David Chandiwana

Elicitation of health state utilities in neuroendocrine tumours

Abstract Background: Neuroendocrine tumours (NETs) are a rare form of neoplasm that can arise in most organs of the body and which share many common pathologic features. Although curative surgery can be conducted for patients with localised disease, once progression occurs and the disease becomes metastatic or un-resectable, treatment aims to extend life and maintain quality-of-life for as long as possible. The aim of the study was to elicit utilities for health state vignettes describing the burdens associated with receiving therapy for advanced NETs. Methods: Health state vignettes were developed by reviewing published literature and conducting in-depth interviews with patients and clinical experts. These states described the burden associated with both stable and progressive disease, in addition to the experience of a number of serious toxicities commonly associated with treatments (grade III/IV diarrhoea, hand-foot syndrome, hyperglycaemia, nausea/vomiting, pneumonitis, rash, stomatitis, and thrombocytopenia). One hundred members of the UK general public valued the states using the time trade-off methodology to determine utility values. Results: Stable disease had a utility value of 0.77 whilst disease progression was associated with a significant decline in health-related quality-of-life (HRQoL) and a value of 0.61. Toxicities experienced in the context of stable disease exhibited varying degrees of impact, with several being deemed as debilitating as disease progression (such as hand-foot syndrome [0.58] and stomatitis [0.56]). Conclusion: Although vignette studies have been criticised for the difficulty in establishing their validity, the collection of health utilities in rare populations is challenging. The findings from this study suggest that advanced NETs is associated with a considerable HRQoL burden, both as a direct result of the disease and the potential of experiencing a number of severe adverse events. These values could assist in future economic evaluation processes.

Cost-effectiveness of pazopanib versus sunitinib for metastatic renal cell carcinoma in the United Kingdom

Background Sunitinib and pazopanib are the only two targeted therapies for the first-line treatment of locally advanced or metastatic renal cell carcinoma (mRCC) recommended by the United Kingdom’s National Institute for Health and Care Excellence. Pazopanib demonstrated non-inferior efficacy and a differentiated safety profile versus sunitinib in the phase III COMPARZ trial. The current analysis provides a direct comparison of the cost-effectiveness of pazopanib versus sunitinib from the perspective of the United Kingdom’s National Health Service based on data from COMPARZ and other sources. Methods A partitioned-survival analysis model with three health states (alive with no progression, alive with progression, or dead) was used to estimate the incremental cost per quality-adjusted life-year (QALY) gained for pazopanib versus sunitinib over five years (duration of follow-up for final survival analysis in COMPARZ). The proportion of patients in each health state over time was based on Kaplan–Meier distributions for progression-free and overall survival from COMPARZ. Utility values were based on EQ-5D data from the pivotal study of pazopanib versus placebo. Costs were based on medical resource utilisation data from COMPARZ and unit costs from secondary sources. Probabilistic and deterministic sensitivity analyses were conducted to assess uncertainty of model results. Results In the base case, pazopanib was estimated to provide more QALYs (0.0565, 95% credible interval [CrI]: −0.0920 to 0.2126) at a lower cost (−£1,061, 95% CrI: −£4,328 to £2,067) versus sunitinib. The probability that pazopanib yields more QALYs than sunitinib was estimated to be 76%. For a threshold value of £30,000 per QALY gained, the probability that pazopanib is cost-effective versus sunitinib was estimated to be 95%. Pazopanib was dominant in most scenarios examined in deterministic sensitivity analyses. Conclusions Pazopanib is likely to be a cost-effective treatment option compared with sunitinib as first-line treatment of mRCC in the United Kingdom.

Cost-effectiveness of zoledronic acid vs clodronic acid for newly-diagnosed multiple myeloma from the United Kingdom healthcare system perspective

Abstract Objective: In the Medical Research Council Myeloma IX Study (MMIX), zoledronic acid (ZOL) 4 mg 3–4/week reduced the incidence of skeletal-related events (SREs), increased progression free survival (PFS), and prolonged overall survival (OS), compared with clodronic acid (CLO) 1600 mg daily, in 1970 patients with newly-diagnosed multiple myeloma (MM). Methods: An economic model was used to project PFS, OS, the incidence of SREs and adverse events and expected lifetime healthcare costs for patients with newly-diagnosed MM who are alternatively assumed to receive ZOL or CLO. The incremental cost-effectiveness ratio [ICER] of ZOL vs CLO was calculated as the ratio of the difference in cost to the difference in quality-adjusted life years (QALYs). Model inputs were based on results of MMIX and published sources. Results: Compared with CLO, treatment with ZOL increases QALYs by 0.30 at an additional cost of £1653, yielding an ICER of £5443 per QALY gained. If the threshold ICER is £20,000 per QALY, the estimated probability that ZOL is cost-effective is 90%. Limitations: The main limitation of this study is the lack of data on the effects of zoledronic acid on survival beyond the end of follow-up in the MMIX trial. However, cost-effectiveness was favourable even under the highly conservative scenario in which the timeframe of the model was limited to 5 years. Conclusions: Compared with clodronic acid, zoledronic acid represents a cost-effective treatment alternative in patients with multiple myeloma.

A Cost Effectivness Analysis of Everolimus Compared with Axitinib in the Treatment of Metastatic Renal Cell Carcinoma in the United Kingdom

Objectives: Metastatic melanoma has a poor prognosis with 10 year survival being < 5%. Standard therapy is the effective but costly Ipilimumab. An emerging 1st line treatment is Tumor Infiltrating Lymphocytes (TIL), with response rates > 50% and expected survival rates of 25%-42% versus 45% (1yr) and 23,5% (2yr) for Ipilimumab. TIL is highly personalized, however complex and requests substantial upfront investments from the hospital in expensive lab-equipment, staff expertise and training, as well as extremely tight hospital logistics. Therefore, an early health economic modelling study, supporting a Coverage with Evidence Development (CED) program, was performed. MethOds: We used a Markov decision model to estimate the expected costs and outcomes (quality adjusted life years; QALYs) for TIL versus Ipilimumab in metastatic melanoma patients from a societal perspective over a life long time horizon. Three mutually exclusive health states (stable disease, progressive disease and death) were modelled, divided in first and second line treatment. Technical failures and non-compliance were incorporated to reflect the dynamic nature of the technology. To inform further research prioritization, Value of Information (VOI) analysis was performed. Results: TIL is expected to yield more QALYs compared to Ipilimumab (0.99 vs 0.52 respectively) at lower total costs (€ 83,588 vs € 87,834 respectively). Based on current information TIL has a probability of 88% for being cost effective at a cost/QALY threshold of € 30,000. Expected Value of Perfect Information (EVPI) amounted to € 1,2 million. Partial EVPI (EVPPI) was highest for survival data (€ 550,000). Expected Value of Sample information was estimated € 355,000 for an optimal sample size of n= 50. cOnclusiOns: TIL is expected to improve QALYs compared to Ipilimumab at lower incremental cost and has the highest probability of being cost-effective. To reduce decision uncertainty, a future clinical trial to investigate survival seems most valuable, and should preferably be undertaken as part of a CED program.

Progression-free survival with endocrine-based therapies following progression on non-steroidal aromatase inhibitor among postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative metastatic breast cancer: a network meta-analysis

Abstract Objective: To quantify the comparative efficacy of currently available endocrine-based therapies (ETs) for postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2−) metastatic breast cancer (mBC) after non-steroidal aromatase inhibitor (NSAI) progression. Design: Network meta-analysis (NMA). Methods: Randomized clinical trials of ETs for HR+/HER2− mBC were identified via a systematic literature review using MEDLINE, Embase, Cochrane Library and key conference proceedings. All trials met the following inclusion criteria: (1) included women with HR+/HER2− mBC; (2) previous treatment with ETs or chemotherapy as first-line therapy; (3) treatment with ET as monotherapy or in combination with targeted therapy; (4) progression-free survival (PFS) was reported; and (5) published in 2007 (when HER2 testing became standardized) or later. Regimens were compared using pairwise hazard ratios (HRs) and 95% credible intervals (CrIs) of PFS obtained from a Bayesian NMA. Treatments with different approved dosages were pooled into the same arm; anastrozole and exemestane were pooled as aromatase inhibitors (AIs) due to clinical similarities. Results: A total of 4 trials and 6 regimens (palbociclib + fulvestrant, everolimus + fulvestrant, everolimus + AI, fulvestrant + AI, fulvestrant and AI) were eligible for inclusion. Palbociclib + fulvestrant and everolimus + AI had 50% and 55% reduced hazard of progression or death vs. AI (95% CrI upper bound ≤1), respectively. Palbociclib + fulvestrant, everolimus + AI and everolimus + fulvestrant had 54%, 58% and 40% reduced hazard vs. fulvestrant (95% CrI upper bound ≤1), while palbociclib + fulvestrant and everolimus + AI had 52% and 55% reduced hazard vs. fulvestrant + AI (95% CrI upper bound ≤1), respectively. Conclusion: Postmenopausal women with HR+/HER2− mBC who had previously failed an NSAI and received palbociclib + fulvestrant, everolimus + AI or everolimus + fulvestrant had longer PFS compared to those who received fulvestrant or AI alone.

Progression-free Survival With First-line Endocrine-based Therapies Among Postmenopausal Women With HR+/HER2– Metastatic Breast Cancer:: A Network Meta-analysis

PURPOSE The comparative efficacy of endocrine-based therapies (ETs) for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) is not well characterized. This network meta-analysis (NMA) synthesized available evidence on progression-free survival (PFS) with first-line ETs for postmenopausal HR+/HER2- mBC. METHODS A systematic literature review identified randomized controlled trials of first-line ETs. Pairwise hazard ratios and 95% credible intervals (CrIs) were obtained via a Bayesian NMA model. Subgroup NMAs were conducted among late progressors (disease-free interval ≥12 months from completion of [neo] adjuvant therapy with letrozole or anastrozole at the time of randomization) and de novo patients, defined as patients whose initial BC diagnosis is mBC. FINDINGS Five trials and 5 regimens (ribociclib + an aromatase inhibitor [AI] [LEE + AI], palbociclib + AI [Pal + AI], fulvestrant 250 mg + AI [Ful250 + AI], fulvestrant 500 mg [Ful500], and AI) were selected. LEE + AI, Pal + AI, Ful250 + AI, and Ful500 had significantly longer PFS versus AI (95% CrI upper-bound ≤1). LEE + AI had a 30% and 29%, and Pal + AI had a 31% and 30%, reduced hazard of progression or death versus Ful250 + AI and Ful500 (95% CrI upper-bound ≤1), respectively. The probability of being the most efficacious was 46% for LEE + AI and 54% for Pal + AI. In subgroup analyses among late progressors, LEE + AI had a 4% reduced hazard of progression or death versus Pal + AI but was not statistically significant. In the de novo analysis, Pal + AI and LEE + AI had a 29% and 40% reduced hazard of progression or death versus Ful500, respectively, but were not statistically significant. In both subgroup analyses, all therapies had significantly longer PFS compared with AI. IMPLICATIONS Pal + AI, LEE + AI, Ful250 + AI, or Ful500 as first-line treatment for HR+/HER2- mBC had longer PFS than AI alone. Given the lack of head-to-head clinical trials comparing the efficacy of recently approved first-line ETs for HR+/HER2- mBC, these results have important clinical implications for the treatment of HR+/HER2- mBC in the first-line setting.

Matching-adjusted indirect treatment comparison of ribociclib and palbociclib in HR+, HER2− advanced breast cancer

Background Ribociclib (RIBO) and palbociclib (PALBO), combined with letrozole (LET), have been evaluated as treatments for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in separate Phase III randomized controlled trials (RCTs), but not head-to-head. Population differences can lead to biased results by classical indirect treatment comparison (ITC). Matching-adjusted indirect comparison (MAIC) aims to correct these differences. We compared RIBO and PALBO in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer using MAIC. Methods Patient-level data were available for RIBO (MONALEESA-2), while only published summary data were available for PALBO (PALOMA-2). Weights were assigned to MONALEESA-2 patient data such that mean baseline characteristics matched those reported for PALOMA-2; the resulting matched cohort was used in comparisons. Limited by the results reported in PALOMA-2, progression-free survival (PFS) was the primary comparison. Cox regression models were used to calculate adjusted hazard ratios (HRs) for PFS, before indirect treatment comparison (ITC) was performed with 95% confidence intervals. An exploratory analysis was performed similarly for overall survival using earlier PALBO data (PALOMA-1). Grade 3/4 adverse events were also compared. Results Racial characteristics, prior chemotherapy setting, and the extent of metastasis were the most imbalanced baseline characteristics. The unadjusted PFS HRs were 0.556 (0.429, 0.721) for RIBO+LET versus LET alone and 0.580 (0.460, 0.720) for PALBO+LET versus LET alone. MAIC adjustment resulted in an HR of 0.524 (0.406, 0.676) for RIBO+LET versus LET. PFS ITC using unadjusted trial data produced an HR of 0.959 (0.681, 1.350) for RIBO versus PALBO, or 0.904 (0.644, 1.268) with MAIC. Unadjusted overall survival HR of RIBO versus PALBO was 0.918 (0.492, 1.710); while exploratory MAIC was 0.839 (0.440, 1.598). ITC of grade 3/4 adverse events yielded a risk ratio of 0.806 (0.604, 1.076). Conclusion MAIC was performed for RIBO and PALBO in the absence of a head-to-head trial: though not statistically significant, the results favored RIBO.

Is progression-free survival a more relevant endpoint than overall survival in first-line HR+/HER2− metastatic breast cancer?

Background Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), metastatic breast cancer (MBC) accounts for 73% of all MBCs. Endocrine therapy (ET) is the basis of first-line (1L) therapy for patients with HR+/HER2− MBC. Novel therapies have demonstrated improvements in progression-free survival (PFS) compared to ET. The clinical relevance of PFS is being debated, as there is no proven direct correlation with overall survival (OS) benefit to date. We reviewed studies of HR+/HER2− MBC to assess PFS and other factors that influence OS and treatment response, and health-related quality of life (HRQoL). Methods The Embase®, Medline®, and Cochrane databases were systematically searched to identify studies in adult women with HR+/HER2− MBC, published between January 2006 and January 2017, and written in English. Phase II and III randomized controlled trials (RCTs), observational, and retrospective studies were included. Results Seventy-nine RCTs were identified: 58 (73%) in the 1L+ setting and 21 (27%) in second-line or greater settings. PFS hazard ratios (HRs) were reported in 61 (77%) studies; 31 (39%) reported significant PFS improvements. OS was reported in 44 (41%) studies; 12 (15%) reported significant OS improvements. Significant improvements in both PFS and OS were reported in only 6 (8%) studies (1 Phase II; 5 Phase III). Patients with HER2− MBC received, on average, ≥5 lines of therapy, with no consistent treatment pathway. Baseline characteristics, prior therapies, and the type and number of post-progression therapies significantly impacted OS. PFS, response rates, and HRQoL decreased with each line of therapy (EuroQol 5 Dimensions: 0.78 1L vs. 0.70 post-progression). Conclusion Few RCTs in HR+/HER2− MBC have demonstrated significant improvements in OS. Factors other than choice of 1L therapy impact OS, including post-progression therapies, which cannot be controlled in RCTs. This study emphasizes the importance of PFS improvement in 1L treatment of HR+/HER2− MBC.

Progression-free survival/time to progression as a potential surrogate for overall survival in HR+, HER2– metastatic breast cancer

Background Several recent randomized controlled trials (RCTs) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) have demonstrated significant improvements in progression-free survival (PFS); however, few have reported improvement in overall survival (OS). The surrogacy of PFS or time to progression (TTP) for OS has not been formally investigated in HR+, HER2− MBC. Methods A systematic literature review of RCTs in HR+, HER2− MBC was conducted to identify studies that reported both median PFS/TTP and OS. The correlation between PFS/TTP and OS was evaluated using Pearson’s product–moment correlation and Spearman’s rank correlation. Subgroup analyses were performed to explore possible reasons for heterogeneity. Errors-in-variables weighted least squares regression (LSR) was used to model incremental OS months as a function of incremental PFS/TTP months. An exploratory analysis investigated the impact of three covariates (chemotherapy vs hormonal/targeted therapy, PFS vs TTP, and first-line therapy vs second-line therapy or greater) on OS prediction. The lower 95% prediction band was used to determine the minimum incremental PFS/TTP months required to predict OS benefit (surrogate threshold effect [STE]). Results Forty studies were identified. There was a statistically significant correlation between median PFS/TTP and OS (Pearson =0.741, P=0.000; Spearman =0.650, P=0.000). These results proved consistent for chemotherapy and hormonal/targeted therapy. Univariate LSR analysis yielded an R2 of 0.354 with 1 incremental PFS/TTP month corresponding to 1.13 incremental OS months. Controlling the type of treatment (chemotherapy vs hormonal/targeted therapy), line of therapy (first vs subsequent), and progression measure (PFS vs TTP) led to an improved R2 of 0.569 with 1 PFS/TTP month corresponding to 0.78 OS months. The STE for OS benefit was 5–6 months of incremental PFS/TTP. Conclusion We demonstrated a significant association between PFS/TTP and OS, which may justify the use of PFS/TTP as a surrogate for OS benefit in HR+, HER2− MBC.