Palumbo A, et al. ASCO 2016:LBA4

Background

Daratumumab is a human anti-CD38 monoclonal antibody with both direct and indirect anti-myeloma activity. In a previous phase II trial, daratumumab demonstrated single-agent activity in heavily pretreated patients with relapsed or refractory multiple myeloma (RRMM), achieving an overall response rate (ORR) of 31% and median overall survival (OS) of 20.1 months.1 At ASCO 2016, results from a pre-specified interim analysis of the first randomized phase III trial for daratumumab (in combination with bortezomib and dexamethasone) in patients with RRMM were presented.2

Study design

  • The CASTOR study is a phase III, multicentre, randomized, open-label, active-controlled trial comparing daratumumab in combination with bortezomib and dexamethasone (DVd) vs. bortezomib and dexamethasone alone (Vd) in patients with RRMM who have received ≥1 prior lines of therapy.
  • Patients with prior exposure to bortezomib who were not refractory to this agent were eligible for study participation.
  • The primary endpoint of the study was progression-free survival (PFS).
  • Secondary endpoints included:
    • Time to progression (TTP);
    • OS;
    • ORR, very good partial response (VGPR), complete response (CR);
    • Minimal residual disease (MRD);
    • Time to response; and
    • Duration of response.

Study Design

Study Design

Key findings

Baseline characteristics and patient disposition

  • Patients were enrolled in the study between September 2014 and September 2015.
  • The clinical cut-off date was January 11, 2016 and the median follow-up was 7.4 months (range: 0–14.9 months).
  • Baseline demographics and disease characteristics were well balanced between treatment arms.
  • The median age of patients included in the study was 64 years (range: 30–88).
  • Of the 498 patients randomized in this study, approximately 61% of patients received prior autologous stem cell transplant (ASCT), 68% received prior proteasome inhibitors (PI) treatment, 76% received prior immunomodulatory agents (IMiDs), and 48% received prior PIs and IMiDs.
  • Thirty-three percent of patients were IMiD-refractory and 32% of patients were refractory to their last line of therapy.
  • More patients discontinued treatment in the Vd arm (44%) compared with the DVd arm (31%).
    • The most common reasons for discontinuation in the daratumumab arm and the control arm were progressive disease (19% vs. 25%, respectively) and adverse events (AEs) (8% vs. 10%, respectively).

Efficacy

  • The addition of daratumumab to bortezomib and dexamethasone significantly prolonged PFS compared with bortezomib and dexamethasone alone (median PFS: not reached vs. 7.2 months), with a 61% reduction in the risk of disease progression or death (HR = 0.39, 95% CI: 0.28–0.53), p <0.0001). (Figure 1)
    • The 1-year PFS rate for the DVd arm was 60.7% vs. 26.9% in the Vd arm.
  • A PFS benefit favouring the DVd arm was observed for all subgroups analyzed. (Figure 2)
  • In patients receiving only one prior line of therapy, median PFS was not reached for the DVd arm and was 7.5 months for the Vd arm (HR = 0.31, 95% CI: 0.18–0.52, p <0.0001) and the 1-year PFS rate was 77.5% vs. 29.4%, respectively.
  • TTP was also improved in the DVd arm compared to the Vd arm (median TTP: not reached vs. 7.3 months), with a 70% reduction in the risk of disease progression (HR = 0.30, 95% CI: 0.21–0.43), p <0.0001).
    • The 1-year TTP rate for the DVd arm was 65.4% vs. 28.8% in the Vd arm.
  • DVd significantly improved ORR (83% vs. 63%, p <0.0001), rate of VGPR or better (59% vs. 29%, p <0.0001), and rate CR or better (19% vs. 9%, p = 0.0012) compared with Vd alone.
  • MRD negativity rates were nearly 5-fold higher in the DVd arm vs. the control arm (14% vs. 3%).
  • In the daratumumab arm, the time to achieve partial response was approximately 1 month and the time to achieve CR was approximately 12 months. (Figure 3)
  • In cross-trial comparisons of other PI-based combination therapy studies, the DVd combination in this study reported the highest PFS and ≥CR rate. (Table 1)

Figure 1. Progression-free survival

Figure 1. Progression-free survival

Figure 2. Progression-free survival: subgroup analysis

Figure 2. Progression-free survival: subgroup analysis

Figure 3. Time to response

Figure 3. Time to response

Table 1. Comparison of PI-based studies

Table 1. Comparison of PI-based studies

Safety

  • The most common all grade treatment-emergent AEs (TEAEs) in the DVd and Vd arm respectively were:
    • Thrombocytopenia (59% vs. 44%);
    • Sensory peripheral neuropathy (47% vs. 38%);
    • Diarrhea (32% vs. 22%);
    • Anemia (26% vs. 31%);
    • Upper respiratory tract infection (25% vs. 18%);
    • Cough (24% vs. 13%);
    • Fatigue (21% vs. 25%); and
    • Constipation (20% vs.16%).
  • The DVd arm had a higher frequency of grade 3/4 thrombocytopenia (45% vs. 33%) and neutropenia (13% vs. 4%) than the Vd arm; however, this did not translate into an increase in bleeding events (all grades: 7% vs. 4%, respectively) or infections (grade 3/4: 21% vs. 19%, respectively).
  • Seven percent of patients in the DVd arm and 9% in the Vd arm discontinued therapy due to a TEAE.
    • Only 0.4% of patients in the DVd arm and 3% of patients in the Vd arm discontinued therapy due to any grade sensory peripheral neuropathy.
  • Infusion related reactions (IRRs) occurred in 45% of patients in the DVd arm (grade 3 IRRs: 9%).
  • Of the patients experiencing IRRs, 98% experienced the event during the first infusion.
  • The most common IRRs experienced (all grades/grade 3) were dyspnea (11%/2%), bronchospasm (9%/3%), and cough (7%/0%).
  • No grade 4 or 5 IRRs were observed.
  • Two patients discontinued DVd due to IRRs (bronchospasm in one patient and bronchospasm, laryngeal edema, and skin rash in the other patient).

Key conclusions

  • DVd significantly improved PFS, TTP, and ORR compared with Vd alone.
  • The treatment benefit of DVd vs. Vd was consistent across all subgroups.
  • DVd doubled VGPR and CR rates.
  • DVd was not associated with any cumulative toxicities.
  • The combination of daratumumab, bortezomib, and dexamethasone can potentially be considered a new standard of care for patients with RRMM who would currently be receiving Vd alone.

References: 1. Usmani SZ, Weiss BM, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood 2016;128:37–44. 2. Palumbo A, Chanan-Khan A, Weisel K, et al. Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myelomas (RRMM): CASTOR study. J Clin Oncol (ASCO Annual Meeting) 2016;34(Suppl):abstr LBA4.

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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.