FDA Grants 2 Traditional Approvals for Acalabrutinib

Acalabrutinib (Calquence; AstraZeneca), a second-generation Bruton tyrosine kinase inhibitor, received 2 traditional approvals from the FDA on January 16: in combination and as monotherapy for adult patients with mantle cell lymphoma (MCL).1 The combination regimen, which encompasses acalabrutinib, bendamustine, and rituximab, was approved for use in the setting of previously untreated MCL ineligible for autologous hematopoietic stem cell transplantation, while acalabrutinib monotherapy can now be used for previously treated MCL.

The application for traditional approval was supported by data from the phase 3 randomized, double-blind, placebo-controlled, multicenter ECHO trial (NCT02972840), which compared acalabrutinib with bendamustine and rituximab (BR) plus placebo.2

Acalabrutinib previously received priority review and orphan drug designations, as well as an accelerated approval in 2017. | Image Credit: © wladimir1804 - stock.adobe.com

Combination Acalabrutinib

In combination, the application for acalabrutinib previously received priority review—which shortens the FDA’s review period from 10 to 6 months—and orphan drug designations, meaning there are significant unmet needs for the proposed treatment and it offers substantial improvement compared with currently available treatments.3,4

In the trial, 598 patients (all at least 65 years old) were enrolled from the US and around the world, and randomized 1:1, with efficacy evaluated by progression-free survival (PFS). Patients had to be treatment naïve; have pathologically confirmed MCL, with chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1 in association with other relevant markers; have an Eastern Cooperative Oncology Group performance status of 2 or below; and agree to use contraception during the study and for 6 and 12 months after the final doses of bendamustine and rituximab, respectively, whichever was later.

The trials regimens were rituximab 90 mg/m2 on days 1 and 2 plus rituximab 375 mg/m2 on day 1 for 6 cycles plus 100-mg acalabrutinib or placebo twice daily. Maintenance rituximab—every 2 cycles for 2 years—was administered when patients in either arm experienced a partial response or better, and patients in the placebo arm could crossover to the treatment arm if they experienced disease progression.5

Acalabrutinib plus BR led to a 27% reduction in risk of death (HR, 0.73; 95% CI, 0.57-0.94; P = .016), as well as 34% PFS improvement over a median follow-up of 49.8 months vs the placebo group1:

• Acalabrutinib plus BR: 66.4 (95% CI, 55.1 months-not estimable) months
• BR plus placebo: 49.6 (95% CI, 36.0-64.1) months

Overall, there were serious adverse reactions in 69% of patients in the treatment group, and 12% of patients experienced adverse reactions that led to their death. Any treatment-emergent adverse event (AE) was seen in 99.7% of the acalbrutinib arm and 99% of the placebo arm. Pneumonia, COVID-19, pyrexia, second primary malignancy, rash, febrile neutropenia, atrial fibrillation, sepsis, and anemia occurred in at least 2% of patients.

Monotherapy Acalabrutinib

Single-agent acalabrutinib received accelerated approval almost 10 years ago in adults who had received at least 1 prior therapy, supported by data from the phase 2, open-label ACE-LY-004 (NCT02213926).6 At that time, data showed an 81% (95% CI, 73%-87%) overall response rate, which was the primary end point, and a complete response rate of 40% (95% CI, 31%-49%). Mediation duration of response had not been reached, at 15.2 months of follow-up, and median time to best response was 1.9 months.

The recommended dose for both approvals is oral 100 mg every 12 hours until disease progression or unacceptable toxicity.

References

1. FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma. News release. FDA. January 16, 2025. Accessed January 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-bendamustine-and-rituximab-previously-untreated-mantle-cell-lymphoma

2. A study of BR alone versus in comnbination with acalbrutinib in subjects with previously untreated MCL. ClinicalTrials.gov. Updated November 29, 2024. Accessed January 17, 2025. https://clinicaltrials.gov/study/NCT02972840

3. Priority review. FDA. Updated January 4, 2018. Accessed January 17, 2025. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review

4. Designating an orphan product: drugs and biological products. FDA. Updated August 12, 2024. Accessed January 17, 2025. https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/designating-orphan-product-drugs-and-biological-products

5. 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.

6. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. News release. FDA. October 31, 2017. Accessed January 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-acalabrutinib-mantle-cell-lymphoma