Acalabrutinib Regimen Demonstrates Promising Response Rates in MCL

December 11, 2018
Wayne Kuznar

Combination therapy with acalabrutinib plus bendamustine and rituxumab showed an overall response rate in excess of 90% of patients with treatment-na&iuml;ve mantle cell lymphoma and an ORR of 85% in patients with relapsed/refractory disease in an ongoing open-label phase Ib study.<sup>&nbsp;</sup>The safety profile was consistent with expected safety profiles for acalabrutinib and BR, said Tycel Phillips, MD, who presented the data at the 2018 American Society of Hematology Annual Meeting.

Tycel Phillips, MD

Combination therapy with acalabrutinib (Calquence) plus bendamustine (Treanda) and rituxumab (Rituxan; BR) showed an overall response rate (ORR) in excess of 90% of patients with treatment-naïve mantle cell lymphoma (MCL) and an ORR of 85% in patients with relapsed/refractory disease in an ongoing open-label phase Ib study.1The safety profile was consistent with expected safety profiles for acalabrutinib and BR, said Tycel Phillips, MD, who presented the data at the 2018 American Society of Hematology (ASH) Annual Meeting.

Among the 17 responses in the treatment-naïve subset (n =18), there were 13 patients (72%) who had a complete response (CR) and 4 others (22%) with a partial response (PR). Of the 17 responders in the 20-patient subset with relapsed/refractory MCL, there were 13 CRs (65%), 4 PRs (20%), and 1 with stable disease.

Median progression-free survival (PFS) was not reached in either of the 2 cohorts.

BR is standard first-line therapy for MCL. Acalabrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, was approved by the FDA in 2017 for the treatment of MCL in adults who have received at least 1 prior therapy. The study presented here assessed its efficacy and safety in both the first- and second-line setting in combination with BR.

“Obviously this is a small study, but the combination looks safe and effective,” said Phillips, a clinical researcher at the University of Michigan in Ann Arbor. “Based on information that was presented at last year’s ASH, most people are initiating BTK inhibitors earlier in the treatment course. Anything we can do to improve upon the duration of response with a BTK inhibitor would be optimal, so we treat them with bendamustine or give them bendamustine in the second-line setting, which is also a reasonable option in these patients.”

Although the data are not yet mature enough to get a true sense of PFS with the combination, “the responses we have are comparable to what we would expect with a combination with a synergistic mechanism,” he said.

Patients were enrolled from 15 sites across 3 countries. Eligible patients were those with confirmed MCL with documentation of monoclonal CD20-positive B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1, an ECOG performance status ≤2, and adequate cardiovascular function. In order to be enrolled, patients must not have received any prior BTK or BCL-2 inhibition therapy.

Patients received oral acalabrutinib, 100 mg twice daily, plus bendamustine, 90 mg/m2intravenously on days 1 and 2, and rituximab, 375 mg/m2intravenously on day 1, in each 28-day cycle. Acalabrutinib was given until disease progression or intolerance; BR was repeated every 28 days for up to 6 cycles. Patients with treatment-naïve MCL who achieved a PR or CR received rituximab maintenance therapy (375 mg/m2every other cycle for up to 12 doses starting on cycle 8).

At baseline, 61% of the treatment-naïve group and 50% of the relapsed/refractory group were ≥65 years. Bulky disease ≥10 cm was present in 6% and 10%, respectively, and 11% and 15%, respectively, were high risk by the simplified MCL International Prognostic Index. Some 89% and 95%, respectively, had Ann Arbor stage IV disease. The time from initial diagnosis to first dose was a median of 2 months (range, 0.6-50.5) in the treatment-naïve group and 62 months (range, 8.1-99.4) in the relapsed/refractory group.

The median number of prior therapies in the relapsed/refractory cohort was 2 (range, 1-4) and 45% were refractory to their most recent treatment.

The median time on study was 20.6 months (range, 0.6-26.1) for treatment-naïve patients and 16.9 months (range, 1.2-26.6) for relapsed/refractory patients; 72% of treatment-naïve and 50% of relapsed/refractory patients completed 6 cycles of BR with acalabrutinib.

Among the responders, the median times to initial response were 1.9 months (range, 1.6-2.8) in the treatment-naïve group and 1.8 months (range, 1.6-2.3) in the relapsed/refractory group. The median times to best response were 1.9 (range, 1.6-10.1) and 2.0 months (range, 1.6-14.8), respectively.

Dose-limiting toxicity (DLT) was evaluated in the first 6 patients per cohort after completing 1 cycle. No DLTs were observed in either cohort.

In the treatment-naïve cohort, grade ≥3 adverse events (AEs) in ≥10% of patients were neutropenia (39%) and pneumonia (11%). Serious AEs occurring in ≥2 patients included pneumonia (grade 3, n = 2 [11%]) and pyrexia (grade 1, n = 2 [11%]). One patient had grade 4 pulmonary alveolar hemorrhage attributed to acalabrutinib that led to discontinuation of the study treatment.

In the relapsed/refractory cohort, grade ≥3 AEs in ≥10% were neutropenia (50%) and diarrhea (10%). One patient had grade 1 pneumonia and 2 had grade 3 pneumonia. Three patients had a grade 3 major hemorrhage considered to be unrelated to acalabrutinib.

Overall, 1 patient had a grade 5 AE of pneumonitis.

The high CR rate with acalabrutinib plus BR supports further study of the combination, said Phillips. The study has also added a chemotherapy-free arm of acalabrutinib plus venetoclax (Venclexta). Additionally, a phase III randomized placebo-controlled study of BR alone versus BR plus acalabrutinib in patients with newly diagnosed MCL is ongoing (NCT02972840).

Reference:

Phillips TJ, Smith SD, Jurczak W, et al. Safety and efficacy of acalabrutinib plus bendamustine and rituximab (BR) in patients with treatment-naive (TN) or relapsed/refractory (R/R) mantle cell lymphoma (MCL).&nbsp;Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA.&nbsp;Abstract 4144.