Patient-reported Outcomes Endpoints Research Articles

PROpwr: a Shiny R application to analyze patient-reported outcomes data and estimate power

ABSTRACT Patient Reported Outcomes (PROs) are widely used in quality of life (QOL) studies, health outcomes research, and clinical trials. The importance of PRO has been advocated by health authorities. We propose this R shiny web application, PROpwr, that estimates power for two-arm clinical trials with PRO measures as endpoints using Item Response Theory (GRM: Graded Response Model) and simulations. PROpwr also supports the analysis of PRO data for convenience of estimating the effect size. There are seven function tabs in PROpwr: Frequentist Analysis, Bayesian Analysis, GRM power, T-test Power Given Sample Size, T-test Sample Size Given Power, Download, and References. PROpwr is user-friendly with point-and-click functions. PROpwr can assist researchers to analyze and calculate power and sample size for PRO endpoints in clinical trials without prior programming knowledge.

Datopotamab deruxtecan (Dato-DXd) vs chemotherapy (CT) in previously treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Patient-reported outcomes (PROs) from the TROPION-Breast01 study.

1006 Background: In the primary analysis of the Phase 3 TROPION-Breast01 study (NCT05104866), Dato-DXd showed a statistically significant and clinically meaningful improvement in progression-free survival vs investigator’s choice of CT (ICC) (HR 0.63 [95% CI 0.52‒0.76]; p<0.0001) (Bardia et al, ESMO 2023). Here we report PROs from TROPION-Breast01. Methods: Patients with inoperable or metastatic HR+/HER2‒ BC, with disease progression on endocrine therapy and for whom endocrine therapy was unsuitable and who had received 1‒2 prior lines of systemic CT, were randomized 1:1 to Dato-DXd (6 mg/kg Q3W, n=365) or ICC (eribulin/vinorelbine/capecitabine/gemcitabine, n=367). PROs were measured at prespecified timepoints, including secondary PRO endpoints of time to deterioration (TTD) in global health status (GHS)/QoL, physical functioning, and pain based on EORTC QLQ-C30, and exploratory PRO endpoints based on additional questionnaires. Results: PRO questionnaire compliance was 82.5% at baseline in both arms and remained similar across arms over time. TTD was delayed in Dato-DXd vs ICC arms for all secondary endpoints. In an analysis of time to first deterioration (primary analysis), median TTD (HR [95% CI]) in GHS/QoL was 3.4 vs 2.1 months (0.85 [0.68–1.06]), physical functioning was 5.6 vs 3.5 months (0.77 [0.61–0.99]), and pain was 3.5 vs 2.8 months (0.85 [0.68–1.07]); in an analysis of time to confirmed deterioration (sensitivity analysis), median TTD in GHS/QoL was 9.0 vs 4.8 months (0.76 [0.58–0.98]), physical functioning was 12.5 vs 6.2 months (0.77 [0.59–1.01]), and pain was 9.0 vs 5.5 months (0.72 [0.55–0.94]). The Table shows TTD in other selected functioning and symptom scales from EORTC. Patient-reported symptomatic AEs (measured by PRO-CTCAE and EORTC) were generally consistent with clinician-reported safety data, and patient-reported treatment tolerability (measured by PGI-TT) was comparable between arms. Conclusions: In TROPION-Breast01, TTD was delayed in the Dato-DXd vs ICC arms for GHS/QoL, physical functioning, pain, and most other symptoms and functioning scales. PRO data complement the improvement in efficacy and manageable safety profile demonstrated with Dato-DXd vs ICC in the primary analysis, supporting Dato-DXd as a potential new, well tolerated therapeutic option in this setting. Clinical trial information: NCT05104866 . [Table: see text]

Immunotherapy related patient-reported outcomes from five randomized controlled trials in patients with triple negative breast cancer: A systematic review.

e23167 Background: Immunotherapy (IO) has improved clinical outcomes in patients with early-stage Triple Negative Breast Cancer (TNBC) receiving neoadjuvant therapy and certain patient subsets in the metastatic setting. This study aims to evaluate IO-related Patient-Reported Outcomes (PRO) in patients older than 65 years. Methods: We searched Medline ALL (Ovid), Embase (Elsevier), Cochrane Central (Wiley), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform. The searches combined terms reflecting (1) the immune checkpoint inhibitors atezolizumab, durvalumab, and pembrolizumab; (2) breast cancer; and (3) randomized controlled trials. Results were limited to items published in English from 2013 through September 2023. We excluded review articles and clinical trial records without results. Two independent reviewers (C.S. and M.L.) screened the studies using the systematic review management tool Covidence, and conflicts were resolved by a third reviewer (W.I.Z.). We included studies that reported on PRO in adults with TNBC receiving any of the three immunotherapies of interest. Results: Five publications composed of two peer-reviewed papers and three abstracts were identified, including 3878 total patients and 3184 with PRO. Three pembrolizumab studies had 2643 total patients (2056 with PRO) and two atezolizumab studies (IMPASSION 130, IMPASSION 031) had 1235 total patients (1128 with PRO). The PRO analysis in KEYNOTE 522 included 1145 patients in the neoadjuvant phase and 847 in the adjuvant phase. The PRO analysis in KEYNOTE 355 included total 847 patients and 317 with Combined Positive Score (CPS) ≥10. No study specified PRO data for patients older than 65 years. Baseline completion rates for all studies were > 80%. All studies used standardized PRO instruments, including the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC- QLQ C30) and its Breast Cancer Module (QLQ-BR23), the Functional Assessment of Cancer-Therapy-General (FACT-G GP5), and the EuroQol-5 Dimension (EQ-D5). All studies showed no statistical difference, or clinical meaningful decline in PRO endpoints between patients who received chemo with IO versus chemo with placebo, during and post treatment follow up. The PRO analysis from KEYNOTE 119, which included total 594 patients of which 187 had CPS ≥10, demonstrated that patients receiving single agent chemotherapy had worse PROs related to systemic therapy side effects and hair loss while the pembrolizumab group had decreased worry about future health. None included subgroup analysis by age, including patients older than 65 years. Conclusions: Our systematic review demonstrates that in both early and advanced TNBC, IO did not worsen PRO. Prospective and retrospective data in IO-related PRO in older patient population are needed.

Abstract GS02-01: Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01

Abstract Background: The global, phase 3 TROPION-Breast01 trial (NCT05104866) assessed the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) compared with investigator’s choice of chemotherapy (ICC) in patients (pts) with inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2‒) breast cancer (BC). Primary results were presented at ESMO 2023 (Bardia A, et al. Abstract LBA11). Here we report expanded data from TROPION-Breast01. Methods: Pts aged ≥18 years who had inoperable or metastatic HR+/HER2‒ BC, had disease progression on endocrine therapy (ET) and for whom ET was unsuitable, and had received 1‒2 prior lines of systemic chemotherapy (CT), were eligible. Pts were randomized 1:1 to Dato-DXd (6 mg/kg Q3W) or ICC (eribulin, vinorelbine, capecitabine, or gemcitabine) until progression or unacceptable toxicity. The dual primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1, and overall survival (OS). Results: In total, 732 pts were randomized: 365 to the Dato-DXd arm and 367 to ICC. At data cut-off (Jul 17, 2023), 93/39 pts in the Dato-DXd/ICC groups were ongoing treatment. Pts receiving Dato-DXd had significantly improved PFS vs ICC (HR 0.63 [95% CI 0.52‒0.76]; p<0.0001). Hazard ratios for PFS favored Dato-DXd over ICC across prespecified pt subgroups, including prior lines of CT in the metastatic setting (1 vs 2), prior use of CDK4/6 inhibitor (≤12 months vs >12 months), prior use of endocrine therapy in the metastatic setting ( <6 months vs ≥6 months) and brain metastases (yes vs no). OS data were not mature at this data cut-off. In the Dato-DXd vs ICC arms, 192 (53%) vs 247 (67%) pts had received a subsequent therapy after study treatment discontinuation, including 15 (4%) vs 52 (14%) who received subsequent ADC therapy, and 165 (45%) vs 186 (51%) who received subsequent CT. Median time to first subsequent therapy was 8.2 months in the Dato-DXd arm vs 5.0 months in the ICC arm (HR 0.53 [95% CI 0.45–0.64). Overall, rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was less than half that with ICC. The secondary patient-reported outcome endpoints showed that time to deterioration in physical functioning, pain, and global health status/quality of life were delayed in the Dato-DXd arm compared with ICC. Conclusions: TROPION-Breast01 met its dual primary endpoint of PFS, demonstrating statistically significant and clinically meaningful improvement in PFS with Dato-DXd compared with ICC across all subgroups. Overall, the safety profile and QoL with Dato-DXd was favorable compared with ICC. These data support Dato-DXd as a potential new therapeutic option for pts with inoperable or metastatic HR+/HER2‒ BC who have received 1‒2 prior lines of CT. Citation Format: Aditya Bardia, Komal Jhaveri, Seock-Ah Im, Michelino De Laurentiis, Binghe Xu, Sonia Pernas, Giuliano Borges, David Cescon, Masaya Hattori, Yen-Shen Lu, Noelia Martínez-Jáñez, Erika Hamilton, Shusen Wang, Junji Tsurutani, Kevin Kalinsky, Lu Xu, Sabrina Khan, Neelima Denduluri, Hope Rugo, Barbara Pistilli. Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-01.

Towarda more patient-centered drug development process in clinical trials for patients with myelodysplastic syndromes/neoplasms (MDS): Practical considerations from the International Consortium for MDS (icMDS).

Notable treatment advances have been made in recent years for patients with myelodysplastic syndromes/neoplasms (MDS), and several new drugs are under development. For example, the emerging availability of oral MDS therapies holds the promise of improving patients' health-related quality of life (HRQoL). Within this rapidly evolving landscape, the inclusion of HRQoL and other patient-reported outcomes (PROs) is critical to inform the benefit/risk assessment of new therapies or to assess whether patients live longer and better, for what will likely remain a largely incurable disease. We provide practical considerations to support investigators in generating high-quality PRO data in future MDS trials. We first describe several challenges that are to be thoughtfully considered when designing an MDS-focused clinical trial with a PRO endpoint. We then discuss aspects related to the design of the study, including PRO assessment strategies. We also discuss statistical approaches illustrating the potential value of time-to-event analyses and their implications within the estimand framework. Finally, based on a literature review of MDS randomized controlled trials with a PRO endpoint, we note the PRO items that deserve special attention when reporting future MDS trial results. We hope these practical considerations will facilitate the generation of rigorous PRO data that can robustly inform MDS patient care and support treatment decision-making for this patient population.

Tislelizumab versus Sorafenib in First-Line Treatment of Unresectable Hepatocellular Carcinoma: Impact on Health-Related Quality of Life in RATIONALE-301 Study

Introduction: RATIONALE-301 (NCT03412773) was a global, phase 3 study comparing the efficacy and safety of tislelizumab with sorafenib as first-line (1L) treatment in adult patients with unresectable hepatocellular carcinoma (HCC) that met its primary endpoint of noninferiority in overall survival (OS). This analysis compared health-related quality-of-life (HRQOL) outcomes between the arms. Methods: Systemic therapy-naive adults with HCC were randomized 1:1 to receive tislelizumab (n = 342) or sorafenib (n = 332). HRQOL was assessed using EORTC QLQ-C30, QLQ-HCC18, and EQ-5D-5L. At cycles 4 and 6, a mixed model for repeated measures was performed using key-prespecified patient-reported outcome (PRO) endpoints of the QLQ-C30 and the QLQ-HCC18. Time to deterioration was analyzed with the Kaplan-Meier method using the PRO endpoints. Results: At cycles 4 and 6, patients in the tislelizumab arm had better HRQOL outcomes than the patients in the sorafenib arm per mean-change difference in GHS/QOL, QLQ-C30 physical functioning and fatigue, and QLQ-HCC18 symptom index; however, no differences for pain were observed. Patients in the tislelizumab arm had lower risk of deterioration in GHS/QOL (HR: 0.68; 95% CI: 0.49–0.94), QLQ-C30 physical functioning (HR: 0.45; 95% CI: 0.32–0.63) and fatigue (HR: 0.47; 95% CI: 0.36–0.61), QLQ-HCC18 symptom index (HR: 0.52; 95% CI: 0.34–0.81), and HCC-specific fatigue (HR: 0.59; 95% CI: 0.45–0.79). For pain, both arms had similar risk of deterioration (HR: 0.78; 95% CI: 0.56–1.09). At cycles 4 and 6, patients in the tislelizumab arm maintained in EQ-5D-5L visual analog scale, whereas scores decreased for the patients in the sorafenib arm. Conclusion: Patients with 1L HCC treated with tislelizumab had favorable HRQOL outcomes compared with patients treated with sorafenib, particularly in fatigue and physical functioning. These results, along with favorable safety profile, better response rate, and OS noninferiority, support tislelizumab as a potential 1L treatment option for unresectable HCC.

Characteristics and use of patient-reported outcomes of clinical trials for high-risk neurological medical devices that received FDA premarket approval from 2001 to 2022

Neurological medical devices have revolutionized the management of neurological disorders, providing diagnostic, therapeutic, and monitoring solutions. High-risk neurological devices, such as deep brain stimulation and neurostimulators, offer groundbreaking treatments, emphasizing patient benefits while considering risks. To gain FDA approval, high-risk Class III devices necessitate premarket approval (PMA) applications with pivotal clinical trials, often assessing patient-reported outcomes (PROs). This article analyzes FDA-approved high-risk neurological devices from 2001 to 2022 via the PMA pathway. It explores device characteristics and pivotal clinical trials, and PRO incorporation. Of the 23 identified devices, pain neurology devices (30.4 %) predominated. All devices were therapeutic, with varying study designs. Pain neurology devices notably emphasized PRO endpoints as expected. This study underscores the significance of PROs in assessing device efficacy and safety, offering insights into regulatory processes and patient-centered care in neurological disorder management.

Improvement of Patient-Reported Outcomes Among Heavily Pretreated Patients with Lower-Risk Myelodysplastic Syndromes and High Transfusion Burden Treated with Imetelstat on the IMerge Phase 3 Trial

CONCLUSIONS Transfusion-dependent anemia and related fatigue are commonly associated with lower-risk myelodysplastic syndromes (LR-MDS) and frequently not improved with therapy. Patients with symptoms associated with anemia have an impaired quality of life and inferior overall survival. In IMerge (NCT02598661), the phase 3, randomized, global trial of patients with LR-MDS and a red blood cell transfusion burden of ≥4 U, imetelstat-treated patients had a significantly higher transfusion independence rate than those treated with placebo and showed sustained improvement in patient-reported fatigue via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (Sekeres et al. EHA 2023. P732). Here, we assess the impact of imetelstat on several patient-reported outcomes (PROs) relevant to LR-MDS. Functional Assessment of Cancer Therapy-Anemia (FACT-An; 55 items) and Quality of Life in Myelodysplasia Scale (QUALMS; 38 items) were the main questionnaires used. Analyses included symptom-specific derived scores for the following parameters: dyspnea, measured by 1 FACT-An and 1 QUALMS item; physical function and systemic symptoms, by 3 FACT-An items each; pain, by 2 FACT-An items; and bleeding, by 1 QUALMS item. Higher scores indicated improvement. QUALMS total score and physical burden score were also analyzed. Psychometric analyses were conducted using blinded interim data to document the measurement properties of these item sets and define the scores that would be used to specify PRO end points in IMerge; all analyses were exploratory and were conducted in the intention-to-treat (ITT) population. The overall effect of imetelstat on each score was evaluated from the repeated measurement mixed model (RMMM) comparing the least-squares means (LSMs) of change in score estimated in the 2 treatment groups using all available data while on treatment up to cycle 30. A positive mean change in the dyspnea score was observed throughout the treatment, up to cycle 24, in the imetelstat group but not in the placebo group (Figure). The RMMM analysis showed an overall change in dyspnea score from baseline of 0.53 (by LSM with 95% CI, 0.241-0.825) with imetelstat versus −0.40 (by LSM with 95% CI, −0.794 to 0.003) with placebo, with a significant difference between the treatment groups (LSM difference, 0.93; 95% CI, 0.446-1.411; P < .001; Table). The model-based mean change estimates for each score showed that, despite having high transfusion burden at baseline, patients in the imetelstat group did not experience more deterioration in any of the other outcomes than those in the placebo group (Table). In addition, the QUALMS composite scores suggested significantly improved health outcomes with imetelstat versus placebo based on RMMM. LSM difference was 4.66 (95%CI, 0.862-8.461; P = .016) and 6.34 (95% CI, 1.771-10.913; P = .007) for QUALMS total and QUALMS physical burden, respectively (Table). Findings from multiple validated PRO questionnaires consistently show that patients with red blood cell transfusion-dependent LR-MDS enrolled into the IMerge randomized trial who were treated with imetelstat reported improved fatigue, dyspnea, and QUALMS composite scores (total and physical burden) compared with those in the placebo group. These data indicate that, in addition to improving transfusion burden in patients with LR-MDS, imetelstat targets multiple core symptoms of LR-MDS simultaneously, also improving PROs.

Health-Related Quality of Life (HRQoL) in Patients with Relapsed/Refractory Follicular Lymphoma (R/R FL) Treated with Zanubrutinib+ Obinutuzumab Versus Obinutuzumab Monotherapy: The Rosewood Trial

Introduction: Zanubrutinib is a potent and highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target effects. In the phase 2 ROSEWOOD study (NCT03332017), zanubrutinib plus obinutuzumab (ZO) demonstrated superior efficacy and a manageable safety profile compared with obinutuzumab monotherapy (O) as treatment for patients with heavily pretreated R/R FL. Here, we report HRQoL outcomes from the ROSEWOOD trial. Methods: Patient-reported outcomes (PROs) were secondary endpoints and assessed using the European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients Questionnaire - C30 (EORTC QLQ-C30) and European Quality of Life 5-Dimensions 5-Levels (EQ-5D-5L). Patients completed questionnaires at baseline (cycle 1 day 1, before the first dose of study drug), then every 12 weeks for 2 years, every 24 weeks for the next 2 years, and then annually until disease progression, death, or withdrawal of consent. Compliance rates were calculated as the number of patients who completed questionnaires vs. the number expected to complete questionnaires at each visit in each arm. PRO endpoints included the EORTC QLQ-C30 global health status (GHS), physical and role function domains, and fatigue, pain, nausea/vomiting, and diarrhea symptom domains, assessed via a mixed model for repeated measures (MMRM) analysis at weeks 12 and 24. Clinically meaningful change was defined as ≥5-point mean difference from baseline (Osoba et al., J Clin Oncol 1998). Descriptive analyses, including change over time, were also performed on QLQ-C30 domains and EQ-5D-5L visual analog scale (VAS) scores. Results: A total of 217 patients were randomized to ZO (n=145) and O (n=72), with similar baseline demographics and disease characteristics between the arms. The median (range) duration of study treatment was 12.2 (0.5-44.1) and 10.6 (0.3-30.3) months, respectively. Compliance rates for PRO assessments in both arms were over 80% at week 12, and 85% at week 24. By week 24, patients in the ZO arm had better overall outcomes in the QLQ-C30 domains of role function, pain, and fatigue than those in the O arm, while patients in both arms experienced improvement in GHS, and physical function and symptoms of nausea/vomiting and diarrhea were maintained ( Table). MMRM analyses revealed clinically meaningful improvement from baseline to week 24 for ZO vs O in change in role function (least squares mean difference [95% CI]: 5.6 [-2.3, 13.5]), pain (-4.9 [-12.6, 2.8] points), and fatigue (-4.7 [-11.6, 2.2]). Based on a descriptive analysis, patients in the ZO arm also experienced greater mean improvement from baseline to week 24 vs the O arm in EQ-5D-5L VAS scores (3.1 vs 2.0). Conclusions: In the ROSEWOOD trial, ZO was associated with improved HRQoL in patients with R/R FL. In particular, patients who received the ZO had larger improvements in fatigue, pain symptoms, and role function, than those who received O monotherapy. These findings suggest that zanubrutinib contributed clinically meaningful benefits to patient HRQoL when added to obinutuzumab.

Net Clinical and Quality of Life Benefit of Luspatercept in Transfusion-Dependent MDS: A Win Ratio Analysis Using Data from the Phase 3 MEDALIST Study

Background: Patients with transfusion-dependent (TD) myelodysplastic syndromes (MDS) often experience various anemia-related symptoms and functional impairments. Treatments reducing red blood cell (RBC) transfusion burden could impact these symptoms and/or functions to varying degrees depending on patients' conditions at baseline and warrants the use of composite endpoints, including both clinical outcomes and patient-reported outcomes (PROs) to fully capture these benefits. However, conventional statistical approaches may not satisfactorily assess composite outcomes, especially when the components of the composite outcomes have different types of scales and/or degrees of importance to stakeholders. The win ratio (WR) approach, one of the generalized pairwise comparison methods commonly used for assessing treatments in cardiovascular diseases, offers hierarchical structure, statistical power, and flexibility to address these challenges. Objective: This exploratory analysis used the WR approach to assess the net benefit of luspatercept vs. placebo on composite clinical/PRO endpoints using data from the MEDALIST study. Methods: Four different WR scenarios were performed, in each of which every possible patient-to-patient pair between the luspatercept and placebo arms was compared on a set of relevant clinical/PRO endpoints in a pre-specified order of assumed priority from patients' perspectives, accompanied with a pre-determined rule to assign a win, loss, or tie for luspatercept in each pairwise comparison on each endpoint. If a win or loss could not be determined on a given endpoint, then the next endpoint in the hierarchy was evaluated until a win or loss occurred. Otherwise, if all pre-specified endpoints were evaluated, a tie was assigned. The scenarios considered two clinical endpoints: RBC-transfusion independence [TI] ≥8 weeks over Weeks 1-24 and RBC-TI over Weeks 1-24. PRO endpoints included changes from baseline to the end of Week 24 in five key domains of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), categorized as improvement (≥10-point improvement), stable (10 > change >-10), or worsening (≥10-point worsening). Improvement was considered a better outcome than stable and worsening, and stable was considered better than worsening when determining a win or loss for luspatercept on each of the PRO endpoints. The four different scenarios of composite clinical/PRO endpoints and their order of priority, shown in the Table were pre-specified for assessment . The WR (nominal 95% CI, p-value) for luspatercept on each scenario of the composite clinical/PRO endpoints was calculated as the total number of pairs with a win divided by the total number of pairs with a loss. A WR >1 indicates that luspatercept is more favorable than placebo. Results: 153 patients randomized to the luspatercept arm were compared to 76 patients randomized to the placebo arm, for a total of 11,628 pairwise comparisons within each WR analysis. In all four scenarios, WRs were nominally statistically significantly in favor of luspatercept ( Table). Most wins favoring luspatercept were attributed to wins on the clinical endpoint. Among those pairs who tied on the clinical endpoint, the luspatercept arm experienced more wins (or tied) in almost all of the five PRO endpoints. WRs were similar whether PRO endpoints were prioritized over others or not. Conclusions: The analysis findings indicate that, for two randomly selected patients with low-risk TD MDS, the odds that the patient treated with luspatercept would have a better outcome (if not tied) than the patient with placebo, is significantly higher than 1, ranging between 1.51 to 1.90. The analysis also shows that when multiple clinical and PRO endpoints, especially with different importance to stakeholders, are considered to provide a comprehensive treatment benefit, WR can be a useful and valuable approach for making this evaluation.

Patient-Reported Outcomes in the Phase 3 CARTITUDE-4 Study of Ciltacabtagene Autoleucel Vs Standard of Care in Patients with Lenalidomide-Refractory Multiple Myeloma after 1-3 Lines of Therapy

Introduction: The phase 3 CARTITUDE-4 trial (NCT04181827) in patients with multiple myeloma (MM) after 1-3 lines of therapy compared ciltacabtagene autoleucel (cilta-cel) with standard of care (SOC; pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone). In the primary analysis, a single cilta-cel infusion significantly improved progression-free survival (hazard ratio [HR], 0.26; P<0.0001) and increased the rate and depth of response vs SOC. Here, we present adjusted comparisons of patient-reported outcomes (PROs) from patients randomized to cilta-cel vs SOC in CARTITUDE-4. Methods:419 patients with lenalidomide-refractory MM and 1-3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, were randomized (intent-to-treat [ITT] population) to receive cilta-cel (N=208) or SOC (N=211). European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30; 100-point scale), EuroQoL 5-Dimension 5-Level (EQ-5D-5L; 100-point scale), and Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q; 5-point scale) questionnaires were administered to all patients until disease progression. PRO compliance was calculated as the number of patients whose PROs were received divided by the number whose PROs were expected (ie, all patients on study pre disease progression and before subsequent therapy for each time point). Mixed-model for repeated measures analyses were performed on the ITT population to analyze changes from baseline for each arm and included the baseline PRO score and prognostic characteristics as covariates to balance arms and to adjust for confounders. Assessments after the start of subsequent therapy were excluded. Time to symptom worsening, defined as a clinically meaningful increase (≥0.5 standard deviation of pooled baseline values) without a subsequent reduction in MM symptoms, was assessed using the Kaplan-Meier method. Results: At clinical cut-off on November 1, 2022, 99 patients in the cilta-cel arm and 66 in the SOC arm had both baseline and 12-month PRO assessments, representing data prior to progression. PRO compliance was 100% at baseline and decreased with subsequent visits to 74% in the cilta-cel arm and 81% in the SOC arm at month 12. Patients reported improved functioning and symptom reduction from baseline in the cilta-cel arm, while PRO scores in the SOC arm trended towards worsening or lower degrees of improvement from baseline for most domains and symptoms. The average improvement from baseline to month 12 (least squares [LS] mean change) for patients who received cilta-cel exceeded clinically meaningful thresholds for global health status (10.1 points), pain (-10.2 points), and the visual analogue scale (8.0 points); improvements in fatigue (-9.1 points) and emotional functioning (9.5 points) neared clinically meaningful thresholds (Table). For all other EORTC QLQ-C30 domains, results numerically favored cilta-cel. On the MySIm-Q total symptom scale, the median time until MM symptom worsening in the cilta-cel arm was 23.7 months (95% CI, 22.1-not estimable) and was 18.9 months (95% CI, 16.8-not estimable) in the SOC arm (HR, 0.42). Conclusions:Patients with lenalidomide-refractory MM who had 1-3 prior lines of therapy demonstrated clinically meaningful improvements in health-related quality of life and meaningful reductions in disease-specific symptoms on multiple PRO endpoints after a single cilta-cel infusion. Improvements in health-related quality of life were numerically greater with cilta-cel than with continuously administered SOC treatments across all scales. With previously reported data showing that cilta-cel significantly improves PFS, response rate, and depth of response, these results strengthen the potential for cilta-cel to be a new SOC for patients with lenalidomide-refractory MM after first relapse.

Health-related quality of life outcomes associated with zanubrutinib versus ibrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: results from the ALPINE Trial

Objective The purpose of this analysis was to assess health-related quality of life (HRQoL) in patients treated with zanubrutinib and ibrutinib in the ALPINE trial (NCT03734016). Methods HRQoL was measured by the EORTC QLQ-C30 and EQ-5D-5L at baseline, cycle 1, and every third cycle until the end of treatment. Key patient-reported outcome (PRO) endpoints included global health status (GHS), physical and role functioning, as well as symptoms of fatigue, pain, diarrhea, and nausea/vomiting. A mixed model repeated-measure analysis using key PRO endpoints at key clinical cycles (cycles 7 and 13) was performed. Results 652 patients were randomized to receive zanubrutinib (n = 327) or ibrutinib (n = 325). By cycle 7, GHS scores improved with zanubrutinib versus ibrutinib, and in cycle 13, GHS scores remained higher in the zanubrutinib arm. The zanubrutinib arm experienced clinically meaningful improvements in physical and role functioning, as well as pain and fatigue symptoms at both cycles. Patients in the zanubrutinib arm reported lower diarrhea scores. Nausea/vomiting scores maintained in both arms. EQ-VAS scores showed greater improvement from baseline at both cycle 7 (7.92 versus 3.44) and cycle 13 (7.75 versus 3.92) of treatment with zanubrutinib compared to ibrutinib, respectively. Conclusions Patients with R/R CLL/SLL treated with zanubrutinib demonstrated improvement versus ibrutinib in the GHS scale at cycle 7. Other endpoints continued to improve, suggesting treatment with zanubrutinib positively affected HRQoL over time. Given the generally good HRQoL at baseline in both arms, the differences between the arms were not significant.

Randomized phase III trial evaluating motivational interviewing and text interventions to optimize adherence to breast cancer endocrine therapy (Alliance A191901): the GETSET protocol

BackgroundHormone receptor-positive (HR +) breast cancer is the most common type of breast cancer in the USA but has excellent long-term outcomes in recent decades, in part due to effective oral endocrine therapy (ET). ET medications are typically prescribed for 5 to 10 years, depending on the risk of recurrence, and must be taken daily. One limiting factor to ET efficacy is nonadherence, with high-risk groups for nonadherence including younger women and Black women.MethodsThe Alliance for Clinical Trials in Oncology (Alliance) trial A191901 is an ongoing, four-arm (text message reminder (TMR), motivational interviewing (MI), TMR plus MI, or enhanced usual care) randomized clinical trial that tests the efficacy and effect of two interventions (TMR and/or MI) on improved ET adherence, patient-reported outcomes (PROs), and resource use requirements among HR + breast cancer survivors. Participants are randomized in a 1:1:1:1 ratio to the four arms. With an assumed loss to follow-up of approximately 11%, we plan to recruit 1180 participants. Randomization is stratified based on age and race to ensure balance between the arms, and we oversample younger and Black women, with each group representing 30% of the study population. Participants randomized to an intervention will actively participate in the intervention for 9 months, and all participants will be followed for adherence data and PRO endpoints, through the use of the Pillsy cap medication event monitoring system and Alliance ePRO survey app (i.e., Patient Cloud). The primary analysis will compare Pillsy-measured ET adherence among study arms at 12 months.DiscussionThis multisite study will not only define strategies to improve adherence to breast cancer oral therapies, but it will also potentially support strategies in large cooperative research groups that can increase delivery and tolerability of ET, involve diverse patient populations in clinical research, and engage patients effectively in interventional studies, using remote and cost-effective delivery methods.Trial registrationClinicaltrials.gov NCT04379570. Registered on 7 May 2020.

Patient-reported outcomes (PROs) among men receiving talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment for metastatic castration-resistant prostate cancer (mCRPC): Results from a phase 3 study (TALAPRO-2).

5013 Background: TALAPRO-2 (NCT03395197) showed statistically significant improvement in radiographic progression free survival with TALA + ENZA (n=402) vs PBO + ENZA (n=403) (HR=0.63 95% CI 0.51-0.78; P<0.001) in men receiving 1L treatment for mCRPC. Here we report PRO endpoints from TALAPRO-2. Methods: PROs were assessed at day 1 (baseline) and at scheduled visits until radiographic progression (every 4 weeks until week 53, and then every 8 weeks) using the EORTC QLQ-C30 and its prostate cancer module, QLQ-PR25. Prespecified PRO analyses included overall mean change from baseline (per longitudinal repeated measures mixed-effects model) and time to definitive clinically meaningful (≥10-point change) deterioration (TTD). Between-arm comparisons of TTD were made using a stratified log-rank test and a Cox proportional hazards model. Results: Of the 805 men randomized and treated, 793 had a baseline score followed by at least 1 post-baseline score; TALA + ENZA (n=395), PBO + ENZA (n=398). Although the treatment effect on global health status (GHS)/quality of life (QoL) significantly favored PBO + ENZA, the predefined threshold of clinical meaningfulness was not met; moreover, no significant differences between the arms were observed in any functioning scales. A significantly longer TTD in GHS/QoL was observed for TALA + ENZA; HR=0.780 (95% CI: 0.62, 0.99), P=0.038; median: 30.8 months vs 25.0 months. A numerical greater delay in TTD in urinary symptoms was longer for TALA + ENZA; HR=0.759 (95% CI: 0.543, 1.061), P=0.105; median not reached vs 35.9 months. Additional PRO results will be presented. Conclusions: Compared with PBO + ENZA, in the TALA + ENZA arm there was 1) a modest deterioration disfavoring GHS/QoL (deterioration was not clinically meaningful based on the predefined threshold), and 2) a maintenance in all functioning scales. TTD in GHS/QoL was significantly longer with TALA + ENZA vs PBO + ENZA, reflecting improved disease control. These results complement the benefit-risk assessment of TALAPRO-2. Clinical trial information: NCT03395197 . [Table: see text]

Health-Related Quality of Life Instruments for Clinical Trials in AL Amyloidosis: Report from the Amyloidosis Forum HRQOL Working Group.

Systemic AL (light chain) amyloidosis is a rare protein misfolding disorder associated with plasma cell dyscrasia affecting various organs leading to organ dysfunction and failure. The Amyloidosis Forum is a public-private partnership between the Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research with the goal of accelerating the development of effective treatments for AL amyloidosis. In recognition of this goal, 6 individual working groups were formed to identify and/or provide recommendations related to various aspects of patient-relevant clinical trial endpoints. This review summarizes the methods, findings, and recommendations of the Health-Related Quality of Life (HRQOL) Working Group. The HRQOL Working Group sought to identify existing patient-reported outcome (PRO) assessments of HRQOL for use in clinical trials and practice deemed relevant across a broad spectrum of patients with AL amyloidosis. A systematic review of the AL amyloidosis literature identified 1) additional signs/symptoms not currently part of an existing conceptual model, and 2) relevant PRO instruments used to measure HRQOL. The Working Group mapped content from each identified instrument to areas of impact in the conceptual model to determine which instrument(s) provide coverage of relevant concepts. The SF-36v2® Health Survey (SF-36v2; QualityMetric Incorporated, LLC) and Patient-Reported Outcomes Measurement Information System-29 Profile (PROMIS-29; HealthMeasures) were identified as instruments relevant to patients with AL amyloidosis. Existing evidence of reliability and validity was evaluated with a recommendation for future work focused on estimating clinically meaningful within-patient change thresholds for these instruments. For sponsors, the context of use-including specific research objectives, trial population, and investigational product under study-should inherently drive selection of the appropriate PRO instrument and endpoint definitions to detect meaningful change and enable patient-focused drug development.

Single-arm studies involving patient-reported outcome data in oncology: a literature review on current practice.

Patient-reported outcomes (PROs) are increasingly used in single-arm cancer studies. We reviewed 60 papers published between 2018 and 2021 of single-arm studies of cancer treatment with PRO data for current practice on design, analysis, reporting, and interpretation. We further examined the studies' handling of potential bias and how they informed decision making. Most studies (58; 97%) analysed PROs without stating a predefined research hypothesis. 13 (22%) of the 60 studies used a PRO as a primary or co-primary endpoint. Definitions of PRO objectives, study population, endpoints, and missing data strategies varied widely. 23 studies (38%) compared the PRO data with external information, most often by using a clinically important difference value; one study used a historical control group. Appropriateness of methods to handle missing data and intercurrent events (including death) were seldom discussed. Most studies (51; 85%) concluded that PRO results supported treatment. Conducting and reporting of PROs in cancer single-arm studies need standards and a critical discussion of statistical methods and possible biases. These findings will guide the Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Data in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI) in developing recommendations for the use of PRO-measures in single-arm studies.

Adaptation of the WOMAC for Use in a Patient Preference Study.

To adapt a patient-reported outcome (PRO) measure, the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), into efficacy attributes for a discrete choice experiment (DCE) survey designed to quantify the relative importance of endpoints commonly used in knee osteoarthritis (KOA) trials. The adaptation comprised four steps: (1) selecting domains of interest; (2) determining presentation and framing of selected attributes; (3) determining attribute levels; and (4) developing choice tasks. This process involved input from multiple stakeholders, including regulators, health preference researchers, and patients. Pretesting was conducted to evaluate if patients comprehended the adapted survey attributes and could make trade-offs among them. The WOMAC pain and function domains were selected for adaption to two efficacy attributes. Two versions of the discrete choice experiment (DCE) instrument were created to compare efficacy using (1) total domain scores and (2) item scores for "walking on a flat surface." Both attributes were presented as improvement from baseline scores by levels of 0%, 30%, 50%, and 100%. Twenty-six participants were interviewed in a pretest of the instrument (average age 60years; 58% female; 62% had KOA for ≥ 5years). The participants found both versions of attributes meaningful and relevant for treatment decision-making. They demonstrated willingness and ability to tradeoff improvements in pain and function separately, though many perceived them as inter-related. This study adds to the growing literature regarding adapting PRO measures for patient preference studies. Such adaptation is important for designing a preference study that can incorporate a clinical trial's outcomes with PRO endpoints.

Patient-reported outcomes (PROs) in cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC) treated with enfortumab vedotin (EV) alone or in combination with pembrolizumab (P) in the phase 1b/2 EV-103 Cohort K study.

439 Background: The EV-103 Cohort K trial evaluated 1L EV+P or EV alone (NCT03288545) in pts with la/mUC who were cisplatin-ineligible. EV+P showed a clinically meaningful objective response rate (64.5%; 95% CI, 52.7–75.1) with a manageable safety profile. Because la/mUC is associated with symptoms with a frequent impact on quality of life (QOL) and functioning (Mamtani et al. JCO 2021), we describe the impact of EV+P or EV alone on QOL and symptoms. Methods: In this open-label, Phase 1b/2 trial, cisplatin-ineligible pts with la/mUC were randomized 1:1 to EV+P or EV alone. For exploratory PRO endpoints, pts completed EORTC QLQ-C30 and the BPI-SF at baseline, weekly for cycles 1–3, and once every cycle for the remainder of treatment period. The PRO analysis set included only pts who were treated and completed the questionnaire at baseline. Mixed effect models for repeated measures (MMRM; least squares [LS] mean, standard error [SE]) not adjusted for multiplicity, estimated change vs baseline until Week 24; established thresholds (EORTC QLQ-C30: 10-point change; BPI-SF: 2-point change) were applied to determine clinically meaningful change. Results: Of the 76 pts treated with EV+P, 65 were included in the PRO analysis set. EORTC QLQ-C30 and BPI-SF were completed by 100% and 95%, respectively, at baseline; compliance rates were ≥84% for both instruments through Week 24. In the EORTC QLQ-C30 MMRM analyses, QOL was maintained through Week 24 for EV+P; functioning and symptom scores remained stable over time, with improvements in emotional functioning, pain and sleep disturbance vs observed baseline. In the EV+P arm, clinically meaningful reductions in pain were seen at Week 12 (-12.64 [3.208]) vs baseline and persisted through Week 24 (-13.20 [3.406]). In the BPI-SF MMRM analyses, worst and average pain, pain interference and severity consistently showed improved scores from Week 4–24 for EV+P; clinically meaningful change in worst pain was seen at Week 21 (-2.08 [0.361]). Similar completion and compliance rates were seen for the EV alone PRO analysis set (n=63). EV alone demonstrated clinically meaningful improvements in pain at Week 24 in the EORTC QLQ-C30 (-10.63 [4.110]) and consistent small-to-moderate improvements in the BPI worst and average pain, and pain severity (0.5–1.0 points). Sleep disturbances demonstrated improvement, and other symptom scales, QOL and functional domains remained stable. Conclusions: PRO data showed that EV+P in cisplatin-ineligible pts with la/mUC was associated with preservation or improvement of QOL, functioning, and symptoms. Improvement in pain was demonstrated consistently in both PRO instruments and treatment arms. These PRO data complement the clinical outcomes of EV+P in 1L cisplatin-ineligible pts with la/mUC. Clinical trial information: NCT03288545 .

A Review of Labeling Based on Patient-Reported Outcome Endpoints for New Oncology Drugs Approved by the European Medicines Agency (2017-2021)

ObjectiveA review of new oncology indications approved by the European Medicines Agency (EMA) for 2012-2016 showed that 33% of new drugs had labeling based on patient-reported outcomes (PROs). We reviewed labeling text based on PRO endpoints for new oncology indications approved during 2017-2021. MethodsNew oncology drugs approved by EMA to treat indications of cancers during 2017-2021 were identified from the EMA website. PRO-related language reported in EMA summaries of product characteristics (SmPCs) were summarized and compared with similar findings reported for oncology indications approved during 2012-2016. ResultsReview documents by the EMA during 2017-2021 were available for 49 new oncology drugs for 70 cancer indications. Submissions for 52 (74.3%) of the 70 indications included PRO data for EMA review. Of all submissions, 14 (20.0%) approvals contained PRO-related language in the SmPC. Broad concepts such as health-related quality of life were most common and found in 8 of 14 (57.1%) PRO-related labels. ConclusionPRO-related language appeared in SmPCs for 20% of all indications of new oncology drugs approved by EMA during 2017-2021 compared with approximately 33% of EMA approvals during 2012-2016. PRO-related labeling during the same periods showed a greater decline (from 47% to 27%) for indications of new oncology drugs that also included PRO data. One possible reason for this decline may be the increase in open-label studies from 62% between 2012 and 2016 to approximately 79% between 2017 and 2021.

HPR34 Emerging Role of Patient Reported Outcomes in Drug Approval in Europe

Rapid development in digital technology has offered vast metrics to strengthen patient-reported outcome (PRO) databases. Globally, PRO endpoints have gained momentum in addition to traditional clinical trial endpoints, thereby integrating patients’ perspective into drug approvals. The aim of this research is to evaluate the role of PRO endpoints in decision making process of European Medicines Agency (EMA) for drug approval.