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In ASCEMBL, an open-label, randomized Phase 3 study, asciminib demonstrated superior efficacy and better safety profile compared with bosutinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors. Health-related quality of life (HRQOL) reported by patients is key to understanding the benefit and impact of treatment on patients’ lives, and is becoming increasingly important as the life expectancy of CML-CP patients increases and patients require long-term treatment. In ASCEMBL, patients completed questionnaires to assess CML symptoms and interference with daily life (M.D. Anderson Symptom Inventory – CML [MDASI-CML]), general HRQOL (five-level EQ-5D [EQ-5D-5L], Patient Global Impression of Change – CML [PGIC-CML]), and impact of CML on working life and activity (Work Productivity and Activity Impairment questionnaire – CML [WPAI-CML]). Patients’ CML symptoms and HRQOL remained stable during 48 weeks of treatment with asciminib, with a general trend for decreased CML symptom severity, particularly for fatigue, and improvement in HRQOL. A clinically meaningful increase in diarrhea severity was observed in patients treated with bosutinib compared to asciminib. These data provide better understanding of the patient perspective and treatment impact on HRQOL in a later-line setting, where little information has been published to date.

Objective: In CheckMate 743 (NCT02899299), nivolumab + ipilimumab significantly prolonged overall survival in patients with unresectable malignant pleural mesothelioma (MPM). We present patient-reported outcomes (PROs). Materials and Methods: Patients (N = 605) were randomized to nivolumab + ipilimumab or chemotherapy. Changes in disease-related symptom burden and health-related quality of life (HRQoL) were evaluated descriptively using the Lung Cancer Symptom Scale (LCSS)-Mesothelioma (Meso) average symptom burden index (ASBI), LCSS-Meso 3-item global index (3-IGI), 3-level EuroQol 5-dimensional (EQ-5D-3L) visual analog score (VAS), and EQ-5D-3L utility index. PROs were assessed at baseline and every 2 (nivolumab + ipilimumab) or 3 weeks (chemotherapy) through 12 weeks, every 6 weeks through 12 months, every 12 weeks thereafter, and at specified follow-ups. Mixed-effect model repeated measures (MMRM) and time to deterioration analyses were conducted. Results: Completion rates were generally > 80%. LCSS-Meso ASBI mean changes from baseline trended to improve over time with nivolumab + ipilimumab and deteriorate with chemotherapy, but did not meet clinically important difference thresholds [& PLUSMN;10 score change]. EQ-5D-3L VAS mean scores improved over time with nivolumab + ipilimumab; by week 60, patients had scores consistent with United Kingdom normal population values. MMRM analyses favored nivolumab + ipilimumab for all individual symptoms except cough. Nivolumab + ipilimumab delayed time to definitive deterioration in HRQoL (hazard ratio 0.52 [95% confidence interval 0.36-0.74]) and showed a trend in symptom delay versus chemotherapy. Conclusions: Nivolumab + ipilimumab decreased the risk of deterioration in disease-related symptoms and HRQoL versus chemotherapy and maintained QoL in patients with unresectable MPM.

BackgroundPublished in 2019, a new addendum to the ICH E9 guideline presents the estimand framework as a systematic approach to ensure alignment among clinical trial objectives, trial execution/conduct, statistical analyses, and interpretation of results. The use of the estimand framework for describing clinical trial objectives has yet to be extensively considered in the context of patient-reported outcomes (PROs). We discuss the application of the estimand framework to PRO objectives when designing clinical trials in the future, with a focus on PRO outcomes in oncology trial settings as our example.MainWe describe the components of an estimand and take a naïve PRO trial objective to illustrate how to apply attributes described in the estimand framework to inform construction of a detailed clinical trial objective and its related estimand. We discuss identifying potential post-randomization events that alter the interpretation of the endpoint or render its observation impossible (also defined as intercurrent events) in the context of PRO endpoints, and the implications of how to handle intercurrent events in the construction of the PRO objective. Using a simple objective statement,“What is the effect of treatment X on patient’s quality of life?”,we build up an example estimand statement and also use a previously published phase III oncology clinical trial to illustrate how an estimand for a PRO objective could have been written to align to the estimate framework.ConclusionThe use of the estimand framework, as described in the new ICH E9 (R1) addendum guideline will become a key common framework for developing clinical trial objectives for evaluating effects of treatment. In the context of considering PROs, the framework provides an opportunity to more precisely specify and build the rationale for patient-focused objectives. This will help to ensure that clinical trials used for registration are designed and analysed appropriately, enabling all stakeholders to accurately interpret conclusions about the treatment effects for patient-focused outcomes.

262 Background: This analysis evaluated HRQoL as exploratory endpoints in CheckMate 648, a randomized, open-label, global Phase 3 study, evaluating treatment with N+I, N+CT and CT alone in inoperable advanced, recurrent, or metastatic ESCC. Methods: The effects of N+I vs N+CT vs CT on HRQoL were assessed using the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) (including the GP5 item to assess impact of side effects) and EQ-5D-3L. A mixed model for repeated measures was used to evaluate longitudinal changes from baseline (BL) and differences between treatment groups. Comparison of the risk of being bothered by the side effects of treatment was estimated for the GP5 using generalized estimating equation (GEE). Time to confirmed deterioration (TTCD) was assessed using Kaplan-Meier plots along with Cox proportional hazard models. Analyses were conducted on both the all-randomized population and the subset of patients with PD-L1 expression ≥1%. Results: 970 pts were randomized 1:1:1 to N+I (n=325), N+CT (n=321), or CT (n=324). 90% of pts completed both a BL and at least one on-treatment assessment and were included in the PRO analysis population. FACT-E (all randomized pts). Study showed similar BL scores across all 3 treatment groups. Changes from BL showed a trend towards better HRQoL for pts treated with N+I and N+CT compared to CT alone, however these results were not statistically significant. Patients treated with N+I had significantly decreased risk of experiencing bother associated with the side effects of treatment than patients treated with either N+CT or CT. TTCD analysis demonstrated delayed deterioration for pts treated with N+CT vs CT. Findings for PD-L1 ≥1% subpopulation were similar to all randomized pts. Conclusions: In pts with inoperable advanced, recurrent, or metastatic ESCC, HRQoL is maintained throughout treatment with N+I and N+CT. Trends towards better HRQoL and decreased risk of deterioration were observed with N+I and N+CT compared to CT alone. Clinical trial information: NCT03143153. [Table: see text]

Objectives This study developed, and established the content validity, of a conversation aid tool (CAT) for use in clinical practice with renal cell carcinoma (RCC) patients who receive a curative nephrectomy and are at high-risk of recurrence. The CAT was pilot tested in a sample of RCC patients to establish whether the CAT increases knowledge of RCC, treatment options (such as adjuvant therapy), and care options. Methods A cross-sectional, mixed methods design was used involving initial, exploratory interviews with RCC patients, RCC specialists and a steering group. Further content validation interviews were conducted with RCC patients and specialists. A web-based survey was conducted with RCC patients (N = 60), to compare the CAT versus a standard of care (SOC) consultation comparator tool on patient knowledge. Results Findings from exploratory interviews were used to develop the CAT. Content validation interviews demonstrated that the CAT was well understood and relevant to RCC patients. The web-based survey demonstrated that viewing the CAT significantly improved participants knowledge of RCC, and care options, when compared to the SOC. Conclusion The findings highlight that the CAT is a relevant, comprehensive and well-understood tool for use in the post-nephrectomy consultation. Practice implications Use of the CAT may increase patient knowledge of RCC and care options.

In drug development, we ask ourselves which population, endpoint and treatment comparison should be investigated. In this context, we also debate what matters most to the different stakeholders that are involved in clinical drug development, for example, patients, physicians, regulators and payers. With the publication of draft ICH E9 addendum on estimands in 2017, we now have a common framework and language to discuss such questions in an informed and transparent way. This has led to the estimand discussion being a key element in study development, including design, analysis and interpretation of a treatment effect. At an invited session at the 2018 PSI annual conference, PSI hosted a role-play debate where the aim of the session was to mimic a regulatory and payer scientific advice discussion for a COPD drug. Including role-play views from an industry sponsor, a patient, a regulator and a payer. This paper presents the invented COPD case-study design and considerations relating to appropriate estimands are discussed by each of the stakeholders from their differing viewpoints with the additional inclusion of a technical (academic) perspective. The rationale for each perspective on approaches for handling intercurrent events is presented, with a key emphasis on the application of while-on-treatment and treatment policy estimands in this context. It is increasingly recognised that the treatment effect estimated by the treatment policy approach may not always be of primary clinical interest and may not appropriately communicate to patients the efficacy they can expect if they take the treatment as directed.

Background: In the phase I I I CheckMate 227 s tudy, fi r s t - l ine nivolumab þ ipilimumab significantly prolonged progression-free survival (co-primary endpoint) versus chemotherapy in patients with advanced nonesmall-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; 10 mutations/megabase). Aim: To evaluate patient-reported outcomes (PROs) in this population. Methods: Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ- 5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. Results: In the high TMB population, PRO questionnaire completion rates were w90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab þ ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab þ ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab þ ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4e22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab þ ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures. Conclusion: First-line nivolumab þ ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB, This work was supported by Bristol-Myers Squibb and Ono Pharmaceutical

9568 Background: The TFI after discontinuation of study therapy has been reported to be longer with NIVO+IPI compared to NIVO or IPI alone, but QoL during the TFI has not been reported in advanced melanoma (MEL) studies. 1-y data from CheckMate (CM) 067 showed maintenance of QoL after treatment (tx) discontinuation with NIVO or NIVO+IPI. Here, we present long-term QoL results from CM 067 during the TFI (period off study tx and free of subsequent therapy), based on an updated 4-y dataset. Methods: In CM 067, 945 pts were randomized 1:1:1 to receive NIVO 3 mg/kg + placebo; NIVO 1 mg/kg + IPI 3 mg/kg × 4, then NIVO 3 mg/kg; or IPI 3 mg/kg × 4 + placebo. Patient-reported outcomes (PRO) were collected using the EORTC QLQ-C30 (5 functional domains, 9 symptoms, global health status) and EQ-5D-3L (utility index, visual analog scale) at baseline, on-tx visits, and follow-up (FU) visits 1 (FU1; 30 d after last dose) and 2 (FU2; 84 d after FU1). EQ-5D-3L was also collected at survival FU visits every 3 mo after FU2 in the first year and every 6 mo thereafter. Within the PRO analysis population, 480 of 764 pts who discontinued protocol tx (for any reason, including drug toxicity; n = 155) had PRO scores, collected prior to initiation of subsequent anticancer therapy, evaluated. Mean changes in PRO scores from last on-tx visit were reported for each FU visit. Results: Across tx arms, PRO scores were maintained from last on-tx visit to FU1 or FU2 for pts who discontinued for any reason. EORTC QLQ-C30 functional and symptom scales remained stable during the TFI. Among pts who discontinued tx due to toxicity, clinically meaningful deterioration in QoL was observed in a few subscales at FU1, but QoL was restored to the same level as the last on-tx visit in all except one subscale by FU2. PRO scores remained stable beyond FU2 for the EQ-5D-3L, regardless of reason for discontinuation. Data interpretation at later FU visits was limited due to smaller sample sizes. Sensitivity analyses for mean change in PRO scores from randomization to FU visits will be presented. Conclusions: QoL was maintained during the TFI, compared to last on-tx visit, in pts with MEL treated with NIVO or NIVO+IPI.

9551 Background: Early CheckMate 067 data showed maintenance of QoL in patients with advanced melanoma treated with NIVO with or without IPI based on 1-year data; however, the long-term QoL of these patients has not been evaluated previously. The patient-reported outcomes (PRO) analyses presented here for CheckMate 067 is the first time QoL results have been evaluated in this melanoma population over a 4-year period. Methods: In CheckMate 067, 945 patients were randomized 1:1:1 to receive NIVO (3mg/kg Q2W) + placebo (PBO), NIVO+IPI (1mg/kg+3mg/kg Q3W X 4) followed by NIVO (3mg/kg Q2W), or IPI (3mg/kg Q3W X 4) + PBO. PRO data were collected using the EORTC QLQ-C30 (5 functional domains, 9 symptoms, global health status) and EQ-5D-3L (utility index, VAS) at baseline, weeks 1 and 5 of each 6-week tx cycle, and off-tx follow-up (FU) visits. Mean changes in PRO scores from baseline (randomization) were evaluated descriptively for the PRO analysis population, with conclusions drawn from time points with ≥30 patients completing assessments per tx arm. Least square mean changes from baseline were assessed using a longitudinal mixed model analysis adjusting for repeated measures, including all on-tx data for patients. Results: Completion rates at baseline ranged from 89-92% across tx arms. Of 813 patients included in the PRO analysis population (278 NIVO, 274 NIVO+IPI, 261 IPI), > 200 receiving tx remained for the first year, > 100 receiving tx remained after 2 years, and > 50 receiving tx remained after 3 years. QoL, including assessment of functioning and symptom burden, was maintained for the duration of tx and in FU, with no sustained clinically meaningful deterioration in any tx arm. Global health status (EORTC QLQ-C30) and general QoL (EQ-5D-3L VAS) were also maintained during prolonged tx. Overall, results from the mixed model analysis support the long-term maintenance of QoL over the course of tx. Conclusions: Patient-reported QoL and symptoms in patients with advanced melanoma were maintained from baseline during extended tx with NIVO with or without IPI. Clinical trial information: NCT01844505.

Summary Background New evidence has suggested that people with asthma who are homozygous for arginine at aminoacid 16 of the β 2 -adrenergic receptor (ADRB2) might not benefit from longacting β 2 -agonist therapy. We, therefore, investigated whether ADRB2 polymorphisms affect response to longacting β 2 -agonists in combination with inhaled corticosteroids. Methods Asthmatics were stratified by ADRB2 genotype in two studies to assess the effects of inhaled corticosteroids plus longacting β 2 -agonists on asthma exacerbations. In study 1 (double-blind), 2250 asthmatics were randomly assigned to budesonide plus formoterol maintenance and reliever therapy, fixed-dose budesonide plus formoterol, or fixed-dose fluticasone plus salmeterol for 6 months. Study 2 (open-label) consisted of 405 asthmatics and compared an adjustable regimen of budesonide plus formoterol with fixed-dose budesonide plus formoterol and fixed-dose fluticasone plus salmeterol for 7 months. The relation between ADRB2 polymorphism, severe asthma exacerbations, and other asthma outcomes was analysed. Primary endpoints for studies 1 and 2 were severe asthma exacerbation and asthma control as assessed by measures of exacerbations, respectively. Findings In study 1, Gly16Arg genotype had no effect on the percentage of participants with severe exacerbations across all treatment groups (99 [12%] of 833 Gly/Gly, 110 [11%] of 1028 Gly/Arg, and 32 [9%] of 361 Arg/Arg participants). Secondary endpoints, including forced expiratory volume in 1 s, peak expiratory flow, use of as-needed medication, and number of nights with awakenings were similar between genotype groups. No relation was recorded between ADRB2 haplotype and primary and secondary endpoints. In study 2, the frequency of asthma exacerbations (15 [9%] of 168 Gly/Gly, 13 [8%] of 169 Gly/Arg, and 6 [9%] of 67 Arg/Arg participants) and other study endpoints were closely similar for all ADRB2 genotypes. Interpretation Since we showed no pharmacogenetic effect of ADRB2 variation on therapeutic response in asthma, patients, irrespective of their genotype, can continue to receive inhaled corticosteroids plus longacting β 2 -agonists.

Background Evidence suggests that variation in the length of the poly-C repeat in the 3′ untranslated region (3′UTR) of the β2-adrenergic receptor gene (ADRB2) may contribute to interindividual variation in β-agonist response. However, methodology in previous studies limited the assessment of the effect of sequence variation in the context of poly-C repeat length. The objectives of this study were to design a novel genotyping method to fully characterize sequence variation in the ADRB2 3′UTR poly-C repeat in asthma patients treated with inhaled corticosteroid and long-acting β2-adrenergic agonist (ICS/LABA) combination therapy, and to analyze the effect of the poly-C repeat polymorphism on clinical response. Methods In 2,250 asthma patients randomized to treatment with budesonide/formoterol or fluticasone/salmeterol in a six-month study (AstraZeneca study code: SD-039-0735), sequence diversity in the ADRB2 poly-C repeat region was determined using a novel sequencing-based genotyping method. The relationship between the poly-C repeat polymorphism and the incidence of severe asthma exacerbations, and changes in pulmonary function and asthma symptoms from baseline to the average during the treatment period, were analyzed. Results Poly-C repeat genotypes were assigned in 97% (2,192/2,250) of patients. Of the 13 different poly-C repeat alleles identified, six alleles occurred at a frequency of >5% in one or more population in this study. The repeat length of these six common alleles ranged from 10 to 14 nucleotides. Twelve poly-C repeat genotypes were observed at a frequency of >1%. No evidence of an association between poly-C repeat genotype and the incidence of severe asthma exacerbations was observed. Patients’ pulmonary function measurements improved and asthma symptoms declined when treated with ICS/LABA combination therapy regardless of poly-C repeat genotype. Conclusions The extensive sequence diversity present in the poly-C repeat region of the ADRB2 3′UTR did not predict therapeutic response to ICS/LABA therapy.

Udgivelsesdato: 2009-Aug The platelet P2Y(12) receptor is the target of clopidogrel therapy, which has been shown to reduce thromboembolic complications of atherosclerotic disease but has limitations in terms of variability of response and irreversibility of effect. This receptor is also a target for ticagrelor (AZD6140), the first reversibly binding oral P2Y(12) receptor antagonist that does not require metabolic activation and yields more consistent inhibition of platelet aggregation than clopidogrel therapy. Single nucleotide polymorphisms (SNPs) have been described in the gene for this receptor (P2RY12), some of which have been associated with variability in platelet reactivity. SNPs in P2RY1 and ITGB3 have also been reported by some groups to affect platelet reactivity to adenosine diphosphate (ADP). We assessed whether SNPs in these genes influenced the pharmacodynamic response to ticagrelor in patients enrolled in both the DISPERSE study (stable atherosclerotic disease) and the DISPERSE2 study (non-ST-segment elevation acute coronary syndromes). Platelet aggregation data (at baseline and 4 weeks) and DNA samples from clopidogrel-naive Caucasian patients treated with ticagrelor were available for 151 patients. Seventy four SNPs within three genes were genotyped. After adjustment for multiple comparisons, none of these SNPs were found to significantly influence inhibition of ADP-induced platelet aggregation by ticagrelor.

Using the North American Rheumatoid Arthritis Consortium (NARAC) candidate gene and genome-wide single-nucleotide polymorphism (SNP) data sets, we applied regression methods and tree-based random forests to identify genetic associations with rheumatoid arthritis (RA) and to predict RA disease status. Several genes were consistently identified as weakly associated with RA without a significant interaction or combinatorial effect with other candidate genes. Using random forests, the tested candidate gene SNPs were not sufficient to predict RA patients and normal subjects with high accuracy. However, using the top 500 SNPs, ranked by the importance score, from the genome-wide linkage panel of 5742 SNPs, we were able to accurately predict RA patients and normal subjects with sensitivity of approximately 90% and specificity of approximately 80%, which was confirmed by five-fold cross-validation. However, in a complete training-testing framework, replication of genetic predictors was less satisfactory; thus, further evaluation of existing methodology and development of new methods are warranted.