Resistance-Targeting BTK Inhibitor ARQ 531 Active Across B-Cell Malignancies

Jennifer A. Woyach, MD

The investigational Bruton tyrosine kinase (BTK) inhibitor ARQ 531 demonstrated safety and clinical activity across a range of B-cell malignancies, a preliminary clinical trial showed.

Overall, 14 of 47 patients had partial responses (PRs) with ARQ 531, which targets the BTK-C481S mutation associated with resistance to ibrutinib (Imbruvica). An additional 10 patients had stable disease associated with tumor reduction of as much as 48%. Responses were observed in patients with chronic lymphocytic leukemia (CLL), Richter’s transformation (RT), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL).

Across a range of doses as high as 75 mg QD, no dose-limiting toxicity occurred, and treatment with ARQ 531 was associated with a low frequency of toxicities. No atrial fibrillation or bleeding occurred, Jennifer Woyach, MD, an associate professor at The Ohio State University Comprehensive Cancer Center—James, said at the 2019 ASH Annual Meeting.

“You can definitely see that responses are very good,” Woyach told OncLive in an interview at ASH. “This and other studies of other agents in this class have confirmed the efficacy of this class of drugs, the reversible BTK inhibitors.”

“For this study, two things really are striking,” continued Woyach, “One is that 89% of patients with [BTK C481S—mutated CLL] who were treated at the recommended phase II 65-mg dose responded. [Further], half of the people with Richter’s transformation responded, and Richter’s is a very unmet need in CLL, very difficult to treat. Seeing that kind of activity early on is really encouraging.”

Despite major advances in the treatment of B-cell malignancies, cases of primary and secondary resistance continue to emerge, are associated with poor outcomes, and have limited treatment options. Woyach said 80% to 85% of patients who progress on BTK inhibitor therapy do so because of emergence of the BTK-C481S mutation.

AMQ-531 is an orally available, reversible, dual inhibitor of wild-type and C481S-mutant BTK. The drug has demonstrated superiority over ibrutinib in mouse models of CLL and DLBCL and targets ibrutinib-resistant CLL, RT, and other B-cell malignancies, Woyach and colleagues noted in a poster presentation.

The presentation described results of a phase I dose-escalation trial involving patients with relapsed or refractory B-cell malignancies. The objectives were to evaluate the safety, pharmacology, and anticancer activity of ARQ-531 in patients with BTK-C481S resistance mutations.

The 47 patients enrolled in the study had a median age of 65, and men accounted for 85% of the total. The cohort comprised 29 patients with CLL/SLL, and 18 with B-cell non-Hodgkin lymphomas: 9 with RT, 3 with DLBCL, 4 with FL, and 1 each with mantle cell lymphoma and Waldenstrom macroglobulinemia (WM). They had received a median of 4 (range, 1-12) prior systemic regimens.

Investigators evaluated ARQ 531 doses ranging from ≤30 mg QD to 75 mg QD. The 13 patients who received the recommended phase II dose consisted of 5 patients with CLL, 7 with RT, and 1 with WM.

Eight of 9 patients with high-risk relapsed/refractory CLL achieved PRs with the 65-mg dose. Three of 6 patients with RT treated with the 65-mg dose also had PRs. The remaining 3 responses all occurred at ARQ 531 doses ≥45 mg. Three additional patients with RT were able to proceed with CAR T-cell therapy.

The 1 dose-limiting toxicity in the trial (grade 3 generalized rash) occurred in a patient with CLL treated with the 65-mg dose. The most common adverse events (AEs; all patients/grades) were hypertension (34%), back pain (32%), nausea (30%), fatigue (30%), rash (28%), constipation (28%), peripheral edema (26%), pyrexia (26%), headache (26%), diarrhea (23%), upper respiratory tract infection (23%), and cough (23%). The most common grade ≥3 AEs included decreased neutrophil count (19%), and decreased platelets, anemia, and hypertension (13% each).

Drug-related AEs were uncommon. Grade ≥3 drug-related AEs consisted of 6 cases (13%) of decreased neutrophil count, 2 (4%) cases of decreased platelets, and one case (2%) of rash.

With respect to pharmacokinetics, the 65-mg dose of ARQ 531 achieved a steady-state mean C_min exceeding 1 µM and plasma half-life of 56 hours. At the recommended phase II dose, ARQ 531 drives complete pBTK inhibition.

Woyach et al reported that ongoing clinical development of ARQ 531 includes phase II studies in relapsed/refractory CLL, RT, and multiple B-cell malignancies. Plans for trials of combination therapy and earlier lines of therapy are in development.

Woyach J, Stephens DM, Flinn IW, et al. Final results of phase 1, dose escalation study evaluating ARQ 531 in patients with relapsed or refractory B-cell lymphoid malignancies. Presented at: 2019 ASH Annual Meeting; December 7-10; Orlando, FL. Abstract 4298.