Acalabrutinib Demonstrates Favorable Long-Term Efficacy in CLL

Acalabrutinib (Calquence) continued to show favorable efficacy with a tolerable safety profile in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to final data from the pivotal phase 3 ASCEND trial (NCT02970318) that were virtually presented during the 2020 European Hematology Association Annual Congress.¹

Results showed that 82% of patients with relapsed/refractory disease who received acalabrutinib were alive and free from disease progression at 18 months versus 48% of patients who received physician’s choice of rituximab (Rituximab) combined with idelalisib (Zydelig) or bendamustine.

The median PFS was not reached in the acalabrutinib arm versus 16.8 months in the control arm. When the control arm was broken into subgroups of those who received rituximab in combination with idelalisib and rituximab plus bendamustine, the median PFS was 16.2 months and 18.6 months, respectively.

After a median follow-up of 22 months, the median overall survival (OS) and duration of response (DOR) had also not been reached with acalabrutinib.

“The final results from ASCEND confirm the findings reported at the interim analysis and support the favorable efficacy and safety of acalabrutinib versus standard-of-care regimens in patients with relapsed/refractory CLL,” Paolo Ghia, MD, PhD, lead author of the study and professor of medical oncology at the Università Vita-Salute San Raffaele, said during a virtual presentation during the meeting.

Acalabrutinib has previously been approved in 9 countries to treat adult patients with CLL, and 14 countries for patients with mantle cell lymphoma (MCL) who have been treated with a minimum of 1 prior therapy, according to a press release by AstraZeneca. In the United States, the agent received regulatory approval in November 2019 for use in adult patients with CLL.²

The approval was based partly on results from this trial, which showed that at a median follow-up of 16.1 months, the median PFS was not reached with acalabrutinib versus 16.5 months on the control arm (HR, 0.31; 95% CI, 0.20-0.49; P <.0001); this translated to a 69% reduction in the risk of progression or death. Furthermore, at 12 months, 88% of patients who received acalabrutinib did not experience disease progression versus 68% of those on the control arm.^3,4

Due to this agent's off-target kinase inhibition, investigators hypothesized that it could have an improved safety profile compared with other agents in the space.

For the phase 3 trial, patients had to be aged ≥18 years, had a diagnosis of CLL as defined by the International Workshop on Chronic Lymphocytic Leukemia, had received ≥1 prior systemic therapy for their disease, and had an ECOG performance status of ≤2. Those with known central nervous system lymphoma or leukemia, as well as those with significant cardiovascular disease were not eligible for enrollment.

Additionally, patients who had prior exposure to a BCL-2 or BCR inhibitor were also excluded. Prior treatment with bendamustine was permitted if the investigator’s choice for treatment was rituximab plus idelalisib.

A total of 310 patients with relapsed/refractory CLL were randomized 1:1 to receive 100 mg of acalabrutinib twice daily (n = 155), or investigator's choice of oral idelalisib at 150 mg twice daily plus rituximab (n = 119) or investigator’s choice of intravenous bendamustine at 70 mg/m2 plus rituximab (n = 36). Treatment was continued until disease progression or unacceptable toxicity. After confirmed disease progression, crossover from the control arm to the acalabrutinib arm was permitted. The primary end point of the trial was PFS, and key secondary end points included ORR, OS, and safety. The data cutoff date for the analysis was August 1, 2019.

Patients had a median age of 67 years, and more than half, or 67.1% (n = 208) were male. Furthermore, 48.7% of patients (n = 151) had bulky disease of ≥5 cm. With regard to prior treatment, 48.1% of patients (n = 149) received 1 prior line, 27.7% (n =86) received 2 prior lines, 13.2% (n = 41) had 3 prior lines, and 11.0% (n = 34) received ≥4 prior lines. The median number of prior lines of therapy was 2. Most of the patients had received previous therapy with alkylators other than bendamustine (85.2%), followed by anti-CD20 monoclonal antibodies (80.3%), and purine analogues (68.7%).

Additional results from the trial showed that acalabrutinib prolonged PFS in patients with high-risk features such as del(17p) as well as those whose tumors harbored TP53 mutations and unmutated IGHV. The investigator-assessed PFS for those with del(17p) and TP53 mutations in the acalabrutinib arm had a HR of 0.11 (95% CI, 0.04-0.34) versus a HR of 0.29 (95% CI, 0.19-0.45) in those without the mutations. In patients with unmutated IGHV, the HR for investigator assessed PFS was 0.28 with acalabrutinib (95% CI, 0.18-0.43) versus 0.30 (95% CI, 0.12-0.76) for those with mutated IGHV.

Investigators examined how PFS would be affected in patients with high-risk features and found that acalabrutinib was able prolong PFS in cases with del(17p)/TP53 mutations, as well as unmutated IGHV. Acalabrutinib was also found to perform better when it came to duration of response—85.4% (95% CI,77%-91%) versus IdR/BR's rate of 49.4% (95% CI, 40%-58%). The agent was found to prolong PFS in comparison with the control across all prespecified subgroups analyzed.

With regard to responses, the DOR was found to be longer with acalabrutinib versus the control. Specifically, the median DOR had not been reached versus 18.0 months with the control (HR, 0.19; 95% CI, 0.11-0.33). The estimated 18-month DOR rate was also higher with acalabrutinib versus the control, at 85.4% versus 49.4%, respectively.

In terms of safety profile, acalabrutinib was found to be well tolerated. The incidences of grade ≥3 adverse effects (AEs), serious AEs, treatment-related AEs, drug discontinuations, as well as dose modifications were all higher with idelalisib plus rituximab than they were with either acalabrutinib or bendamustine/rituximab. All-grade AEs were reported in 96% of patients (n = 148) who received acalabrutinib, versus 99% (n = 117) and 80% (n = 28) of those who received rituximab in combination with idelalisib and bendamustine, respectively. Grade ≥3 events occurred in 55% (n = 85), 90% (n = 106), and 49% (n = 17) of patients, respectively. Ten grade 5 events were reported in the acalabrutinib arm versus 6 and 3 events in the rituximab/idelalsib and rituximab/bendamustine arms, respectively.

The most commonly occurring any-grade AEs reported in ≥15% of patients who received acalabrutinib included headache (22%), neutropenia (21%), diarrhea (20%), and upper-respiratory tract infection (20%). In terms of grade 3 or higher AEs, investigators reported neutropenia (17%), anemia (16%), and pneumonia (13%) with the agent.

Serious AEs reported in ≥5% of patients in any group included pneumonia (6%, acalabrutinib; 10%, rituximab/idelalisib; and 3%, rituximab/bendamustine), diarrhea (1%, 14%, and 0%, respectively), and pyrexia (1%, 7%, and 3%, respectively).

Bleeding events of any were of clinical interest with acalabrutinib and they were found to be more common in those who received the agent. However, the incidence of major hemorrhaging events was low and determined to be comparable across all arms of the study.

“Overall these data from the ASCEND study support the use of acalabrutinib in patients with relapsed/refractory CLL, including patients with high-risk features,” concluded Ghia.

References

1. Ghia P, Pluta A, Wach M, et al. Acalabrutinib vs idelalisib plus rituximab (IDR) or bendamustine plus rituximab (BR) in relapsed/refractory (R/R) chronic lymphocytic leuemia (CLL): ASCEND final results. Presented at: 2020 European Hematology Association Annual Congress; June 11-21, 2020; Virtual. bit.ly/2YedlKA.
2. Calquence approved in the US for adult patients with chronic lymphocytic leukaemia. News release. AstraZeneca. Nov. 21, 2019. Accessed June 15, 2020. bit.ly/3diuI0N.
3. FDA takes second action under international collaboration, approves new treatment option for patients with chronic lymphocytic leukemia. FDA. November 21, 2020. Accessed June 15, 2020. bit.ly/33bw74m.
4. Calquence prescribing information. Revised November 21, 2020. Accessed June 15, 2020. bit.ly/35kyfID.