Final Results for the 1703 Phase 1b/2 Study of Elotuzumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma

Abstract INTRODUCTION Elotuzumab (Elo) is a humanized IgG1 monoclonal antibody targeted against Signaling Lymphocytic Activation Molecule F7 (SLAMF7, also known as CS1). Through both direct activation and engagement of natural killer cells, Elo selectively targets and kills SLAMF7-expressing myeloma cells. In Ph1 of the 1703 multicenter, open-label, dose-escalation study, intravenous (IV) Elo, escalated from 5 to 20 mg/kg plus lenalidomide (Len) and low-dose dexamethasone (dex), resulted in an 82% objective response rate (ORR) in patients with relapsed/refractory multiple myeloma (RRMM).1 Here we report final Ph1 and Ph2 results. METHODS Patients with RRMM treated with ≥1 prior therapy in Ph1 or 1–3 prior therapies in Ph2 were enrolled (NCT00742560). Methods for the Ph1 portion have been described previously.1 Patients in the Ph2 cohort were randomized to 10 or 20 mg/kg Elo. Treatment was administered in 28-day cycles; patients received IV Elo on Days 1, 8, 15, and 22 for cycles 1–2 and on Days 1 and 15 for subsequent cycles. Patients also received oral Len (25 mg; Days 1–21) and oral dex (28 mg plus 8 mg IV on Elo dosing days, or 40 mg once weekly). Treatment continued until disease progression or unacceptable toxicity. All patients in Ph2 received a premedication regimen before Elo dosing to mitigate infusion reactions (IRs). Elo was infused at up to 2 mL/min for cycles 1–4 and could be escalated up to 5 mL/min for subsequent cycles. The primary endpoint was ORR (≥partial response) according to International Myeloma Working Group criteria; secondary endpoints included progression-free survival (PFS) and safety.1 RESULTS In Ph1, 28 patients were treated (5 mg/kg, n=3; 10 mg/kg, n=3; 20 mg/kg, n=22) and median PFS was 33 months. In Ph2, 73 patients (median age 63 years; range 39–82) were treated (10 mg/kg, n=36; 20 mg/kg, n=37). The median number of treatment cycles was 22 (range 3–49) for the 10 mg/kg group and 16 (range 1–51) for the 20 mg/kg group. At data cut-off (16 January 2014), 13 patients in Ph2 (10 mg/kg, n=6; 20 mg/kg, n=7) were still on treatment and 60 patients had discontinued due to disease progression (57%), adverse events (AEs; 20%), or other reasons (23%). Overall, ORR was 84% (10 mg/kg, 92%; 20 mg/kg, 76%). A stringent complete response/complete response (sCR/CR) was seen in 14% of patients, 43% had a very good partial response (VGPR), and 27% had a partial response (PR). Median time to objective response was 1 month (range 0.7–19). Median PFS was 29 months (10 mg/kg, 32 months; 20 mg/kg, 25 months). When stratified by level of response, median PFS was not reached for patients with sCR/CR (n=10) and was reached at 36 and 16 months for VGPR (n=31) and PR (n=20), respectively. The most common treatment-emergent AEs were diarrhea (66%), muscle spasms (62%), fatigue (56%), constipation (51%), nausea (48%), and upper respiratory tract infection (47%), similar to those reported for Ph1.1 Serious AEs were experienced by 58% of patients, most commonly pneumonia (12%). Seven patients (10%) had IRs at a flow rate ≤2 mL/min. Flow rate was increased for those who did not have an IR at 2 mL/min. A total of 46 patients received infusions at a rate >2 mL/min, 31 of whom received infusions at the maximum rate of 5 mL/min. No new AEs were seen at rates >2 mL/min compared with ≤2 mL/min; 1 patient (2%) had an IR (Grade 1 nausea) at >2 mL/min. Overall rate of IRs was 11%. At the time of this analysis, 5 deaths across the Ph1 and Ph2 cohorts were reported in the database. Active follow-up on overall survival has been initiated and more complete information is planned to be reported in the final presentation. CONCLUSIONS In this Ph1b/2 study, Elo in combination with Len/dex demonstrated robust and clinically meaningful efficacy as measured by ORR and PFS. Elo/Len/dex was generally well tolerated at all doses studied with no dose-limiting toxicities observed. No new safety signals were observed in Ph2. Elo administration at rates up to 5 mL/min resulted in a low incidence of IRs. The novel mechanism of action of Elo and its apparent safety and efficacy when combined with Len/dex in this study support the ongoing Elo Ph3 Clinical Development Program in RRMM and first-line multiple myeloma. 1Lonial S, et al. J Clin Oncol. 2012:30:1953-9. This study is being funded by Bristol-Myers Squibb in collaboration with AbbVie Biotherapeutics. Professional medical writing and editorial assistance was provided by Kathryn Rees at Caudex Medical and was funded by Bristol-Myers Squibb. Disclosures Richardson: Bristol-Myers Squibb, Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Elotuzumab is an investigational agent being studied for the treatment of multiple myeloma. Jagannath:Celgene; Bristol-Myers Squibb; Sanofi-Aventis: Honoraria. Moreau:Bristol-Myers Squibb, Celgene, Novartis, Millenium, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx: Consultancy; Bristol-Myers Squibb, Celgene, Janssen, Millenium, Novartis, Onyx, SkylineDx: Honoraria; Celgene, Janssen, Onyx: Speakers Bureau; Bristol-Myers Squibb, Celgene, Janssen, Millenium, Novartis, Onyx, SkylineDx: Advisory board, Advisory board Other. Facon:Bristol-Myers Squibb and Celgene: Consultancy, Speakers Bureau. Vij:Onyx: Honoraria, Research Funding; Sanofi: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Millennium: Honoraria; Celgene: Honoraria, Research Funding; Array: Honoraria. White:Celgene, Janssen: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees. Reece:Celgene, Janssen: Consultancy; Otsuka, Celgene, Janssen, Millenium, Novartis, Merck, Bristol-Myers Squibb: Research Funding; Otsuka, Celgene, Janssen, Millenium, Novartis, Amgen: Honoraria. Benboubker:Celgene: Consultancy; Celgene, Millennium: The TAKEDA Oncology Company, Onyx Therapeutics, Lilly and Company: Honoraria. Zonder:Bristol-Myers Squibb: Consultancy. Tsao:AbbVie: Employment. Anderson:Celgene, Onyx, Millennium, Gilead, Sanofi-Aventis, Bristol-Myers Squibb: Consultancy; Oncopep, Acetylon: Equity Ownership; Celgene, Onyx, Millennium, Gilead, Sanofi-Aventis, Bristol-Myers Squibb, Oncopep, Acetylon: Membership on an entity's Board of Directors or advisory committees. Bleickardt:Bristol-Myers Squibb: Employment. Singhal:AbbVie: Employment. Lonial:Millennium, Celgene, Novartis, Bristol-Myers Squibb, Onyx: Consultancy, Research Funding.

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