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.

Patient Characteristics, Testing and Treatment Patterns, and Outcomes in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multinational, Real-World Study.

INTRODUCTION: Treatment landscape for advanced/metastatic NSCLC (aNSCLC) has evolved considerably over the past few decades with the advent of targeted therapies for epidermal growth factor receptor-mutated (EGFRm+) aNSCLC treatment. This study described real-world patient and disease characteristics, treatment and practice patterns, and clinical, economic, and patient-reported outcomes (PROs) in patients with EGFRm+ aNSCLC. METHODS: Data were derived from the Adelphi NSCLC Disease Specific Programme™ (DSP™), a point-in-time survey conducted between July and December 2020. The survey included oncologists and pulmonologists, and their consulting patients (with physician-confirmed EGFRm+ aNSCLC) from nine countries: the US, Brazil, the UK, Italy, France, Spain, Germany, Japan, and Taiwan. All analyses were descriptive. RESULTS: Overall, 542 physicians reported data for 2857 patients (mean age 65.6 years), and most patients were female (56.0%), white (61.0%), and had stage IV disease at initial diagnosis (76.0%), and adenocarcinoma histology (89.0%). Most patients received EGFR-tyrosine kinase inhibitors (TKI) therapy in first- (91.0%), second- (74.0%), and third-line (67.0%). The most common tumor samples and methods for EGFR detection were EGFR-specific mutation detection tests (44.0%) and core needle biopsy (56.0%). Median time to next treatment was 14.0 (IQR 8.0-22.0) months and disease progression was the main physician-reported reason for early discontinuation. The most common physician-reported disease symptoms were cough (51.0%), fatigue (37.0%), and dyspnea (33.0%). In patients assessed for PROs, mean EQ-5D-5L index and FACT-L health utility scores were 0.71 and 83.5, respectively. On average, patients lost 10.6 h of work/week for approximately 29.2 weeks due to EGFRm+ aNSCLC. CONCLUSION: This real-world multinational data set showed that most patients with EGFRm+ aNSCLC were treated per the country relevant clinical guidelines, with progression as the main reason for early treatment discontinuation. For the included countries, these findings may offer a useful benchmark for decision makers to determine future allocation of healthcare resources for patients with EGFRm+ aNSCLC.

Treatment Patterns, Clinical Outcomes and Health Care Resource Utilisation in Patients with EGFR-mutated Metastatic Non-Small Cell Lung Cancer: A Real-World Study in South Korea.

BACKGROUND: Despite the dynamic treatment landscape for EGFR mutant-positive metastatic non-small cell lung cancer (EGFRm+ mNSCLC), most of the earlier studies have focused on US or Western populations. OBJECTIVE: The objective of this study was to explore real-world treatment patterns and outcomes of South Korean patients with EGFRm+ mNSCLC. METHODS: Retrospective chart review of adult patients with EGFRm+ mNSCLC who received systemic treatment between January-2019 and June-2019. RESULTS: A total of 162 patients were included from 21 hospitals, with a median follow-up of 15.6 months. Median age was 65.0 years, 22% had central nervous system metastasis, and 57% and 38% had exon 19 deletion and exon 21 L858R, respectively. Among 144 patients (89%) who received first-line EGFR-tyrosine kinase inhibitor, afatinib was most the common (44%), followed by gefitinib (28%) and erlotinib (13%). First-line chemotherapy was more common when an EGFR-mutation was detected after versus before first-line treatment initiation (31% vs 5%). Discontinuation of first-line treatment was mostly due to disease-progression (81%) and toxicity (7%). Among 58 (78%) patients who received second-line treatment, osimertinib was the most common (40%). Most (60%) patients reported ≥1 Grade ≥3 adverse event during first-line treatment. Following initiation of first-line treatment, physician visits and chest X-rays were the most frequent healthcare utilisation events. Rates of emergency-room visits and hospitalization were 12% and 16%, respectively, with a mean length-of-stay of 10.4 days. At 12 months, overall survival rate was 95%, and numerically worse for patients with exon 21 versus 19 mutations. CONCLUSIONS: Characteristics and clinical outcomes of Korean patients with EGFRm+ mNSCLC in real-world practice were comparable to those observed in clinical trials. As osimertinib was not reimbursed for first-line treatment before study completion, further investigation is warranted to explore evolving treatment practice.

Outcomes for Recurrent Mantle Cell Lymphoma Post-Ibrutinib Therapy: A Retrospective Cohort Study from a Japanese Administrative Database.

INTRODUCTION: Treatment options in patients with mantle cell lymphoma (MCL) failing ibrutinib are limited, with no standard therapies defined. This study aimed to investigate real-world treatment patterns and outcomes for patients with MCL following ibrutinib. METHODS: This study utilized a de-identified hospital-based claims database (Medical Data Vision) in Japan. Eligible patients were adults who were diagnosed with MCL and had received antitumor drugs between December 2010 and July 2020. Patients were followed from the first antitumor drug treatment until the end of available data up to July 2021. Time-to-event analyses utilized the Kaplan-Meier method. Factors for receiving post-ibrutinib therapy were explored with logistic regression analysis. RESULTS: Of the 1386 patients who started antitumor drug therapy, 247 patients received and discontinued ibrutinib at any line of therapy. Among them, 137 patients (55.5%) received subsequent therapy. The median age at the end of ibrutinib therapy was 77 (range 42-95), and 44 patients had a dependent activity of daily living (ADL). Factors negatively associated with receiving post-ibrutinib therapy after discontinuation of ibrutinib were age ≥ 75 years (odds ratio [95% CI] 0.46 [0.26-0.80]) and emergency hospital admissions (0.37 [0.17-0.84]). Immediate post-ibrutinib therapy regimens were highly diverse, with BR (bendamustine, rituximab) only prescribed in more than 10% of patients. The median duration of post-ibrutinib therapy was 1.5 months (95% CI 1.07-2.07). The median overall survival from the end of ibrutinib therapy in patients regardless of the receipt of post-ibrutinib therapy (n = 247), in those who did not receive post-ibrutinib therapy (n = 110), and in those who received post-ibrutinib therapy (n = 137) was 5.6 months (95% CI 3.8-8.7), 2.3 months (95% CI 1.2-3.9), and 8.7 months (95% CI 5.6-13.8), respectively. The most common adverse event during post-ibrutinib therapy was infection, with the use of anti-infectives (17%). CONCLUSIONS: Patients with MCL previously treated with ibrutinib have poor ability to carry out ADL and experience very poor outcomes. New safe, effective therapies are needed.

Efficacy and safety of first-line therapies in EGFR-mutated advanced non-small-cell lung cancer: a network meta-analysis.

Aim: To evaluate the comparative efficacy and safety of identified first-line therapies for patients with EGFR mutation-positive (EGFRm+) advanced non-small-cell lung cancer (NSCLC), with a focus on ramucirumab + erlotinib. Methods: In the absence of head-to-head studies, a Bayesian network meta-analysis was conducted using randomized clinical trial data to evaluate first-line systemic therapies with erlotinib/gefitinib as the reference treatment. Results: For progression-free survival, ramucirumab + erlotinib was comparable to osimertinib and dacomitinib in the primary analysis. Conclusion: The analysis showed ramucirumab + erlotinib efficacy to be comparable to best-in-class treatment options for previously untreated patients with EGFRm+ advanced NSCLC. Registration information: PROSPERO ID: CRD42020136247.

A cost-effectiveness analysis of first-line induction and maintenance treatment sequences in patients with advanced nonsquamous non-small-cell lung cancer in France.

BACKGROUND: Comparative effectiveness and cost-effectiveness data for induction-maintenance (I-M) sequences for the treatment of patients with nonsquamous non-small-cell lung cancer (nsqNSCLC) are limited because of a lack of direct evidence. This analysis aimed to compare the cost-effectiveness of I-M pemetrexed with those of other I-M regimens used for the treatment of patients with advanced nsqNSCLC in the French health-care setting. MATERIALS AND METHODS: A previously developed global partitioned survival model was adapted to the France-only setting by restricting treatment sequences to include 12 I-M regimens most relevant to France, and incorporating French costs and resource-use data. Following a systematic literature review, network meta-analyses were performed to obtain hazard ratios for progression-free survival (PFS) and overall survival (OS) relative to gemcitabine + cisplatin (induction sequences) or best supportive care (BSC) (maintenance sequences). Modeled health-care benefits were expressed as life-years (LYs) and quality-adjusted LYs (QALYs) (estimated using French EuroQol five-dimension questionnaire tariffs). The study was conducted from the payer perspective (National Health Insurance). Cost- and benefit-model inputs were discounted at an annual rate of 4%. RESULTS: Base-case results showed pemetrexed + cisplatin induction followed by (→) pemetrexed maintenance had the longest mean OS and PFS and highest LYs and QALYs. Costs ranged from €12,762 for paclitaxel + carboplatin → BSC to €35,617 for pemetrexed + cisplatin → pemetrexed (2015 values). Gemcitabine + cisplatin → BSC, pemetrexed + cisplatin → BSC, and pemetrexed + cisplatin → pemetrexed were associated with fully incremental cost-effectiveness ratios (ICERs) of €16,593, €80,656, and €102,179, respectively, per QALY gained versus paclitaxel + carboplatin → BSC. All other treatment sequences were either dominated (ie, another sequence had lower costs and better/equivalent outcomes) or extendedly dominated (ie, the comparator had a higher ICER than a more effective comparator) in the model. Sensitivity analyses showed the model to be relatively insensitive to plausible changes in the main assumptions, with none increasing or decreasing the ICER by more than ~€20,000 per QALY gained. CONCLUSION: In the absence of direct comparative trial evidence, this cost-effectiveness analysis indicated that of a large number of I-M sequences used for the treatment of patients with nsqNSCLC in France, pemetrexed + cisplatin → pemetrexed achieved the best clinical outcomes (0.28 incremental QALYs gained) versus paclitaxel + carboplatin → BSC.

Health state utility values associated with advanced gastric, oesophageal, or gastro-oesophageal junction adenocarcinoma: a systematic review.

OBJECTIVES: To systematically identify utility values associated with advanced gastric cancer (GC), oesophageal cancer (OC), or gastro-oesophageal junction (GEJ) cancer. Utility values relating to health states are an essential component for cost-utility analysis (CUA). METHODS: MEDLINE, Embase, Cochrane Library, and EconLit databases were reviewed for relevant studies using a pre-defined search strategy. Studies eligible for inclusion reported health state utility values (HSUVs) using direct (standard gamble [SG] and time-trade-off [TTO]) and indirect (such as EuroQol 5D [EQ-5D], short-form 6D [SF-6D], and the 15-dimensional instrument [15D]) methods for patients with advanced GC, OC, or GEJ cancer. RESULTS: A total of 539 unique publications were identified, of which eight met the inclusion criteria (GC, n = 2; mixed population [gastrointestinal cancers], n = 4; OC, n = ). The most commonly used instrument to estimate HSUVs was the EQ-5D (n = 7). Utilities were also estimated using the SF-6D and the 15D in the same study (n = 1). Direct elicitation methods included the TTO (n = 2) and SG (n = 1). Across the eight identified publications, health states and study populations were heterogeneous and sample sizes were limited. LIMITATIONS: This review, as with all summaries of this nature, is only as robust as the data derived from the identified studies. The systematic review process does not resolve any design issues or biases associated with the original studies. CONCLUSIONS: Limited data estimate HSUVs in patients with advanced GC, OC, or GEJ cancer. Utilities for advanced GC alone and advanced OC alone were reported in only two publications for each cancer type. No publications considered advanced GEJ utilities alone, and four publications considered utilities for a mixed population of gastrointestinal cancer types. Comparisons are confounded by heterogeneity across the identified publications. Further research into HSUVs associated with advanced GC and OC is required to improve the evidence available for use in CUAs.

Outcomes and resource use of non-small cell lung cancer (NSCLC) patients treated with first-line platinum-based chemotherapy across Europe: FRAME prospective observational study.

INTRODUCTION: FRAME was a prospective observational study that captured real-world data on patients with advanced or metastatic non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapies as first-line treatment (FLT) across Europe. As previously reported, most patients observed in the study had initiated FLT with either pemetrexed, gemcitabine, vinorelbine or taxanes in combination with a platinum. Baseline patient and disease characteristics including age, performance status, and histology varied (all p<0.01) across cohorts. METHODS: Consenting adult patients initiating FLT for advanced or metastatic NSCLC with platinum-based chemotherapy, with or without a targeted agent, entered the study between April 2009 and February 2011. The choice of FLT was left to physicians' discretion per routine clinical practice. The primary objective was to evaluate overall survival (OS) across platinum-based doublet chemotherapy cohorts and key secondary objectives included the evaluation of OS in patients with different histological subtypes of NSCLC. Survival outcomes were assessed using Kaplan-Meier analysis, and unadjusted estimates are presented. RESULTS: Median OS in months was 10.3 across cohorts (n=1524), 10.7 for pemetrexed (n=569), 10.0 for gemcitabine (n=360), 9.1 for taxanes (n=295), and 10.7 for vinorelbine (n=300). For patients with non-squamous NSCLC who received cisplatin (n=616, 40% of total), median OS in months was 10.6 across the cohorts, 11.6 for pemetrexed, 8.4 for gemcitabine, 9.6 for taxanes, and 9.9 for vinorelbine. CONCLUSIONS: FRAME describes real-world treatment patterns and survival for patients initiating FLT for advanced or metastatic NSCLC between 2009 and 2011 across Europe.

Influence of histology and biomarkers on first-line treatment of advanced non-small cell lung cancer in routine care setting: baseline results of an observational study (FRAME).

FRAME is a prospective observational study of first-line treatments for advanced non-small cell lung cancer (NSCLC). This interim analysis examines the influence of histology and biomarkers on therapeutic decisions. Baseline characteristic, treatment, and diagnostic procedure data were collected on European patients with stage IIIB/IV NSCLC who were treated with any first-line platinum-based doublet, with or without targeted agents, in routine clinical practice. A total of 1567 patients were observed in 11 countries between April 2009 and February 2011. Patients were mostly non-Asian (96.4%), male (71.5%), smokers (84.4%) with stage IV NSCLC (76.6%) and a performance status of 0-1 (82.2%). Median age was 64 years (range, 33-87). First-line treatments were platinum-based combinations with pemetrexed (36.3%), gemcitabine (23.0%), vinorelbine (19.2%), taxanes (18.9%), or other (2.6%), with concurrent targeted agents in 8.4% of patients (mainly bevacizumab, 7.3%). Diagnosis was based on histology in 70.6%, cytology in 20.3%, and both in 9.1% of patients. The final diagnosis was nonsquamous in 72.2% (including 'not otherwise specified [NOS]' in 11.0%), squamous in 24.4%, and other in 3.4% of patients, with the most common reasons for NOS diagnosis being 'subtyping not technically possible' (42.9%) and 'not important for treatment decision' (40.5%). Only 1.1% (6 patients) in the pemetrexed cohort and 0.9% (1 patient) of patients who received bevacizumab had squamous cell carcinoma. At least one immunohistochemical (IHC) marker was used in 53.5% of patients (thyroid transcription factor-1 [TTF-1]: 47.5%, cytokeratin 7 [CK7]: 38.6%, cytokeratin 5/6 [CK5/6]: 17.9%, p63: 8.8%, cluster of differentiation 56 [CD56]: 4.2%, cytokeratin 14 [CK14]: 1.9%, and other: 24.2%). Testing for additional biomarkers was less common, with the most common being for epidermal growth factor receptor (EGFR) mutation status (26.0%). Physician-reported key factors influencing treatment choice were 'histopathological/cytological diagnosis' (77.4%), 'performance status' (63.2%), and 'age' (52.8%). Similar factors were identified using logistic regression models. Frequent histological testing was observed, likely resulting in few NOS diagnoses. In addition, IHC and predictive biomarkers were routinely assessed. Histology, performance status, and age were key factors influencing first-line treatment choice in the routine care of patients with advanced NSCLC. Clinical Trials. gov registry identifier number: NCT01067794.

Second-line therapy for non-small cell lung cancer in clinical practice: final results and treatment pathways from the SELECTTION observational study.

OBJECTIVES: SELECTTION was a multinational, prospective observational study to assess the choice of and the time from initiation of second-line treatment to treatment discontinuation for any reason in patients with non-small cell lung cancer. METHODS: Treatment cohorts were constructed based on prescribed second-line treatments that were at the discretion of the treating physicians, for 1013 patients enrolled in 11 countries. Propensity score analysis was conducted to assess whether the cohorts were comparable. Time from initiation of second-line treatment to treatment discontinuation was the primary endpoint. Reasons for treatment discontinuation, overall survival, progression-free survival and choice of second-line treatment were secondary endpoints. RESULTS: The treatment cohorts were pemetrexed (46.2%), docetaxel (22.9%), erlotinib (20.4%) and other treatments (10.5%). Analyses of baseline data and propensity scores showed that the erlotinib cohort comprised substantially different patients compared with the pemetrexed and docetaxel cohorts: patients in the erlotinib cohort were more likely to be women, never-smokers, have adenocarcinoma and worse performance status. Therefore, comparisons of outcomes between cohorts were not appropriate. Although disease progression was the most common reason for treatment discontinuation in all cohorts, erlotinib patients tended to continue treatment after disease progression, whereas in the docetaxel and pemetrexed cohorts, discontinuation occurred soon after disease progression. CONCLUSIONS: In real-world clinical practice the profiles of patients assigned to erlotinib were distinctly different from those assigned to pemetrexed or docetaxel. The most common reason for treatment discontinuation was progressive disease, reflecting adherence to clinical recommendations. It is difficult to extrapolate these findings to the present, as both clinical practice and the approved indications for NSCLC treatments have evolved substantially.

Cost-effectiveness analysis of pemetrexed versus docetaxel in the second-line treatment of non-small cell lung cancer in Spain: results for the non-squamous histology population.

BACKGROUND: The objective of this study was to conduct a cost-effectiveness evaluation of pemetrexed compared to docetaxel in the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) for patients with predominantly non-squamous histology in the Spanish healthcare setting. METHODS: A Markov model was designed consisting of stable, responsive, progressive disease and death states. Patients could also experience adverse events as long as they received chemotherapy. Clinical inputs were based on an analysis of a phase III clinical trial that identified a statistically significant improvement in overall survival for non-squamous patients treated with pemetrexed compared with docetaxel. Costs were collected from the Spanish healthcare perspective. RESULTS: Outcomes of the model included total costs, total quality-adjusted life years (QALYs), total life years gained (LYG) and total progression-free survival (PFS). Mean survival was 1.03 years for the pemetrexed arm and 0.89 years in the docetaxel arm; QALYs were 0.52 compared to 0.42. Per-patient lifetime costs were 34677 euros and 32343 euros, respectively. Incremental cost-effectiveness ratios were 23967 euros per QALY gained and 17225 euros per LYG. CONCLUSIONS: Pemetrexed as a second-line treatment option for patients with a predominantly non-squamous histology in NSCLC is a cost-effective alternative to docetaxel according to the 30000 euros /QALY threshold commonly accepted in Spain.

Costs and health-related quality of life effects of hysterectomy in patients with benign uterine disorders.

OBJECTIVE: To gain knowledge about the utility of hysterectomy in a real-world setting and to relate the utility of the intervention to its costs. DESIGN: Prospective observational study. SETTING: University referral hospital in Helsinki. POPULATION: A total of 337 women entering for routine hysterectomy due to a benign disease (210 benign uterine or ovarian cause, 20 endometriosis, 51 uterovaginal prolapse, 56 menorrhagia). METHODS: Patients filled in the 15D health-related quality of life (HRQoL) questionnaire before and six months after the operation. Costs were examined from the perspective of secondary care provider. Benefits of surgery were extrapolated till the end of remaining statistical life expectancy of each woman in the prolapse group and until menopause in the other groups. MAIN OUTCOME MEASURES: HRQoL and cost per quality-adjusted life year (QALY) gained. RESULTS: Mean [standard deviation (SD)] HRQoL score (on a 0-1 scale) in the whole group improved from the preoperative of 0.905 (0.073) to 0.925 (0.077) six months after the operation (p < 0.001). The largest mean (SD) improvement was seen in patients with endometriosis [0.048 (0.067)] followed by those with menorrhagia [0.024 (0.054)], benign uterine or ovarian cause [0.018 (0.071)], and prolapse [0.017 (0.055)]. In the whole group, the intervention produced a mean (SD) of 0.222 (1.270) QALYs at mean (SD) direct hospital cost of euro3,138 (2,098). Consequently, the cost per QALY gained in the whole group was euro14,135 varying from euro3,720 to 31,570 in the disease groups. CONCLUSIONS: The cost per QALY gained for hysterectomy for benign uterine disorders is strongly dependent on the indication for surgery.