Phase 1b Data Support Continued Investigation of Acalabrutinib Plus BR in MCL

BTK inhibitors in combination with chemotherapy may bolster the frontline treatment armamentarium for patients with mantle cell lymphoma (MCL), although further research is needed to confirm early-phase findings, according to Tycel Phillips, MD.

Updated findings from a phase 1b trial (NCT02717624) evaluating the efficacy and safety of acalabrutinib (Calquence) plus bendamustine and rituximab (Rituxan; BR) showed that at a median follow-up of 47.6 months, patients with previously untreated MCL who received the combination achieved an overall response rate (ORR) of 94.4% and a complete response (CR) rate of 77.8%. Additionally, at a median follow-up of 20.4 months, 85.0% of patients with relapsed/refractory MCL responded to the combination, and 70% achieved a CR.¹

Supported by these findings, the phase 3 ECHO trial (NCT02972840) is evaluating BR with or without acalabrutinib in patients with treatment-naïve MCL.² The primary end point of this trial is progression-free survival.

“[Considering] the overall findings, we’re still trying to figure out the best role for BTK inhibitors and frontline chemotherapy in patients with MCL,” Phillips said in an interview with OncLive^®.

In the interview, Phillips discussed the rationale and design of this phase 1b trial, highlighted key efficacy and safety findings in the treatment-naïve and relapsed/refractory patient cohorts, and postulated next steps on the horizon for investigating BTK inhibitors in combination with chemotherapy in patients with MCL.

Phillips is an associate professor in the Division of Lymphoma in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope in Duarte, California.

OncLive: What was the rationale for investigating acalabrutinib plus BR in this phase 1b trial in patients with treatment-naïve or relapsed/refractory MCL?

Phillips: We evaluated a patient population [that included] newly diagnosed patients who were ineligible for intensive chemotherapy and transplant. BR is a standard regimen in that treatment arena. Acalabrutinib is a second-generation covalent BTK inhibitor that has demonstrated single-agent efficacy in patients with relapsed/refractory MCL. We aimed to combine these drugs to see whether we could improve upon the frontline regimen of BR. We evaluated safety and efficacy in both the [frontline and] relapsed and refractory settings, with an aim to mostly focus on patients with treatment-naïve disease.

What were this trial’s key inclusion criteria?

The treatment-naïve cohort [enrolled] patients with newly diagnosed, untreated MCL who had never received any prior lines of therapy. The patients in the relapsed/refractory cohort needed to have received at least 1 prior line of therapy that did not include a covalent BTK inhibitor.

What were the key efficacy findings from this phase 1b trial in both the treatment-naïve and relapsed/refractory patient cohorts?

In the treatment-naïve patients, we saw an ORR of 94.4%, and [we saw an ORR of] 85.0% in the relapsed/refractory patients. We evaluated CR rate, which is what we aim for in this patient population. We saw a 77.8% CR rate in the treatment-naïve cohort [and a] 70% [CR rate] in the relapsed/refractory cohort. [With] positron emission tomography/computed tomography alone, the CR rate was 88.9% in the treatment-naïve cohort and 80.0% in the relapsed/refractory cohort. Another key outcome was duration of response [DOR], which was not reached in the treatment-naïve cohort and 43.5 months in the relapsed/refractory cohort.

How do the efficacy findings with acalabrutinib plus BR in this trial’s relapsed/refractory cohort compare with the expected efficacy with acalabrutinib alone in that population?

The single-agent data [with acalabrutinib] are not mature. Ideally, in the BTK inhibitor cohorts in other BTK inhibitor studies in general, patients will achieve CRs, and DORs will approach up to 60 months. Although the combination did probably lead to improved efficacy based on some of the early data with acalabrutinib [monotherapy], overall, the addition of bendamustine probably did not add much [benefit] in the relapsed/refractory patient population to what we can probably get with a single-agent BTK inhibitor alone.

Considering that and the increased infection risks that come with adding bendamustine to BTK inhibitors, the combination will likely not move forward in the second-line setting. However, it did have enough of a signal in the frontline setting to spark the ECHO trial, which is investigating BR vs BR and acalabrutinib in patients unfit or ineligible for autologous stem cell transplant.

What was the safety profile with the combination across the entire phase 1b trial population?

We didn’t notice any significant cardiac events, which is important, but we may see some of these signals with additional follow-up. We saw an increased risk of infection with the combination. We also saw some neutropenic episodes and thrombocytopenia, most likely from the chemotherapy, although the neutropenia aspect was probably construed by [the combination], and the infections were a contribution of [all the] drugs together.

What does the future look like for acalabrutinib combinations in patients with MCL?

We’ll probably continue to collect additional safety findings [from this phase 1b trial] as [time goes] on. We’ll also determine the DOR from the patients in the frontline [cohort].

[Other] next steps [include] the readout of the ECHO study for chemotherapy plus acalabrutinib. [That trial] may open a second cohort evaluating acalabrutinib, venetoclax [Venclexta], and rituximab in treatment-naïve patients. That may be the next avenue where acalabrutinib will go in frontline MCL as we wait for the ECHO trial to read out.

The [phase 3] SHINE trial [NCT01776840] unfortunately did not read out as people had hoped. As the ECHO trial hopefully reads out, we’ll get a clearer picture of where these drugs fit. Combinations with chemoimmunotherapy may not be the ideal place for these drugs in the frontline setting. However, we’ll wait to see.

Zanubrutinib [Brukinsa] is another second-generation BTK inhibitor. [The phase 2 CHESS trial (NCT04624958)] took a slightly different approach by avoiding the addition of chemotherapy to the BTK inhibitor. We’ll see which of these avenues plays out and shows the most benefit in this patient population.

References

1. Phillips T, Wang M, Robak T, et al. Safety and efficacy of acalabrutinib, bendamustine, and rituximab in patients with treatment-naive or relapsed/refractory mantle cell lymphoma: phase Ib trial. Presented at: 2023 EHA Congress; June 8-15, 2023; Frankfurt, Germany. Abstract P1094.
2. A study of BR alone versus in combination with acalabrutinib in subjects with previously untreated MCL. ClinicalTrials.gov. Updated June 13, 2023. Accessed July 18, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT02972840