The FDA has approved acalabrutinib for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma as either an initial or subsequent therapy.
The FDA has approved acalabrutinib (Calquence) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) as either an initial or subsequent therapy.1
This is the second agent to be approved under the FDA’s Project Orbis in collaboration with the Australian Therapeutic Goods Administration and Health Canada.
“Today, as part of a US, Australian, and Canadian collaboration known as Project Orbis, the US approved a new treatment option for those living with chronic lymphocytic leukemia or small lymphocytic lymphoma. The FDA’s Project Orbis provides a framework for concurrent submission and review of oncology drug applications among the FDA’s international partners,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in a press release. “We are pleased to continue working alongside our Australian and Canadian colleagues to facilitate new treatment options for patients and the FDA looks forward to working with other countries in future application reviews.”
The supplemental approval for acalabrutinib in CLL/SLL was supported by findings from 2 randomized phase III clinical trials: ELEVATE-TN and ASCEND.
ELEVATE-TN (ACE-CL-007) is a multicenter, open-label phase III trial that investigated the combination of acalabrutinib and obinutuzumab (Gazyva) versus obinutuzumab and chlorambucil chemotherapy or acalabrutinib monotherapy in patients with newly diagnosed CLL (NCT02475681). A total of 535 patients were randomized 1:1:1 between the 3 treatment arms.
The primary end point of the trial was progression-free survival (PFS) and secondary end points included objective response rate (ORR), time to next treatment (TTNT), overall survival (OS), and adverse events.
According to a press release from AstraZeneca, the developer of the BTK inhibitor, in June, the trial met its primary end point as of the interim analysis.2Acalabrutinib in combination with obinutuzumab demonstrated a statistically significant and clinically meaningful improvement in PFS compared with obinutuzumab plus chlorambucil. A statistically significant PFS benefit was also seen with the use of single-agent acalabrutinib as compared with obinutuzumab and chlorambucil.
The hazard ratio for PFS for the acalabrutinib and obinutuzumab arm compared with the obinutuzumab and chlorambucil arm was 0.10 (95% CI, 0.006-0.17;P<.0001) and was 0.20 (95% CI, 0.13-0.30;P<.0001) for single-agent acalabrutinib versus obinutuzumab and chlorambucil. Patients were followed for a median of 28.3 months of follow-up.3
ASCEND is an international, multicenter, open-label, phase III trial that investigated the use of single-agent acalabrutinib compared with rituximab (Rituxan) and either idelalisib (Zydelig) or bendamustine in patients with relapsed or refractory CLL (NCT02970318).
The trial enrolled 310 patients who were randomized 1:1 to receive 100 mg of acalabrutinib twice daily or one of the combination regimens. Patients in the ASCEND trial had previously received ≥1 prior systemic therapy, had CD20-positive disease, and had an ECOG performance status of 0 to 2.
The primary end point of the ASCEND trial was also PFS as assessed by independent review committee and secondary end points included physician-assessed PFS, ORR, OS, duration of response, TTNT, and patient-reported outcomes.
A press release from the company also announced that the trial met its primary end point of improved PFS with acalabrutinib monotherapy compared with either combination regimen as of an interim analysis.4
Additionally, findings from the ASCEND trial were presented at the 2019 EHA Annual Congress. As of the meeting, the acalabrutinib arm had not yet reached a median PFS compared with 16.5 months in the rituximab-based combination therapy arm (HR, 0.31; 95% CI, 0.20-0.49; P<.0001).5Similar PFS benefits were seen across patient subgroups.
The ORR by IRC assessment in the acalabrutinib arm was 81% (95% CI, 74%-87%) compared with 76% (95% CI, 68%-82%) with rituximab/idelalisib or rituximab/bendamustine (P= .22). The median DOR was not reached in the acalabrutinib arm versus 13.6 months (95% CI, 11.9-not reached) in the rituximab-based therapy arm (HR, 0.33; 95% CI, 0.19-0.59; P<.0001).
At a median follow-up of 16.1 months, the OS had not yet been reached in either treatment arm (HR, 0.84; 95% CI, 0.42-1.66;P= .6). Of note, 51% of the patients receiving rituximab-based combinations who had disease progression then crossed over to receive acalabrutinib.
Treatment discontinuation due to adverse events (AEs) was observed in 11% of patients in the acalabrutinib arm; 49% of patients receiving rituximab and idelalisib and 17% receiving rituximab and bendamustine also discontinued due to AEs. Richter transformation occurred in 4 patients in the acalabrutinib arm and in 5 patients in the rituximab-based therapy arm.
At least 1 AE of any grade was observed in 94% of patients in the acalabrutinib arm and in 99% and 80% of patients receiving the idelalisib and bendamustine combinations, respectively. Serious AEs were observed in 29%, 56%, and 26% of patients receiving acalabrutinib, rituximab/idelalisib, and rituximab/bendamustine, respectively. Grade 5 AEs were reported in 6 patients in the acalabrutinib arm and in 7 patients in the rituximab-based therapy arm.
According to press releases from the company, both trials showed that the safety and tolerability of acalabrutinib was consistent with the established safety profile for the BTK inhibitor.2,3
The median PFS has not been reached in the acalabrutinib arms of either trial yet, and the median OS has not been yet reached in any arm of either trial.3
Review of the acalabrutinib supplemental application occurred through the FDA’s Real-Time Oncology Review pilot program in collaboration with regulatory agencies from Australia and Canada.
Previously, the FDA granted acalabrutinib with priority review and breakthrough therapy designations in this setting.
Acalabrutinib is also approved for use in the treatment of patients with relapsed or refractory mantle cell lymphoma.