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Clinical Efficacy of Daratumumab Monotherapy in Patients with Heavily Pretreated Relapsed or Refractory Multiple Myeloma

2015; Elsevier BV; Volume: 126; Issue: 23 Linguagem: Inglês

10.1182/blood.v126.23.29.29

1528-0020

Saad Z. Usmani, Brendan M. Weiss, Nizar J. Bahlis, Andrew R. Belch, Sagar Lonial, Henk M. Lokhorst, Peter M. Voorhees, Paul G. Richardson, A. Kate Sasser, Amy Axel, Huaibao Feng, Clarissa Uhlar, Jianping Wang, Imran Khan, Tahamtan Ahmadi, Hareth Nahi,

Cancer therapeutics and mechanisms

Abstract Introduction : Daratumumab (DARA) is a novel human CD-38-targeting monoclonal antibody in clinical development for multiple myeloma (MM). In two clinical studies (NCT00574288 [GEN501] and NCT01985126 [Sirius]), DARA monotherapy showed remarkable clinical activity and was well tolerated in heavily treated patients (pts) with relapsed and refractory (RR) MM (Lokhorst HM. J Clin Oncol 2014;32 Suppl:abstr 8513. Lonial S. J Clin Oncol 2015;33 Suppl: abstr LBA8512). A combined analysis of efficacy of 16 mg/kg DARA in these two studies is presented. Methods : GEN501, a first-in-human open-label, two-part (Part 1 dose escalation; Part 2 dose expansion) study, enrolled pts with MM that had relapsed after or were refractory to ≥2 prior therapies. Sirius, an open-label, two-part study, enrolled pts with MM with ≥3 prior therapies, including a PI or IMiD, or were refractory to both a PI and an IMiD. Eligibility criteria included pts with absolute neutrophil count ≥1000/mm3, hemoglobin ≥7.5 g/dL, platelet count ≥75×109/L (GEN501) or ≥50×109/L (Sirius), and alanine aminotransferase ≤3.5 (GEN501) or ≤2.5 (Sirius) times the upper limit of normal. In GEN501 Part 2, the first 16 mg/kg DARA infusion was followed by a 3 week rest period, and then qw for 7 weeks, q2w for 14 weeks, and q4w thereafter. In Sirius, 16 mg/kg DARA was infused qw for 8 weeks, q2w for 16 weeks, and q4w thereafter. The combined analysis comprised pts treated with 16 mg/kg DARA in Sirius and Part 2 of GEN501. In both studies overall response rates (ORR) were assessed according to IMWG response criteria. Results: The combined analysis included 148 pts (42 and 106 pts from GEN501 and Sirius, respectively). The median (range) age was 64 (31-84) years. Median time since initial diagnosis was 5.8 and 4.8 years in GEN501 and Sirius, respectively, and 62% and 82% of pts had received >3 prior therapies, respectively. In GEN501, 76% of pts were refractory to their last therapy and 64% were refractory to both a PI and IMiD; a greater proportion of pts in Sirius were refractory to their last therapy (97%) and double refractory to a PI and IMiD (95%). The ORR was 36% in GEN501 and 29% in Sirius; the ORR for the combined analysis was 31%. Best overall response is shown in Table. Responses deepened over time and the combined rate of very good partial response (VGPR) or better was 11% with 2 pts with complete responses (CR) and 3 with stringent CRs (sCR) across the two studies. In the combined analysis, median duration of response was 7.6 months and 46% of responders remained progression free at 1-year after a median follow-up of 9.3 months. Median overall survival (OS) had not been reached at median follow-up times of 10.2 months (GEN501) and 9.3 months (Sirius). The estimated 1-year OS rate (95% CI) was 77% (58-88), 65% (51-76), and 69% (58-77) for GEN501, Sirius, and the combined analysis, respectively. Forty-four of 46 responders were still alive at the time of the primary analysis. At a subsequent data cutoff for the combined analysis, after a median follow-up of 14.8 months, the estimated median OS was 19.9 months (95% CI, 15.1 - not estimable). ORR was similar across prespecified subgroups which included age, ISS stage, number of prior therapies, and refractory status. Conclusions : Single-agent DARA (16 mg/kg) demonstrated remarkable clinical activity (31% ORR) in a combined analysis of two studies in heavily pretreated MM pts. The quality of the observed responses (11% VGPR or better, 2 CRs, and 3 sCRs) was noteworthy in this highly refractory population. DARA shows promising activity in pts who have exhausted other approved myeloma treatment options. Table. Best Overall Response. 16 mg/kg MMY2002 n (%) GEN501 Part 2 n (%) Total n (%) Combined analysis set 106 42 148 Best response Stringent Complete Response (sCR) 3 (2.8) 0 3 (2.0) Complete response (CR) 0 2 (4.8) 2 (1.4) Very good partial response (VGPR) 10 (9.4) 2 (4.8) 12 (8.1) Partial response (PR) 18 (17.0) 11 (26.2) 29 (19.6) Minimal response (MR) 5 (4.7) 4 (9.5) 9 (6.1) Stable disease (SD) 46 (43.3) 22 (52.4) 68 (45.9) Progressive disease (PD) 18 (17.0) 0 18 (12.2) Not evaluable (NE) 6 (5.7) 1 (2.4) 7 (4.7) Overall response (sCR+CR+VGPR+PR) 31 (29.2) 15 (35.7) 46 (31.1) Disclosures Usmani: Celgene Corporation: Consultancy, Honoraria; Janssen: Research Funding; Onyx: Consultancy, Honoraria, Research Funding. Weiss:Janssen and Millennium: Consultancy; Janssen and Onclave: Research Funding. Bahlis:Johnson & Johnson: Research Funding; Amgen: Consultancy; Johnson & Johnson: Consultancy; Johnson & Johnson: Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Lonial:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Lokhorst:Genmab: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Voorhees:Janssen, Celgene, GlaxoSmithKline,Onyx Pharmaceuticals and Oncopeptides: Consultancy, Research Funding; Array BioPharma, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Millennium/Takeda and Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Axel:Janssen: Employment. Feng:Janssen: Employment. Uhlar:Janssen: Employment. Wang:Janssen: Employment. Khan:Janssen: Employment. Ahmadi:Janssen: Employment. Nahi:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.