Phase Ib Study of Ianalumab (VAY736) and Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL) on Ibrutinib Therapy
Authors: Rogers Kerry A. , Flinn Ian W. , McGarry Carolyn , Gou Liangke Connie , Hassounah Nadia , Woo Janghee , Byrd John C. 
Published: November 2020

Introduction:
B cell activating factor receptor (BAFF-R) promotes the maturation and survival of normal and malignant B cells. VAY736 is a human investigational Fc-engineered afucosylated monoclonal antibody (mAb) targeting BAFF-R and enhancing NK-cell mediated antibody-dependent cellular cytotoxicity (ADCC). VAY736 demonstrated superior ADCC compared with anti-CD20 mAbs in the clinic and showed promising antileukemic activity in CLL preclinical models (McWilliams EM, et al. Blood Adv 2019;3:447-460). Although Bruton tyrosine kinase inhibitors such as ibrutinib and recently acalabrutinib have become the standard treatment for many patients (pts) with CLL, these agents require indefinite treatment and result in cumulative toxicity. Ibrutinib + VAY736 has synergy in preclinical studies prompting the hypothesis that this combination may deepen responses and allow pts to discontinue ibrutinib.
Methods:
This Phase Ib dose escalation/expansion trial (NCT03400176) of VAY736 + ibrutinib enrolled pts with R/R CLL who were receiving ibrutinib following relapse from another approved therapy and had either failed to achieve a CR after &gt;1 y of ibrutinib treatment or had developed a mutation associated with resistance to ibrutinib. Pts received VAY736 IV at 0.3, 1, 3, or 9 mg/kg every 2 weeks + oral ibrutinib at 420 mg daily for 6 28-day cycles. After 6 cycles, pts with a CR discontinued VAY736 and received ibrutinib for an additional 2 cycles; a protocol amendment allowed all other pts to continue VAY736 + ibrutinib for an additional 2 cycles. Pts achieving CR and minimal residual disease (MRD)-negativity at Day 1 of Cycle 9 (C9D1) could discontinue ibrutinib at the investigator's discretion. The primary objective was to characterize the safety and tolerability of the combination and to determine the maximum tolerated dose (MTD)/recommended dose for expansion.
Results:
A total of 15 pts (median age: 65 years; ECOG PS 0: 93%) were treated by the data cutoff (June 9, 2020). Overall, 11 pts completed and 3 discontinued combination treatment (primarily due to disease progression); 1 pt remains on treatment. Most pts (73%) had an ibrutinib resistance mutation at baseline (mainly [82%] BTKC481) and 33% had received ≥4 prior regimens (median: 3, range: 1-5); median duration of prior ibrutinib was 4.1 y (range: 0.2-8.3). Baseline cytogenetics were (not mutually exclusive): 27% del(17)(p13.1), 80% unmutated IGHV, 80% stimulated complex karyotypes (≥3 abnormalities), 60% del(13)(q14), and 7% +12.
No dose-limiting toxicities have been observed and the MTD has not been reached. A total of 14 (93%) pts experienced an AE regardless of cause. Four (27%) pts experienced AEs of grade ≥3, including decreased neutrophil count (n=3), hypophosphatemia (n=2), decreased white blood cell count, leukocytosis, increased lymphocyte count, hypertension, hypokalemia, and hypomagnesemia (n=1 each).
The overall response at C9D1 was CR in 6 (40%) pts, SD in 4 (27%) pts, PD in 4 (27%) pts, and not assessed in 1 (7%) pt (still on treatment). The mean baseline CLL cells in bone marrow for the CR, SD, and PD groups were 27% (range: 0.8-60.6%), 13% (range: 2.5-27%), and 66% (range: 47-77.9%). Three (20%) pts with CR achieved MRD-negativity and were able to discontinue CLL-directed therapy including ibrutinib; they remained in CR for 1-16 months after ibrutinib discontinuation. The median percentage change from baseline in blood MRD was -92.8% (range: -100%; -16.7%; Figure 1) and in bone marrow MRD was -89.6% (range: -100%; -32.6%). Of the pts who had baseline ibrutinib-resistance mutations and C9D1 assessments, 1 pt (1/6) tested negative for ibrutinib-resistance mutations at C9D1. None of the pts who were ibrutinib-resistance mutation negative at baseline (4/4) developed mutations by C9D1.
VAY736 concentration increased with dose, accumulated after repeated dosing in combination with ibrutinib, and achieved linear PK at 3 mg/kg or above. Tissue receptor occupancy was &gt;99% for VAY736 doses of 3 mg/kg or above. Free BAFF was accumulated to steady state with no dose relationship.
Conclusions:
VAY736 + ibrutinib had an acceptable safety profile and demonstrated promising preliminary activity in pts with R/R CLL on ibrutinib, providing clinical evidence of a potential to discontinue ibrutinib by VAY736 add-on therapy. Further investigation of this combination including in pts on 1st line ibrutinib and other ibrutinib combinations is ongoing.

Disclosures
Rogers: AstraZeneca: Consultancy, Other: Travel Funding; Janssen: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Research Funding; Acerta Pharma: Consultancy; Pharmacyclics: Consultancy. Flinn:Juno Therapeutics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Nurix Therapeutics: Consultancy; BeiGene: Consultancy, Research Funding; Loxo: Research Funding; Calithera Biosciences: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Vincera Pharma: Consultancy; Roche: Consultancy, Research Funding; Teva: Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Infinity Pharmaceuticals: Research Funding; Incyte: Research Funding; Takeda: Consultancy, Research Funding; IGM Biosciences: Research Funding; Johnson & Johnson: Other; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Triphase Research & Development Corp.: Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Constellation Pharmaceuticals: Research Funding; Merck: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; ArQule: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; Curio Science: Consultancy; Acerta Pharma: Research Funding; Forma Therapeutics: Research Funding; Forty Seven: Research Funding; AbbVie: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Agios: Research Funding; Genentech, Inc.: Research Funding; Great Point Partners: Consultancy; Iksuda Therapeutics: Consultancy. McGarry:Novartis: Current Employment. Gou:Novartis: Current Employment. Hassounah:Novartis: Current Employment. Woo:Novartis: Current Employment. Byrd:Leukemia and Lymphoma Society: Other; Trillium: Research Funding; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Acerta Pharma: Research Funding; Syndax: Research Funding; Vincera: Research Funding.