Michael DeRosa

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

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

Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial

BACKGROUND Patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options and poor prognosis. Nivolumab significantly improved survival of this patient population when compared with standard single-agent therapy of investigators choice in Checkmate 141; here we report the effect of nivolumab on patient-reported outcomes (PROs). METHODS CheckMate 141 was a randomised, open-label, phase 3 trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who progressed within 6 months after platinum-based chemotherapy. Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240) or investigators choice (n=121) of methotrexate (40-60 mg/m2 of body surface area), docetaxel (30-40 mg/m2), or cetuximab (250 mg/m2 after a loading dose of 400 mg/m2) until disease progression, intolerable toxicity, or withdrawal of consent. On Jan 26, 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over investigators choice therapy (primary endpoint; described previously). The protocol was amended to allow patients in the investigators choice group to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life-5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment groups in PROs were analysed by ANCOVA among patients with baseline and at least one other assessment. All randomised patients were included in the time to clinically meaningful deterioration analyses. Median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org, number NCT02105636. FINDINGS Patients were enrolled between May 29, 2014, and July 31, 2015, and subsequently 361 patients were randomly assigned to receive nivolumab (n=240) or investigators choice (n=121). Among them, 129 patients (93 in the nivolumab group and 36 in the investigators choice group) completed any of the PRO questionnaires at baseline and at least one other assessment. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from -2·1 to 5·4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By contrast, eight (53%) of the 15 domains in the investigators choice group showed clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, -24·5 to 2·4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in no domains in the nivolumab group and eight (44%) of 18 domains in the investigators choice group. Patients in the nivolumab group had a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the investigators choice group (7·3 vs -7·8). Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab versus investigators choice for 13 (37%) of 35 domains assessed across the three questionnaires. INTERPRETATION In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigators choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigators choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting. FUNDING Bristol-Myers Squibb.

Impact of Nivolumab versus Docetaxel on Health-Related Quality of Life and Symptoms in Patients with Advanced Squamous Non–Small Cell Lung Cancer: Results from the CheckMate 017 Study

Introduction: In the phase III CheckMate 017 study, nivolumab prolonged overall survival versus docetaxel in previously treated patients with advanced squamous NSCLC. Study objectives included health‐related quality of life (HRQoL) and symptom assessments. Methods: Patients serially completed the Lung Cancer Symptom Scale (LCSS) and European Quality of Life Five Dimensions (EQ‐5D) questionnaires. The LCSS average symptom burden index (ASBI) (mean score for six lung cancer–specific symptoms; range 0–100), LCSS three‐item global index, EQ‐5D utility index, and EQ‐5D visual analog scale scores were analyzed. The proportion of patients exhibiting clinically meaningful improvement (a ≥10‐point decrease) in ASBI scores by week 12 was a secondary end point. Mixed‐effect model repeated measures analysis of HRQoL changes from baseline and analyses of time to HRQoL deterioration were conducted. Results: Baseline mean plus or minus SD LCSS ASBI scores were similar in the nivolumab (29.6 ± 16.4) and docetaxel (29.6 ± 14.7) groups. By week 12, the proportions of patients (95% confidence interval) with clinically meaningful improvement in ASBI scores were 20.0% (13.6–27.7) with nivolumab and 21.9% (15.3–29.8) with docetaxel. At weeks 16 to 54, significant improvements in ASBI scores from baseline were seen with nivolumab; clinically meaningful improvements were observed at weeks 42 to 84. No significant changes in ASBI scores from baseline were observed with docetaxel; at week 36, a clinically meaningful deterioration was seen. Improvements in HRQoL with nivolumab versus with docetaxel were supported by other measures, and time to first HRQoL deterioration was longer. Conclusion: Nivolumab alleviates symptom burden and improves health status versus docetaxel as second‐line squamous NSCLC treatment.

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

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

Impact of Pediatric Acute Otitis Media on Child and Parental Quality of Life and Associated Productivity Loss in Malaysia: A Prospective Observational Study

BackgroundAcute otitis media (AOM) affects both child and parental quality of life (QoL). Data on QoL associated with AOM in Malaysia is sparse, and the burden of indirect costs have not been previously reported.ObjectiveTo determine the effect of pediatric AOM on child and parental QoL in Malaysia and its economic impact (indirect costs).MethodsWe utilized a set of QoL questionnaires (PAR-AOM-QOL, OM-6, and EQ-5D) combined with questions addressing work/productivity loss and financial costs associated with caring for a child during his or her illness in an observational, multicenter, prospective study.ResultsOne hundred and ten AOM patients aged ≤5 years were included in the analysis. The majority of respondents were the patient’s mother. Parental QoL was negatively affected for both emotional and daily disturbance scales, but the level of disturbance was low. Using OM-6, the greatest negative impact was on the child’s QoL, followed by caregiver concerns, physical suffering, and emotional distress. Using EQ-5D, a moderately positive relationship between parents’ emotional disturbance and daily disturbance, and a weak, negative correlation between parental emotional disturbance and parental health status was found. Parents with paid employment took an average of 21 h from work to care for their child, at an average cost of 321.8 Malaysian ringgit (US

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

97) in addition to their contribution to direct medical costs. Productivity losses whilst at work, uncompensated wage losses, and leisure time losses are also reported.ConclusionsThis study found that AOM is associated with some negative impact on parental QoL and significant economic impact at both patient and societal levels. The findings provide useful data on healthcare resource utilization and disease burden of AOM in Malaysia.

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

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

3011 Evaluation of overall health status in patients with advanced squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 017

POSTER DISCUSSION SESSION 1 SATURDAY, AUGUST 27, 2016 e 08:00 e 09:15 PD1.01 (also presented as P2.46) LCSS as a Marker of Treatment Benefit With Nivolumab vs Docetaxel in Pts With Advanced Non-Squamous NSCLC From Checkmate 057 Richard J. Gralla, David Spigel, Bryan Bennett, Fiona Taylor, John R. Penrod, Michael Derosa, Homa Dastani, Lucinda Orsini, Clarissa Mathias, Martin Reck Albert Einstein College of Medicine, Bronx/NY/UNITED STATES OF AMERICA, Sarah Cannon Research Institute, Nashville/TN/UNITED STATES OF AMERICA, Adelphi Values, Boston/MA/UNITED STATES OF AMERICA, Bristol-Myers Squibb, Princeton/NJ/ UNITED STATES OF AMERICA, Núcleo de Oncologia da Bahia, Salvador/BRAZIL, Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf/ GERMANY Background: Nivolumab (nivo) is the first antie programmed death-1 agent to demonstrate a survival benefit vs docetaxel (doc) in patients (pts) with previously treated advanced (adv) non-squamous (NSQ) and SQ NSCLC. Here we report the impact of nivo vs doc on disease-related symptoms in pts with adv NSQ NSCLC from the CheckMate 057 study. Method: Lung Cancer Symptom Scale (LCSS) was assessed every other cycle (Q4W) for nivo and every cycle (Q3W) for doc for the first 6 mo on treatment (tx), then every 6 wks and at 2 post-tx follow-up visits. LCSS includes the average symptom burden index (ASBI; based on 6 symptoms: anorexia, fatigue, cough, dyspnea, hemoptysis, and pain) and the 3-item global index (3-IGI; symptom distress, interference with activities, and health-related quality of life [HRQoL]). LCSS changes from baseline (BL) and time to first deterioration (TTD) in symptoms were estimated. Results: Analyses of mean changes from BL in the LCSS ASBI and 3-IGI indicated numerical differences favoring nivo vs doc emerging at the first common assessment (wk 12) and persisting throughout the entire assessment period. At common assessments with >10 pts in each arm (to wk 48), the differences were significant (CIs excluding no difference) for the ASBI at wks 12, 24, 30, and 42, and for the 3-IGI at wks 24 and 30. Five of 6 symptoms (including pain and fatigue) and 2 of 3 items of the 3-IGI (HRQoL and symptom distress) had significant differences favoring nivo at 1 common assessments. TTD (based on the minimally important difference [MID]) was longer with nivo vs doc for the ASBI (HR1⁄40.65; 95% CI: 0.49, 0.85) and 3-IGI (HR1⁄40.63; 95% CI: 0.48, 0.82), with Kaplan-Meier curves between tx arms separating at z2 months. TTD for individual symptoms within the ASBI and individual items of the 3IGI showed a similar pattern. The proportion of pts with improvement in the LCSS ASBI greater than the MID by wk 12 was similar for nivo (17.8%; 95% CI: 13.6, 22.7) and doc (19.7%; 95% CI: 15.2, 24.7). Conclusion: These results from this large, phase III study indicate that pts with previously treated adv NSQ NSCLC had significantly better symptom burden outcomes and HRQoL while on tx with nivo vs doc. TTD was significantly longer in nivovs doc-treated pts. Clinical Trial Registration: NCT01673867 Reused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2016 ASCO Annual Meeting. All rights reserved. PD1.02 (also presented as P2.47) The Role of PD-L1 Expression as a Predictive Biomarker in Advanced NSCLC: An Update of a Network Meta-Analysis Pedro Aguiar Jr., Gilberto Lopes, Ilka Santoro, Hakaru Tadokoro, Carmelia Barreto, Ramon De Mello Clinical Oncology, Universidade Federal de São Paulo, São Paulo/BRAZIL, Oncoclinicas do Brasil, São Paulo/BRAZIL, Universidade Federal de São Paulo, São Paulo/BRAZIL, Universidade do Algarve, Faro/PORTUGAL Background: Advanced lung cancer still portends a poor prognosis. Programmed cell death 1 (PD-1) is a negative costimulatory factor expressed on the surface of T-cells. It binds to one of its ligands; PD-L1 or PD-L2 expressed on the surface of neoplastic cells and inhibits cytotoxic T-cell responses. Several antibodies were developed against PD-1 or PD-L1 achieving encouraging Journal of Thoracic Oncology Vol. 11 No. 10S: S171-S175