Reck M, et al. ESMO 2016:1217PD

Background

In the randomized, open-label, phase III study CheckMate 057, the anti-programmed death-1 antibody nivolumab demonstrated superior overall survival (OS) and a favourable safety profile compared with docetaxel in previously treated patients with advanced non-squamous (SQ) non-small cell lung cancer (NSCLC).1 Additionally, CheckMate 057 examined patient-reported outcomes (PROs), including symptom burden and health status. The impact of nivolumab versus docetaxel on overall patient-reported health status in this study population was presented at ESMO 2016.2

Study design

  • CheckMate 057 was a randomized, open-label, international phase III study comparing nivolumab with docetaxel in patients with non-SQ NSCLC that had progressed on or after platinum-based doublet chemotherapy.

Study Design

Study Design

  • For this portion of the study, the research questions were as follows:
    • Do changes from baseline in health status differ by treatment?
    • Does health status of patients who remain on treatment improve?
    • Does time to deterioration of health status differ by treatment?
  • The health status PRO measures studied in CheckMate 057 were the EuroQol-five dimensions (EQ-5D) visual analogue scale (VAS) and the EQ-5D utilities index (UI).
  • The symptom burden PRO measures studied were the Lung Cancer Symptom Scale (LCSS) average symptom burden index (ASBI) and the LCSS 3-item global index.
  • The EQ-5D and LCSS were assessed every other cycle (i.e., every four weeks) for nivolumab, and every cycle (i.e., every three weeks) for docetaxel for the first six months on treatment, then every six weeks and at two post-treatment follow-up visits.
  • The EQ-5D was also assessed during survival follow-up: every three months for the first year and then every six months thereafter.
  • Analyses were completed using the primary dataset (database lock March 18, 2015).

Key findings

Baseline characteristics and disposition

  • Baseline demographics and disease characteristics were balanced between the nivolumab and docetaxel groups.
  • EQ-5D and LCSS completion rates were relatively similar between the two treatment arms, although rates in the nivolumab arm were slightly higher at baseline:
    • EQ-5D: 83.6% for nivolumab vs. 80.0% for docetaxel; and
    • LCSS: 82.2% for nivolumab vs. 76.6% for docetaxel.

EQ-5D results

  • EQ-5D VAS changes from baseline within each treatment arm were as follows:
    • Nivolumab: brief statistically significant worsening from baseline was observed at Week 4, followed by estimated improvements until Week 78; from Weeks 16–36, improvements from baseline were statistically significant, with clinically meaningful improvements (i.e., greater than the scale-defined minimally important difference) at Weeks 24 and 36.
    • Docetaxel: no statistically significant changes from baseline were reported at any on-treatment assessment.
  • For EQ-5D UI, no statistically significant changes from baseline were reported at any on-treatment assessment for either treatment arm, apart from a worsening at Week 4 for nivolumab.
  • Between arms, no significant on-treatment differences in EQ-5D VAS or UI scores at specific assessments were observed.
  • There was a significant improvement from baseline in the EQ-5D VAS for patients treated with nivolumab, compared with no change for patients treated with docetaxel.
  • Significant between-treatment arm differences in changes from baseline were observed favouring nivolumab for the EQ-5D VAS.
  • The analysis for the EQ-5D UI showed no differences from baseline within either of the treatment arms or between treatment arms.
  • Time to first deterioration (TTD) in health status in the EQ-5D VAS was slower with nivolumab vs. docetaxel, with Kaplan-Meier curves separating at approximately four months. (Figure 1)
  • TTD in the EQ-5D UI was similar between arms (HR = 0.90; 95% CI: 0.69–1.17).

LCSS results

  • A similar percentage of patients treated with nivolumab and docetaxel had demonstrated a clinically meaningful improvement in the LCSS ASBI by Week 12 (17.8% [52/292] and 19.7% [57/290], respectively).
  • LCSS ASBI changes from baseline within each treatment arm were as follows:
    • Nivolumab: brief statistically significant worsening at Week 4, followed by estimated improvements until Week 78; from Weeks 16–54, improvements from baseline were statistically significant.
    • Docetaxel: statistically significant worsening at Week 9; other changes from baseline through Week 48 indicated stable symptoms.
  • Numerical differences in mean LCSS ASBI changes from baseline favouring the nivolumab arm emerged at the first common assessment (Week 12) and persisted throughout the on-treatment assessment period.
    • At common assessments with ≥10 patients in each arm (to Week 48), differences were statistically significant for the LCSS ASBI at Weeks 12, 24, 30, and 42, favouring the nivolumab arm.
  • Analyses of mean changes from baseline in the LCSS 3-item global index indicated numerical differences favouring the nivolumab arm, emerging at the first common assessment (Week 12) and persisting throughout the on-treatment assessment period.
    • At common assessments with >10 patients in each arm (to Week 48), differences were significant for the LCSS 3-item global index at Weeks 24 and 30, favouring the nivolumab arm.
  • Patients treated with nivolumab showed significant improvement from baseline in the LCSS 3-item global index.
  • For patients treated with docetaxel, statistically significant deterioration was observed for the LCSS ASBI and 3-item global index.
  • Significant between-treatment arm differences were observed in favour of nivolumab for the LCSS ASBI and 3-item global index.
  • TTD in the LCSS ASBI was slower with nivolumab vs. docetaxel, with Kaplan-Meier curves separating at approximately two months; a similar relationship was observed for the LCSS 3-item global index (HR = 0.63; 95% CI: 0.48–0.82). (Figure 2)

Figure 1. Time to first disease-related deterioration in EQ-5D VAS

Figure 1. Time to first disease-related deterioration in EQ-5D VAS

Figure 2. Time to first disease-related deterioration in LCSS ASBI

Figure 2. Time to first disease-related deterioration in LCSS ASBI

Key conclusions

  • Together, both the EQ-5D VAS and the LCSS indicated better preservation of health status, health-related quality of life, and symptom control with nivolumab vs. docetaxel in this trial of patients with pretreated, advanced non-SQ NSCLC.
    • No differences within or between arms were observed with the EQ-5D UI.
  • Both the EQ-5D VAS and the LCSS indicated relative improvement in PROs for nivolumab over docetaxel.
  • It is notable that these improvements were seen earlier with the LCSS than with the EQ-5D VAS, and that both PRO instruments indicated benefit earlier than the separation of the survival curves, which also favoured nivolumab.

References: 1. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627–39. 2. Reck M, Brahmer J, Bennett B, et al. Overall health status (HS) in patients (pts) with advanced non-squamous (NSQ) NSCLC treated with nivolumab (nivo) or docetaxel (doc) in CheckMate 057. Ann Oncol (ESMO Annual Meeting) 2016;27(Suppl 6):vi424. Abstract 1217PD.

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Canadian Perspectives

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Carolyn Owen, MD
Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, UK. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre & Tom Baker Cancer Centre, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.

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Graeme Fraser, MD, MSc, FRCPC
Dr. Graeme Fraser graduated from the University of Western Ontario (UWO) and completed post-graduate training in Internal Medicine and Hematology at UWO and McMaster University, respectively. His training in malignant hematology was supported by a National Cancer Institute of Canada–Terry Fox Foundation Clinical Research Fellowship. Dr. Fraser is a hematologist at the Juravinski Cancer Centre/Hamilton Health Sciences in Hamilton, Ontario, and he is an Associate Professor in the Department of Oncology. His research interests include the care of adolescent and young adult cancer patients, clinical trials in chronic lymphocytic leukemia, lymphoma, and myeloma, and practice guideline development as a member of the Cancer Care Ontario Program in Evidence-Based Care.

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Laurie H. Sehn, MD, MPH
Dr. Laurie H. Sehn is a Clinical Assistant Professor at the BC Cancer Agency and the University of British Columbia in Vancouver. She has been a medical oncologist and clinical investigator with the Lymphoma Tumour Group since 1998. Dr. Sehn has served on the Board of Directors of Lymphoma Canada (LC) since 2002 and is now Director of Research Fellowships for LC. Her research interests include the lymphoid cancers with particular focus on the biology and treatment of large-cell
lymphoma, the application of new imaging techniques such as PET scanning to lymphoma management, and innovative new approaches to treatment.

Investigator Commentaries

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Alessandra Tedeschi, MD
Dr. Alessandra Tedeschi obtained her medical degree from the University of Bologna, Italy and subsequently trained in hemato-oncology at the University of Ancona, Italy. She completed two research stages on lymphoproliferative disorders in the Department of Hematology at the Niguarda Hospital in Milan, Italy. Dr. Tedeschi has been a consultant in Hematology at the Niguarda Cancer Center, Niguarda Hospital in Milan, Italy since 1999. Her clinical work focuses on the treatment of patients with indolent lymphoproliferative disorders and her research interests include the study of chronic lymphocytic leukemia (CLL) and Waldenström’s macroglobulinemia. Dr. Tedeschi is a principal and co-investigator on many national and international trials in CLL. She has published over 60 peer-reviewed research articles.

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Veronique Leblond, MD
Dr. Veronique Leblond is a Professor and Head of the Department of Hematology at Pitié–Salpêtrière Hospital, Paris, France. She is the chair of the French Innovative Leukemia Group (FILO), focusing on acute leukemia, chronic lymphocytic leukemia (CLL), and Waldenström’s macroglobulinemia (WM), which includes more than 90 centres in France and Belgium. Dr. Leblond is responsible for a rare tumour network (K-VIROGREF) dedicated to the management of transplant recipients with virus-induced tumours, funded by the French National Cancer Institute (INCA) in 2012, and she is the head of GRECHY (Groupe de Recherche Clinique Hémopathie Lymphoïde) at the Pierre and Marie Curie University in Paris, France. She is also a member of the French Society of Hematology and the American Society of Hematology. Dr. Leblond was the principal investigator of several biological and clinical trials in WM and CLL. She received the Robert Kyle award in 2008 and the Waldenström award in 2012. Dr. Leblond is connected to several very active patient associations and charities including Laurette Fugain, SiLLC (Soutien et Information à la Leucémie Lymphoïde Chronique et la Maladie de Waldenström), International WM Foundation, and Waldenström France. She is an author of over 280 research articles, books, and book chapters.

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Simon Rule, MD
Dr. Simon Rule is a Professor in Hematology at the Institute of Translational & Stratified Medicine, Plymouth University Peninsula Schools of Medicine & Dentistry, and a Hematologist at the Derriford Hospital in Plymouth, United Kingdom (UK). He has been a member of the National Cancer Research Network (NCRN) Lymphoma Committee since 2000 and serves as Chair of the NCRN Low Grade Lymphoma Clinical Studies Group. Dr. Rule’s clinical research interests are in non-Hodgkin lymphoma (NHL) and new drug development, with a specific interest in mantle cell lymphoma. Dr. Rule has been an author of over 70 publications in peer-reviewed journals. Over the last five years, Dr. Rule has been the Chief Investigator on 12 National studies and Principal Investigator on over 40 studies, mostly involving NHL. Within the UK, Dr. Rule runs all of the national clinical trials for mantle cell lymphoma.

Expert Commentary

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Clemens-Martin Wendtner, MD
Dr. Clemens-Martin Wendtner is a Professor of Medicine and the Director of the Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine at the Klinikum Schwabing, Munich — an academic hospital of the University of Munich. He completed his MD at the University of Münster in 1993. Thereafter, he received postdoctoral training at the Max-Planck-Institute in Martinsried, Germany and at the National Institutes of Health (NIH) in Bethesda, U.S.A., until 1995. After a clinical fellowship at the University of Munich, he gained his German and U.S.A. licence (ECFMG) in Internal Medicine before specializing as a hematologist and oncologist at the same institution. Dr. Wendtner received his postdoctoral lecture qualification at the University of Munich in 2002, and since 2004, has been a full professor of Internal Medicine, Hematology, and Medical Oncology at the University of Cologne. Dr. Wendtner is a member of multiple national and international societies in the field of Medicine and has won several research awards, including first prize at the 6th International Symposium on Biological Therapy of Cancer in Munich, and a merit award from the American Society of Clinical Oncology. As a founding member of the German CLL Study Group (GCLLSG), he participates on the Steering Committee and is Secretary of the GCLLSG. He has been principal investigator for numerous phase I–III clinical studies, and his interests focus on the development of new therapies in the field of CLL.

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Tony SK Mok, MD, FRCP(C), FRCP, FHKCP, FHKAM
Professor Tony Mok studied medicine at the University of Alberta and subsequently completed his fellowship training at the Princess Margaret Hospital in Toronto. After practising oncology and internal medicine for seven years in Toronto, he returned to Hong Kong in 1996 to pursue an academic career. Prof. Mok is a Li Shu Fan Medical Foundation Named Professor and Chairman of Clinical Oncology at The Chinese University of Hong Kong, Hong Kong. His main research interest focuses on biomarker and molecular targeted therapy in lung cancer. He co-founded the Lung Cancer Research Group, and has led a number of important multinational clinical trials, which include the IPASS (IRESSA Pan-Asia Study), a landmark study that established the role of first-line gefitinib in patients with EGFR mutation. Prof. Mok is the Past President of the International Association for the Study of Lung Cancer (IASLC), Past Chair of the American Society of Clinical Oncology (ASCO) International Affairs Committee, a member of the ASCO Publications Committee and Vice Secretary of the Chinese Society of Clinical Oncology (CSCO). Prof. Mok has contributed to over 200 articles in international peer-reviewed journals, including the New England Journal of Medicine, Science, Lancet, and Journal of Clinical Oncology, and contributed to multiple editorials and textbooks. He is an Editor on Thoracic Oncology for the Journal of Clinical Oncology. He has also authored eight books in Chinese and hosted three television series in Hong Kong.

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Barbara Melosky, MD, FRCP(C)
Dr. Barbara Melosky is a Clinical Associate Professor of Medicine at the University of British Columbia and a medical oncologist at the BC Cancer Agency in Vancouver. She graduated from medical school at the University of Manitoba, and did a residency in internal medicine and an oncology fellowship at the University of British Columbia. Dr. Melosky is currently working in the fields of lung and gastrointestinal malignancies with a special interest in the side effects of targeted therapy. She sits on the Executive Committee for the Lung Disease Site NCIC Clinical Trials Group and is the annual Chair of the Canadian Lung Cancer Conference.

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Sandeep Sehdev, MD
Dr. Sandeep Sehdev is an Assistant Professor (adjunct) at McMaster University in Hamilton and a medical oncologist serving the William Osler Health System in Brampton and Etobicoke and the Headwaters Healthcare Centre in Orangeville. He graduated from medical school at the University of Ottawa and completed a residency in oncology at the University of Toronto and Princess Margaret Hospital. Dr. Sehdev is currently a general community oncologist and continuing health education lead for oncology with a special interest in advocacy, community oncology and patient education, and applications of technology in learning. He has been involved in multiple multicentre clinical trials.