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3107 Safety and Efficacy of Daratumumab Monotherapy in Patients with Heavily Pretreated Relapsed and Refractory Multiple Myeloma: Final Results from GEN501 and Sirius

Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Sunday, December 10, 2017, 6:00 PM-8:00 PM
Bldg A, Lvl 1, Hall A2 (Georgia World Congress Center)

Saad Z Usmani, MD1, Hareth Nahi2*, Brendan M Weiss, MD3, Nizar J. Bahlis, MD4, Andrew Belch5*, Henk M Lokhorst6*, Peter M. Voorhees, MD7, Paul G Richardson, MD8, Clarissa Uhlar9*, Jianping Wang9*, Ming Qi9* and Sagar Lonial, MD10

1Levine Cancer Institute/Carolinas HealthCare System, Charlotte, NC
2Karolinska Institute, Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, Stockholm, Sweden
3Division of Hematology-Oncology, Department of Medicine, Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
4Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada
5Cross Cancer Institute, Edmonton, AB, Canada
6Department of Hematology, VU University Medical Center, Amsterdam, Netherlands
7Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC
8Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
9Janssen Research & Development, Spring House, PA
10Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA

Introduction: Daratumumab (DARA) is a CD38-targeting IgGκ monoclonal antibody with antimyeloma activity mediated by both on-tumor and immunomodulatory mechanisms of action. In two clinical studies (NCT00574288 [GEN501] and NCT01985126 [SIRIUS]), DARA monotherapy induced rapid, deep, and durable responses with a favorable safety profile in patients with heavily treated, relapsed and refractory multiple myeloma (Lokhorst HM. N Engl J Med 2015;373[13]:1207-1219. Lonial S. Lancet 2016;387[10027]:1551-1560). A combined analysis of patients who received 16 mg/kg DARA in these studies at a median follow-up of 20.7 months was reported previously (Usmani SZ. Blood 2016;128[1]:37-44). Here, we present the final safety and efficacy findings for these patients after median follow-up of approximately 3 years.

Methods: GEN501 was a first-in-human, open-label, phase 1/2 study comprising a dose-escalation phase (Part 1) and a dose-expansion phase (Part 2). The study enrolled patients with MM that had relapsed after or was refractory to ≥2 prior therapies. In Part 2, patients received an initial infusion of 16 mg/kg DARA, which was followed by a 3-week rest period and then by DARA infusions once weekly (QW) for 7 weeks, once every 2 weeks (Q2W) for 14 weeks, and once every 4 weeks (Q4W) thereafter. SIRIUS was an open-label phase 2 study of DARA in patients with MM who had received ≥3 prior therapies, including a proteasome inhibitor (PI) or immunomodulatory drug (IMiD), or who were double refractory to a PI and an IMiD. Patients (n = 106) received 16 mg/kg DARA IV QW for 8 weeks, Q2W for 16 weeks, and Q4W thereafter. Patients treated with 16 mg/kg DARA in GEN501 Part 2 and in SIRIUS were included in this combined analysis. Overall response rate (ORR) was calculated based on computerized algorithm results from both studies.

Results: The combined analysis included 148 patients (42 from GEN501 Part 2 and 106 from SIRIUS) who were treated with 16 mg/kg DARA. Seventy-six percent of patients had received >3 prior therapies. Ninety-one percent of patients were refractory to their last line of therapy, and 87% were refractory to both a PI and an IMiD. In the combined analysis set, the median duration of follow-up was 36.6 (range 0.5-42.3) months.

The most common (≥20%) treatment-emergent adverse events (TEAEs) observed across the 2 studies were unchanged from previous reports: fatigue (42%), nausea (30%), anemia (28%), back pain (27%), cough (26%), upper respiratory tract infection (22%), neutropenia (21%), thrombocytopenia (21%), pyrexia (20%), and nasal congestion (20%). The most common (≥5%) grade 3 or 4 TEAEs were anemia (18%), thrombocytopenia (14%), neutropenia (10%), and hypertension (5%). Infusion-related reactions were observed in 71 (48%) patients and predominantly occurred during the first infusion.

ORR was 30.4% (95% confidence interval [CI], 23.1-38.5), with 20 (13.5%) patients achieving VGPR or better and 7 (4.7%) achieving CR or better (Table). In both studies, deep responses were maintained over time. Among responders, the median duration of response was 8.0 months (95% CI 6.5-14.7), and 19.6% (95% CI 9.0-33.2) of responders remained progression free at 3 years. Median overall survival (OS) was 20.5 months (95% CI 16.6-28.1, Figure), and the 3-year OS rate was 36.5% (95% CI 28.4-44.6). Case reports of patients with prolonged, ongoing responses will be described.

Conclusions: After 3 years of median follow-up, single-agent DARA continues to demonstrate a favorable safety profile with no new safety signals. Deep and durable responses continue to be maintained in a subset of these heavily pretreated patients. With over one-third of patients remaining alive after 3 years of study entry, these findings highlight the activity of single-agent DARA in this heavily pretreated population.

Disclosures: Usmani: Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Research Funding; Array BioPharma: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weiss: Janssen: Research Funding; Alnylam: Honoraria; Janssen: Honoraria; Prothena: Research Funding; Prothena: Honoraria. Bahlis: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Belch: Amgen, Celgene, Takeda: Honoraria. Lokhorst: OncoImmune: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Voorhees: Novartis: Consultancy; Amgen: Speakers Bureau; Takeda: Consultancy; Oncopeptides: Consultancy; Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy. Richardson: Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Uhlar: Janssen: Employment. Wang: Janssen: Employment. Qi: Johnson & Johnson, LLC: Equity Ownership; Janssen: Employment.

*signifies non-member of ASH