Cost-effectiveness analysis of pazopanib in second-line treatment of advanced soft tissue sarcoma in Spain.

PURPOSE: To assess the efficiency of pazopanib compared with trabectedin in the treatment of adult patients with selective subtypes of advanced soft-tissue sarcoma (STS) after chemotherapy failure. METHODS: The progression of STS was modeled using a partitioned survival analysis model. Survival curves for pazopanib and trabectedin were modeled using data from PALETTE phase III clinical trial and based on unadjusted indirect comparison. Effectiveness was measured in quality-adjusted life years (QALY). The Spanish National Health System perspective was considered over a 10-year time horizon, including direct health care costs (, 2014). A discount rate of 3% was applied to both costs and outcomes. The robustness of the results was evaluated using univariate and probabilistic sensitivity analyses (PSA). RESULTS: Pazopanib was associated with better health outcomes than trabectedin (0.705 versus 0.686 QALY). Pazopanib also showed lower direct health care costs (21,861 versus 45,338), mainly due to lower cost of pharmacological treatment (13,762 versus 33,392), administration (57 versus 2,955) and AE management (658 versus 1,695) costs. PSA confirmed that pazopanib was a dominant option in 71% of the simulations performed. CONCLUSIONS: In this analysis, and from a health economics perspective, pazopanib was the option of choice versus trabectedin in the treatment of adult patients with advanced soft-tissue sarcoma after chemotherapy failure.

Trabectedin for the treatment of advanced metastatic soft tissue sarcoma: a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of trabectedin (PharmaMar) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of advanced metastatic soft tissue sarcoma (aMSTS), as part of the Institute's single technology appraisal (STA) process. The School of Health and Related Research (ScHARR) was commissioned to act as the Evidence Review Group (ERG). This paper provides a description of the company submission, the ERG review and NICE's subsequent decisions. The ERG produced a review of the evidence for the clinical and cost effectiveness of the technology contained within the manufacturer's submission to NICE. The ERG also independently modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. The main evidence was derived from a single phase II randomized controlled trial (RCT) conducted in liposarcoma and leiomyosarcoma only, in which the licensed dose of trabectedin was compared with a different dose of trabectedin. Additional data were also presented from three uncontrolled phase II trials. Supplementary studies were used to represent best supportive care (BSC). The median overall survival (OS) was 13.9 months for the licensed dose of trabectedin in the main randomized controlled trial (RCT) and ranged from 9.2 months to 12.8 months in the other studies included. Supplementary studies supplied by the manufacturer, and assumed to represent BSC, had median OS of 5.9-6.6 months. The progression-free survival (PFS) rates at 6 months for trabectedin were 35.5 % in the main RCT and 24.4-29 % in the other studies included. The PFS rates at 6 months were 8-14 % for BSC. In the manufacturer's original submission to NICE, the base-case incremental cost-effectiveness ratio (ICER) of trabectedin compared with BSC was approximately £44,000 per QALY gained. After amendment of errors identified by the ERG, the ICER reported by the manufacturer increased to approximately £61,000. The ERG concluded that, despite clarifications from the manufacturer and the revisions made to the model, there was still considerable uncertainty in the ICER. The NICE Appraisal Committee (AC) gave a negative initial recommendation, although indicated that trabectedin in aMSTS met the end-of-life criteria. Subsequently, the manufacturer submitted a patient access scheme (PAS) where any cycles beyond the fifth were provided at no cost by the manufacturer. This improved the ICER to approximately £34,000 per QALY gained. The AC gave a positive recommendation, subject to the implementation of the PAS.

Growth modulation index as metric of clinical benefit assessment among advanced soft tissue sarcoma patients receiving trabectedin as a salvage therapy.

BACKGROUND: The growth modulation index (GMI) is the ratio of time to progression with the nth line (TTP(n)) of therapy to the TTP(n)(-1) with the n-1th line. GMI >1.33 is considered as a sign of activity in phase II trials. PATIENTS AND METHODS: This retrospective analysis evaluated the concordance between the GMI and the efficacy outcomes in 279 patients with advanced soft tissue sarcoma (ASTS) treated with trabectedin 1.5 mg/m² (24-h infusion every 3 weeks) in four phase II trials. RESULTS: One hundred and forty-two (51%) patients received one prior line and 137 ≥ 2 lines. The median TTP(n) was 2.8 months (range 0.2-26.8), whereas the median TTP(n)(-1) was 4.0 months (0.3-79.5). The median GMI was 0.6 (0.0-14.4). Overall, 177 patients (63%) had a GMI <1; 21 (8%) a GMI equal to 1-1.33 and 81 (29%) a GMI >1.33, which correlated with the median overall survival in those patients (9.1, 13.9 and 23.8 months, respectively, P = 0.0005). A high concordance rate between the GMI and response rate (P < 0.0001) and progression-free survival (PFS, P < 0.0001) was observed. Good performance status (PS) was the only factor associated with GMI >1.33 (PS = 0; P < 0.04). CONCLUSIONS: A high GMI was associated with favorable efficacy outcomes in patients treated with trabectedin. Further research is needed to assess GMI as an indicator in this setting.

Trabectedin for the treatment of relapsed ovarian cancer.

The paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of trabectedin for the treatment of relapsed platinum-sensitive ovarian cancer, based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submission addressed only part of the decision problem and did not provide evidence to compare trabectedin (Yondelis®, PharmaMar) and pegylated liposomal doxorubicin hydrochloride (PLDH) (Caelyx®, Schering-Plough) with key comparators. The submission's direct comparison evidence came from one reasonable-quality randomised controlled trial (RCT) of trabectedin and PLDH versus PLDH alone (ET743-OVA-301). The results of the RCT were subdivided into the entire platinum-sensitive population (> 6-month relapse after initial platinum-based chemotherapy) and partially platinum-sensitive (≥ 6- to 12-month relapse) and fully platinum-sensitive (> 12-month relapse) populations. The outcomes included were overall survival, progression-free survival measured by three types of assessor, response rates, adverse effects of treatment, health-related quality of life and cost per quality-adjusted-life-year (QALY) gained. A mixed treatment comparison (MTC) meta-analysis comparing trabectedin and PLDH with single-agent PLDH within the entire platinum-sensitive population, with paclitaxel or with topotecan also formed part of the submission. The RCT data showed that trabectedin plus PLDH compared with PLDH monotherapy had a significant effect on overall survival only within the partially platinum-sensitive subgroup. PFS results reported by the independent radiologists showed significant effects in favour of the trabectedin and PLDH arm for the entire and partially platinum-sensitive populations only. Rates of grade 3 and 4 adverse events were mostly higher in the trabectedin and PLDH arm than in the PLDH alone arm. There were several issues regarding the undertaking of the MTC, and thus the data were not considered robust. Furthermore, the ERG did not believe the MTC to be necessary to answer the decision problem. The manufacturer submitted a de novo cost-effectiveness model. The main analysis compared trabectedin in combination with PLDH versus paclitaxel, topotecan and PLDH (each as monotherapy) in the entire platinum-sensitive population, using results estimated from the MTC. Additional analyses were presented comparing trabectedin in combination with PLDH versus PLDH monotherapy using direct evidence from the OVA-301 trial for the fully, partially and entire platinum-sensitive populations. The cost per QALY gained for trabectedin in combination with PLDH versus PLDH monotherapy was estimated to be £ 70,076 in the main analysis. In the additional analyses, the cost per QALY gained for trabectedin in combination with PLDH versus PLDH monotherapy was £ 94,832, £ 43,996 and £ 31,092 for the entire, partially and fully platinum-sensitive populations, respectively. Additional work was undertaken by the ERG using patient-level data and amending some assumptions to provide a better statistical fit to the Kaplan-Meier data than the exponential distribution assumed by the manufacturer. The ERG base-case estimate of the cost per QALY of trabectedin in combination with PLDH ranged from £46,503 to £54,607 in the partially platinum-sensitive population. At the time of writing, trabectedin in combination with PLDH for the treatment of women with relapsed platinum-sensitive ovarian cancer is not recommended by NICE in the final appraisal determination.

Trabectedin in the treatment of metastatic soft tissue sarcoma: cost-effectiveness, cost-utility and value of information.

BACKGROUND: to assess the cost-effectiveness of trabectedin compared with end-stage treatment (EST) after failure with anthracycline and/or ifosfamide in metastatic soft tissue sarcoma (mSTS). DESIGN: analysis was carried out using a probabilistic Markov model with trabectedin → EST and EST arms, three health states (stable disease, progressive disease and death) and a lifetime perspective (3% annual discount rate). Finnish resources (drugs, mSTS, adverse events and travelling) and costs (year 2008) were used. Efficacy was based on an indirect comparison of the STS-201 and European Organisation for Research and Treatment of Cancer trials. QLQ-C30 scale scores were mapped to 15D, Short Form 6D and EuroQol 5D utilities. The outcome measures were the cost-effectiveness acceptability frontier, incremental cost per life year gained (LYG) and quality-adjusted life year (QALY) gained and the expected value of perfect information (EVPI). RESULTS: trabectedin → EST was associated with 14.0 (95% confidence interval 9.1-19.2) months longer survival, €36 778 higher costs (€32 816 using hospital price for trabectedin) and €31 590 (€28 192) incremental cost per LYG with an EVPI of €3008 (€3188) compared with EST. With a threshold of €50 000 per LYG, trabectedin → EST had 98.5% (98.2%) probability of being cost-effective. The incremental cost per QALY gained with trabectedin → EST was €42 633-47 735 (€37 992-42 819) compared with EST. The results were relatively insensitive to changes. CONCLUSION: trabectedin is a potentially cost-effective treatment of mSTS patients.

Trabectedin for the treatment of advanced metastatic soft tissue sarcoma.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of trabectedin for the treatment of advanced metastatic soft tissue sarcoma, in accordance with the licensed indication, based on the evidence submission from the manufacturer to NICE as part of the single technology appraisal (STA) process. The outcomes stated in the manufacturer's definition of the decision problem were overall survival (OS), progression-free survival (PFS), response rates, adverse effects of treatment, health-related quality of life, and cost per quality-adjusted life-year (QALY) gained. The clinical evidence was derived from one randomised controlled trial (RCT), in which the licensed dose of trabectedin was compared with a different dose of trabectedin, and three phase II studies. In the RCT, the median OS was 13.9 months for the licensed dose of trabectedin, which was not significantly different from that for the comparator dose of trabectedin, which was 11.8 months. From the phase II uncontrolled trials, median OS was reported as 9.2 or 12.8 months. The RCT reported significantly superior PFS for the licensed dose of trabectedin (median 3.3 months) over the comparator trabectedin dose (median 2.3 months). One phase II uncontrolled trial reported median PFS as 1.9 months in the licensed dose of trabectedin. The RCT reported PFS rates at 6 months were 35.5% for the licensed dose of trabectedin, and 27.5% for the comparator dose of trabectedin. From the phase II uncontrolled trials, PFS rates at 6 months were 24.4% or 29%. For the RCT, deaths attributed to trabectedin occurred in 3.1% of the licensed dose, and 2.3% of the comparator group. The most common severe adverse events were neutropenia, although with a low rate of febrile neutropenia, thrombocytopenia, and aspartate aminotransferase and alanine aminotransferase elevation, although these were reported to be non-cumulative and reversible. Following dialogue iterations with the ERG team, the manufacturer revised the model twice. However, despite revisions, errors/inconsistencies were found in the latest version of the model and were corrected by the ERG (only for the base case). In the latest manufacturer's submission, the cost per QALY gained of trabectedin compared with best supportive care (BSC) was estimated to be 56,985 pounds for the base case using effectiveness from the STS (Soft Tissue Sarcomas)-201 trial for trabectedin and a pool analysis of the European Organisation for Research and Treatment of Cancer data set for BSC. This analysis was constrained to patients with L-sarcomas only. When the joint uncertainty between parameters was considered, the cost-effectiveness acceptability curve showed that trabectedin has a very low probability of being cost-effective at a threshold of 30,000 pounds per QALY gained compared with BSC for any scenario. The guidance has yet to be issued by NICE.

Positive modulators of AMPA receptors as a potential treatment for schizophrenia.

There is a consensus that current treatments of schizophrenia do not offer satisfactory efficacy for negative and cognitive symptoms. Recently, the dopaminergic hyperfunction hypothesis of schizophrenia has been enriched by the addition of the glutamatergic hypofunction concept. Accordingly, agents enhancing glutamatergic transmission should provide benefit in psychosis. In fact, some preclinical studies suggest that positive modulators of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptors, previously developed mainly for dementia, may fulfill such expectations. These agents attenuate various biochemical or behavioral effects produced by amphetamine or methamphetamine and enhance the action of antipsychotics. More importantly, preliminary clinical studies with the most advanced member of this class, CX-516(Cortex Pharmaceuticals Inc), indicate beneficial action on negative and cognitive symptoms as an add-on treatment t o clozapine. If these observations are confirmed in a larger scale clinical trial, this approach could be a major improvement in the treatment of schizophrenia.

CX-516 Cortex pharmaceuticals.

CX-516 is one of a series of AMPA modulators under development by Cortex, in collaboration with Shire and Servier, for the potential treatment of Alzheimer's disease (AD), schizophrenia and mild cognitive impairment (MCI) [234221]. By June 2001, CX-516 was in phase II trials for both schizophrenia and attention deficit hyperactivity disorder (ADHD) [412513]. A phase II trial in fragile X syndrome and autism was expected to start in May 2002 [449861]. In October 2001, Cortex was awarded a Phase II SBIR grant of $769,818 from the National Institutes of Mental Health to investigate the therapeutic potential of AMPAkines in schizophrenia. This award was to support a phase IIb study of CX-516 as a combination therapy in schizophrenia patients concomitantly treated with olanzapine. The trial was to enroll 80 patients and employ a randomized, double-blind, placebo-controlled design in which the placebo group was to receive olanzapine plus placebo and the active group was to receive olanzapine plus CX-516 [425982]. In April 2000, Shire and Cortex signed an option agreement in which Shire was to evaluate CX-516for the treatment of ADHD. Under the terms of the agreement, Shire would undertake a double-blind, placebo-controlled evaluation of CX-516 involving ADHD patients. If the study proved effective, Shire would have the right to convert its option into an exclusive worldwide license for the AMPAkines for ADHD under a development and licensing agreement. Should Shire elect to execute this agreement, Shire would bear all future developmental costs [363618]. By February 2002, Cortex and Servier had revealed their intention to begin enrolment for an international study of an AMPAkine compound as a potential treatment for MCI in the near future. Assuming enrollment proceeded as anticipated, results were expected during the second quarter of 2003 [439301]. By May 2002, phase II trials were underway [450134]. In March 2002, Cortex was awarded extended funding under the University of California BioSTAR projectfor the research project: 'Ampakine modulation of brain neurotrophin expression: a novel therapeutic strategy'. This funding was expected to amount to $193,000 over a two-year period [444872].