Patient-reported outcomes in clinical trials

Patient-reported outcomes (PROs) are progressively being included in clinical trials to provide information about treatment benefits identified by the patients themselves that extend the data on traditional clinical trial endpoints, such as disease free survival, overall survival, progression-free survival, and response rate. PROs may have a greater impact for patients than other endpoints. For example, patients may be prepared to forgo some increase in progression-free survival in return for reduced treatment-related toxicity. PROs may also be an indicator of disease response and have value as prognostic factors. This article discusses the way PROs can be defined and incorporated into clinical trials to enhance the value of clinical trials data and improve the understanding of the clinical benefits of a specific treatment, not only for health care professionals, but for patients and caregivers. The importance and relevance of a patient-centered perspective and shared decision making in defining value and determining treatment benefit is increasingly recognized. However, despite the acknowledged value of PROs, their inclusion in clinical trials remains far from ideal. New guidelines from the research community and technological improvements in data collection and analytics will increase the quality and the importance of PROs as standard methods for the evaluation of medical studies and in the drugs approval process.

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Indicadores (Outcomes) Primários e Secundários em Ensaios Clínicos Oncológicos: Definição e Usos

Acta Médica Portuguesa ◽

10.20344/amp.5286 ◽

2014 ◽

Vol 27 (4) ◽

pp. 498

Author(s):

António Vaz-Carneiro ◽

Ricardo Da Luz ◽

Margarida Borges ◽

João Costa

Keyword(s):

Clinical Trials ◽

Methodological Issue ◽

Objective Response ◽

Disease Free Survival ◽

Progression Free Survival ◽

Free Survival ◽

Patient Reported ◽

Oncology Clinical Trials ◽

Alternative Drug ◽

Selection Of

Introduction: The proof of efficacy from a therapeutic intervention in oncology must be defined through well conducted clinical trials. One of the most important methodological issue is the outcome selection needed to calculate measures of association allowing definition of clinical efficacy. Material and Methods: We designed a narrative revision based on some of the international regulatory instructions from drug agencies, as well as consensus papers from scientific oncology societies, listing and critically assessing each outcome used in oncology clinical trials. Results: We identified as being the most important outcomes in oncology trials the overall survival, the progression free survival/ disease-free survival, the toxicity, the quality of life/patient- reported outcomes and the objective response rate. Discussion: The selection of the primary outcome must be based on therapeutic efficacy as well as toxicity, expected survival, alternative drug regimens and even disease prevalence. Conclusion: The selection of efficacy outcomes for clinical trials in oncology is very important and its selection must be well justified, and depends on the type of disease, the patients and the drug being studied. Keywords: Clinical Trials as Topic; Neoplasms; Medical Oncology; Treatment Outcome.

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Association of progression-free survival with patient-reported outcomes and survival: results from a randomised phase 3 trial of panitumumab

British Journal of Cancer ◽

10.1038/sj.bjc.6604053 ◽

2007 ◽

Vol 97 (11) ◽

pp. 1469-1474 ◽

Cited By ~ 57

Author(s):

S Siena ◽

M Peeters ◽

E Van Cutsem ◽

Y Humblet ◽

P Conte ◽

...

Keyword(s):

Patient Reported Outcomes ◽

Progression Free Survival ◽

Phase 3 ◽

Free Survival ◽

Patient Reported

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Patient-reported outcomes in drug development for hematology

Hematology ◽

10.1182/asheducation-2015.1.496 ◽

2015 ◽

Vol 2015 (1) ◽

pp. 496-500 ◽

Cited By ~ 4

Author(s):

Catherine Acquadro ◽

Antoine Regnault

Keyword(s):

Clinical Trials ◽

Drug Development ◽

Patient Reported Outcomes ◽

Clinical Decision Making ◽

Well Being ◽

New Drugs ◽

Specific Situation ◽

Treatment Benefit ◽

Hematologic Diseases ◽

Patient Reported

Abstract Patient-reported outcomes (PROs) are any outcome evaluated directly by the patient himself and based on the patient's perception of a disease and its treatment(s). PROs are direct outcome measures that can be used as clinical meaningful endpoints to characterize treatment benefit. They provide unique and important information about the effect of treatment from a patient's view. However, PROs will only be considered adequate if the assessment is well-defined and reliable. In 2009, the FDA has issued a guidance, which defines good measurement principles to consider for PRO measures intended to give evidence of treatment benefit in drug development. In hematologic clinical trials, when applied rigorously, they may be used to evaluate overall treatment effectiveness, treatment toxicity, and quality of patient's well-being at short-term and long-term after treatment from a patient's perspective. In situations in which multiple treatment options exist with similar survival outcome or if a new therapeutic strategy needs to be evaluated, the inclusion of PROs as an endpoint can provide additional data and help in clinical decision making. Given the diversity of the hematological field, the approach to measurement needs to be tailored for each specific situation. The importance of PROs in hematologic diseases has been highlighted in a number of international recommendations. In addition, new perspectives in the regulatory field will enhance the inclusion of PRO endpoints in clinical trials in hematology, allowing the voice of the patients with hematologic diseases to be taken into greater consideration in the development of new drugs.

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Niraparib Maintenance Therapy in Patients With Recurrent Ovarian Cancer After a Partial Response to the Last Platinum-Based Chemotherapy in the ENGOT-OV16/NOVA Trial

Journal of Clinical Oncology ◽

10.1200/jco.18.02238 ◽

2019 ◽

Vol 37 (32) ◽

pp. 2968-2973 ◽

Cited By ~ 15

Author(s):

Josep M. del Campo ◽

Ursula A. Matulonis ◽

Susanne Malander ◽

Diane Provencher ◽

Sven Mahner ◽

...

Keyword(s):

Ovarian Cancer ◽

Partial Response ◽

Maintenance Therapy ◽

Clinical Benefit ◽

Patient Reported Outcomes ◽

Progression Free Survival ◽

Recurrent Ovarian Cancer ◽

Free Survival ◽

Platinum Based Chemotherapy ◽

Patient Reported

PURPOSE In the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274 ), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer who had a response to their last platinum-based chemotherapy. The objective of the study was to assess the clinical benefit and patient-reported outcomes in patients who had a partial response (PR) and complete response (CR) to their last platinum-based therapy. PATIENTS AND METHODS A total of 553 patients were enrolled in the trial. Of 203 patients with a germline BRCA mutation (g BRCAmut), 99 had a PR and 104 had a CR to their last platinum-based therapy; of 350 patients without a confirmed g BRCAmut (non–g BRCAmut), 173 had a PR and 177 had a CR. Post hoc analyses were carried out to evaluate safety and the risk of progression in these patients according to g BRCAmut status and response to their last platinum-based therapy. Ovarian cancer–specific symptoms and quality of life were assessed using the Functional Assessment of Cancer Therapy–Ovarian Symptom Index. RESULTS Progression-free survival was improved in patients treated with niraparib compared with placebo in both the g BRCAmut cohort (PR: hazard ratio [HR], 0.24; 95% CI, 0.131 to 0.441; P < .0001; CR: HR, 0.30; 95% CI, 0.160 to 0.546; P < .0001) and the non–g BRCAmut cohort (PR: HR, 0.35; 95% CI, 0.230 to 0.532; P < .0001; CR: HR, 0.58; 95% CI, 0.383 to 0.868; P = .0082). The incidence of any-grade and grade 3 or greater adverse events was manageable. No meaningful differences were observed between niraparib and placebo in PR and CR subgroups with respect to patient-reported outcomes. CONCLUSION Patients achieved clinical benefit from maintenance treatment with niraparib regardless of response to the last platinum-based therapy.

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Early tumor shrinkage identifies long-term disease control and survival in patients with lung cancer treated with atezolizumab

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000500 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000500 ◽

Cited By ~ 1

Author(s):

Ashley M Hopkins ◽

Ganessan Kichenadasse ◽

Chris S Karapetis ◽

Andrew Rowland ◽

Michael J Sorich

Keyword(s):

Lung Cancer ◽

Patient Reported Outcomes ◽

Hazard Analysis ◽

Progression Free Survival ◽

Survival Outcomes ◽

Tumor Shrinkage ◽

Treatment Benefit ◽

Early Tumor Shrinkage ◽

Patient Reported ◽

Early Tumor

BackgroundPreliminary evidence indicates that early tumor shrinkage (ETS) following immune checkpoint inhibitor (ICI) initiation may be associated with survival outcomes in patients with advanced melanoma. ETS has not been explored as a biomarker of survival outcomes or patient-reported outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with ICIs.MethodsThe study pooled data from patients with NSCLC in the randomized trials OAK and POPLAR (atezolizumab vs docetaxel; n=1464), and single-arm atezolizumab trials BIRCH and FIR (n=797). The association between ETS (≥10% decrease in pretreatment sum-of-longest diameters of target-lesions at 6 weeks) and overall survival (OS), progression-free survival (PFS), time to deterioration (TDD) in health-related quality-of-life (HRQoL) and physical function (PF) was assessed using Cox proportional hazard analysis.ResultsETS occurred in 20% of atezolizumab-treated patients with NSCLC within OAK and POPLAR and was associated with highly favorable OS (HR 0.33, p<0.001), PFS (HR 0.31, p<0.001), TDD in HRQoL (HR 0.73, p=0.01) and PF (HR 0.52, p<0.001). The results were replicated in the BIRCH and FIR data. Atezolizumab-treated patients achieving ETS had markedly improved OS compared with docetaxel-treated patients achieving ETS (24-month OS 55% vs 32%); PFS was also markedly improved (24-month PFS 31% vs 4%). In contrast, for patients not achieving ETS, atezolizumab-treatment was associated with more modest OS (24-month OS 23% vs 20%) and PFS (24-month PFS 3% vs 1%) improvement compared with docetaxel. Overall, the effect size for ETS within the atezolizumab-treated patients was significantly greater than that in the docetaxel-treated patients (P(interaction)=0.002 for OS and P(interaction)<0.001 for PFS).ConclusionsETS is an easily measurable biomarker, predictive of highly favorable survival and patient-reported outcomes with atezolizumab treatment for advanced NSCLC. Further, ETS identifies patients with significantly greater treatment benefit for ICI therapy.

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Randomized, double-blind phase III study of pazopanib versus placebo in patients with metastatic renal cell carcinoma who have no evidence of disease following metastasectomy: A trial of the ECOG-ACRIN cancer research group (E2810).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4502 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4502-4502 ◽

Cited By ~ 5

Author(s):

Leonard Joseph Appleman ◽

Maneka Puligandla ◽

Sumanta K. Pal ◽

Wayne Harris ◽

Neeraj Agarwal ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Cell Carcinoma ◽

Renal Cell ◽

Patient Reported Outcomes ◽

Disease Free Survival ◽

Double Blind ◽

Free Survival ◽

Patient Reported ◽

Disease Free

4502 Background: Patients with no evidence of disease (NED) after metastasectomy for metastatic renal cell carcinoma (mRCC) are at high risk of recurrence, but no systemic therapy has been shown to benefit this population. Pazopanib is an inhibitor of VEGFR and other kinases that improves progression-free survival in patients with measurable RCC metastatic disease. We performed a randomized, double-blind, placebo-controlled multicenter study to test the hypothesis that pazopanib would improve disease-free survival in patients with mRCC rendered NED after metastasectomy Methods: Patients with NED following metastasectomy were randomized 1:1 to receive pazopanib starting at 800 mg daily vs. placebo for 52 weeks. Patients were stratified by 1 vs. > 1 site of resected disease, and by disease-free interval ≤ vs. > 1 year. Clinical assessment for toxicity and patient-reported outcomes were performed every 4 weeks, and restaging scans every 12 weeks. The study was designed to observe a 42% improvement in disease-free survival (DFS) from 25% to 45% at 3 years. Results: From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events had been observed (92% information). The median follow-up from randomization was 30 months (range 0.4 – 66.5 months). The study did not meet the primary endpoint: hazard ratio (95% CI) for DFS was 0.85 (0.55, 1.31) p= 0.47 in favor of pazopanib. At the time of unblinding, 22/129 (17%) of subjects had died. The HR for overall survival (OS) was 2.65 (1.02, 6.9) in favor of placebo ( p= 0.05). Patient-reported outcomes and laboratory correlates will be reported separately. Conclusions: 52 weeks of pazopanib did not improve DFS compared to blinded placebo in patients with mRCC who were NED after metastasectomy. There was a trend toward worse overall survival with pazopanib. Clinical trial information: NCT01575548.

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Patient-reported outcomes and final overall survival results from the randomized phase 3 PENELOPE trial evaluating pertuzumab in low tumor human epidermal growth factor receptor 3 (HER3) mRNA-expressing platinum-resistant ovarian cancer

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2019-000370 ◽

2019 ◽

Vol 29 (7) ◽

pp. 1141-1147 ◽

Cited By ~ 3

Author(s):

Domenica Lorusso ◽

Felix Hilpert ◽

Antonio González Martin ◽

Joern Rau ◽

Petronella Ottevanger ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Patient Reported Outcomes ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Free Survival ◽

End Point ◽

Platinum Resistant ◽

Patient Reported ◽

Epidermal Growth

IntroductionThe PENELOPE trial evaluated pertuzumab added to chemotherapy for biomarker-selected platinum-resistant ovarian cancer. As previously reported, pertuzumab did not statistically significantly improve progression-free survival (primary end point: HR 0.74, 95% CI 0.50 to 1.11), although results in the paclitaxel and gemcitabine cohorts suggested activity. Here, we report final overall survival and patient-reported outcomes.Patients and methodsEligible patients had ovarian carcinoma that progressed during/within 6 months of completing ≥4 platinum cycles, low tumor human epidermal growth factor receptor 3 (HER3) mRNA expression, and ≤2 prior chemotherapy lines. Investigators selected single-agent topotecan, gemcitabine or weekly paclitaxel before patients were randomized to either placebo or pertuzumab (840→420 mg every 3 weeks), stratified by selected chemotherapy, prior anti-angiogenic therapy, and platinum-free interval. Final overall survival analysis (key secondary end point) was pre-specified after 129 deaths. Patient-reported outcomes (secondary end point) were assessed at baseline and every 9 weeks until disease progression.ResultsAt database lock (June 9, 2016), 130 (83%) of 156 randomized patients had died. Median follow-up was 27 months in the pertuzumab arm versus 26 months in the control arm. In the intent-to-treat population there was no overall survival difference between treatment arms (stratified HR 0.90, 95% CI 0.61 to 1.32; p=0.60). Results in subgroups defined by stratification factors indicated heterogeneity similar to previous progression-free survival results. Updated safety was similar to previously published results. Compliance with patient-reported outcomes questionnaire completion was >75% for all validated patient-reported outcomes measures. Pertuzumab demonstrated neither beneficial nor detrimental effects on patient-reported outcomes compared with placebo, except for increased diarrhea symptoms.DiscussionConsistent with the primary results, adding pertuzumab to chemotherapy for low tumor HER3 mRNA-expressing platinum-resistant ovarian cancer did not improve overall survival, but showed trends in some cohorts. Except for increased diarrhea symptoms, pertuzumab had no impact on patient-reported outcomes.ClinicalTrials.gov: ClinicalTrials.gov: NCT01684878.

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Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair–Deficient/Microsatellite Instability–High Metastatic Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2017.76.9901 ◽

2018 ◽

Vol 36 (8) ◽

pp. 773-779 ◽

Cited By ~ 490

Author(s):

Michael J. Overman ◽

Sara Lonardi ◽

Ka Yeung Mark Wong ◽

Heinz-Josef Lenz ◽

Fabio Gelsomino ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Metastatic Colorectal Cancer ◽

Mismatch Repair ◽

Clinical Benefit ◽

Patient Reported Outcomes ◽

Progression Free Survival ◽

Free Survival ◽

Dna Mismatch ◽

Patient Reported

Purpose Nivolumab provides clinical benefit (objective response rate [ORR], 31%; 95% CI, 20.8 to 42.9; disease control rate, 69%; 12-month overall survival [OS], 73%) in previously treated patients with DNA mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC); nivolumab plus ipilimumab may improve these outcomes. Efficacy and safety results for the nivolumab plus ipilimumab cohort of CheckMate-142, the largest single-study report of an immunotherapy combination in dMMR/MSI-H mCRC, are reported. Patients and Methods Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. Primary end point was investigator-assessed ORR. Results Of 119 patients, 76% had received ≥ two prior systemic therapies. At median follow-up of 13.4 months, investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80%. Median duration of response was not reached; most responses (94%) were ongoing at data cutoff. Progression-free survival rates were 76% (9 months) and 71% (12 months); respective OS rates were 87% and 85%. Statistically significant and clinically meaningful improvements were observed in patient-reported outcomes, including functioning, symptoms, and quality of life. Grade 3 to 4 treatment-related adverse events (AEs) occurred in 32% of patients and were manageable. Patients (13%) who discontinued treatment because of study drug-related AEs had an ORR (63%) consistent with that of the overall population. Conclusion Nivolumab plus ipilimumab demonstrated high response rates, encouraging progression-free survival and OS at 12 months, manageable safety, and meaningful improvements in key patient-reported outcomes. Indirect comparisons suggest combination therapy provides improved efficacy relative to anti–programmed death-1 monotherapy and has a favorable benefit-risk profile. Nivolumab plus ipilimumab provides a promising new treatment option for patients with dMMR/MSI-H mCRC.

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