FDA Approves Acalabrutinib Plus Bendamustine and Rituximab for Previously Treated MCL

The FDA has approved acalabrutinib (Calquence) plus bendamustine and rituximab (Rituxan; BR) for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT).1

The regulatory agency also granted full approval to single-agent acalabrutinib for use in adult patients with previously treated MCL. Previously, in October 2017, the monotherapy had received accelerated approval for use in adult patients with MCL after at least 1 previous therapy based on findings from the ACE-LY-004 phase II trial (NCT02213926).2 Acalabrutinib given at 100 mg twice daily led to an overall response rate (ORR) of 81% (95% CI, 73%-87%), which included a complete response (CR) rate of 40% (95% CI, 31%-49%).

The approval of acalabrutinib plus BR was supported by findings from the phase 3 ECHO trial (NCT02972840).1 At a median follow-up of 49.8 months, the median progression-free survival (PFS) was significantly longer in the acalabrutinib arm (n = 299), at 66.4 months (95% CI, 55.1-not estimable [NE]) vs 49.6 months (95% CI, 36.0-64.1) in the placebo arm (n = 299; HR, 0.73; 95% CI, 0.57-0.94; P = .016).

ECHO Trial Overview

The multicenter, double-blind, placebo-controlled trial enrolled patients with previously untreated, pathologically confirmed MCL who were at least 65 years of age and were not intended to receive HSCT (n = 598).1,4 Patients were also required to have documentation of a chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1 in association with other relevant markers; an ECOG performance status of 0 to 2; and agree to use effective forms of contraception during the study.3

Patients were randomly assigned 1:1 to receive bendamustine at 90 mg/m2 on days 1 and 2 plus rituximab at 375 mg/m2 on day 1 for 6 cycles paired with either 100 mg of oral acalabrutinib or placebo given twice daily.4 If patients in either arm experienced a partial response (PR) or better, they received maintenance rituximab every 2 cycles for 2 years. Treatment continued until disease progression or unacceptable toxicity. After disease progression, those on the placebo arm were permitted to crossover to the acalabrutinib arm.

The study's primary end point was PFS per independent review committee (IRC) assessment. Key secondary end points included objective response rate (ORR) by IRC assessment, overall survival (OS), and safety.

Additional Efficacy Data

Data presented during the 2024 EHA Congress showed that acalabrutinib plus BR led to an ORR of 91.0%, which comprised a complete response (PR) rate of 66.6% and a PR rate of 24.4%. Placebo plus BR led to an ORR of 88.0%, which included CR and PR rates of 53.5% and 34.4%, respectively.

Including crossover, the median OS in both the acalabrutinib and placebo arms was NE (HR, 0.86; 95% CI, 0.65-1.13; log-rank P = .2743).

Safety Insights

Any treatment-emergent adverse effect (TEAE) occurred in 99.7% of those in the acalabrutinib arm vs 99.0% of those in the placebo arm; these AEs were grade 3 or higher for 88.9% and 88.2% of patients, respectively, and grade 5 for 12.1% and 10.1% of patients, respectively. Serious AEs occurred in 69.0% of those in the acalabrutinib arm vs 62.0% of those in the placebo arm; they were grade 3 or higher in 64.3% and 55.9% of patients, respectively.

TEAEs related to acalabrutinib occurred in 68.0% of patients; those related to placebo occurred in 55.6% of patients. TEAEs led to discontinuation of acalabrutinib or placebo for 42.8% and 31.0% of patients, respectively.

AEs of interest in the acalabrutinib arm included infections (any grade, 78.1%; grade ≥3, 41.1%), hypertension (12.1%; 5.4%), second primary malignancies (9.8%; 5.4%), atrial fibrillation (6.1%; 3.7%), and major bleeding (2.4%; 2.0%).

Moreover, 32.4% of patients who received acalabrutinib plus BR died; 10.0% died from disease progression.

References

1. FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma. FDA. January 16, 2024. Accessed January 16, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-bendamustine-and-rituximab-previously-untreated-mantle-cell-lymphoma
2. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. FDA. October 31, 2017. Accessed January 16, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-acalabrutinib-mantle-cell-lymphoma
3. A study of BR alone versus in combination with acalabrutinib in subjects with previously untreated MCL. ClinicalTrials.gov. Updated November 29, 2024. January 16, 2025. https://clinicaltrials.gov/study/NCT02972840
4. Wang ML, Mayer J, Belada D, et al. Acalabrutinib plus bendamustine and rituximab in untreated mantle cell lymphoma: results from the phase 3, double-blind, placebo-controlled ECHO trial. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract LBA3439.