1. Nalley, Catlin

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Bruton tyrosine kinase (BTK) inhibitors have shown activity in follicular lymphoma. Clinical responses have been reported among patients with refractory/relapsed disease who were treated with ibrutinib (Blood 2018;131(2):182-190, Blood 2016;128:1217). Additionally, treatment-naive patients who received ibrutinib in combination with rituximab had an overall response rate (ORR) of 82 percent (Blood 2016;128:1804).

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In a recent study, researchers took a closer look at acalabrutinib, a highly selective potent, covalent inhibitor of BTK (J Clin Oncol 36, 2018 (suppl; abstr 7549)).


Study Details

In part 1 of ACE-LY-003, a multicenter, open-label, phase Ib/II study, investigators evaluated acalabrutinib alone or in combination with rituximab in treatment-naive and R/R follicular lymphoma.


The primary endpoint was to determine the safety of the agent alone or with rituximab in patients with refractory/relapsed disease. Secondary endpoints include safety of acalabrutinib with rituximab in patients with treatment-naive follicular lymphoma; pharmacokinetics and pharmacodynamics; and ORR, duration of response, and progression-free survival.


Patients with R/R follicular lymphoma were randomized to acalabrutinib alone or in combination with rituximab; treatment-naive patients received only the combination therapy. "In 28-day cycles, rituximab (375 mg/m2 IV) was given weekly in Cycle 1 and on Day 1 of Cycles 2-6; acalabrutinib (100 mg PO bid [two patients received 200 mg qd]) was given until progressive disease or intolerance," according to study authors.


Patients with confirmed grade 1, 2, or 3a follicular lymphoma could be included in the study. In the R/R cohort, eligible patients relapsed or were refractory to one or more lines of prior therapy. Other eligibility requirements included patients 18 or older; measurable lymphadenopathy or extranodal lymphoid malignancy; and an ECOG performance status of <=2.


Patients were excluded if they had previous BTK therapy, required treatment with vitamin K antagonists or protein pump inhibitors, and had significant cardiovascular disease.


Safety, Efficacy Findings

From January 2015 to October 2016, investigators enrolled and treated 13 treatment-naive and 27 R/R patients. The median age was 66 years (range 32-83), 98 percent had ECOG PS <=1, and 88 percent had stage III/IV disease, according to study authors. Patients with R/R disease received a median of two prior therapies (range 1-5).


In terms of safety, the most common adverse events (AEs) were primarily grade 1/2. Investigators found that AEs reported in the monotherapy cohort were similar to those reported in the combination group.


Common AEs (any grade) among all patients included fatigue, headache, diarrhea, nausea, and sinusitis. Common grade 3/4 AEs, included hypertension (8%), increased alanine aminotransferase (5%), increased aspartate aminotransferase (5%), and cellulitis (5%). There were no grade 5 events reported.


At a median follow-up of 22 and 7.6 months, 62 percent of treatment-naive and 26 percent of R/R patients, respectively, were still on treatment, according to investigators. Discontinuation of treatment was mainly due to pharmacodynamics and adverse events.


In terms of efficacy, researchers reported an ORR of 92 percent among treatment-naive patients. Relapsed/refractory patients receiving acalabrutinib alone had an ORR of 33 percent compared to 38 percent among those who underwent combination therapy. Median PFS was not reached in the treatment-naive cohort. Among R/R follicular lymphoma patients, PFS was 12 months in the monotherapy group versus 8.3 months in the acalabrutinib plus rituximab arm.


"PK parameters and pharmacodynamics in patients with follicular lymphoma were consistent with those reported in previous acalabrutinib studies in CLL and mantle cell lymphoma," study authors reported. "[In this study,] acalabrutinib PK parameters were similar in R/R and treatment-naive patients and in the presence or absences of rituximab."


Based on the findings of this trial, the researchers determined acalabrutinib alone or in combination with rituximab demonstrated promising activity in follicular lymphoma patients. "Durable responses were observed in patients with R/R disease, including those who failed multiple prior therapies."


Investigators found that acalabrutinib's "pharmacokinetic and selectivity profiles allow twice-daily dosing with minimal off-target effects, while achieving near complete and continuous BTK inhibition over the dosing interval.


"Acalabrutinib, alone and combined with rituximab, was well-tolerated and yielded promising response rates in follicular lymphoma," study authors concluded. "These results support further evaluation of acalabrutinib in [this disease]."


Catlin Nalley is associate editor.


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