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31 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)Clinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. CLL: Therapy, excluding Transplantation: First Line Treatment
Hematology Disease Topics & Pathways:
antibodies, Leukemia, Biological, Diseases, Therapies, CLL, enzyme inhibitors, gene therapy, Clinically relevant, Lymphoid Malignancies
Saturday, December 7, 2019: 7:30 AM
Hall D, Level 2 (Orange County Convention Center)

Jeff P. Sharman, MD1, Versha Banerji, MD2, Laura Maria Fogliatto, MD, PhD3, Yair Herishanu, MD4*, Talha Munir, MD5*, Renata Walewska6*, George Follows7*, Karin Karlsson, MD8*, Paolo Ghia, MD, PhD9, Gillian Corbett10*, Patricia Walker, MBBS11*, Miklos Egyed12*, Wojciech Jurczak, MD, PhD13*, Gilles A. Salles, MD, PhD14, Ann Janssens15*, Florence Cymbalista, MD, PhD16*, William G. Wierda, MD, PhD17, Steven Coutre, MD18, John M. Pagel, MD, PhD, DSc19, Alan Skarbnik, MD20,21, Manali Kamdar, MD22, Jennifer Woyach, MD23, Raquel Izumi, PhD24, Veerendra Munugalavadla, PhD24, Priti Patel, MD24, Min Hui Wang, PhD24*, Sofia Wong24* and John C Byrd, MD25

1Willamette Valley Cancer Institute and Research Center & US Oncology, Eugene, OR
2Department of Internal Medicine, Biochemistry & Medical Genetics, University of Manitoba, Research Institute in Oncology and Hematology, Winnipeg, MB, Canada
3Universidade Federal do Rio Grande do Sul (UFRS), Porto Alegre, Brazil
4Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
5Haematological Malignancy Diagnostic Service (HMDS), St. James’s Institute of Oncology, Leeds, United Kingdom
6Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, United Kingdom
7Department of Haematology, Addenbrooke's Hospital NHS Trust, Cambridge, United Kingdom
8Department of Hematology, Oncology and Radiation Physics, Skane University Hospital, Lund, Sweden
9Università Vita-Salute San Raffaele and IRCCS San Raffaele Scientific Institute, Milan, Italy
10Department of Medicine, Tauranga Hospital, Tauranga, New Zealand
11Department of Haematology, Alfred Health-Monash University, Melbourne, VIC, Australia
12Department of Hematology, Somogy County Mór Kaposi General Hospital, Kaposvár, Hungary
13Department of Hematology, Jagiellonian University Medical College, Kraków, Poland
14service d'hématologie clinique, Hospices civils de Lyon, centre hospitalier Lyon Sud, Pierre-Bénite, France
15Hematology Department, University of Leuven, Leuven, Belgium
16Bobigny: Hématologie, CHU Avicennes, Bobigny, France
17University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX
18Stanford Univ. School of Med., Stanford, CA
19Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA
20Novant Health, Charlotte, NC
21Hackensack University Medical Center, Hackensack, NJ
22Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado Cancer Center, Aurora, CO
23The Ohio State University Comprehensive Cancer Center, Columbus, OH
24Acerta Pharma, South San Francisco, CA
25Comprehensive Cancer Center, The Ohio State University, Columbus, OH

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: AbbVie: Honoraria; Alexion: Honoraria; 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. 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: AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Janssen: 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: Amgen: Honoraria, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, 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. 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; Pharmacyclics LLC: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; Miragen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Gilead Sciences: Research Funding; GSK/Novartis: Research Funding. Coutre: Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; BeiGene: Other: Travel, Accommodations, Expenses & Data Safety Monitoring Committee; Genentech: Consultancy. Pagel: AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Skarbnik: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau. Kamdar: AstraZeneca: Consultancy; University of Colorado: Employment; Celgene: Consultancy; Seattle Genetics: Speakers Bureau; Pharmacyclics: Consultancy. Woyach: Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Izumi: AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib patents. Munugalavadla: Acerta Pharma: Employment; Gilead Sciences: Equity Ownership; AstraZeneca: Equity Ownership. Patel: Acerta Pharma: Employment, Equity Ownership; AstraZeneca: Equity Ownership. Wang: Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Wong: Acerta Pharma: Employment. Byrd: Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; Acerta: Research Funding; Acerta: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; BeiGene: Research Funding; BeiGene: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau.

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