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2631 Investigating the Addition of Ianalumab (VAY736) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL) on Ibrutinib Therapy: Results from a Phase Ib Study

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Clinical Trials, Lymphoid Leukemias, Biological therapies, Adults, CLL, Workforce, Diseases, Therapies, Lymphoid Malignancies, Monoclonal Antibody Therapy, Study Population
Sunday, December 12, 2021, 6:00 PM-8:00 PM

Kerry A. Rogers, MD1, Ian W. Flinn, MD, PhD2, Deborah M. Stephens3, Thomas J. Kipps, MD, PhD4*, Sarah Larson, MD5, Carolyn McGarry, BA6*, Nadia B. Hassounah, PhD7*, Liangke Connie Gou, PhD6*, Janghee Woo, MD, PhD7 and John C. Byrd, MD8

1Division of Hematology, The Ohio State University, Columbus, OH
2Sarah Cannon Research Institute, Nashville, TN
3University of Utah School of Medicine, Salt Lake City, UT
4Center for Novel Therapeutics, Moores Cancer Center, University of California San Diego, La Jolla, CA
5Ronald Reagan UCLA Medical Center, Los Angeles, CA
6Early Development Analytics, Novartis Pharma AG, East Hanover, NJ
7Oncology Translational Research, Novartis Institutes for BioMedical Research, Cambridge, MA
8Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH

Introduction:

B-cell activating factor receptor (BAFF-R) enhances the survival and regulation of normal and malignant B cells. VAY736 is a human monoclonal antibody (mAb) targeting BAFF-R that targets BAFF-R+ B cells for elimination by antibody-dependent cell-mediated cytotoxicity (ADCC). VAY736 has anti-leukemia activity in preclinical CLL models that is superior to that of anti-CD20 mAbs (McWilliams EM, et al. Blood Adv 2019;3:447–460). Although Bruton’s tyrosine kinase inhibitors (BTKis; acalabrutinib, ibrutinib) are the current standard of care for CLL, the indefinite length of monotherapy required may result in cumulative clinical or economic toxicity and/or acquired treatment resistance. In preclinical models, adding VAY736 to ibrutinib significantly improved survival and reduced disease burden, suggesting that this combination may augment the anti-leukemia response and allow patients (pts) to discontinue ibrutinib.

Methods:

This dose escalation/expansion trial (NCT03400176) enrolled pts with CLL undergoing either first- or second-line therapy with ibrutinib and whose disease failed to achieve a complete response (CR) after >1 year of therapy or who had CLL with a mutation associated with ibrutinib resistance. Pts received oral ibrutinib (420 mg) once daily and VAY736 IV at 0.3, 1, 3, or 9 mg/kg once every 2 weeks. In the expansion, pts were enrolled into 2 arms depending on whether ibrutinib resistance mutations were present at baseline. Pts received VAY736 + ibrutinib for up to 6 28-day cycles. After 6 cycles, pts with a CR discontinued VAY736 and received ibrutinib for an additional 2 cycles; all other pts continued VAY736 + ibrutinib for those 2 cycles. Pts achieving undetectable minimal residual disease (uMRD) at C9D1 could discontinue ibrutinib at the investigator’s discretion. This study aimed to characterize the safety and tolerability of VAY736 + ibrutinib, determine the recommended dose for expansion (RDE), and explore the efficacy of this combination.

Results:

A total of 32 pts (median age 65 years; ECOG PS 0: 91%) were treated prior to data cutoff (May 10, 2021). Overall, 19 pts completed therapy and 4 discontinued VAY736 + ibrutinib (primarily due to disease progression); 4 pts remain on VAY736 + ibrutinib and 5 pts continue to receive ibrutinib. Of the enrolled pts, 44% had CLL cells with mutations associated with ibrutinib resistance (mainly [71%] BTKC481); the median number of prior regimens was 1 (range: 0.0–14.0); median duration of prior ibrutinib therapy was 3.5 years (range: 0.2–8.3). Baseline cytogenetics were (not mutually exclusive): 19% del(17)(p13.1), 75% unmutated IGHV, 59% stimulated complex karyotypes (≥3 abnormalities), 34% del(11)(q22.3), 44% del(13)(q14), and 6% +12.

No dose-limiting toxicities were observed and the RDE was 3 mg/kg, based on pharmacokinetics, exposure-to-response relationship, pharmacodynamics, safety, and in vitro ADCC. Twelve (38%) pts experienced AEs of Grade ≥3, most common (occurring in ≥2 pts) were neutrophil count decreased (n=5), lymphocyte count decreased (n=2), hypophosphatemia (n=2), and elevated lipase (n=2).

The overall response at C9D1 for evaluable pts (n=21) was 38% CR, 5% CRi, 14% PR, 24% SD, and 19% PD (Fig. 1A). Thirteen (41%) pts achieved uMRD in blood. Eight pts (42%, 8/19) and 8 pts (42%, 8/19) had uMRD in blood and bone marrow (BM) at end of treatment (EoT), respectively. Among those, 6 pts were elected to discontinue ibrutinib and remained off treatment for 0.2–26.2 months and were still off therapy at the data cutoff. The median percentage change from baseline in MRD was –99.0% (range: –100.0% to –16.7%) and –97.3% (range: –100.0% to 1346.3%) in blood and BM, respectively. None of the pts who enrolled with CLL cells lacking mutations associated with ibrutinib resistance (11/11) developed mutations by C9D1. Although 1 pt with PLCG2 mutation eradicated mutant clones at EoT with VAY736, the response may vary depending on the type of mutation (Fig. 1B).

Conclusions:

VAY736 + ibrutinib was well tolerated with an acceptable safety profile enabling dose expansion. Clinical activity was observed including multiple pts attaining uMRD status in blood and BM, allowing 6 to discontinue ibrutinib therapy for an extended period. These data provide clinical evidence of the potent anti-leukemia activity of VAY736 and the potential to safely discontinue ibrutinib or other BTKi by VAY736 add-on therapy.

Disclosures: Rogers: AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Janssen: Research Funding. Flinn: Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Seattle Genetics: Research Funding. Stephens: Abbvie: Consultancy; JUNO: Research Funding; Novartis: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; CSL Behring: Consultancy; Arqule: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Mingsight: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy. Kipps: Oncternal Therapeutics, Inc.: Current equity holder in publicly-traded company, Patents & Royalties: Cirmtuzumab, Research Funding; Pharmacyclics/AbbiVie: Honoraria, Research Funding; Genentech/Roche: Honoraria; Celgene: Honoraria, Research Funding; VelosBio, Inc.: Research Funding; Janssen, Gilead, Dava Oncology,: Honoraria; Breast Cancer Research Foundation: Honoraria, Research Funding; Md Anderson Cancer Center: Research Funding; Gilead: Honoraria; National Cancer Institute/NIH: Honoraria, Research Funding; OncLive: Honoraria; Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS): Research Funding; California Institute for Regenerative Medicine (CIRM): Research Funding; European Research Initiative on CLL (ERIC): Honoraria; Dava Oncology: Honoraria; Patient Power, LLC: Honoraria; iwNHL: Honoraria; NCCN CLL/SLL Hairy Cell Leukemia Panel Meeting: Honoraria. Larson: TORL biotherapeutics: Current holder of individual stocks in a privately-held company; Abbvie: Research Funding; Bioline: Research Funding; BMS: Research Funding; Celgene: Research Funding; GSK: Research Funding; Janssen: Research Funding; Juno: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Takeda: Research Funding. McGarry: Novartis Institutes for Biomedical Research: Current Employment. Hassounah: Novartis Institutes for Biomedical Research: Current Employment, Patents & Royalties: unrelated . Gou: Novartis Pharma AG: Current Employment. Woo: Novartis: Current Employment, Current equity holder in publicly-traded company. Byrd: Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria.

*signifies non-member of ASH