Survival and quality-of-life outcomes in early-stage NSCLC patients: a literature review of real-world evidence.

Aim: Assess the long-term survival and quality-of-life outcomes in early-stage NSCLC (eNSCLC) patients. Methods: Review of long-term survival and quality-of-life after curative treatment in eNSCLC patients in observational studies. Results: Disease-free proportion decreased in stage III vs stage I patients. Recurrence-free proportion decreased with age and disease stage. Advanced stage and vascular invasion increased risk of late recurrence. Conditional 5-year relative survival rates did not exceed 87%, indicating higher mortality in eNSCLC survivors. Lower conditional survival rates and relative survival rates were associated with older age and advanced disease. Survivors of eNSCLC had poorer physical quality-of-life. Conclusion: Despite curative-intent therapy, survivors of eNSCLC still face significant risks of recurrence, excess mortality, and diminished quality-of-life.

Early-stage NSCLC (eNSCLC) encompassing stage I and II, and resectable stage III disease is initially managed with curative-intent surgery and adjuvant chemotherapy to reduce the risk of recurrence. However, understanding the true curative potential and long-term outcomes is crucial for optimal clinical management. A literature review was conducted to identify observational studies describing long-term survival and quality-of-life outcomes following curative intent therapy in patients with eNSCLC. The proportion of patients who remained disease-free over time (without recurrence or death) statistically significantly decreased in patients with stage III disease compared with stage I disease. Similarly, the proportion of patients who remained recurrence-free over time decreased with increasing age and disease stage. A considerable risk of late recurrence (recurrence five or more years following resection) remained, increasing with advanced stage and tumor characteristics such as vascular invasion. Conditional 5-year relative survival rates did not exceed 87% in any study, indicating higher rates of all-cause mortality in long-term survivors of eNSCLC compared with members of the general population of the same age. Lower conditional 5-year relative survival rates, and 5 and 10-year relative survival rates were associated with older age and higher pathologic stage. Compared with the general population, survivors of eNSCLC reported significantly poorer physical quality-of-life, suggesting that symptoms persist after treatment. Overall, real-world evidence suggests that after standard curative-intent therapy, survivors of eNSCLC may not be considered fully cured, indicating a need for more effective adjuvant treatment in addition to the current standard of care.

Systematic Literature Review to Identify Cost and Resource Use Data in Patients with Early-Stage Non-small Cell Lung Cancer (NSCLC).

BACKGROUND: Approximately 2 million new cases and 1.76 million deaths occur annually due to lung cancer, with the main histological subtype being non-small cell lung cancer (NSCLC). The costs and resource use associated with NSCLC are important considerations to understand the economic impact imposed by the disease on patients, caregivers and healthcare services. OBJECTIVE: The objective of this systematic literature review (SLR) is to provide a comprehensive overview of the available direct medical costs, direct non-medical costs, indirect costs, cost drivers and resource use data available for patients with early-stage NSCLC. METHODS: Electronic searches were conducted via the Ovid platform in March 2021 and June 2022 and were supplemented by grey literature searches. Eligible patients had early-stage (stage I-III) resectable NSCLC and received treatment in the neoadjuvant or adjuvant setting. There was no restriction on intervention or comparators. Publication date was restricted to 2011 onwards, and English language publications or non-English language publications with an English abstract were of primary interest. Due to the anticipation of many studies meeting the inclusion criteria, analyses were restricted to full publications from countries of primary interest (Australia, Brazil, Canada, China, France, Germany, Italy, Japan, South Korea, Spain, UK and the US) and those with > 200 patients. The Molinier checklist was applied to conduct quality assessment. RESULTS: Forty-two full publications met the eligibility criteria and were included in this SLR. Early-stage NSCLC was associated with significant direct medical costs and healthcare utilisation, and the economic burden of the disease increased with its progression. Surgery was the primary cost driver in stage I patients, but as patients progressed to stage II and III, treatments such as chemotherapy and radiotherapy, and inpatient care became the main cost drivers. There was no significant difference in resource use between patients with early-stage disease. However, these data were heavily US-centric and there was a paucity of data relating to direct non-medical and indirect costs associated with early-stage NSCLC. CONCLUSIONS: Preventing disease progression for patients with NSCLC could reduce the economic burden of NSCLC on patients, caregivers and healthcare systems. This review provides a comprehensive overview of the available cost and resource use data in this indication, which is important in guiding the decisions of policy makers regarding the allocation of resources. However, it also indicates a need for more studies comparing the economic impact of NSCLC in markets in addition to the US.

Cost-effectiveness analysis of adjuvant atezolizumab in stage II-IIIA non-small cell lung cancer expressing ≥50% PD-L1: A United Kingdom health care perspective.

OBJECTIVES: Atezolizumab monotherapy has marketing authorisation by the Medicines and Healthcare products Regulatory Agency as adjuvant treatment following complete resection for adults with stage II-IIIA non-small cell lung cancer (NSCLC) whose tumours have PD-L1 expression on ≥ 50% of tumour cells and whose disease has not progressed following adjuvant platinum-based chemotherapy. This study evaluated the cost-effectiveness of atezolizumab vs best supportive care (BSC) in the licensed patient population from a UK perspective. MATERIALS AND METHODS: Patient characteristics and clinical inputs were derived from the global, randomised, open-label, phaseIII IMpower010 trial. A Markov model with the following health states was developed: disease-free survival (DFS), locoregional recurrence, first-line metastatic recurrence, second-line metastatic recurrence, and death (all partitioned based on receipt of treatment, excluding death). The base case model used a lifetime time horizon (40 years) and 3.5% discounting annually after the first year. DFS from IMpower010 was analysed with parametric survival models to extrapolate outcomes for time points beyond trial follow-up. The models were adjusted to avoid overestimating results for patients with recurrences in the longer term. Grade ≥ 3 treatment-related adverse events with incidences ≥ 2% were included. Health state utility values were derived from the literature and past NICE appraisals. Sensitivity and scenario analyses assessed uncertainty around assumptions and parameter estimates. RESULTS: In the base case analysis, atezolizumab therapy resulted in an expected gain of 1.87 quality-adjusted life-years (QALYs) corresponding to an incremental cost-effectiveness ratio of £20,392/QALY for atezolizumab vs BSC, demonstrating cost-effectiveness. Results were most influenced by discount effects and utility in the on-treatment DFS state. Scenario analyses were consistent with the base case results. CONCLUSION: Atezolizumab after adjuvant chemotherapy is cost-effective for adults with NSCLC in the UK.

Treatment patterns and survival of patients with locoregional recurrence in early-stage NSCLC: a literature review of real-world evidence.

Approximately 10-50% of patients treated for early-stage (I-III), resectable non-small cell lung cancer (eNSCLC) will develop locoregional recurrence. There is a lack of prospective trials evaluating optimal post-surgery follow-up for this patient population, and treatment guidelines recommend salvage therapies such as surgery, local ablative therapy, and (chemo)radiotherapy. A literature review was conducted according to pre-defined criteria to identify observational studies describing treatment patterns and survival outcomes in patients with eNSCLC who experienced locoregional recurrence. Results showed that, in real-world clinical practice, around 80% of patients with locoregional recurrence underwent any form of active treatment. The most frequently administered treatments were chemotherapy (35.7%), chemoradiotherapy (31.2%), radiotherapy (20.3%), and surgery alone (12.8%). Chemoradiotherapy was associated with improved PFS and OS compared with radiotherapy, while no statistically significant survival benefits were observed for patients receiving surgery in addition to these treatments. The overall survival of patients following treatment for locoregional recurrence was generally poor, and the proportion of patients who experienced any form of post-treatment re-recurrence ranged from 35 to 72%. These findings highlight the need to develop more effective treatment strategies for locoregional recurrence, including preventative treatments, and strategies to improve the survival outcomes of those who do develop locoregional recurrence.

A Network Meta-Analysis of Cancer Immunotherapies Versus Chemotherapy for First-Line Treatment of Patients With Non-Small Cell Lung Cancer and High Programmed Death-Ligand 1 Expression.

In the absence of head-to-head trials of first-line treatments for metastatic non-small cell lung cancer (NSCLC), synthesis of available evidence is needed. We conducted a systematic literature review and network meta-analysis of randomized controlled trials in patients with stage IV NSCLC and high programmed death-ligand 1 (PD-L1) expression. Patients with other-stage NSCLC or without PD-L1 expression and populations with < 80% stage IV NSCLC were excluded. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events. English records from MEDLINE and Embase published through October 2020 were eligible, supplemented by hand searches of other sources. Three evidence networks were constructed based on histology (mixed, squamous, non-squamous). OS and PFS results were analyzed applying Bayesian fractional polynomial random-effects models. Hazard ratios over time with 95% credible intervals (CrIs) and expected differences in OS and PFS between each cancer immunotherapy regimen and the chemotherapy common comparator were generated. Seventeen clinical trials were included after screening 32,527 records. Heterogeneity and risk of bias were generally low across trials. In the mixed-histology network of PD-L1-high patients, expected OS was significantly longer with atezolizumab (estimated difference: 10.4 months [95% CrI: 1.9, 18.2]), pembrolizumab (7.2 [2.2, 12.3]), and cemiplimab (13.0 [4.2, 21.0]) versus chemotherapy but not with nivolumab (3.5 [-2.5, 10.6]) or nivolumab plus ipilimumab (6.7 [-0.5, 14.2]) versus chemotherapy. OS improvements were not significant compared with chemotherapy for any regimen in the squamous and non-squamous networks, except pembrolizumab plus chemotherapy in the non-squamous network. All regimens showed significantly longer expected PFS versus chemotherapy in the non-squamous network, whereas the increases were not significant in the mixed or squamous networks. ORR was significantly higher with pembrolizumab and cemiplimab versus chemotherapy in the mixed-histology network, with sintilimab in the non-squamous network, and with combination regimens, including pembrolizumab or atezolizumab, in the squamous and non-squamous networks, except with atezolizumab plus carboplatin, paclitaxel, and bevacizumab. Survival and safety versus chemotherapy were generally similar across cancer immunotherapies and histology networks. These findings may support treatment decisions for patients with high PD-L1 status receiving first-line treatment for NSCLC.

A nonparametric method to detect increased frequencies of adverse drug reactions over time.

Signal detection is routinely applied to spontaneous report safety databases in the pharmaceutical industry and by regulators. As an example, methods that search for increases in the frequencies of known adverse drug reactions for a given drug are routinely applied, and the results are reported to the health authorities on a regular basis. Such methods need to be sensitive to detect true signals even when some of the adverse drug reactions are rare. The methods need to be specific and account for multiplicity to avoid false positive signals when the list of known adverse drug reactions is long. To apply them as part of a routine process, the methods also have to cope with very diverse drugs (increasing or decreasing number of cases over time, seasonal patterns, very safe drugs versus drugs for life-threatening diseases). In this paper, we develop new nonparametric signal detection methods, directed at detecting differences between a reporting and a reference period, or trends within a reporting period. These methods are based on bootstrap and permutation distributions, and they combine statistical significance with clinical relevance. We conducted a large simulation study to understand the operating characteristics of the methods. Our simulations show that the new methods have good power and control the family-wise error rate at the specified level. Overall, in all scenarios that we explored, the method performs much better than our current standard in terms of power, and it generates considerably less false positive signals as compared to the current standard.

A Database Cohort Study to Assess the Risk of Angioedema Among Patients with Heart Failure Initiating Angiotensin-Converting Enzyme Inhibitors in the USA.

INTRODUCTION: Real-world evidence on the risk of angioedema associated with angiotensin-converting enzyme inhibitors (ACEIs) in patients with heart failure (HF) is scarce. OBJECTIVE: This non-interventional study aimed to estimate the incidence of and risk factors for angioedema in patients with HF initiating an ACEI in real-world practice. METHODS: This was a retrospective cohort study using claims data from the PharMetrics Plus database, supplemented with consumer health data, from 1 January 2007 to 31 March 2015. Patients with HF initiating an ACEI were followed up for a maximum of 1 year, until the first occurrence of angioedema or until cohort exit. Angioedema incidence rates were estimated and stratified by potential risk factors such as race, age, sex, and time from initiation of ACEI therapy. For each risk factor, the unadjusted and adjusted hazard ratio (HR) was calculated; exploratory analyses were carried out to account for all potential confounders. RESULTS: We identified 21,639 patients with HF initiating an ACEI (mean age 58 years; 35.6% women; mean follow-up 205 days). The 1-year incidence of angioedema per 1000 patient-years was 3.3 [95% confidence interval (CI) 2.4-4.5]. The incidence was higher in Black [6.2 (95% CI 3.1-12.5)] than in non-black [2.9 (95% CI 2.1-4.1)] patients, higher in women [5.2 (95% CI 3.4-7.9)] than in men [2.3 (95% CI 1.5-3.6)], and greatest in the first 30 days of ACEI therapy. CONCLUSIONS: The risk of angioedema in patients with HF initiating an ACEI observed in this study is in line with published estimates for the general patient population treated with ACEIs.

Assessing switchability for biosimilar products: modelling approaches applied to children's growth.

The present paper describes two statistical modelling approaches that have been developed to demonstrate switchability from the original recombinant human growth hormone (rhGH) formulation (Genotropin(®) ) to a biosimilar product (Omnitrope(®) ) in children suffering from growth hormone deficiency. Demonstrating switchability between rhGH products is challenging because the process of growth varies with the age of the child and across children. The first modelling approach aims at predicting individual height measured at several time-points after switching to the biosimilar. The second modelling approach provides an estimate of the deviation from the overall growth rate after switching to the biosimilar, which can be regarded as an estimate of switchability. The results after applying these approaches to data from a randomized clinical trial are presented. The accuracy and precision of the predictions made using the first approach and the small deviation from switchability estimated with the second approach provide sufficient evidence to conclude that switching from Genotropin(®) to Omnitrope(®) has a very small effect on growth, which is neither statistically significant nor clinically relevant.

AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women.

Antagonism of the calcium-sensing receptor in the parathyroid gland leads to parathyroid hormone (PTH) release. Calcilytics are a new class of molecules designed to exploit this mechanism. In order to mimic the known bone-anabolic pharmacokinetic (PK) profile of s.c. administered PTH, such molecules must trigger sharp, transient and robust release of PTH. The results of two early clinical studies with the orally-active calcilytic AXT914, a quinazolin-2ne derivative are reported. These were GCP-compliant, single and multiple dose studies of PK/PD and tolerability in healthy volunteers and postmenopausal women. The first study, examined single ascending doses (4 to 120 mg) and limited multiple doses (60 or 120 mgq.d. for 12 days) of AXT914. The second study was a randomized, double-blind, active- and placebo-controlled, 4-week repeat-dose parallel group study of healthy postmenopausal women (45 and 60 mg AXT914, placebo, 20 µg Forteo/teriparatide/PTH(1-34) fragment). AXT914 was well tolerated at all doses and reproducibly induced the desired PTH-release profiles. Yet, 4 weeks of 45 or 60 mg AXT914 did not result in the expected changes in circulating bone biomarkers seen with teriparatide. However total serum calcium levels increased above baseline in the 45 and 60 mg AXT914 treatment groups (8.0% and 10.7%, respectively), compared to that in the teriparatide and placebo groups (1.3% and 1.0%, respectively). Thus the trial was terminated after a planned interim analysis due to lack of effect on bone formation biomarkers and dose-limiting effects on serum calcium. In conclusion, AXT914 was well tolerated but the observed transient and reproducible PTH-release after repeat oral administration of AXT914 which showed an exposure profile close to that of s c. PTH, did not translate into a bone anabolic response and was associated with a persistent dose-related increase in serum calcium concentrations.

ATF936, a novel oral calcilytic, increases bone mineral density in rats and transiently releases parathyroid hormone in humans.

Parathyroid hormone (PTH), when injected daily as either the intact hormone PTH(1-84) or the active fragment PTH(1-34) (teriparatide), is an efficacious bone anabolic treatment option for osteoporosis patients. Injections lead to rapid and transient spikes in hormone exposure levels, a profile which is a prerequisite to effectively form bone. Oral antagonists of the calcium-sensing receptor (calcilytics) stimulate PTH secretion and represent thus an alternative approach to elevate hormone levels transiently. We report here on ATF936, a novel calcilytic, which triggered rapid, transient spikes in endogenous PTH levels when given orally in single doses of 10 and 30mg/kg to growing rats, and of 1mg/kg to dogs. Eight weeks daily oral application of 30mg/kg of ATF936 to aged female rats induced in the proximal tibia metaphysis increases in bone mineral density, cancellous bone volume and cortical and trabecular thickness as evaluated by computed tomography. In healthy humans, single oral doses of ATF936 produced peak PTH levels in plasma after a median time of 1h and levels returned to normal at 24-h post-dose. The average maximum PTH concentration increase from baseline was 1.9, 3.6, and 6.0-fold at doses of 40, 70, and 140mg. ATF936 was well tolerated. The sharp, transient increase in PTH levels produced by the oral calcilytic ATF936 was comparable to the PTH profile observed after subcutaneous administration of teriparatide. In conclusion, ATF936 might hold potential as an oral bone-forming osteoporosis therapy.

Rapid and robust response of biochemical markers of bone formation to teriparatide therapy.

Teriparatide, a parathyroid hormone analogue, is a potent anabolic treatment for postmenopausal osteoporosis. Studies have shown that teriparatide induces large increases in biochemical markers of bone formation after 1 month of therapy followed by a delayed increase in bone resorption markers. The aims of this study were to (1) describe changes in bone turnover markers during 28 days of treatment with teriparatide; (2) identify the earliest time point by which most subjects showed a biochemical response to teriparatide; (3) identify potential biomarkers of positive bone response; (4) describe changes in bone turnover markers 4 weeks after stopping teriparatide. We recruited 15 osteopenic postmenopausal women, ages 55-69 (mean 62) years. All received 20 microg teriparatide subcutaneously for 28 days. Serum levels of the bone formation markers type I collagen N-terminal propeptide (PINP), type I collagen C-terminal propeptide (PICP), osteocalcin (OC), bone alkaline phosphatase (bone ALP), and the bone resorption markers crosslinked C-telopeptide of type I collagen (Sbeta-CTX), crosslinked N-telopeptide of type I collagen (S-NTX) and tartrate-resistant acid phosphatase type 5b (TRACP5b) were measured on 11 occasions: three times before dosing (baseline) and on days 3, 7, 10, 14, 19, 24 and 28 and at day 56 (i.e., 28 days after stopping teriparatide ). During the first 2 days of teriparatide treatment, PINP levels increased rapidly, by 8.2% (90% confidence interval (CI) 6.9%, 9.5%) and continued to increase until the end of treatment to 110.8%. PICP and OC showed a similar, but less pronounced, pattern. All three markers increased by at least 75% at day 28. A small, transient decrease in bone resorption markers occurred over the same period. Following cessation of treatment, concentrations of bone formation markers decreased to within 20% of baseline values by day 56. In conclusion, the bone formation markers PINP, PICP and OC show a rapid and robust increase in response to teriparatide, which is noticeable during the first week of therapy. PINP is the most responsive marker. These findings have important implications for monitoring patients treated with teriparatide and may also inform the design of studies of new anabolic agents for osteoporosis.

Absolute oral bioavailability and disposition of deferasirox in healthy human subjects.

Deferasirox is a novel iron chelator formulated as tablets for dispersion (suspension) for once-a-day oral administration. The current study evaluated the absolute bioavailability of a single 375-mg oral dose of deferasirox administered in the form of tablets compared with a 130-mg intravenous infusion of deferasirox. Since this was a first-in-man study using the deferasirox intravenous (IV) formulation, the safety and tolerability of the IV formulation was evaluated in a pilot phase with a lower dose (65 mg) in 3 subjects prior to the main phase. The main study phase consisted of 17 healthy male volunteers. Plasma concentrations of deferasirox were measured following each treatment, and pharmacokinetic parameters including absolute oral bioavailability were determined. Absolute oral bioavailability of the deferasirox tablets was 70% (90% confidence interval, 62%-80%). Deferasirox was characterized as having a low plasma clearance of 3.53 (+/- 0.87) L/h. A small volume of distribution of deferasirox at steady state (V(ss)) of 14.37 (+/-2.69 L) was determined, indicating a low tissue distribution.

Effect of food, type of food, and time of food intake on deferasirox bioavailability: recommendations for an optimal deferasirox administration regimen.

Deferasirox (ICL670) is representative of a new class of tridentate iron chelators, formulated as tablets for dispersion. Deferasirox has exhibited high potency and a clinically manageable safety profile in preclinical models and in an extensive clinical program. The effect of food and time of food intake on the pharmacokinetics of deferasirox was investigated in healthy volunteers and patients with transfusional hemosiderosis. The bioequivalence of a single oral dose of deferasirox (20 mg/kg) was assessed following administration either before a high-fat or standard breakfast or concurrent with a standard breakfast in comparison with fasted conditions in healthy volunteers. The bioavailability of deferasirox was determined following a single oral dose (20 mg/kg) under fed and fasted conditions in patients. These data show that the type of food, caloric content, and fat content of the meal influence the bioavailability of deferasirox when consumed concomitantly. In contrast, this is not the case when deferasirox is administered at least 30 minutes before a meal. In conclusion, it is recommended that deferasirox be administered at least 30 minutes prior to meals. When this is not feasible, deferasirox should be administered consistently at the same time before meals to limit the sources of variability that affect absorption.

Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in pediatric patients with beta-thalassemia major.

BACKGROUND AND OBJECTIVES: Deferasirox (ICL670) is a novel once-daily oral iron chelator developed for the treatment of chronic iron overload from blood transfusions. This study evaluated the safety and tolerability of deferasirox in pediatric patients with transfusion-dependent beta-thalassemia major. Efficacy and pharmacokinetic assessments were secondary objectives. DESIGN AND METHODS: Forty patients equally stratified into two age groups--children (2 to <12 years) and adolescents (12-17 years)--were treated with deferasirox for 48 weeks. All received once-daily deferasirox 10 mg/kg/day with modifications allowed after 12 weeks' treatment. Safety, liver iron concentration (LIC), serum ferritin and pharmacokinetics were assessed. RESULTS: Thirty-nine patients completed the study. One withdrew due to a skin rash. Adverse events were typical of this population, but only four were considered related to the study drug: mild nausea (two adolescents) and moderate skin rash (two children). There were no serious adverse events related to the study drug. Five patients briefly interrupted treatment due to elevated transaminases with no recurrences when treatment resumed. The mean deferasirox dose was 11.3 mg/kg/day. Overall LIC increased gradually from week 12 as mean daily iron intake was higher than excretion. Steady-state plasma levels of deferasirox and its iron complex, Fe-[deferasirox]2, were comparable between children and adolescents. INTERPRETATION AND CONCLUSIONS: Deferasirox was well tolerated by this pediatric population. Toxicities known to be associated with other commercially available iron chelators were not observed. The dose employed was too low to induce a net negative iron balance in this regularly transfused population. Pharmacokinetic data support a once-daily dosing regimen based on body weight.