Acalabrutinib Shows Early Clinical Efficacy, Safety in Activated B-cell DLBCL

Paolo Strati, MD

The safety profile of acalabrutinib (Calquence) in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is consistent with previous studies of the agent. Additionally, the observed efficacy, pharmacokinetics, and pharmacodynamic activity of the agent in this patient population supports further evaluation, according to data published in Haematologica.¹

“Acalabrutinib is a safe and effective treatment for a subgroup of patients with diffuse large B-cell lymphoma,” wrote lead study author Paolo Strati, MD, an assistant professor of Lymphoma-Myeloma at MD Anderson Cancer Center told Targeted OncologyTM, in an interview.

There are 2 major subtypes of DLBCL lymphoma. The first is germinal center B-cell (GCB) DLBCL and the second is activated B-cell (ABC) DLBCL. Chronic active B-cell receptor (BCR) signalizing and NK-kB pathway activation is caused by the genetic abnormalities associated with ABC DLBCL. Bruton tyrosine kinase (BTK) plays a major role in the BCR signaling pathway.

A study of the irreversible BTK inhibitor ibrutinib (Imbruvica) found that response rates were higher in patients with ABC DLBCL (37%) than in patients with GCB DLBCL (5%). A similar trend was seen with tirabrutinib (Velexbru), which had a response rate of 35% for non-GCB DLBCL compared with 0 in the GCB cohort.

A phase 1 study (NCT02112526) aims to determine the efficacy of acalabrutinib in de novo ABC DLBCL. The open-label trial has an actual enrollment of 21 participants and an estimated study completion date of December 2025. The primary end point of the study is the safety profile of acalabrutinib. Secondary end points include area under plasma concentration, maximum observed plasma concentration, pharmacodynamics, and overall response rate (ORR).²

During the study, all patients received acalabrutinib 100 mg twice daily in repeated 28-day cycles. Cycles were repeated until disease progression or unacceptable toxicity.

In order to participate in the study, patients must be between 18 and 130 years old, have pathologically confirmed de novo ACB DLBCL, relapsed or refractory disease, and at least 1 measurable disease site. Patients with significant cardiovascular disease, malabsorption syndrome, or are pregnant or breast feeding are unable to participate.

The median age of participates was 64, 48% were male, and 71% were white. Sixty-seven percent had an ECOG score of 1 and over half, 57%, had Ann Arbor stage IV disease at baseline. Additionally, 24% had undergone prior autologous stem cell transplantation. The median number of prior systemic regiments was 3 (range, 1-5) and 81% had received prior cyclophosphamide, doxorubicin (Lipodox), vincristine (Marqibo), and prednisolone (Omnipred) plus rituximab (Rituxan), or (R-CHOP).

At the time of data cutoff on October 20, 2017, 20 of 21 (95%) participants had discontinued the study. Eighty-one percent discontinued due to disease progression, 9.5% due to a grade 5 adverse event (AE), and 4.8% to peruse alternative cancer therapy. Eight deaths were reported; however, none were considered related to the study drug. One patient remained on therapy at the time of data cutoff and had maintained a complete response (CR) since December 2016 through the last follow-up assessment in August 2020.

The median duration of exposure to acalabrutinib was 2.3 months (range, 0.5-22.5) and the median relative dose intensity was 98.1% (range, 6.3-100%). Two dose reductions were required. One was due to grade 2 orthostatic hypotension, and the other due to prescription of a strong CYP3A inhibitor. One or more doses were withheld for 7 or more days in 3 patients, 2 of which were due to grade 3 abdominal pain that was not considered related to acalabrutinib.

The ORR was 24% (n = 5). Of the 5 patients who responded, 5 achieved a CR while one achieved a partial response (PR). The median duration of response was 7.8 months (95% Confidence Interval [CI], 1.8 to not reached). In the 15 patients for which NanoString subtyping was available, 9 ABC, 5 GCB, and 1 unclassified subtype was identified. The ORR for the ABC subgroup was 33%, with 22% achieving a CR. In the GCB subgroup, 1 patient achieved a CR and no PRs were reported. Disease progression was seen in 1 patient in the ABC subgroup after 13.7 months. One patient with GCB subtype disease remained on treatment at the time of data cutoff at 15.9 months.

Based on the Kaplan-Meier analysis, the median progression-free survival was 1.9 months (95% CI: 1.8-2.7) and the overall survival was 15.5 months (95% CI, 4.0-not reached). Of the 21 patients, 11 went on to receive subsequent lines of therapy, with a median time to next treatment of 4 months (95% CI, 3.0-7.5).

Pharmacokinetic data was available for 14 patients. The steady-state mean maximum concentration and area under the concentration time curve were observed between both responders (n = 5) and non-responders (n = 9). The median steady-state BTK target occupancy was 97% to 99% throughout the dosing interval. Complete target coverage by acalabrutinib was indicated by BTK target occupancy being >90% at all time points, independent of clinical response.

Ninety-five percent of patients experienced a treatment-emergent AE, most commonly diarrhea (43%) and fatigue (43%). Grade 3/4 treatment-emergent AEs were seen in 29% of patients. Treatment-related AEs occurred in 76% of patients, with 24% experiencing grade 3/4 treatment-related AEs. Grade 3 serious AEs, pyrexia and a positive B virus test, were observed in 2 patients.

No atrial fibrillation, hypertension, tumor lysis syndrome, or grade ≥3 bleeding were reported. Any-grade AEs of note included hemorrhage in eight (38%) and infections in 11 (52%) patients.

“Acalabrutinib could be safely combined with other agents [that are] active in DLBCL non-GCB subtype, to provide chemotherapy-free options for these patients,” wrote Strati.

_REFERENCES:

_{1.Strati P, de Vos S, Ruan J, Maddocks KJ, et al. Acalabrutinib for treatment of diffuse large B-cell lymphoma: results from a phase 1b study. Haematologica. 2021;106(10):2774-2778; doi: 10.3324/haematol.2021.278654.}

_{2. Acalabrutinib (ACP-196), a Btk inhibitor, for treatment of de novo activated b-cell (ABC) subtype of diffuse large B-cell lymphoma. ClinicalTrials.gov. Accessed October 6, 2021. https://bit.ly/3uLgXCq.}