ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL)

Background: Acalabrutinib is a highly selective, covalent irreversible Bruton tyrosine kinase inhibitor with minimal activity against other kinases. Acalabrutinib has demonstrated durable responses as a single agent or combined with O in treatment-naïve (TN) CLL. Here, interim results are presented for the multicenter, open-label Phase 3 ELEVATE-TN study (NCT02475681), which evaluated the efficacy and safety of acalabrutinib + O vs acalabrutinib alone vs O + Clb in pts with TN CLL. Methods: Eligible pts had TN CLL requiring treatment per iwCLL criteria and were aged ≥65 y or <65 y with coexisting conditions (CIRS score >6, creatinine clearance <70 mL/min). Pts were randomized 1:1:1 to receive oral acalabrutinib (100 mg twice daily continuously) alone or combined with intravenous O (1000 mg on Days 1, 2 [split 100/900], 8, and 15 of Cycle 2, and Day 1 of subsequent 28-day cycles for a total of 6 cycles), or O plus oral Clb (0.5 mg/kg on Days 1 and 15 of each 28-day cycle for 6 cycles). Pts were stratified by del(17p) status, ECOG status (≤1 vs 2), and geographic region. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS) with acalabrutinib + O vs O + Clb. Key secondary endpoints included IRC-assessed PFS with acalabrutinib vs O + Clb, IRC-assessed overall response rate (ORR), overall survival (OS), and safety. Minimal residual disease (MRD) in peripheral blood or bone marrow was assessed in pts with investigator-assessed complete response (CR)/CR with incomplete marrow recovery (CRi). Crossover to acalabrutinib monotherapy was allowed for pts in the O + Clb arm with IRC-confirmed progression. Results: From 9/14/2015-2/8/2017, 535 pts were randomized to the acalabrutinib + O (n=179), acalabrutinib (n= 179), or O + Clb (n=177) arms. The median age was 70 y (range, 41-91); 69% had high- and 12% had very high-risk CLL IPI scores. At a median follow-up of 28 mo, acalabrutinib + O significantly prolonged PFS vs O + Clb (median not reached [NR] vs 22.6 mo; HR 0.10, 95% CI 0.06-0.18, P<0.0001), reducing the risk of progression or death by 90% (Figure). Acalabrutinib (median NR) also prolonged PFS vs O + Clb (HR 0.20, 95% CI 0.13-0.31, P<0.0001). Estimated 30-mo PFS rates with acalabrutinib + O, acalabrutinib, and O + Clb were 90%, 82%, and 34%, respectively. PFS improvement with acalabrutinib + O or acalabrutinib vs O + Clb was consistent across subgroups examined including del(17p) (HR [95% CI]; 0.13 [0.04-0.46]; 0.20 [0.06-0.64]). Median OS was not reached in any arm; (HR [95% CI]; acalabrutinib + O vs O + Clb, 0.47 [0.21-1.06], P=0.0577; acalabrutinib vs O + Clb, 0.60 [0.28-1.27], P=0.1556). In the acalabrutinib + O, acalabrutinib, and O + Clb arms, the estimated 30-mo OS rates were 95%, 94%, and 90%, respectively. Five pts (3%) in the acalabrutinib + O arm, 11 pts (6%) in the acalabrutinib arm, and 55 pts (31%) in the O + Clb arm had received a next therapy; 45 pts (25%) in the O + Clb arm crossed over to the acalabrutinib monotherapy arm. IRC-assessed ORR was higher with acalabrutinib + O (94%; 95% CI, 89.3%-96.5%) vs O + Clb (79%; 95% CI, 71.9%-83.9%; P<0.0001); the ORR with acalabrutinib monotherapy was 85%. CR rates were higher with acalabrutinib + O (13%) vs O + Clb (5%); there was 1 CR in the acalabrutinib monotherapy arm. MRD data will be presented. The median treatment duration was 27.7 mo for acalabrutinib + O (range, 2.3-40.3) and acalabrutinib (range, 0.3-40.2) and 5.6 mo (range, 0.9-7.4) for O + Clb. Common adverse events (AEs) are shown in the Table. AEs were similar between the acalabrutinib-containing arms. Infusion reactions were less frequent with acalabrutinib + O (13%) than with O + Clb (40%). AEs led to treatment discontinuation in 20 pts (11%) on acalabrutinib + O, 16 pts (9%) on acalabrutinib, and 25 pts (14%) on O + Clb. With >2 y of follow-up, 79.3% of pts in both the acalabrutinib-containing arms remain on single-agent acalabrutinib. AEs of interest (acalabrutinib + O or acalabrutinib vs O + Clb) were atrial fibrillation (any grade: 3% or 4% vs 1%), bleeding (any grade/Grade ≥3: 43%/2% or 39%/2% vs 12%/0%), and hypertension (Grade ≥3: 3% or 2% vs 3%). Conclusions: Acalabrutinib + O and acalabrutinib monotherapy significantly improved PFS vs O + Clb, with tolerable safety in pts with TN CLL. Despite cross over for disease progression in the O + Clb arm, a trend toward improved OS was observed in both acalabrutinib arms, though longer follow-up is needed. Disclosures Sharman: AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding. Banerji:CIHR: Research Funding; LLSC: Research Funding; Research Manitoba: Research Funding; CCMF: Research Funding; CancerCare Manitoba/University of Manitoba: Employment; CAPhO: Honoraria; BIOGEN: Other: Licensing fee; Dana-Farber Cancer Institute: Other: Licencing fee; Gilead: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Licensing fee, Research Funding; Abbvie: Consultancy, Honoraria. Herishanu:Janssen: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Munir:Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; AbbVie: Honoraria. Walewska:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Speakers Bureau; Takeda: Other: Travel grant; Novartis: Other: travel grant. Follows:Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Karlsson:Skane University Hospital: Employment. Ghia:AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Juno/Celgene: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Corbett:Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Tauranga Hospital: Employment; Pathlab Waikato: Equity Ownership. Walker:Peninsula Health (public hospital): Employment; Alfred health (public hospital): Employment; Roche: Other: Travel grant. Jurczak:Incyte: Research Funding; Takeda: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Roche: Research Funding; Gilead: Research Funding; Celgene: Research Funding; MorphoSys: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Research Funding. Salles:Epizyme: Consultancy, Honoraria; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events. Janssens:Novartis: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; abbvie: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; idem consultancy: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Cymbalista:AstraZeneca: Honoraria; Janssen: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Gilead: Honoraria; Abbvie: Honoraria. Wierda:Juno Therapeutics: Research Funding; Janssen: Research Funding; Cyclcel: Research Funding; KITE pharma: Research Funding; Loxo Oncology Inc.: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Acerta Pharma Inc: Research Funding; P

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