Docirbrutinib generated responses in patients with relapsed/refractory CLL/SLL, MCL, and other non-Hodgkin lymphomas.
Docirbrutinib (AS-1763), an investigational, noncovalent, pan-mutant Bruton tyrosine kinase (BTK) inhibitor, produced durable responses in patients with heavily pretreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and other non-Hodgkin lymphomas (NHLs), according to updated results from an ongoing phase 1b study (NCT05602363) presented in a poster session at the
Docirbrutinib elicited an overall response rate (ORR) of 100% in patients with MCL who received the treatment at the 400-mg twice-daily dose level (n = 4), which was identified as the provisional recommended phase 2 dose (RP2D); 3 patients achieved complete responses (CRs), and the remaining 4 patients achieved partial responses (PRs). Regarding patients with other NHLs who received docirbrutinib at the RP2D, patients with Waldenström macroglobulinemia achieved an ORR of 100% (n = 1), those with marginal zone lymphoma (MZL; n = 2) achieved an ORR of 50%, and no patients with follicular lymphoma responded. Patients in the trial with CLL/SLL who received docirbrutinib at the RP2D (n = 11) achieved an ORR of 73%.
“These results support the continued development of docirbrutinib toward the next phase of investigation,” Nitin Jain, MD, and coauthors wrote in the poster.
Jain is a professor of medicine in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.
The study is evaluating the agent in patients who are aged at least 18 years with an ECOG performance status of 2 or lower. Patients also need to have received at least 2 prior lines of systemic therapy, including a covalent BTK inhibitor.
If patients have transformed disease prior to or during screening, have received proton pump inhibitors within 7 days of their first dose, have undergone major surgery within 4 weeks of their first dose of docirbrutinib, or have known central nervous system involvement via systemic lymphoma, they are not being enrolled in the study.2
Highlights of Docirbrutinib Across B-Cell Malignancies
The trial comprises a dose-escalation phase and dose-expansion cohorts. The dose-escalation phase starts with 100-mg twice-daily doses of docirbrutinib, and the doses increase by 100 mg until a maximum dose of 500 mg.1 There are 3 cohorts in the study: a CLL/SLL cohort, an NHL cohort, and a cohort of patients who have been previously treated with pirtobrutinib (Jaypirca).
Baseline characteristics from the current readout revealed that patients in the CLL/SLL cohort (n = 33) had a median age of 69 years (range, 56-86); the median age was 68 years (range, 46-84) in the NHL cohort (n = 25), and patients in both cohorts had received a median of 4 prior lines of therapy. All patients with CLL/SLL had prior covalent BTK inhibitor exposure, and 64% of these patients had also received a BCL2 inhibitor. In the NHL cohort, 36% of patients had prior covalent BTK inhibitor exposure, and 4% of patients had been previously exposed to a BCL2 inhibitor. Regarding noncovalent BTK inhibitors, 9% and 8% of patients in each respective cohort had been previously exposed.
Among patients in the CLL/SLL cohort, BTK mutations were identified in 43%, and PLCG2 mutations were identified in 7%; 38% of patients harbored 17p deletions and/or TP53 mutations, and 97% of patients had unmutated IGHV.
Across all dose levels, the ORR among patients with CLL/SLL (n = 28) was 57%, with a median progression-free survival (PFS) that was not yet reached and a 12-month PFS rate of 72%. Four patients maintained their PFS beyond 24 months.
At the RP2D in the CLL/SLL cohort, 6 of 7 patients who were exposed to both a covalent BTK inhibitor and a BCL-2 inhibitor achieved a PR or PR with lymphocytosis. Among patients with BTK C481 mutations (n = 4), 75% experienced a PR, including 1 patient with concurrent BTK C481S and L528W mutations and another with concurrent BTK C481S and PLCG2 mutations.
In the cohort of patients who were previously treated with pirtobrutinib, 3 with CLL remained on treatment, with 1 achieving stable disease (SD) and 2 not yet evaluable for response. Out of the 2 patients with MCL who were previously treated with pirtobrutinib, 1 achieved SD, and 1 had progressive disease.
Any-grade treatment-emergent adverse effects (TEAEs) occurred in 88% of all evaluable patients across every cohort (n = 58), with grade 3 or higher TEAEs occurring at a rate of 43% and serious TEAEs occurring at a rate of 24%. TEAEs led to dose interruption or reduction in 36% of patients, treatment discontinuation in 2% of patients, and death in 3% of patients. No cases of drug-related atrial fibrillation or hypertension were reported. The most common TEAEs reported in at least 10% of patients included diarrhea, nausea, upper respiratory tract infection, dizziness, constipation, cough, fatigue, urinary tract infection, and COVID-19.
