Bryan Bennett

Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial.

BACKGROUND In the phase 3 CheckMate 025 study, previously treated patients with advanced renal cell carcinoma who were randomly assigned to nivolumab had an overall survival benefit compared with those assigned to everolimus. We aimed to compare health-related quality of life (HRQoL) between treatment groups in this trial. METHODS CheckMate 025 was an open-label study done at 146 oncology centres in 24 countries. Patients were randomly assigned to treatment between Oct 22, 2012, and March 11, 2014. Patients with advanced renal cell carcinoma were randomly assigned (1:1, block size of four) to receive nivolumab every 2 weeks or everolimus once per day. The study was stopped early at the planned interim analysis in July, 2015, because the study met its primary endpoint. A protocol amendment permitted patients in the everolimus group to cross over to nivolumab treatment. All patients not on active study therapy are being followed up for survival. At the interim analysis, HRQoL was assessed with the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) and European Quality of Life (EuroQol)-5 Dimensions (EQ-5D) questionnaires. Prespecified endpoints were to assess, in each treatment group, disease-related symptom progression rate based on the FKSI-DRS and changes in reported global health outcomes based on the EQ-5D. Other endpoints were post hoc. We calculated the proportion of FKSI-DRS questionnaires completed using the number of patients with non-missing data at baseline and at least one post-baseline visit. We defined FKSI-DRS completion as completion of five or more of the nine items in the questionnaire; otherwise data were treated as missing. FKSI-DRS symptom index score was prorated for missing items. We made no adjustments for missing EQ-5D data. We used descriptive statistics and multivariate analyses, including mixed-effects model repeated-measures, for between group comparisons. Analyses were powered according to the original study protocol, and we analysed FKSI-DRS and EQ-5D data for all patients who underwent randomisation and had a baseline assessment and at least one post-baseline assessment. CheckMate 025 is registered with ClinicalTrials.gov, number NCT01668784. FINDINGS HRQoL data were collected at baseline for 362 (88%) of 410 patients in the nivolumab group and 344 (84%) of 411 patients in the everolimus group. The mean difference in FKSI-DRS scores between the nivolumab and everolimus groups was 1·6 (95% CI 1·4-1·9; p<0·0001) with descriptive statistics and 1·7 (1·2-2·1; p<0·0001) with mixed-effects model repeated-measures analysis. In terms of FKSI-DRS score, more patients had a clinically meaningful (ie, an increase of at least 2 points from baseline) HRQoL improvement with nivolumab (200 [55%] of 361 patients) versus everolimus (126 [37%] of 343 patients; p<0·0001). Median time to HRQoL improvement was shorter in patients given nivolumab (4·7 months, 95% CI 3·7-7·5) than in patients given everolimus (median not reached, NE-NE). INTERPRETATION Nivolumab was associated with HRQoL improvement compared with everolimus in previously treated patients with advanced renal cell carcinoma. FUNDING Bristol-Myers Squibb.

Development of a Consensus Statement for the Definition, Diagnosis, and Treatment of Acute Exacerbations of Idiopathic Pulmonary Fibrosis Using the Delphi Technique

IntroductionThere is a lack of agreed and established guidelines for the treatment of acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). This reflects, in part, the limited evidence-base underpinning the management of AE-IPF. In the absence of high-quality evidence, the aim of this research was to develop a clinician-led consensus statement for the definition, diagnosis and treatment of AE-IPF.MethodsA literature review was conducted to obtain published material on the definition and treatment of AE-IPF. The results of this review were circulated to an online panel of clinicians for review. Statements were then shared with ten expert respiratory clinicians who regularly treat patients with IPF. A Delphi technique was then used to develop a consensus statement for the definition, diagnosis and treatment of AE-IPF. During the first round of review, clinicians rated the clarity of each statement, the extent to which the statement should be included and provided comments. In two subsequent rounds of review, clinicians were provided with the group median inclusion rating for each statement, and any revised wording of statements to aid clarity. Clinicians were asked to repeat the clarity and inclusion ratings for the revised statements.ResultsThe literature review, online panel discussion, and face-to-face meeting generated 65 statements covering the definition, diagnosis, and management of AE-IPF. Following three rounds of blind review, 90% of clinicians agreed 39 final statements. These final statements included a definition of AE-IPF, approach to diagnosis, and treatment options, specifically: supportive measures, use of anti-microbials, immunosuppressants, anti-coagulants, anti-fibrotic therapy, escalation, transplant management, and long-term management including discharge planning.ConclusionThis clinician-led consensus statement establishes the ‘best practice’ for the management and treatment of AE-IPF based on current knowledge, evidence, and available treatments.FundingBoehringer Ingelheim Ltd., Bracknell, West Berkshire, UK.

Health-related quality of life and its association with medication adherence in active pulmonary tuberculosis– a systematic review of global literature with focus on South Africa

IntroductionTuberculosis (TB) is a leading cause of morbidity and mortality in South Africa. Clinical parameters are important objective outcomes in TB; however they often are not directly correlated with subjective well-being of the patient, but can be assessed using patient-reported outcome (PRO) measures. Health-related quality of life (HRQOL) is a specific PRO generally multi-dimensional in nature and includes physical, mental and social health domains. The inclusion of HRQOL PROs in trials and clinical practice can provide additional information beyondclinical and microbiological parameters. Furthermore, HRQOL may be associated with medication adherence. This review focuses on patient-reported HRQOL and its association with medication adherence in TB patients in South Africa.MethodsA comprehensive search strategy was developed focusing on the impact of TB on patient-reported HRQOL,the existence of a conceptual framework of TB-specific HRQOL, determinants of medication adherence and the association of HRQOL with medication adherence. Data were extracted from all identified articles and additionaldata extraction was performed by two independent reviewers with special focus on longitudinal studies in order to understand changes of HRQOL and adherence over time. Research gaps were identified with regard to patient-reported HRQOL and medication adherence.ResultsA total of 66 articles met the eligibility criteria. Ten HRQOL studies and one adherence study used a longitudinal design, none of these in South Africa. A variety of different generic and disease-specific HRQOL measures were identified in the articles. In South Africa four HRQOL and five adherence studies (non-longitudinal) were published. Similar factors (socio-demographic, socio-economic, disease-related, therapy-related and psycho-social aspects) affect HRQOL and adherence. Although standard TB treatment improved all health domains, psychological well-being and social functioning remained impaired in microbiologically cured patients after treatment.ConclusionWhile evidence of TB impact on HRQOL and medication adherence and their association exists, it is verylimited for the South African situation. No valid and reliable TB-specific HRQOL measures were identified in this systematicreview. An assessment of HRQOL in TB patients in South Africa is required as this may assist with improving current disease management programmes, medication adherence and national treatment guidelines.

How to evaluate health-related quality of life and its association with medication adherence in pulmonary tuberculosis – designing a prospective observational study in South Africa

Introduction: Health-related quality of life (HRQOL) has become an important measure to identify and shape effective and patient-relevant healthcare interventions innovations through outcomes. Adherence to tuberculosis (TB) treatment is a public health concern. The main objective of this research is to develop a study design for evaluation of HRQOL and its association with medication adherence in TB in South Africa. Methodology: A conceptual framework for HRQOL in TB has been developed to identify Patient-Reported Outcomes and Quality of Life Database (PROQOLID), (n.d.) measures for HRQOL and adherence and to generate an endpoint model. Two generic (SF-12 and EQ-5D-5L), one disease-specific (St. George’s Respiratory Questionnaire) and one condition-specific (Hospital Anxiety and Depression Scale) measure for HRQOL and Morisky Medication Adherence Scale for adherence assessment were identified. All measures are applied in a longitudinal multi-center study at five data collection time points during standard TB treatment. Statistical analysis includes multivariable analysis. Change over time in the physical component score of SF-12 is defined as primary endpoint. Sample size estimation based thereupon has led to a recruitment target of 96 patients. This study is on-going. Discussion: This is the first longitudinal study in South Africa which evaluates HRQOL and its association with medication adherence in TB in a comprehensive manner. Results will help to improve current treatment programs and medication adherence and will support the identification of sustainable health innovations in TB, determining the value of new products, and supporting decision making with regard to health policy and pricing.

Health-related quality of life in South African patients with pulmonary tuberculosis

Background The evaluation of patient-reported health-related quality of life (HRQOL) in pulmonary tuberculosis (TB) contributes to a comprehensive understanding of the burden associated with this disease. The aim of this study was to assess the overall impact of TB on the health status and on single health domains identified in the WHO definition of health, including physical, mental and social health aspects. Methods Four instruments for HRQOL evaluation were applied in a longitudinal multicentre study during six-month standard TB treatment in South Africa. These included the generic SF-12 and EQ-5D-5L, the disease-specific St. George´s Respiratory Questionnaire (SGRQ) and the condition-specific Hospital Anxiety and Depression Scale (HADS). Statistical analysis included significance testing, univariable and multivariable analysis, and repeated measures ANOVA. Change over time in the physical component score (PCS) of SF-12 was defined as primary endpoint. A target sample size of 96 patients was estimated. Results HRQOL of the study participants was impaired in all physical, mental and psycho-social health domains at treatment start. HRQOL improved significantly and in a clinically meaningful manner during the course of standard TB treatment, over the period of the study. The greatest improvement (95%) was observed in mental health. Younger patients with higher education and who were employed had a better HRQOL. Discussion This study demonstrates the need for an integrative understanding of TB with HRQOL as core element to inform gaps in current TB management. Improvements in the management of TB following an integrative patient-centred approach will contribute towards meeting the United Nations Sustainable Development Goal 3 (SDG3) target and will support the End TB strategy of the WHO.

The Humanistic Burden of Small Cell Lung Cancer (SCLC): A Systematic Review of Health-Related Quality of Life (HRQoL) Literature

Background: Little is known about the humanistic burden of small cell lung cancer (SCLC), specifically the impact on health-related quality of life (HRQoL). The aim of this systematic literature review was to explore the impact of SCLC on HRQoL and the patient reported outcomes (PROs) used to capture this impact. Methods: We conducted a systematic search of Medline®, Embase, and PsycINFO, oncology organization websites and conference proceedings within the past 10 years. Articles reporting HRQoL outcomes of SCLC patients were selected. Results: Twenty-seven eligible publications were identified. Global or overall impact on HRQoL (n = 21) was reported most often, with considerably fewer reporting individual domains that comprise HRQoL. Results indicated that HRQoL was negatively impacted in SCLC patients in comparison to the normal population in most domains. Overall, the domains measuring physical functioning and activities of daily living were most impacted. However, results on cognitive and emotional functioning were inconclusive. The impact on HRQoL may be least in both limited disease and extensive disease (ED) SCLC patients who have responded to treatment, and greatest in ED patients who were treatment naïve. The most frequently used PROs were the EORTC QLQ-C30 core cancer instruments, the lung cancer specific module the EORTC QLQ-LC13, LCSS, and EQ-5D. Conclusion: There exists a paucity of reporting on SCLC HRQoL outcomes. This extends to the reporting of domain level scores and by patient sub-group. Greater reporting at a granular level is recommended to allow for more robust conclusions to be made.

Measuring Health-Related Quality of Life in Tuberous Sclerosis Complex – Psychometric Evaluation of Three Instruments in Individuals With Refractory Epilepsy

Tuberous sclerosis complex (TSC) is a rare genetic disease associated with significant disease burden and considerable impact on health-related quality of life (HRQL). Currently no disease-specific clinical outcome assessments evaluate HRQL in individuals with TSC. A multi-center phase III study EXIST-3 (NCT01713946) assessed the efficacy and safety of two trough exposure ranges (Low exposure, LE: 3–7 ng/mL and high exposure, HE: 9–15 ng/mL) of adjunctive everolimus in patients aged 2–65 years with TSC and refractory partial-onset seizures (N = 366). Three age-specific HRQL measures were included as secondary endpoints including: quality of life in childhood epilepsy (QOLCE; caregiver-report for aged 2- < 11), the Quality of Life in Epilepsy Inventory for Adolescents-48 (QOLIE-AD-48; self-report, aged ≥ 11- < 18), and the Quality of Life in Epilepsy Inventory-31-Problems (QOLIE-31-P; self-report, aged ≥ 18). Intellectual ability was evaluated using the Wechsler Non-Verbal (WNV) Scale of Ability. Post hoc analyses were performed on the core phase primary data from EXIST-3 to evaluate the psychometric properties of the HRQL measures and calculate meaningful change estimates. Results showed that a significant subset of the trial sample (4–21 year olds) scored in the intellectual disability range, as assessed by the WNV. Psychometric analyses of the three epilepsy measures (including reliability, validity, and ability to detect change) supported the appropriateness for use in TSC. Distribution-based meaningful change estimates were generated for each HRQL measure, with estimates for the QOLIE-31-P total score largely consistent with the published literature. To our knowledge, this is the first evaluation using clinical trial data to establish the psychometric properties of the QOLCE, QOLIE-AD-48, and QOLIE-31-P for use in individuals with TSC. These findings increase confidence in the measures as valid and reliable for use in clinical trials and future research in patients with TSC.

Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057

BACKGROUND Nivolumab, a programmed death-1 inhibitor, prolonged overall survival and had a favourable safety profile versus docetaxel in previously treated patients with advanced non-squamous non-small cell lung cancer (NSCLC) in the phase III CheckMate 057 trial. AIM To evaluate health-related quality of life (HRQoL) using patient-reported outcomes. METHODS Disease-related symptoms and general health status were assessed using two validated patient-reported instruments, the Lung Cancer Symptom Scale (LCSS) and the European Quality of Life Five Dimensions (EQ-5D), respectively. The proportion of patients with disease-related symptom improvement at 12 weeks on the LCSS average symptom burden index (ASBI) was a secondary end-point. LCSS 3-item global index (3-IGI), EQ-5D utility index and EQ-5D visual analogue scale (VAS) scores were also determined. Mixed-effects model repeated measures (MMRM) and time to first deterioration analyses assessed longitudinal changes. RESULTS Mean baseline LCSS ASBI scores were similar in both arms. By week 12, rates of disease-related improvement (95% confidence interval) were similar between nivolumab (17.8% [13.6-22.7]) and docetaxel (19.7% [15.2-24.7]); however, numerical differences in LCSS ASBI mean change from baseline favoured nivolumab. Subsequently, LCSS ASBI scores improved with nivolumab and worsened with docetaxel, with statistically significant between-arm differences at weeks 12, 24, 30 and 42. HRQoL improvements with nivolumab versus docetaxel were also supported by the LCSS 3-IGI, EQ-5D VAS and MMRM analysis. Time to first HRQoL deterioration was longer with nivolumab than with docetaxel. CONCLUSION Nivolumab improved disease-related symptoms and overall health status versus docetaxel for second-line treatment of advanced non-squamous NSCLC. CLINICAL TRIAL REGISTRATION NCT01673867.

Association between Health-Related Quality of Life and Medication Adherence in Pulmonary Tuberculosis in South Africa

Background: Health-related quality of life (HRQOL) and adherence to treatment are two often inter-related concepts that have implications for patient management and care. Tuberculosis (TB) and its treatment present a major public health concern in South Africa. The study aimed to evaluate the association between HRQOL and adherence in TB patients in South Africa. Methods: Four self-reported HRQOL and one self-reported adherence measures were used in an observational longitudinal multicentre study during 6-month standard TB treatment. These included the generic Short-Form 12 items (SF-12) and European Quality of Life 5 dimensions 5 levels (EQ-5D-5L), the disease-specific St. Georges Respiratory Questionnaire (SGRQ) and the condition-specific Hospital Anxiety and Depression Scale (HADS) for HRQOL. Adherence was measured by the Morisky Medication Adherence Scale 8 items (MMAS-8). The relationship between both concepts was examined in 131 patients using Spearmans rho correlations, and linear regression models. Results: HRQOL improved over 6-month TB treatment, whereas adherence mean scores stayed constant with participants attaining a medium average level. Around 76% of patients reported to be high adherers and 24% were reporting a medium or low adherence. Associations between HRQOL and adherence were mainly weak. High adherence at treatment start was positively related to improvements in anxiety and depression after 6-month treatment. The overall improvement in pain and discomfort, and psychosocial health aspects over treatment time was positively, but weakly associated with adherence at 6 months of treatment. Conclusion: A positive relationship exists between adherence and HRQOL in TB in a South African setting, but this relationship was very weak, most likely because HRQOL is affected by a number of different factors and not limited to effects of adherence. Therefore, management of TB patients should, besides adequate drug treatment, address the specific mental and psychosocial needs.

P2.46 (also presented as PD1.01): LCSS as a Marker of Treatment Benefit With Nivolumab vs Docetaxel in Pts With Advanced Non-Squamous NSCLC From Checkmate 057:Track: Immunotherapy

Richard J. Gralla, David Spigel, Bryan Bennett, Fiona Taylor, John R. Penrod, Michael Derosa, Homa Dastani, Lucinda Orsini, Clarissa Mathias, Martin Reck Albert Einstein College of Medicine, Bronx/NY/UNITED STATES OF AMERICA, Sarah Cannon Research Institute, Nashville/TN/UNITED STATES OF AMERICA, Adelphi Values, Boston/MA/UNITED STATES OF AMERICA, Bristol-Myers Squibb, Princeton/NJ/ UNITED STATES OF AMERICA, Núcleo de Oncologia da Bahia, Salvador/BRAZIL, Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf/ GERMANY