Vecabrutinib, a reversible, noncovalent Bruton’s tyrosine kinase inhibitor, exhibited evidence of clinical activity in adults with B-cell malignancies without producing any grade ≥3 treatment-related adverse events.
John Allan, MD
Vecabrutinib, a reversible, noncovalent Bruton’s tyrosine kinase (BTK) inhibitor, exhibited evidence of clinical activity in adults with B-cell malignancies without producing any grade ≥3 treatment-related adverse events (TEAEs), according to data presented at the 2019 ASH Annual Meeting.
Among 29 patients who were previously exposed to ibrutinib (Imbruvica) and subsequently treated with vecabrutinib as part of a phase Ib/II dose escalation trial, there have been no patients with an objectively defined response, but 7 patients did experience stable disease.1 Three of 5 patients who dose escalated to cohort 5 (300 mg twice daily) have stable disease, 2 of whom remain on treatment.
“We anticipate that with higher doses, we may start to see responses, as we are starting to see a potential signal at the doses that we’re at right now,” John Allan, MD, said in an interview with OncLive. “The longest patient on study is approaching about a year and has been through all of the dose cohorts and has been escalated…so we see some signs of stability of disease and in some of the more recent patients at higher dose levels, we’ve had close to partial responses and they remain on study.”
Mutations in BTK cysteine residue C481, which is required for covalent bond formation, occurs in most patients with chronic lymphocytic leukemia who have relapsed while on covalent BTK inhibition. Vecabrutinib, a noncovalent inhibitor of wild-type and C481S-mutated BTK, binds to the BTK kinase domain independent of C481, which suggests that it might have activity in both covalent BTK inhibitor-relapsed and -naïve disease, said Allan.
“The class in general is felt to be able to potentially overcome BTK mutations, which are the major reason for covalent-bound BTK inhibitor resistance, and therefore these agents have improved pharmacokinetics that might be able to regain efficacy in these BTK-mutated resistant patients to covalent-bound inhibitors,” said Allan, assistant professor of medicine, Weill Cornell Medicine, New York City.
Of the 29 patients enrolled so far, 23 have chronic lymphocytic leukemia (CLL). As part of phase Ib of the study, they were treated in an open-label fashion using a modified 3+3 design, starting at 25 mg twice daily (cohort 1). Dose escalation has progressed to 400 mg (cohort 6), with no dose-limiting toxicities (DLTs). Cohort 7 will receive vecabrutinib at 500 mg twice daily, is planned before a phase 2 study in CLL/small lymphocytic leukemia (SLL) commences.
Patients must have received ≥2 prior regimens and progressed on therapy with a covalent BTK inhibitor. Patients continue to receive vecabrutinib until time of progression or intolerable toxicity. The safety period for assessment of DLT is cycle 1 (4 weeks).
Three patients received treatment in cohort 1, 10 in cohort 2 (50 mg twice daily), 7 in cohort 3 (100 mg twice daily), 4 in cohort 4 (200 mg twice daily), and 5 in cohort 5 (400 mg twice daily). In addition to the 23 patients with CLL, 2 had mantle cell lymphoma, 3 had Waldenstrom Macroglobulinemia, and 1 had marginal zone lymphoma. The median number of prior regimens is 4.
At screening, among the 23 patients with CLL, 78% had mutated or deleted TP53, 61% had BTK C481 mutations, 13% had phospholipase C gamma 2 (PLCg2) mutations, and 57% had del(17p). Some 83% had unmutated IVHV.
There were 10 serious AEs in 7 patients, none of which were considered drug-related. These included cellulitis, intestinal perforation, pleural effusion, pain in extremity, lymphocytosis, deep vein thrombosis, hematuria, myelitis, and sepsis.
The most common TEAEs of any grade were anemia (35%), headache (28%), and night sweats (24%). Headache and nausea (10% each) were the 2 most common drug-related TEAEs. To date, no drug-related grade 3 or 4 TEAEs have been observed at dose levels >50 mg.
Of the 7 patients with stable disease, 4 had BTK C481S mutations and 3 had BTK C481 wild type disease. All other patients in cohorts 1 to 5 had disease progression at or before the first response assessment and discontinued treatment, other than 1 patient who withdrew consent.
The pharmacokinetic profile of vecabrutinib showed sustained exposure over the dosing interval. Exposure and median steady-state trough concentrations continue to increase with vecabrutinib dose.
Phase II of the study will focus on patients with BTK inhibitor-resistant, mutationally defined CLL/SLL and those with prior BTK inhibitor intolerance.
Allan JN, Pinilla-Ibarz J, Gladstone DE, et al. 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. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 3041. bit.ly/2sWpJl2.