FDA Approves Acalabrutinib for Mantle Cell Lymphoma

Richard Pazdur, MD

The FDA has granted an accelerated approval to acalabrutinib (Calquence) as a treatment for adult patients with mantle cell lymphoma (MCL) following at least 1 prior therapy.

The approval was based on findings from the 124-patient ACE-LY-004 phase II trial, in which the investigator assessed objective response rate (ORR) was 81% with acalabrutinib (95% CI, 73%-87%). The complete response (CR) rate with acalabrutinib was 40% and the partial response (PR) rate was 41%.

The approval for the novel BTK inhibitor acalabrutinib arrived several months ahead of expectations under the Prescription Drug User Fee Act and followed a breakthrough therapy designation from the FDA for MCL in early August.

“Mantle cell lymphoma is a particularly aggressive cancer,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “For patients who have not responded to treatment or have relapsed, Calquence provides a new treatment option that has shown high rates of response for some patients in initial studies.”

In the ACE-LY-004 study, 124 patients with MCL received oral acalabrutinib at 100 mg twice daily. The median age of patients was 68 years, and most were male (80%). The median time since diagnosis was 46.3 months and 93% of patients had an ECOG performance status of 0 or 1. The median number of prior treatments was 2 (range, 1-5), which included stem cell transplant for 18% of patients. Those treated with a prior BTK inhibitor were excluded from the trial.

At a median follow-up of 15.2 months, the ORR by independent review committee was 80% (95% CI, 72%-87%), which was comprised evenly of CR and PR rates of 40%. The median duration of response was not yet reached at the time of analysis, with responses ongoing at 20+ months. The median time to best response was 1.9 months.

Of the 124 patients in the phase II trial, 80 were ≥65 years of age and 32 were ≥75 years. Overall, there were no meaningful efficacy differences observed between those ≥65 years of age and those younger. Additionally, the safety profile was similar between the two age groups, according to the FDA.

The most common adverse events (AEs) of any grade were anemia (46%), thrombocytopenia (44%), headache (39%), neutropenia (36%), diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%). The most common grade ≥3 AEs were neutropenia (15%), thrombocytopenia (12%), anemia (10%), and diarrhea (3.2%).

Serious AEs associated with acalabrutinib included hemorrhage, infections, and atrial fibrillation. In a database of 612 patients treated with acalabrutinib monotherapy across clinical trials, 18% of patients experienced grade ≥3 infections, most frequently pneumonia. In this safety group, atrial fibrillation and atrial flutter of any grade occurred in 3% of patients, with 1% having a grade 3 event. Overall, bleeding, bruising, or petechiae events of any grade occurred in approximately 50% of patients, with grade ≥3 events seen in 2% of patients.

The median duration of treatment with acalabrutinib was 16.6 months (range, 0.1-26.6), with 73.4% of patients receiving the medication for ≥6 months and 59.7% of patients on treatment for ≥1 year. Overall, dose reductions due to AEs were required for 1.6% of patients and dose discontinuations were required for 6.5%.

“The acalabrutinib approval represents an important development for patients currently battling mantle cell lymphoma, an aggressive type of blood cancer that is typically diagnosed at an advanced stage and associated with a high relapse rate," lead investigator of the study Michael L. Wang, MD, Professor, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, said in a statement. "In addition to the overall response rate, the high complete response rate of 40% seen in this trial illustrates the potential of acalabrutinib to help patients.”

Findings from the ACE-LY-004 study have not yet been formally published or presented, with data from the study solely released in the package insert along with the approval. AstraZeneca, the company developing the drug, told OncLive that the data are slated to be presented at a medical meeting later this year.

Under the accelerated approval program, full approval for acalabrutinib is contingent on findings from confirmatory trials. Currently, the phase III ACE-LY-308 clinical trial is evaluating acalabrutinib in combination with bendamustine and rituximab (BR) versus placebo plus BR for patients with untreated MCL.