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

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