Patient-reported Outcomes Endpoints Research Articles

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.

P662: PATIENT-REPORTED OUTCOMES FROM A PHASE 3 RANDOMIZED STUDY OF ZANUBRUTINIB VERSUS BENDAMUSTINE PLUS RITUXIMAB (BR) IN PATIENTS WITH TREATMENT-NAÏVE (TN) CLL/SLL

Background: Zanubrutinib is an oral, highly selective, next-generation Bruton tyrosine kinase (BTK) inhibitor. In cohort 1 of the phase 3 SEQUOIA trial (BGB-3111-304; NCT03336333), efficacy and safety of zanubrutinib and BR were compared in adult patients (pts) with TN chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without del(17p). Aims: Here, we report the health-related quality of life (HRQoL) outcomes from an interim analysis of the SEQUOIA trial. Methods: Patient-reported outcomes (PROs) were secondary endpoints and assessed using the EORTC QLQ-C30 and EQ-5D-5L VAS. Patients completed these questionnaires at baseline, every 12 weeks for 96 weeks, and then every 24 weeks until disease progression, death, or withdrawal from study. The PRO endpoints included global health status (GHS), physical and role functions, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting, measured by QLQ-C30, with critical clinical cycles of Weeks 12 and 24. Descriptive analyses were performed on all questionnaire responses, and a mixed model for repeated measures was performed on the PRO endpoints at Weeks 12 and 24. Results: Baseline demographics and disease characteristics between the zanubrutinib (n=241) and BR (n=238) arms were similar. Across all pts, adjusted completion rates for PROs (# of pts who completed the questionnaire at each cycle divided by # of pts expected to complete the questionnaires) were high (~80%) at Weeks 12 and 24. Compared with pts who received BR, pts treated with zanubrutinib experienced greater improvements in HRQoL at Weeks 12 and 24 as reported on the QLQ-C30 (Table). By Week 24, significant improvements were observed with zanubrutinib vs BR in GHS, physical functioning, role functioning as well as greater reductions in diarrhea, fatigue, and nausea/vomiting. Per EQ-5D-5L VAS, comparable improvements from baseline between zanubrutinib and BR in the health status were observed at Weeks 12 (4.3 vs 3.5) and 24 (4.5 vs 4.9), respectively. Image:Summary/Conclusion: In the SEQUOIA trial, zanubrutinib was associated with significant improvements in HRQoL in pts with TN CLL/SLL without del(17p), as indicated by the PRO endpoints of the GHS, physical and role functions, and greater reductions in symptoms of fatigue, diarrhea and nausea/vomiting compared with BR.

P663: HEALTH-RELATED QUALITY OF LIFE OUTCOMES ASSOCIATED WITH ZANUBRUTINIB VS IBRUTINIB MONOTHERAPY IN PATIENTS WITH RELAPSED/REFRACTORY (RR) CLL/SLL: RESULTS FROM THE RANDOMIZED PHASE 3 ALPINE TRIAL

Background: In the phase 3 ALPINE trial (BGB-3111-305; NCT03734016), efficacy and safety of zanubrutinib, a highly selective, next-generation Bruton tyrosine kinase inhibitor (BTKi), were compared with the first-generation BTKi, ibrutinib, in adult patients with RR chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Aims: This abstract, based on the interim analysis of the ALPINE trial, describes the effects of zanubrutinib monotherapy and ibrutinib monotherapy on the health-related quality of life (HRQoL). Methods: Health-related quality of life was examined by patient-reported outcomes (PROs) measures assessed by EORTC QLQ-C30 and EQ-5D-5L at baseline, Cycle 1, and then every 3rd cycle until end of treatment. Key PRO endpoints included global health status (GHS), physical and role functions, and fatigue, pain, diarrhea, and nausea/vomiting. Descriptive analysis on all the scales was conducted as was a mixed model repeated-measure (MMRM) analysis of the longitudinal QLQ-C30 data. Data presented are from key cycles (7 and 13), corresponding to 6 and 12 months of treatment, respectively. Results: In the intent-to-treat population (N=652; zanubrutinib, n=327; ibrutinib, n=325), adjusted completion rates were high (>85%) in both arms at Cycles 7 and 13. On the QLQ-C30, estimated mean treatment differences and 95% CI in key PRO endpoints demonstrated treatment differences, in favor of zanubrutinib, in GHS, physical functioning, and fatigue in Cycle 7, and diarrhea in Cycle 13 (Table). Mean change from baseline (SD) in EQ-5D-5L VAS showed consistently more improvement with zanubrutinib compared with ibrutinib at both Cycle 7 (8.4 [18.2] vs 4.0 [16.6]) and Cycle 13 (6.8 [18.8] vs 5.2 [17.5]). Image:Summary/Conclusion: In the ALPINE trial, patients with RR CLL/SLL who received zanubrutinib monotherapy reported improvements in key HRQoL endpoints compared with patients who received ibrutinib monotherapy.

Quality of life of patients with soft tissue sarcoma treated with doxorubicin in the ANNOUNCE phase III clinical trial.

Background: Patient-reported outcomes (PROs), including health-related quality of life, are recommended to be routinely collected in clinical trials, but data are limited from trials of sarcoma patients. In this analysis, pooled PRO data are reported from patients with advanced or metastatic soft tissue sarcoma (STS) enrolled to the ANNOUNCE phase III trial of doxorubicin-based therapy. Methods: ANNOUNCE was a phase III trial that randomized 509 patients with STS to receive up to eight cycles of doxorubicin with olaratumab or placebo, followed by single-agent olaratumab or placebo. Dexrazoxane was allowed at any cycle of treatment. Participants completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30, which is scored 0–100), and Brief Pain Inventory Short Form Modified (mBPI-sf, scored from 0–10) at each treatment cycle. A descriptive analysis of the longitudinal data was conducted overall and by cumulative dose of doxorubicin received to inform the clinical care of patients with STS. Worsening on the QLQ-C30 was defined as a change of 10 points or more at any post-baseline assessment. Worsening on the mPBI-sf was defined as an increase of ≥2 points from baseline. Results: The majority of participants completed the baseline and at least one subsequent PRO assessment within the trial (n = 460, 90.4% EORTC QLQ-C30; n = 454, 89.2%, mBPI-sf). Patients with STS enrolled to the ANNOUNCE trial had clinically meaningful problems with physical function and pain before initiating doxorubicin. Overall, those with fewer symptoms or better function at baseline received higher cumulative doxorubicin dose throughout the study. At baseline, mean QLQ-C30 fatigue was 29.9 with a median time to first worsening of 0.9 months, and mean nausea/vomiting was 6.5 with 1.4 months until worsening; mean physical function was 78.3 with median time to worsening of 2.1 months and mean health status was 66.8 with median time to first worsening of 1.6 months. Median time to worsening of pain was 7.9 months. Conclusion: Patients with advanced or metastatic sarcoma reported a relatively rapid decline in PROs during doxorubicin-based treatment, with patients with poorer symptoms at baseline (specifically fatigue), subsequently receiving less doxorubicin therapy. The availability of detailed summary data from the patient perspective during doxorubicin-based treatment may inform future care of these patients and can provide a resource for the development of PRO endpoints in future trials.

Evaluation of Patient-Reported Outcomes (PROs) Protocol Content and Reporting for Clinical Trials that Lead to the approval of frontline Immune Checkpoint Blockade Combination for Patients with Advanced Renal Cell Carcinoma - The Patients' Voice or a Missed Opportunity.

Immune checkpoint blockade (ICB) is a rapidly emerging field of oncology that has revolutionized the metastatic renal cell carcinoma (mRCC) treatment. Four recent treatment regimens Nivolumab-Ipilimumab, Pembrolizumab-Axitinib, Nivolumab-Cabozantinib, and Pembrolizumab-Lenvatinib-have demonstrated improved clinical endpoints compared to standard of care and are endorsed by NCCN (2021). However, data on patient-reported outcomes (PROs) for patients receiving these regimens are limited. We conducted a comparative assessment of the quality and standardization of PROs endpoints and data reported for these randomized controlled trials (RCTs). We systematically identified all RCTs evaluating combination ICB for ccRCC. PROs-specific data were abstracted from the final version of 4 RCT protocols, as well as clinical and PROs specific manuscripts published between April 2018 and April 2021. We used 3 previously published guides standardizing PROs research to objectively score the data: (i) 24-point PROEAS; (ii) 12-point SPIRIT-PRO; and (iii) 14-point CONSORT-PRO. The CheckMate 214, KEYNOTE 426, CheckMate 9ER, and CLEAR studies had PROEAS scores of 88% (21/24), 37% (9/24), 83% (20/24), and 16% (4/24), respectively, and SPIRIT-PRO scores of 50% (6/12), 75% (9/12), 66% (8/12), and 41% (5/12) respectively. The CONSORT-PRO scores were 86% (12/14) for CheckMate 214 and 43% (6/14) for CheckMate 9ER, but scores were not available for the CLEAR and KEYNOTE 426 studies because of a lack of sufficient data. The average SPIRIT-PRO score across the 4 RCTs was 58%, indicating a reasonable adoption of PROs research in data management and analysis. The CheckMate 214 trial had the longest follow-up and most comprehensive published PROs data. Our analysis identified the limitations of current PROs data in combination ICB approved for mRCC. This analysis will enable clinicians to better interpret the current PROs results and emphasize the importance of better incorporation of PROs endpoints in future mRCC trial design.

Examining the Impact of Tislelizumab Added to Chemotherapy on Health-Related Quality-of-Life Outcomes in Previously Untreated Patients With Nonsquamous Non-Small Cell Lung Cancer.

PurposeThis study assessed the effects of tislelizumab, a programmed cell death protein 1 inhibitor, in combination with chemotherapy versus chemotherapy alone as first-line treatment on health-related quality of life (HRQoL) in patients with advanced nonsquamous non–small cell lung cancer (nSQ-NSCLC).MethodsPatients in this randomized, open-label, multicenter phase III study RATIONALE 304 (NCT03663205) with histologically confirmed stage IIIB/IV nSQ-NSCLC were randomized 2:1 to tislelizumab plus platinum-pemetrexed (arm T + PP) or platinum-pemetrexed alone (arm PP). Health-related QoL was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Lung Cancer. Key patient-reported outcome endpoints include mean score change from baseline at weeks 12 (during chemotherapy) and 18 (following chemotherapy) in the 30-item Quality of Life Questionnaire Core's global health status/quality of life (GHS/QoL) and time to deterioration in GHS/QoL.ResultsThree hundred thirty-two patients received at least 1 dose of study drug and completed at least 1 HRQoL assessment. Global health status/QoL score improved in arm T + PP at week 18 (between-group least square mean difference, 5.7; 95% confidence interval [CI], 1.0–10.5; P = 0.018). Patients in arm T + PP experienced greater reduction in coughing (−5.9; 95% CI, −11.6 to −0.1; P = 0.044), dyspnea (−3.8; 95% CI, −7.8 to 0.1; P = 0.059), chest pain (−6.2; 95% CI, −10.8 to −1.6; P = 0.008), and peripheral neuropathy (−2.6; 95% CI, −5.5 to 0.2; P = 0.066). Median time to deterioration in GHS/QoL was not achieved for either arm.DiscussionThe addition of tislelizumab to platinum-based chemotherapy was associated with improvements in nSQ-NSCLC patients' HRQoL as well as the important disease-specific symptoms of coughing, chest pain, and dyspnea.ClinicalTrials.gov Identifier: NCT03663205

Abstract P4-10-01: Quality of life and symptom severity in the PALLAS randomized trial of palbociclib with adjuvant endocrine therapy in early breast cancer (AFT-05)

Abstract P4-10-01: Quality of life and symptom severity in the PALLAS randomized trial of palbociclib with adjuvant endocrine therapy in early breast cancer (AFT-05)

Abstract GS4-09: Quality of life results from OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)-adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER-2 negative early breast cancer

Abstract Background: The primary results from the OlympiA trial were recently reported (NEJM, 2021) after an interim analysis demonstrated statistically significant invasive disease-free survival (DFS) benefit from 1 year of olaparib (OL) vs. placebo (PL) after 2.5 yrs median follow-up. Although there were fewer deaths with OL than PL, overall survival (OS) did not reach the statistical significance threshold prespecified for interim analysis. The initial publication also reported on the adverse event profile, which was similar to that previously reported, as well as Global Health Status/Quality of Life (GHQ), a secondary endpoint for the Patient-Reported Outcome (PRO) sub-study. The full protocol-specified PRO analyses are presented here. Methods: The OlympiA randomized phase III trial (NCT02032823, BIG 6-13, NSABP B-55) tested the role of 1 year of adjuvant OL after completion of (neo)adjuvant chemotherapy and definitive local therapy on invasive DFS, distant DFS and OS, and sought to collect PRO data from all eligible patients (pts) prior to randomization, on treatment (trt) (6 and 12 months [mos]), and after trt (18 and 24 mos) using validated questionnaires available in multiple languages. Fatigue, the primary PRO endpoint, was measured with the FACIT-Fatigue Scale in which a clinically meaningful (CM) difference is ≥3 points. Secondary PRO endpoints included gastrointestinal (GI) symptoms (nausea and vomiting [NV], diarrhea) and multiple quality of life (QOL) domains assessed with the EORTC QLQ-C-30 questionnaire (CM differences: small 5-10 points, moderate 10-20 points [Osoba, 1998]). The primary protocol-specified PRO hypothesis was that during trt pts treated with OL may experience greater fatigue severity at 6 and 12 mos. Secondary PRO hypotheses included: a) pts receiving OL may experience greater severity of GI symptoms at 6 and 12 mos with no difference by 24 mos; b) no difference in fatigue severity post-trt at 18 and 24 mos; and c) no difference in QOL over duration of the PRO sub-study between OL and PL as measured by the GHQ score and other EORTC QLQ-C30 subscales. A mixed model for repeated measures analysis compared the primary and secondary endpoints scores. Separate analyses were performed for neoadjuvant (NAC) and adjuvant (AC) chemotherapy subgroups due to differences in interval from NAC and AC to randomization. Two-sided p-values <0.05 were considered statistically significant. Results: Of 1,836 randomized pts, 1,751 (NAC: 875 [OL:440, PL: 435], AC: 876 [OL:436, PL:440]) were included in the PRO sub-study. Baseline QOL and symptom scores did not differ between OL and PL. Fatigue severity was statistically significantly greater in pts treated with OL than with PL at 6 mos (diff OL vs. PL: NAC -1.3 [95%CI -2.4, -0.2], p=0.024; AC -1.3 [-2.3,-0.2], p=0.017) and 12 mos (NAC -1.5 [-2.8,-0.2] p=0.025; AC -1.3 [-2.4,-0.1] p=0.027); however, the differences did not meet the pre-specified criterion for CM with the FACIT-Fatigue Scale. There were no meaningful differences in fatigue severity at 18 and 24 mos. NV symptom severity was worse in pts treated with OL than with PL with small differences at 6 mos (NAC: 6.0 [4.0, 8.0], p<0.001, AC: 5.3 [3.4,7.2], p<0.001) and 12 mos (NAC: 6.3 [4.4, 8.2], p<0.001, AC: 4.5 [2.8,6.2], p<0.001), and no differences at 18 and 24 mos. In general, there were no CM differences between OL and PL in terms of other symptoms and QOL subscales with improvements in functioning over time. Conclusions: Increased trt-emergent symptoms with OL were small and resolved after trt. QOL scores were similar and slowly improved during the 24 mos after (neo) adjuvant chemotherapy. Support: U10CA180868, -180822, UG1CA189867, AstraZeneca, Merck and Co, Inc. NCT02032823 Citation Format: Patricia A Ganz, Hanna Bandos, Tanja Spanic, Sue Friedman, Volkmar Müller, Sherko Kümmel, Suzette Delaloge, Etienne Brain, Masakazu Toi, Hideko Yamauchi, Eduardo-Martínez de Dueñas, Anne Armstrong, Seock-Ah Im, Chuangui Song, Hong Zheng, Tomasz Sarosiek, Priyanka Sharma, Giovanna Rossi, Priya Rastogi, Anitra Fielding, Richard D Gelber, Christine Campbell, Judy E Garber, Charles E Geyer, Jr, Andrew NJ Tutt, On behalf of the OlympiA Trial Steering Committeeand Investigators. Quality of life results from OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)-adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER-2 negative early breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-09.

Abstract P4-10-02: Patient-reported outcomes in EA1131: A randomized phase III trial of platinum vs. capecitabine in patients with residual triple-negative breast cancer after neoadjuvant chemotherapy

Abstract Background: Understanding health-related quality of life (HRQOL), including side effects, is critical to guide supportive care during chemotherapy. The EA1131 trial demonstrated that Platinum (Plat) was unlikely to improve outcomes compared to capecitabine (Cape) in patients with stage II-III triple-negative breast cancer (TNBC) of basal subtype and ≥1 cm residual disease after neoadjuvant chemotherapy (NAC), supporting Cape as the continued standard of care. Patient-reported outcomes (PRO) were administered as a sub-study to understand HRQOL and symptoms from the patient’s perspective. Methods: EA1131 was amended in 9/2017 to add PRO endpoints and all patients enrolled after this amendment were eligible for the PRO sub-study. The Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (FBSI) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity Subscale (NtxS; Plat arm only) were administered at baseline (BL), cycle 3 day 1 (C3D1), and following treatment at 6 and 15 months. Due to early trial termination, the PRO sub-study target accrual (n=362) was not reached. It was hypothesized that HRQOL, assessed by the FBSI-Treatment Side Effect (TSE) subscale (range 0-16, higher score = less side effects, better HRQOL), would indicate fewer post-treatment side effects at 6 and 15 months following Plat compared to Cape. The Wilcoxon rank sum test was used to compare FBSI-TSE subscale scores and total FBSI scores (range 0-64, higher score = better overall HRQOL) between arms at BL, C3D1, 6 months and 15 months. Two-sample t-tests were used to compare change in FBSI-TSE subscale scores and total FBSI scores from BL to C3D1 between arms. Change in NtxS scores (range 0-44, higher score = less neurotoxicity) from BL to C3D1 was evaluated with the paired t-test. Analyses were exploratory and p-values <0.05 considered significant without multiple comparisons adjustment. Results: Of 331 patients eligible for the PRO sub-study (156 Plat arm, 175 Cape arm), 296 (89.4%) completed ≥1 PRO. Mean FBSI-TSE subscale scores were better for Cape at BL (Cape 14.5, Plat 13.9, p-value 0.02), for Plat at C3D1 (Cape 13.5, Plat 14.0, p-value 0.04), and did not differ at 6 months (Cape 14.6, Plat 14.7, p-value 0.70) or 15 months (Cape 14.9, Plat 14.5, p-value 0.44). FBSI-TSE subscale scores worsened from BL to C3D1 for Cape but not for Plat (mean change Cape -0.72, mean change Plat 0.15, p-value 0.003). FBSI-TSE subscale change scores from BL to C3D1 exceeded the threshold for clinically meaningful worsening (> 1.5 points) in 27% of patients on Cape and 23% of patients on Plat (p-value 0.51). Mean total FBSI scores did not differ between arms at any time (BL: Cape 50.6, Plat 49.7; C3D1: Cape 48.1, Plat 48.0; 6 months: Cape 49.9, Plat 51.1; 15 months: Cape 53.3, Plat 50.3; all p > 0.05). Mean change in total FBSI scores from BL to C3D1 did not differ between arms (Cape -2.20, Plat -1.83, p = 0.75). Mean (standard deviation) NtxS scores for the Plat arm were 38 (6.3), 36.1 (7.8), 36 (7.1) and 34.5 (7.9) at BL, C3D1, 6 months and 15 months, respectively. Mean NtxS score decreased (indicating worsening neurotoxicity) from BL to C3D1 (p-value 0.006). Conclusions: Despite more frequent severe toxicity by CTCAE criteria for Plat than Cape, patient-reported side effects worsened during treatment with Cape but not Plat. Overall, changes in HRQOL were small for both arms and resolved after therapy. However approximately one-fourth of patients had clinically meaningful worsening side effects on both arms. PRO-assessed neurotoxicity increased in the Plat arm. This PRO sub-study demonstrates that PROs capture toxicities beyond CTCAE criteria and provides novel data about patients’ experience during adjuvant chemotherapy following NAC for TNBC. Citation Format: Karen L Smith, Fengmin Zhao, Ingrid A Mayer, Amye J Tevaarwerk, Sofia F Garcia, Carlos L Arteaga, William F Symmans, Ben H Park, Brian L Burnette, Della F Makower, Margaret Block, Kimberly A Morley, Chirag R Jani, Craig Mescher, Shabana J Dewani, Ursa Brown-Glaberman, Lisa E Flaum, Erica L Mayer, William M Sikov, Eve T Rodler, Angela M DeMichele, Joseph A Sparano, Antonio C Wolff, Kathy D Miller, Lynne I Wagner. Patient-reported outcomes in EA1131: A randomized phase III trial of platinum vs. capecitabine in patients with residual triple-negative breast cancer after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-02.

A Review of Patient-Reported Outcome Labeling of FDA-Approved New Drugs (2016-2020): Counts, Categories, and Comprehensibility

ObjectivesA review of new drug approvals (NDAs) by the US Food and Drug Administration (FDA) for 2006 to 2015 showed that approximately 20% of new drugs had labeling based on patient-reported outcomes (PROs). The purpose of this study was to review labeling text based on PRO endpoints for NDAs from 2016 to 2020, with a special focus on the comprehensibility of such statements when included. MethodsWe reviewed drug approval reports on the Drugs@FDA web page of the FDA website to determine the number of NDAs from 2016 to 2020. For all identified NDAs, drug approval package and product labels were reviewed. NDAs from 2016 to 2020 were grouped by disease category as per International Classification of Diseases 10th Revision. Data were summarized for diseases that traditionally rely on PROs for evaluating treatment benefit (PRO dependent) and for diseases that traditionally do not rely on PROs (non-PRO dependent). Results were compared with NDAs from 2006 to 2010. ResultsNDAs amounting to 228 were identified from 2016 to 2020, 26.3% of which had labeling statements based on PRO endpoints. From 2006 to 2015 and from 2016 to 2020, PRO labeling statements were included in 46.5% (46 of 99) and 50.0% (47 of 94), respectively, of NDAs for PRO-dependent new molecular entities and in 6.0% (12 of 199) and 9.7% (13 of 199), respectively, of NDAs for non–PRO-dependent new molecular entities. Comprehensibility of labeling statements based on PRO endpoints was judged to be complex in 56.7% of product labels. ConclusionsThe increase in labeling text based on PRO endpoints in product labels is encouraging. However, there is room for improvement on the comprehensibility of labeling statements based on PRO endpoints.

Patient-Reported Outcomes in a Phase 3, Randomized, Open-Label Study Evaluating the Efficacy of Axicabtagene Ciloleucel (Axi-Cel) Versus Standard of Care Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma (ZUMA-7)

Patient-Reported Outcomes in a Phase 3, Randomized, Open-Label Study Evaluating the Efficacy of Axicabtagene Ciloleucel (Axi-Cel) Versus Standard of Care Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma (ZUMA-7)

Trends in patient-reported outcome use in early phase dose-finding oncology trials - an analysis of ClinicalTrials.gov.

ABSTRACTBackgroundPatient‐reported adverse events (AEs) may be a useful adjunct to clinician‐assessed AEs for assessing tolerability in early phase, dose‐finding oncology trials (DFOTs). We reviewed DFOTs on ClinicalTrials.gov to describe trends in patient‐reported outcome (PRO) use.MethodsDFOTs commencing 01 January 2007 – 20 January 2020 with ‘PROs’ or ‘quality of life’ as an outcome were extracted and inclusion criteria confirmed. Study and PRO characteristics were extracted. Completed trials that reported PRO outcomes and published manuscripts on ClinicalTrials.gov were identified, and PRO reporting details were extracted.Results5.3% (548/10 372) DFOTs included PROs as an outcome. 231 (42.2%) were eligible: adult (224, 97%), solid tumour (175, 75.8%), and seamless phase 1/2 (108, 46.8%). PRO endpoints were identified in more trials (2.3 increase/year, 95% CI: 1.6–2.9) from an increasing variety of countries (0.7/year) (95% CI: 0.4–0.9) over time. PROs were typically secondary endpoints (207, 89.6%). 15/77 (19.5%) completed trials reported results on the ClinicalTrials.gov results database, and of those eight included their PRO results. Eighteen trials had published manuscripts available on ClinicalTrials.gov. Three (16.7%) used PROs to confirm the maximum tolerated dose. No trials identified who completed the PROs or how PROs were collected.ConclusionsPRO use in DFOT has increased but remains limited. Future work should explore the role of PROs in DFOT and determine what guidelines are needed to standardise PRO use.

Impact of Blinding on Patient-Reported Outcome Differences Between Treatment Arms in Cancer Randomized Controlled Trials.

Some concerns have been raised about potential bias in patient-reported outcome (PRO) results from open-label cancer randomized controlled trials (RCTs). We investigated if open-label trials favor the experimental treatment over the standard treatment more frequently than blinded trials. We also examined if the effect of blinding differs for distal vs more proximal PROs. We assessed 538 RCTs with a PRO endpoint conducted in the most prevalent cancers, of which 366 (68.0%) were open-label, 148 (27.5%) were blinded, and 24 (4.5%) were categorized as unclear. In our multivariable logistic regression model, we did not observe a statistically significant association of the independent variable treatment concealment (blinded vs open-label) on the dependent variable measuring the proportion of trials favoring the experimental treatment (adjusted odds ratio = 1.19, 95% confidence interval = 0.79 to 1.79; 2-sided P = .40). This was also the case when comparing distal and proximal PROs. Our findings provide novel evidence-based data that support the validity of PRO results from open-label cancer RCTs.

Investigating Trends in the Quality of Reporting of Patient-Reported Outcomes in Oncology Over Time: Analysis of 631 Randomized Controlled Trials Published Between 2004 and 2019

ObjectivesIncomplete reporting of key information on patient-reported outcomes (PROs) in randomized controlled trials (RCTs) in oncology has been highlighted repeatedly as a major barrier to the use of study findings in clinical practice. We investigated whether the quality of reporting of PRO data in cancer RCTs has improved over the last 15 years. MethodsWe identified all cancer RCTs with PRO endpoints conducted across the most prevalent solid tumor types worldwide published between 2004 and 2019. The quality of PRO reporting was assessed using the International Society for Quality of Life Research recommended standards, which include important aspects related to assessment methodology, statistical analyses, and interpretation of data. ResultsWe assessed a total of 631 cancer RCTs in breast (n = 187), lung (n = 131), prostate (n = 120), colorectal (n = 107), and gynecological (n = 86) cancer. We observed a higher adherence to the International Society for Quality of Life Research reporting criteria in the more recently published studies. In a multivariable linear regression analysis, we observed a statistically significant improvement in the quality of PRO reporting over time (P<.001), and this relationship was independent of other measured confounding factors, such as sample size and study sponsorship. Overall, the quality of PRO reporting was higher for studies published after the publication of the Consolidated Standards of Reporting Trials-PRO Extension. ConclusionsThe quality of PRO reporting in cancer RCTs published in the last 15 years has improved significantly. Our findings are encouraging because better reporting of PRO results may translate into a greater impact of study findings on real-world practice.

Inclusion of Patient-Reported Outcomes in Adolescent and Young Adult Phase III Therapeutic Trials: An Analysis of Cancer Clinical Trials Registered on ClinicalTrials.gov

ObjectivesThere is a paucity of research on the impact of cancer treatment on the health-related quality of life (HRQOL) of adolescent and young adult (AYA) patients with cancer. Patient-reported outcomes (PROs) are self-report measures used to assess HRQOL and symptom burden. The extent to which PROs have been included in trials that include common AYA cancer types has not been previously assessed. MethodsTherapeutic phase 3 trials among common AYA cancer types (Hodgkin lymphoma, non-Hodgkin lymphoma, acute lymphoblastic leukemia, sarcomas, and germ cell tumors) initiated between 2007 and 2020 were identified on ClinicalTrials.gov. The proportions and characteristics of trials including a PRO endpoint were assessed. For comparison with an older population, the proportion of breast and colorectal therapeutic phase 3 trials including PRO endpoints were assessed. ResultsEighty-seven studies met the inclusion criteria. Overall, 20.7% of therapeutic phase 3 AYA trials included a PRO endpoint, and only one trial published PRO data. Germ cell tumors (42.9%) and non-Hodgkin lymphoma (40%) trials had the highest proportions of PRO inclusion. The European Organization for Research and Treatment of Cancer generic, cancer-specific quality of life questionnaire was the most commonly used PRO measure; nevertheless, the measures used varied within and between cancer types. The proportion of trials including a PRO endpoint did not change significantly between 2007 to 2013 and 2014 to 2020 (18.6% vs 22.7%, P=.79). ConclusionsFew therapeutic phase 3 AYA cancer trials include PRO endpoints, fewer publish PRO data, and there is no homogeneity in the measures administered. Therapeutic trials represent an underused opportunity to capture PRO data in the AYA population with the goal of improving HRQOL outcomes.

A Systematic Literature Review of Patient-Reported Outcome Instruments Used in Sickle Cell Disease

Introduction: Patients with sickle cell disease (SCD) often have recurrent episodes of acute severe pain (vaso-occlusive crises, VOCs), which result in repeated hospital admissions and use of pharmacological treatments, and can negatively impact patients' health-related quality of life (HRQL). Most SCD randomized clinical trials (RCTs) are designed to evaluate efficacy in relation to changes in the number of VOCs and their impact on HRQL. We conducted a systematic literature review (SLR) to identify patient-reported outcome (PRO) and healthcare resource utilization (HCRU) instruments used in RCTs and real-world studies and to evaluate their psychometric properties with a view to provide recommendations of appropriate PRO endpoints for use in clinical trials for SCD treatments in the United States (US).Methods: An SLR was conducted to search, identify and summarize validated PRO instruments that have been used by patients with SCD in the US and their caregivers. MEDLINE and EMBASE were searched using terms synonymous with “sickle cell disease” and “psychometric properties” of PRO instruments for articles published in English between 1997 and March 2017 focusing on pediatric patients (5-17 years) and their caregivers, and adults (≥18 years). Studies were included if results were based on assessing psychometric properties of PRO instruments and if the studies were interventional or observational in design. Exclusion criteria included studies conducted in non-US populations, reporting on non-validated generic questionnaires or without any psychometric data. Conference abstracts, narrative reviews, letters to the editor, laboratory studies and case reports/series were excluded. The quality of PRO instruments in the included studies was assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist, a well-established checklist to measure the methodological quality and performance of PRO instruments across a number of domains as reported in psychometric evaluation studies.Results: The SLR identified 504 references for title/abstract screening. Of these, 46 full-text articles were further assessed for inclusion and 19 articles were included. Two additional articles were identified from manual reference checks of relevant SLRs. Thus, a total of 21 US-based studies assessing 10 child and 15 adult PRO instruments in SCD were included in the review. No validated PRO instruments were found that measured caregiver burden in SCD and no validated HCRU instruments for any SCD population were identified. The review of pediatric studies identified the most commonly reported instrument to be the Pediatric Quality of Life Inventory (PedsQL), while most of the adult instruments (9 of 15) focused on evaluating self-efficacy/-esteem and pain in relation to SCD. Only one instrument, the Adult Sickle Cell Quality of Life Measurement (ASCQ-Me), was identified as evaluating HRQL in adults. Out of the 25 PRO instruments reviewed for both children and adults, only 3 out of 10 and 5 out of 15 instruments, respectively, were specifically developed for these age groups with SCD. There were little or no data on validation conducted in SCD development cohorts for most instruments. Additionally, the included studies did not assess minimally important differences in any of the instruments reviewed. In terms of instruments' psychometric properties, most instruments (9 of 15) identified for adult populations had strong internal reliability; however, there was often insufficient information to assess the content validity, construct validity, responsiveness and test-retest reliability of the instruments identified for both child and adult populations.Conclusions: Limited evidence on the psychometric properties of PRO instruments used in patients with SCD was identified. Furthermore, among the instruments reviewed, none was found to sufficiently capture all the PRO aspects of SCD and its complications on patients' HRQL for use as key trial endpoints. Further research should validate, or develop if no instrument is in existence, PRO instruments to assess HRQL of patients with SCD, PRO instruments for caregivers and HCRU instruments. DisclosuresSarri:Evidera: Employment. Bhor:Novartis: Employment, Equity Ownership, Research Funding. Abogunrin:Evidera: Consultancy; Novartis: Research Funding. Farmer:Evidera: Employment; Novartis: Research Funding. Nandal:Novartis: Employment, Equity Ownership, Research Funding. Revicki:Novartis: Consultancy, Research Funding.

PMS25 Patient-Reported Outcome Labeling for Rheumatoid Arthritis Drugs Approved in the United States: 2010-2019

Patient-reported outcomes (PROs), defined as any report on the status of a patient’s health condition that comes directly from the patient, have played an increasingly important role in drug development. In 2009 the Food and Drug Administration (FDA) issued final guidance on using PRO measures to support labeling claims, as a means of incorporating the patient perspective into the drug approval process. For rheumatoid arthritis (RA), a chronic inflammatory disease associated with physical symptoms like pain and stiffness, but also changes to functional capacity and quality of life (QOL), PROs are critical to demonstrate the treatment benefit of new drugs. This analysis evaluates the incorporation of PROs into labeling for recent primary approvals of RA drugs. The FDA’s novel drug approvals (2010-2019) were reviewed to identify RA drugs. Drug approval packages and product labeling were accessed via the [email protected] database and analyzed for PRO endpoints, measures, and labeling claims. Clinical trial designs and published study results were retrieved via the ClinicalTrials.gov website and PubMed. Five novel drugs received primary approval for RA indications between 2010 and 2019. Trials supporting approval of all 5 products assessed patients’ perception of their disease activity, functional capacity, QOL, pain and fatigue. Three of the 5 products (60%) evaluated patients’ work limitations/productivity during pivotal trials, while 1 of the 5 (20%) evaluated quality of sleep. All 5 products incorporated PROs in their labeling, with more recent approvals having a greater number of PRO claims. All RA drugs approved in the past decade used PRO assessments during development, and all acquired labeling claims. Our findings underscore the significant impact RA symptoms have on patients’ day-to-day functioning and QOL, the importance of PROs in RA drug development, and the need to standardize functional domains and validated instruments used in registrational trials.