FDA Grants Priority Review to Acalabrutinib in Treatment-Naive Mantle Cell Lymphoma

FDA

The FDA has granted priority review to the supplemental new drug application (sNDA) seeking the approval of acalabrutinib (Calquence) for patients with previously untreated mantle cell lymphoma (MCL).¹

The sNDA is supported by data from the phase 3 ECHO trial (NCT02972840), which were presented at the 2024 EHA Congress. At a median follow-up of 45 months, patients treated with the combination of acalabrutinib, bendamustine, and rituximab (Rituxan; BR; n = 299) experienced a median progression-free survival (PFS) of 66.4 months (95% CI, 55.1–not evaluable [NE]) compared with 49.6 months (95% CI, 36.0-64.1) for those treated with placebo plus BR (n = 299; HR, 0.73; 95% CI, 0.57-0.94; P = .0160).²

The median overall survival (OS) was NE (95% CI, 72.1 months–NE) in the acalabrutinib arm vs NE (95% CI, 73.8 months–NE) in the placebo arm (HR, 0.86; 95% CI, 0.65-1.13; P = .2743). Notably, patients in the placebo arm were permitted to cross over to receive acalabrutinib following disease progression, which was accounted for in the OS analysis. Sixty-nine percent of patients in the placebo arm received a subsequent BTK inhibitor after disease progression.

The target action date for the sNDA under the Prescription Drug User Fee Act is expected in the first quarter of 2025.¹

“Today’s priority review acceptance reinforces the potential of [acalabrutinib] to transform outcomes in untreated MCL. Data from the ECHO trial showed [acalabrutinib] plus chemoimmunotherapy significantly delayed disease progression and showed a trend to improved survival in patients with this currently incurable blood cancer,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, stated in a news release. “We are working closely with the FDA to provide patients this potential new treatment as soon as possible.”

In October 2017, the FDA granted accelerated approval to acalabrutinib for the treatment of adult patients with MCL following at least 1 prior therapy.³

ECHO was a multicenter, double-blind, placebo-controlled study that enrolled patients at least 65 years of age with previously untreated MCL and an ECOG performance status of 0 to 2.²

Patients were randomly assigned 1:1 to receive 100 mg of acalabrutinib or placebo twice per day in combination with 6 cycles of BR comprised of bendamustine at 90 mg/m² on days 1 and 2 and rituximab at 375 mg/m² on day 1 of each cycle. After 6 cycles, patients with a partial response (PR) or better received maintenance rituximab once every 2 cycles for up to 2 years in combination with acalabrutinib or placebo. Treatment with acalabrutinib or placebo continued until progressive disease or unacceptable toxicity.

Key stratification factors included simplified MCL International Prognostic Index score (low vs intermediate vs high) and geographic region (North America vs Western Europe vs other).

PFS as assessed by an independent review committee (IRC) served as the trial’s primary end point. Key secondary end points included IRC-assessed overall response rate (ORR), OS, and safety.

Additional data showed the ORR was 91.0% in the acalabrutinib arm vs 88.0% in the placebo arm. The respective complete response and PR rates were 66.6% and 24.4% in the acalabrutinib arm. In the placebo arm, these rates were 53.5% and 34.4%, respectively.

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.7% of patients in the acalabrutinib arm (n = 297) vs 99.0% of patients in the placebo arm (n = 297). The rates of grade 3 or higher TEAEs were 88.9% and 88.2%, respectively; grade 5 TEAEs were reported in 12.1% and 10.1% of patients, respectively. Serious AEs (SAEs) occurred in 69.0% of patients in the acalabrutinib group vs 62.0% of those in the control arm; the rates of grade 3 or higher SAEs were 64.3% and 55.9%, respectively.

TEAEs deemed related to acalabrutinib were observed in 68.0% of patients in the experimental arm, and 55.6% of patients in the control arm had TEAEs related to placebo. TEAEs led to the discontinuation of acalabrutinib in 42.8% of patients and the discontinuation of placebo in 31.0% of patients.

Any-grade AEs of special interest included atrial fibrillation (acalabrutinib arm, 6.1%; placebo arm, 4.4%), hypertension (12.1%; 15.8%), major bleeding (2.4%; 5.4%), infections (78.1%; 71.0%), and second primary malignancy, excluding non-melanoma skin malignancies (9.8%; 10.8%).

Notably, grade 5 AEs related to COVID-19 occurred in 9.4% of patients in the acalabrutinib arm vs 6.7% of patients in the placebo arm. When censoring for COVID-19–related deaths, the median PFS was NE (95% CI, 66.4 months–NE) in the acalabrutinib arm vs 61.6 months (95% CI, 49.6-68.9) in the placebo arm (HR, 0.64; 95% CI, 0.48-0.84; P = .0017). The median OS was NE (95% CI, NE-NE) in the acalabrutinib arm vs NE (95% CI, 73.8 months–NE) in the placebo arm when censoring for COVID-19 deaths (HR, 0.75; 95% CI, 0.53-1.04; P = .0797).

References

1. Calquence granted priority review in the US for patients with untreated mantle cell lymphoma. News release. AstraZeneca. October 3, 2024. Accessed October 3, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/calquence-granted-priority-review-in-the-us-for-patients-with-untreated-mantle-cell-lymphoma.html
2. 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.
3. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. FDA. October 31, 2017. Accessed October 3, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-acalabrutinib-mantle-cell-lymphoma