Ongoing Results of a Phase 1B/2 Dose-Escalation and Cohort-Expansion Study of the Selective, Noncovalent, Reversible Bruton'S Tyrosine Kinase Inhibitor, Vecabrutinib, in B-Cell Malignancies

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.3041-3041
• Main Authors: Allan, John N., Patel, Krish, Mato, Anthony R., Wierda, William G., Pinilla Ibarz, Javier, Choi, Michael Y., O'Brien, Susan M., Sharman, Jeff P., Shadman, Mazyar, Gladstone, Douglas E, Davids, Matthew S., Pagel, John M., Ward, Renee, Acton, Gary, Taverna, Pietro, Fox, Judith A., Furman, Richard R., Brown, Jennifer R.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-126286

Background: Vecabrutinib is a selective, reversible, noncovalent BTK inhibitor (BTKi) with potent in vitro inhibitory activity against both wild type and C481S-mutated BTK, the most common mutation detected in patients (pts) with CLL relapsing on treatment with covalent BTKi (cBTKi). Methods: This is an open-label, modified 3+3 dose-escalation, cohort expansion phase 1b/2 trial to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and antitumor activity of oral vecabrutinib in adult pts with relapsed/refractory advanced B-cell malignancies who must have received ≥2 prior regimens and progressed on therapy with a cBTKi where available as an approved indication. Prespecified dose levels are 25 to 500 mg PO BID. Patients continue to receive vecabrutinib until time of progression or intolerable toxicity. The safety period for DLT assessment is Cycle 1 (4 weeks). Activity is monitored throughout study treatment and for survival. Molecular profiles, PK, and PD are also evaluated. Results: To date, 27 pts (chronic lymphocytic leukemia [CLL], n=21; mantle cell lymphoma [MCL], n=2; Waldenström's macroglobulinemia [WM], n=3; marginal zone lymphoma (MZL), n=1) have been treated (Cohort 1, 25 mg BID, n=3; Cohort 2, 50 mg BID, n=10; Cohort 3, 100 mg BID n=7, Cohort 4, 200 mg BID n=4, Cohort 5, 300 mg BID n=3): median age 66 yrs (range: 47-77), 96% ECOG PS 0-1, 73% male, median prior regimens 4 (range: 2-9) all including a cBTKi (23 pts ibrutinib, 4 pts acalabrutinib). At screening, 76% (19/25) had mutated or deleted TP53, 48% (12/25) had BTK C481 mutations and 20% (5/25) had phospholipase C gamma 2 (PLCg2) mutations. BTK C481 mutation was found in 11 CLL pts (C481S n= 8 variant allelic frequency [VAF] 7-93%, C481R n=2, [VAF 49%, 77%], C481P n=1 [VAF 28%]) and in one pt with WM (C481S [VAF 8%]). One CLL pt had both BTK C481S (VAF 20%) and T474I (gatekeeper residue, VAF 32%) mutation. Five pts (3 CLL, 1 WM and 1 MZL) had PLCg2 mutations; only one of the CLL pts had an activating PLCg2 mutation (S707F; VAF 8%). Overall, NGS on a panel of 128 genes known to be recurrently mutated in lymphoid malignancies detected a median of 5 mutations/pt; the most common mutated genes were SF3B1 (24%), NOTCH1 and ATM (20% each). Safety: the MTD has not been reached through Cohort 4. Adverse Events (AEs) are available for 24 pts; the most common all-grade AEs were anemia (37.5%), headache, neutropenia and night sweats (each 25%). Drug-related Grade