Combination Ibrutinib and Venetoclax for the Treatment of MCL: Primary End Point Assessment of the Phase 2 AIM Study

Although ibrutinib and venetoclax demonstrate activity in relapsed/refractory (RR) mantle-cell lymphoma (MCL), complete remissions (CRs) are achieved in <25% with either therapy alone. Researchers sought to determine the activity of the combination in a phase 2 study.

The study enrolled 24 patients with MCL, of which 23 were RR and 1 had not been previously treated. The median age of patients was 68 years (range, 47-81 years). The RR patients (n = 23) had a median of 2 (range, 1-6) prior lines of therapy, 29% had failed previous autologous stem-cell transplantation, and 48% were refractory to their last treatment.

Patients received 4 weeks of ibrutinib 560 mg daily, followed by the introduction of venetoclax given in a weekly ramp-up to the target dosage of 400 mg daily. The primary end point was the CR rate at week 16, as assessed by positron emission tomography (PET)/computed tomography scans, bone marrow adipose tissue, flow and molecular minimal residual disease, and endoscopy (in cases of baseline gut involvement). Response was calculated separately with and without knowledge of the PET result by International Working Group criteria (Cheson. JCO. 2007) to compare with published studies (ibrutinib, 9% CR at week 16; venetoclax, best CR rate 21%).

As of data cutoff on January 11, 2017, 18 patients remained on therapy, and 6 stopped treatment—4 patients due to progressive disease, 1 due to an adverse event, and 1 due to unrelated death. The combination of ibrutinib and venetoclax was tolerable, and achieved a CR rate of 63% at week 16 in patients with RR MCL. The median follow-up was 8.3 months with estimated progression-free survival and overall survival of 74% and 81%, respectively, at 1 year. Adverse events ≥20%, irrespective of causality, were diarrhea (83%); fatigue (75%); nausea and/or vomiting (67%); upper respiratory tract infection (42%); gastroesophageal reflux (33%); neutropenia (33%); cough (29%); dyspnea (25%); and anemia, bruising, peripheral neuropathy, and thrombocytopenia (21%). Except for neutropenia (25% grade 3/4), these were predominantly grade 1/2 in severity. Tumor lysis syndrome occurred in 2 patients. The combination of ibrutinib and venetoclax was tolerable and efficacy results compare favorably with historical results, warranting further phase 3 investigation and in chronic lymphocytic leukemia and marginal zone lymphoma.

Tam CSL, et al. ASCO Abstract 7520.