Estimating Long-Term Survival Outcomes for Tumor-Agnostic Therapies: Larotrectinib Case Study.

BACKGROUND: Larotrectinib is a precision oncology treatment for solid tumors with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Larotrectinib efficacy has been evaluated in single-arm basket trials with limited follow-up and sample sizes at the initial regulatory approval due to the rarity of solid tumors with NTRK gene fusion. OBJECTIVES: We aim to demonstrate that trends in progression-free survival (PFS) and overall survival (OS) in survival data with longer follow-up may be predicted from long-term survival estimates from survival data with shorter follow-up, including predictions for median survival when it is not observed in the trial. METHODS: Patient-level data were pooled from 3 clinical trials (NCT02122913, NCT02576431, and NCT02637687) using the 2018 and 2020 data cuts for the same subset of pediatric and adult patients. The Weibull distribution was selected for survival models. Survival predictions using 2018 data were compared to 2020 Kaplan-Meier (KM) curves. RESULTS: A total of 102 patients representing 15 tumor types were included in the analysis, with a mean age of 37 years. When comparing PFS from the 2018 survival prediction to observed 2020 KM data, the 12-month PFS rate was identical (66.6%). The 36-month PFS rate was lower for the 2018 prediction (35.3%) compared to 2020 KM data (44.4%). The median OS had not yet been reached in either data cut but was predicted to be 90 months using the 2018 data. When comparing OS from the 2018 survival prediction to the observed 2020 KM data, the 12-month OS rate was 89.0% and 86.6% and the 48-month OS rate was 67.2% and 63.0%, respectively. CONCLUSION: Long-term PFS predictions deviated from observed PFS rates due to response differences across tumor types and heavy censoring towards the end of the survival curve. However, for OS, the 48-month survival prediction was consistent with the observed 2020 KM estimate

Analyzing Health-Related Quality of Life Data to Estimate Parameters for Cost-Effectiveness Models : An Example Using Longitudinal EQ-5D Data from the SHIFT Randomized Controlled Trial

INTRODUCTION: The aim of this article is to discuss methods used to analyze health-related quality of life (HRQoL) data from randomized controlled trials (RCTs) for decision analytic models. The analysis presented in this paper was used to provide HRQoL data for the ivabradine health technology assessment (HTA) submission in chronic heart failure. METHODS: We have used a large, longitudinal EuroQol five-dimension questionnaire (EQ-5D) dataset from the Systolic Heart Failure Treatment with the I f Inhibitor Ivabradine Trial (SHIFT) (clinicaltrials.gov: NCT02441218) to illustrate issues and methods. HRQoL weights (utility values) were estimated from a mixed regression model developed using SHIFT EQ-5D data (n = 5313 patients). The regression model was used to predict HRQoL outcomes according to treatment, patient characteristics, and key clinical outcomes for patients with a heart rate ≥75 bpm. RESULTS: Ivabradine was associated with an HRQoL weight gain of 0.01. HRQoL weights differed according to New York Heart Association (NYHA) class (NYHA I-IV, no hospitalization: standard care 0.82-0.46; ivabradine 0.84-0.47). A reduction in HRQoL weight was associated with hospitalizations within 30 days of an HRQoL assessment visit, with this reduction varying by NYHA class [-0.07 (NYHA I) to -0.21 (NYHA IV)]. CONCLUSION: The mixed model explained variation in EQ-5D data according to key clinical outcomes and patient characteristics, providing essential information for long-term predictions of patient HRQoL in the cost-effectiveness model. This model was also used to estimate the loss in HRQoL associated with hospitalizations. In SHIFT many hospitalizations did not occur close to EQ-5D visits; hence, any temporary changes in HRQoL associated with such events would not be captured fully in observed RCT evidence, but could be predicted in our cost-effectiveness analysis using the mixed model. Given the large reduction in hospitalizations associated with ivabradine this was an important feature of the analysis. FUNDING: The Servier Research Group

Systematic review of health state utility values in metastatic non-small cell lung cancer with a focus on previously treated patients

Abstract Background Health state utility values (HSUVs) are an important input to economic evaluations and the choice of HSUV can affect the estimate of relative cost-effectiveness between interventions. This systematic review identified utility scores for patients with metastatic non-small cell lung cancer (mNSCLC), as well as disutilities or utility decrements relevant to the experience of patients with mNSCLC, by treatment line and health state. Methods The MEDLINE®, Embase and Cochrane Library databases were systematically searched (September 2016) for publications describing HSUVs in mNSCLC in any treatment line. The EQ-5D website, the School of Health and Related Research Health Utilities Database (ScHARRHUD) and major pharmacoeconomic and clinical conferences in 2015–2016 were also queried. Studies in adults with previously treated mNSCLC were selected for further analysis. The information extracted included study design, description of treatment and health state, respondent details, instrument and tariff, HSUV or (dis) utility decrement estimates, quality of study, and appropriateness for use in economic evaluations. Results Of 1883 references identified, 36 publications of 34 studies were included: 19 reported EQ-5D scores; eight reported HSUVs from valuations of vignettes made by members of the public using standard gamble (SG) or time trade-off (TTO); two reported SG or TTO directly elicited from patients; two reported EQ-5D visual analogue scale scores only; one reported Assessment of Quality of Life instrument scores; one reported HSUVs for caregivers to patients with mNSCLC using the 12-item Short-Form Health Survey; and one estimated HSUVs based on expert opinion. The range of HSUVs identified for comparable health states showed how differences in study type, tariff, health state and the measures used can drive variation in HSUV estimates. Conclusions This systematic review provides a set of published HSUVs that are relevant to the experience of adult patients previously treated for mNSCLC. Our review begins to address the challenge of identifying reliable estimates of utility values in mNSCLC that are suitable for use in economic evaluations, and also highlights how varying estimates result from differences in methodology

A sequential therapy with sorafenib followed by regorafenib against single-line atezolizumab and bevacizumab in advanced hepatocellular carcinoma (HCC): Indirect treatment comparisons (ITC) using the RESORCE study.

537 Background: Our objective was to explore ITC of sequential therapy with sorafenib followed by regorafenib (sorego) against atezolizumab+bevacizumab (atezobev) in HCC. Naïvely comparing median Overall Survival (OS) from sorafenib initiation on sorego in the RESORCE trial with atezobev from IMbrave150 is biased by population imbalance and selection of patients who survived on sorafenib in RESORCE. We used unanchored Matching Adjusted Indirect Comparison (MAIC) and novel survivorship bias adjusted anchored ITC (SBITC) to overcome these limitations. Methods: Overall Survival (OS) from sorafenib initiation in RESORCE on sorego were compared with reconstructed Individual Patient Data (IPD) OS based on Kaplan-Meier curves from IMbrave150 on atezobev. In MAIC, the sorego arm of RESORCE was weighted on reported baseline characteristics to match the IMbrave150 atezobev arm. In SBITC, sorafenib IPD from IMbrave150 were sampled with replacement and added to the RESORCE BSC arm to correct for “survivorship bias”. Sample size was sufficient for follow-up prior to RESORCE randomisation to be within 5% of sorafenib follow-up in IMbrave150. Anchored Bucher ITC was used to compare to unadjusted IMbrave150 with bootstrapping to obtain standard errors. Hazard Ratios (HRs) were used to compare OS. Results: MAIC gave an OS HR of 0.75 (95% confidence interval 0.60, 0.93; p-value=0.007). Effective sample size (ESS) was reduced from 379 to 271.75. SBITC gave a HR of 0.63 (0.52, 0.76; p-value &lt;0.001) requiring an average of 83 sorafenib patients to be added from IMbrave150. Conclusions: We proposed MAIC and SBITC to overcome biases in naïve comparisons of OS on sorego with atezobev in HCC. However, MAIC is limited to baseline characteristics in IMbrave150 and does not adjust for “survivorship bias”. SBITC depends on sample size from IMbrave150, and makes no adjustment for imbalance in baseline characteristics. Despite these limitations, our methods were consistent with naïve comparisons and suggested longer OS with sorego compared to atezobev in patients with HCC. </jats:p

Raltitrexed plus cisplatin is cost-effective compared with pemetrexed plus cisplatin in patients with malignant pleural mesothelioma

INTRODUCTION: The National Institute for Health and Clinical Excellence (NICE) has previously recommended pemetrexed plus cisplatin for the treatment of patients with advanced malignant pleural mesothelioma (MPM) and WHO performance status 0-1. Subsequent to this appraisal, randomised controlled trial (RCT) data for raltitrexed plus cisplatin and comparing chemotherapy to active symptom control (ASC) has become available, allowing a more complete analysis of the comparative efficacy and cost-effectiveness of first-line chemotherapy in MPM.METHODS: An adjusted indirect comparison is used to estimate the relative efficacy of raltitrexed plus cisplatin and pemetrexed plus cisplatin. A cost-effectiveness model is used to assess the lifetime costs and health outcomes associated with these comparators and ASC. Patient level data from the EORTC 08983 trial are used to estimate baseline progression and survival rates. Relative treatment effects are taken from RCTs; cost and utility data from the literature.RESULTS: Raltitrexed plus cisplatin and pemetrexed plus cisplatin were not found to be statistically significantly different with respect to overall response, progression free survival or overall survival. The cost-effectiveness analysis found raltitrexed plus cisplatin to be cost-effective at a cost per quality adjusted life year of £13,454 compared to cisplatin and £27,360 compared to ASC. Pemetrexed plus cisplatin is dominated by raltitrexed plus cisplatin as the raltitrexed combination offers marginally higher quality adjusted life years (QALYs) and life years (LYs) at a substantially lower total cost.CONCLUSION: Raltitrexed plus cisplatin is a cost-effective first-line treatment for MPM. This conclusion was maintained across a number of sensitivity analyses.</p