Lead Researcher Discusses Acalabrutinib Plus BR in MCL

Tycel J. Phillips, MD

Acalabrutinib (Calquence) combined with bendamustine, and rituximab (Rituxan; BR) demonstrated encouraging activity with a favorable safety profile in both treatment-naïve and relapsed/refractory patients with mantle cell lymphoma (MCL), according to data presented at the 2018 ASH Annual Meeting.

In the study, patients received oral acalabrutinib 100 mg twice daily, bendamustine at 90 mg/m² intravenously on days 1 and 2, and rituximab at 375 mg/m² on day 1 in each 28-day cycle. Acalabrutinib was given until disease progression or intolerance and BR was repeated every 28 days for up to 6 cycles. Patients with treatment-naïve MCL who achieved partial or complete response received standard rituximab maintenance therapy.

In previously untreated patients, the overall response rate (ORR) was 94% and complete response (CR) rate was 72% with the combination, while the relapsed/refractory arm had an ORR of 85% and a CR rate of 65%. Additionally, the median progression-free survival was not reached in either of the subgroups.

The safety profile was consistent with what has previously been noted for acalabrutinib and BR. Grade ≥3 adverse events (AEs) in ≥10% of treatment-naïve patients were neutropenia (39%) and pneumonia (11%). Moreover, the 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 treatment discontinuation.

In the relapsed/refractory cohort, grade ≥3 AEs in ≥10% of patients were neutropenia (50%) and diarrhea (10%). Additionally, 1 patient experienced grade 1 pneumonia and 2 had grade 3 pneumonia. Three patients had a grade 3 major hemorrhage that were considered to be unrelated to acalabrutinib. Acalabrutinib, a second-generation BTK inhibitor, received FDA approval in October 2017 for the treatment of adult patients with MCL who were treated with at least 1 prior line of therapy.

OncLive: Please provide some background to this study.

In an interview with OncLive, lead study author Tycel J. Phillips, MD, an assistant professor at the University of Michigan Cancer Center, discussed the clinical implications of this regimen for patients with MCL and the next steps with these data.Phillips: MCL is a rare subset of non-Hodgkin lymphoma (NHL); it affects about 5% to 6% of all patients with NHL but is more common in patients who are 65 years and older. We see it more in male patients, too. As of right now, we do not have an official standard of care. Research nowadays is geared toward determining an optimal regimen for these patients, either in the transplant-eligible or -ineligible population. As far as chemotherapy regimens are concerned, BR has been shown to be effective and well tolerated. In the relapsed/refractory setting, as we all know, BTK inhibitors have been very effective.

What was the design of the trial?

What were the key findings?

What are the next steps for this research?

In this study, we had 2 arms: one was evaluating the second-generation BTK inhibitor acalabrutinib plus BR in treatment-naïve patients, [and one evaluated the use of the combination] in the relapsed/refractory setting. The hope is that we could find a safe and tolerable regimen.It was a nonrandomized study, so all patients received the standard dose of BR. Bendamustine was given on days 1 and 2, [while] rituximab [was administered] on day 1. We also gave the standard dose of acalabrutinib throughout the study. In the treatment-naïve arm, patients were given the opportunity to transition to maintenance after initial treatment, [which consisted of] 2 years of rituximab every 2 months.As far as the safety profile, the regimen was deemed to be relatively safe. There were a few patients in both arms who were unable to complete treatment, but these were not thought to be related to the treatment itself. Major AEs were infection, although we did not see as many cases as we had expected. Acalabrutinib led to a high incidence of headaches. As far as efficacy, what we saw was very impressive, particularly in treatment-naïve patients.There is now a phase III study looking at BR plus placebo versus the combination with acalabrutinib. This study is currently enrolling at multiple institutions. We have about 100 patients enrolled at the moment. A phase III study gives the opportunity to actually see if acalabrutinib adds anything to our standard regimen. It is hard to do that in an early-phase trial.

What is your take-home message regarding this trial?

The one thing that this study won't address is whether it can prevent transplant-eligible patients from needing transplant. This is something we would like to know in the future. We have also had recent trials looking at different classes of agents, such as venetoclax (Venclexta) and bortezomib (Velcade).It is important to reiterate that this combination is safe. We are learning that bendamustine is a good agent to combine novel therapies with. It is a very tolerable regimen, especially in the short-term.

Phillips TJ, Smith SD, Jurczak W, et al. Safety and efficacy of acalabrutinib plus bendamustine and rituximab in patients with treatment-naïve or relapsed/refractory mantle cell lymphoma. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, California. Abstract 4144.