamous cell carcinoma after control for smoking. We did not observe a similar effect for NO2 exposure. CONCLUSION: Residential PM2.5 exposure higher than 30 µg/m3 was associated with an increased risk of lung adenocarcinoma in women of Taiwan.

Economic Analysis of Tissue-First, Plasma-First, and Complementary NGS Approaches for Treatment-Naïve Metastatic Lung Adenocarcinoma.

Background: To compare the testing costs and testing turnaround times of tissue-first, plasma-first, and complementary next-generation sequencing (NGS) approaches in patients with treatment-naïve metastatic lung adenocarcinoma. Materials and Methods: We developed a decision tree model to compare three different approaches. Patients were entered into the model upon cancer diagnosis and those with both insufficient tissue specimens and negative liquid-based NGS were subjected to tissue re-biopsy. Actionable gene alterations with the U.S. Food and Drug Administration (FDA)-approved therapies included epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) gene rearrangement, ROS proto-oncogene 1 (ROS1) rearrangement, B-Raf proto-oncogene (BRAF) V600E mutation, rearranged during transfection (RET) gene rearrangement, mesenchymal-epithelial transition factor (MET) mutation, neurotrophic tyrosine receptor kinase (NTRK) gene rearrangement, K-Ras proto-oncogene (KRAS) G12C mutation, and human epidermal growth factor receptor 2 (HER2) mutation. Model outcomes were testing costs, testing turnaround times, and monetary losses taking both cost and time into consideration. We presented base-case results using probabilistic analysis. Stacked one-way and three-way sensitivity analyses were also performed. Results: In terms of testing costs, tissue-first approach incurred US$2,354($1,963-$2,779) and was the most cost-efficient strategy. Complementary approach testing turnaround time (days) of 12.7 (10.8 to 14.9) was found as the least time-consuming strategy. Tissue-first, complementary, and plasma-first approaches resulted in monetary losses in USD of $4,745 ($4,010-$5,480), $6,778 ($5,923-$7,600), and $7,006 ($6,047-$7,964) respectively, and identified the same percentage of patients with appropriate FDA-approved therapies. Costs for liquid-based NGS, EGFR mutation rates, and quantity of tissue specimens were the major determinants in minimizing monetary loss. Plasma-first approach would be the preferable strategy if its testing price was reduced in USD to $818, $1,343, and $1,869 for populations with EGFR mutation rates of 30%, 45%, and 60% respectively. Conclusion: The tissue-first approach is currently the best strategy in minimizing monetary loss. The complementary approach is an alternative for populations with a low EGFR mutation rate. The plasma-first approach becomes increasingly preferable as EGFR mutation rates gradually increase.

Multiple in-hospital counseling increases six-month smoking abstinence among individuals participating in a hospital-initiated smoking cessation program.

BACKGROUND: A cessation program for hospitalized smokers is an effective strategy to achieve smoking abstinence. The effects of multiple in-hospital counseling sessions on 6-month smoking abstinence require further investigation. METHODS: We retrospectively analyzed the data of smokers who participated in hospital-initiated cessation programs at a medical center between 2017 and 2019. Data on age, sex, comorbidities, daily number of cigarettes, cessation motivation, nicotine dependence, cessation medications, discharge diagnosis, length of hospitalization, and intensive care unit admission were collected. We conducted multiple logistic regression analysis to investigate the effect of multiple in-hospital counseling sessions on 6-month sustained smoking abstinence. Sensitivity analyses were carried out excluding participants who underwent post-discharge cessation programs and assuming that the loss to follow-up participants had failure in 6-month smoking abstinence. RESULTS: A total of 1943 participants aged ≥ 20 years were analyzed. Compared with single in-hospital counseling session, the adjusted odds ratios (ORs) for 2 and ≥ 3 counseling sessions were 1.44 (95% confidence interval [CI] 1.05 to 1.98) and 2.02 (95% CI 1.27 to 3.22), respectively, with a significant trend for increasing the number of counseling sessions (P < 0.001). The results remained significant after excluding participants who underwent a post-discharge cessation program or when assuming that lost to follow-up participants had failure in smoking abstinence. CONCLUSION: Multiple in-hospital counseling sessions were associated with a higher 6-month sustained smoking abstinence rate. This strategy could be used to reduce the prevalence of smoking.

Economic Analysis of Exclusionary EGFR Test Versus Up-Front NGS for Lung Adenocarcinoma in High EGFR Mutation Prevalence Areas.

BACKGROUND: This study sought to determine whether exclusionary EGFR mutation testing followed by next-generation sequencing (NGS) is a cost-efficient and timely strategy in areas with high prevalence rates of EGFR mutation. METHODS: We developed a decision tree model to compare exclusionary EGFR testing followed by NGS and up-front NGS. Patients entered the model upon diagnosis of metastatic lung adenocarcinoma. Gene alterations with FDA-approved targeted therapies included EGFR, ALK, ROS1, BRAF, RET, MET, NTRK, and KRAS. Model outcomes were testing-related costs; time-to-test results; monetary loss, taking both costs and time into consideration; and percentage of patients who could be treated by FDA-approved therapies. Stacked 1-way and 3-way sensitivity analyses were performed. RESULTS: Exclusionary EGFR testing incurred testing-related costs of US $1,387 per patient, a savings of US $1,091 compared with the costs of up-front NGS. The time-to-test results for exclusionary EGFR testing and up-front NGS were 13.0 and 13.6 days, respectively. Exclusionary EGFR testing resulted in a savings of US $1,116 in terms of net monetary loss, without a reduction of patients identified with FDA-approved therapies. The EGFR mutation rate and NGS cost had the greatest impact on minimizing monetary loss. Given that the tissue-based NGS turnaround time was shortened to 7 days, up-front NGS testing would become the best strategy if its price could be reduced to US $568 in Taiwan. CONCLUSIONS: In areas with high prevalence rates of EGFR mutation, exclusionary EGFR testing followed by NGS, rather than up-front NGS, is currently a cost-efficient strategy for metastatic lung adenocarcinoma.

The impact of driver mutation on the treatment outcome of early-stage lung cancer patients receiving neoadjuvant immunotherapy and chemotherapy.

Neoadjuvant immunotherapy and chemotherapy have improved the major pathological response (MPR) in patients with early-stage operable non-small cell lung cancer (NSCLC). This study aimed to assess whether the presence of targetable driver mutations affects the efficacy of the combination of immunotherapy and chemotherapy. We enrolled patients with early-stage operable NSCLC who received preoperative neoadjuvant therapy between January 1, 2017, and December 30, 2020. Neoadjuvant therapy was delivered with platinum-doublet chemotherapy; moreover, pembrolizumab was added at the attending physician's discretion based on patient's request. Pathological responses were assessed; moreover, disease-free survival was estimated. Next-generation sequencing was performed in case sufficient preoperative biopsy specimens were obtained. We included 23 patients; among them, 11 received a combination of neoadjuvant immunotherapy and chemotherapy while 12 received neoadjuvant chemotherapy alone. The MPR and pathological complete response rates were 54.5% and 27.3%, respectively, in patients who received a combination of neoadjuvant immunotherapy and chemotherapy. These rates were significantly higher than those in patients who only received neoadjuvant chemotherapy. Three patients in the combination group experienced disease recurrence during the follow-up period even though two of them showed an MPR. These three patients had targetable driver mutations, including an EGFR exon 20 insertion, EGFR exon 21 L858R substitution, and MET exon 14 skipping. Only one patient who remained disease-free had a targetable driver mutation. Among patients with early-stage operable NSCLC requiring neoadjuvant therapy, comprehensive genomic profiling is crucial before the administration of the combination of neoadjuvant immunotherapy and chemotherapy.

Improved survival in patients with unresectable stage III EGFR-mutant adenocarcinoma with upfront EGFR-tyrosine kinase inhibitors.

BACKGROUND: Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been the standard treatment for advanced EGFR-mutant adenocarcinoma, the effects of upfront EGFR-TKI use in unresectable stage III EGFR-mutant adenocarcinoma remain unexplored. Here, we conducted a retrospective study to compare different treatment strategies in these patients. METHODS: From October 2010 to June 2019, patients with unresectable stage III adenocarcinoma who received treatment at a tertiary referral center were enrolled. Patients were classified into three groups: EGFR-mutant adenocarcinoma treated with concurrent chemoradiotherapy (group 1) or EGFR-TKI (group 2) and EGFR wild-type adenocarcinoma treated with concurrent chemoradiotherapy (group 3). Progression-free survival, progression-free survival-2, and overall survival were estimated and compared using Kaplan-Meier and log-rank tests. RESULTS: A total of 92 patients were enrolled; 10, 40, and 42 patients were assigned to groups 1, 2, and 3, respectively. Patients with EGFR mutations who received upfront EGFR-TKIs had significantly longer progression-free and overall survival than those who received upfront concurrent chemoradiotherapy (hazard ratio 0.33 vs. 0.34, p = 0.006 vs. 0.031) according to a Cox model adjusted for possible confounders. Moreover, upfront concurrent chemoradiotherapy did not lead to higher survival rates in patients with EGFR mutations than in those with EGFR wild-type adenocarcinoma (progression-free survival; hazard ratio 0.37, p = 0.036; overall survival; hazard ratio 0.35, p = 0.080) by Cox regression analysis. CONCLUSION: This current study suggests that EGFR-TKIs is a better choice for patients with unresectable stage III EGFR-mutant adenocarcinoma. However, further randomized studies are required to validate the results.

Cost-Effectiveness of Nivolumab Plus Ipilimumab With and Without Chemotherapy for Advanced Non-Small Cell Lung Cancer.

BACKGROUND: First-line treatment with nivolumab plus ipilimumab (N+I) or nivolumab plus ipilimumab with two cycles of chemotherapy (N+I+chemotherapy) improve overall survival and progression-free survival for patients with metastatic non-small cell lung cancer (NSCLC), yet researchers have not concomitantly compared the cost-effectiveness of N+I and N+I+chemotherapy with chemotherapy alone. MATERIALS AND METHODS: Using outcomes data from the CheckMate 227 and CheckMate 9LA phase 3 randomized trials, we developed a Markov model with lifetime horizon to compare the costs and effectiveness of N+I and N+I+chemotherapy versus chemotherapy from the U.S. health care sector perspective. Subgroup analysis by programmed death-ligand 1 (PD-L1) expression levels (≥1% and <1%) and probabilistic analysis were performed. RESULTS: The incremental cost-effectiveness ratio (ICER) of N+I versus chemotherapy was $239,072 per QALY, and $838,198 per QALY for N+I+chemotherapy versus N+I. The ICER of N+I versus chemotherapy was $246,584 per QALY for patients with PD-L1 ≥ 1% and $185,620 per QALY for those with PD-L1 < 1%. In probabilistic analysis, N+I had a 2.6% probability of being cost-effective at a willingness-to-pay threshold of $150,000 per QALY. The probability was 0.4% for patients with PD-L1 ≥ 1% and 10.6% for patients with PD-L1 < 1%. CONCLUSION: First-line N+I or N+I+chemotherapy for metastatic NSCLC was not cost-effective regardless of PD-L1 expression levels from the U.S. health care sector perspective.

Survival benefit of osimertinib combination therapy in patients with T790M-positive non-small-cell lung cancer refractory to osimertinib treatment.

OBJECTIVES: Osimertinib is the main treatment choice for pretreated patients with advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) T790M mutations. However, the choice of subsequent therapy when progressive disease has developed after osimertinib treatment remains a major therapeutic challenge. This study evaluated the efficacy of osimertinib-based combination therapies in patients who developed progressive disease after treatment with osimertinib. MATERIAL AND METHODS: We enrolled NSCLC patients harbouring T790M mutations pretreated with first- or second-generation EGFR tyrosine-kinase inhibitors and were receiving osimertinib at two tertiary referral centres between August 2015 and July 2019, and the subsequent treatment efficacy was assessed. RESULTS: Osimertinib-based combination therapy yielded better overall survival (OS) than chemotherapy alone (not achieved vs. 7.8 months; hazard ratio, 0.39; 95 % confidence interval 0.17-0.89; P = 0.025) according to the Cox proportional hazards model adjusted for possible confounders. Synergism (combination index <1) between AZD9291 and chemotherapy and a higher proportion of apoptosis cells in combination treatment were also demonstrated in the T790M-positive PC9 cell line with acquired resistance to AZD9291. CONCLUSION: Our data supported the hypothesis that osimertinib-based combination therapy is associated with improved OS among patients with clinical progression following the use of osimertinib. These findings warrant further validation in a randomised controlled study.

The Effectiveness and Safety of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer Patients With Stage III/IV: A Multicenter Study.

Immune checkpoint inhibitors (ICIs) have been approved to treat patients with various cancer types, including lung cancer, in many countries. This study aims to investigate the effectiveness and safety of ICIs under different treatment conditions of non-small cell lung cancer patients. A population-based retrospective cohort study was conducted using the electronic health records of three medical centers in Taiwan. From January 01, 2016, to November 30, 2018, a total of 91 ICIs and 300 traditional chemotherapy users who had undergone stage III and IV lung cancer treatment were included in the study. We performed the randomized matched pair design by selecting a Chemotherapy subject for each ICI patient in the sample population. All subjects were monitored from the date of taking ICIs or chemotherapy drugs until the event of death, loss to follow-up, or were occurred with any defined adverse events. Kaplan-Meier estimators and cox proportional hazard regression models were used to compute the overall survival, efficacy, and safety of the ICIs group. The median overall survival (OS) in the ICI and Chemo groups after matching was 11.2 months and 10.5 months, respectively. However, the results showed no significant OS differences between ICIs and chemo groups for both before and after matching (HR,1.30; 95%CI, 0.68-2.46; p=0.428 before matching and HR,0.96; 95CI%, 0.64-1.44; p=0.838 after matching). We observed that with the higher amount of PD-L1, the length of the patients' overall survival was (positive vs. negative PD-L1, HR,0.21; 95%CI, 0.05-0.80; p=0.022). The incidences of serious adverse drug events above grade 3 in the ICIs and traditional chemo groups were 12.7% and 21.5%, respectively. We also found that the number of AEs was less in ICIs than in the Chemo group, and the AEs that occurred after treatments were observed earlier in the ICIs compared to the Chemo group. ICIs drugs were observed to be safer than traditional chemotherapy as they had a lower risk of serious adverse drug events. It is necessary to pay attention to immune-related side effects and provide appropriate treatment. Furthermore, the patient's physical status and PD-L1 test can be used to evaluate the clinical effectiveness of ICIs.

Considering lead-time bias in evaluating the effectiveness of lung cancer screening with real-world data.

Low-dose computed tomography screening can be used to diagnose lung cancer at a younger age compared to no screening. Real-world studies observing mortality after lung cancer diagnosis are subject to lead-time bias. This study developed a method using a nationwide cancer registry and stage shift from trial for the adjustment of lead-time bias. 78,897 Taiwanese nationwide lung cancer patients aged 55-82 were matched with 788,820 referents randomly selected from the general population at a ratio of 1:10 by age, sex, calendar year, and comorbidities, to estimate the pathology- and stage-specific life expectancy (LE). Loss-of-LE is the difference between the LE of cancer patients and that of referents. By multiplying LE and loss-of-LE by the pathology and stage shift in the National Lung Screening Trial (NLST), we compared the effectiveness of cancer screening measured by LE gained and loss-of-LE saved. The mean LEs of stage IA and IV adenocarcinoma were 14.5 and 1.9 years, respectively, indicating a LE gain of 12.6 years. However, the mean loss-of-LEs of stage IA and IV adenocarcinoma were 3.7 and 15.1 years, respectively, with a saving of only 11.4 years, implying an adjustment of different distributions of age, sex, and calendar year of diagnosis from stage shift and a reduction in lead-time bias. Applying such estimations on the results of 10,000 participants with the same pathology and stage shift in the NLST, the benefit of screening using LE gained would be 410.3 (95% prediction interval: 328.4 to 503.3) years. It became 297.1 (95% prediction interval: 187.8 to 396.4) years when using loss-of-LE saved, indicating the former approach would overestimate the effectiveness by 38%. Our approach of multiplying loss-of-LE by pathology and stage shift to estimate loss-of-LE saved could adjust for different distributions of age, sex, and calendar year at early diagnosis and reduce lead-time bias.