Michael Wang, MD,
The novel BTK inhibitor acalabrutinib demonstrated an objective response rate (ORR) of 81% with a complete response (CR) rate of 40% for patients with refractory mantle cell lymphoma (MCL), according to findings from the phase II ACE-LY-004 trial presented at the 2017 ASH Annual Meeting.
The median duration of response (DOR) had not been reached, with 72% of patients still responding at 12 months (95% CI, 62%-80%). At 12 months, the progression-free survival (PFS) rate was 67% (95% CI, 58%-75%) and the 12-month overall survival (OS) rate was 87% (95% CI, 79%-92%). The median PFS and OS had not yet been reached at the time of the analysis.
"Acalabrutinib demonstrated compelling efficacy and a differentiated safety profile, thus providing an alternative therapeutic option for patients with relapsed/refractory mantle cell lymphoma," lead investigator Michael Wang, MD, from the The University of Texas MD Anderson Cancer Center, said during his presentation of the data. "Acalabrutinib's pharmacokinetic and selectivity profiles allow twice-daily dosing with minimal off-target effects, while achieving near complete and continuous BTK inhibition over time."
The single-arm ACE-LY-004 study enrolled 124 patients with relapsed/refractory MCL. Oral acalabrutinib was taken at 100 mg twice daily until disease progression. Most patients were intermediate risk by MIPI score (44%) and 37% had lymph nodes ≥5 cm. Seventy-three percent had extranodal disease.
The median age of patients was 68 years (range, 42-90), and most were male (80%). Overall, 93% of patients had an ECOG performance status of 0 or 1. The median number of prior treatments was 2 (range, 1-5), which included stem cell transplant for 18% of patients. Those treated with a prior BTK inhibitor were excluded from the trial. The most common prior therapy was rituximab as a single-agent or in a combination regimen.
At a median follow-up of 15.2 months, 56% of patients remained on the study. The median time to initial response was 1.9 months (range, 1.5-4.4). The ORR by independent review committee was 80% (95% CI, 72%-87%), which was comprised evenly of CR and PR rates of 40%. A reduction in lymphadenopathy was experienced by 94% of patients.
The 81% ORR was determined by investigator assessment. There was a 91% concordance between the investigator and blinded review for ORR and 94% concordance for CR. Overall, there were no meaningful efficacy differences observed between subgroups of patients in the trial.
The most common adverse events (AEs) of any grade were headache (39%), diarrhea (31%), fatigue (28%), myalgia (21%), cough (19%), nausea (18%), and pyrexia (14%). The most common grade ≥3 AEs were neutropenia (11%), anemia (9%), and pneumonia (5%). Dose discontinuations due to AEs were required for 6% of patients.
Serious AEs associated with acalabrutinib included pneumonia (4%), anemia (3%), health deterioration (2%), sepsis (2%), tumor lysis syndrome (2%), and vomiting (2%). There was 1 grade 3 GI hemorrhage in a patient with a history of GI ulcer. Additionally, there was 1 grade 5 aortic stenosis that was unrelated to treatment.
"The most common AEs were mostly grade 1 or grade 2, there were few discontinuations due to AEs," Wang said. "No atrial fibrillation was observed and the rate of grade ≥3 hemorrhage was low."
In late October 2017, the FDA approved acalabrutinib for patients with MCL following at least 1 prior therapy. The approval arrived several months ahead of expectations under the Prescription Drug User Fee Act and followed a breakthrough therapy designation from the FDA for MCL. The phase III ACE-LY-308 clinical trial is currently evaluating acalabrutinib in combination with bendamustine and rituximab (BR) versus placebo plus BR for patients with untreated MCL.
Wang M, Rule S, Zinzani PL, et al. Efficacy and Safety of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma in the Phase 2 ACE-LY-004 Study. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, Georgia. Abstract 155.