Updated results from the ASCEND Phase III trial showed AstraZeneca’s Calquence (acalabrutinib) maintained a statistically significant progression-free survival (PFS) benefit at three years compared to investigator’s choice of rituximab combined with either idelalisib (IdR) or bendamustine (BR) in adults with relapsed or refractory chronic lymphocytic leukaemia (CLL), the most common type of leukaemia in adults.1,2

These data, presented at the 63rd American Society of Hematology (ASH) Annual Meeting & Exposition, demonstrated Calquence reduced the risk of disease progression or death by 71% versus IdR/BR as assessed by investigators at three years (based on a hazard ratio [HR] of 0.29; 95% confidence interval [CI]: 0.21-0.41; p<0.0001). Similar clinical benefits were observed in an exploratory analysis comparing each regimen with Calquence. Safety and tolerability of Calquence were consistent with earlier findings, with no new safety signals identified.1

Additional safety analyses from the ELEVATE-RR Phase III trial were also presented at ASH to further characterise adverse events (AEs) related to treatment with Bruton’s tyrosine kinase (BTK) inhibitors Calquence and ibrutinib. Overall, patients on ibrutinib experienced a 37% higher burden of AEs of any grade versus patients on Calquence.3

For any grade atrial fibrillation/flutter, a key secondary endpoint in the ELEVATE-RR trial, median time to onset was longer for Calquence versus ibrutinib (28.8 versus 16.0 months), and cumulative incidence was lower at all timepoints from six months through two years.3

Additionally, the ELEVATE-RR Phase III trial showed incidence of all-grade atrial fibrillation/flutter was lower for Calquence across subgroups of age, prior line of therapy and among patients without prior history of heart complications.3 Atrial fibrillation is an irregular heart rate that can increase the risk of stroke, heart failure and other heart-related complications.4

John F. Seymour, MBBS PhD, Peter MacCallum Centre and the Royal Melbourne Hospital, and a lead investigator on the ELEVATE-RR trial, said: “Patients with relapsed or refractory chronic lymphocytic leukaemia face limited options to successfully manage their disease, as they are often older and dealing with significant comorbidities. The risk of cardiac adverse events is an important consideration, especially for treatment with Bruton’s tyrosine kinase inhibitors because they can produce significant morbidity in some cases and also lead patients to discontinue treatment. The ELEVATE-RR data provide compelling evidence that acalabrutinib is a more tolerable option with reduced cardiovascular toxicity, giving clinicians further reassurance when prescribing this medicine that fewer patients will need to cease treatment due to adverse events, thus maintaining ongoing control of their disease, even in this complex setting.”

Anas Younes, Senior Vice President, Haematology R&D, AstraZeneca, said: “These impressive new long-term data support Calquence as the preferred therapy for the most common type of leukaemia in adults, with favourable safety compared to the current standards of care. The totality of the ASCEND and ELEVATE-RR data, in addition to data introducing a new tablet formulation for patients who need alternative methods of taking Calquence, continues to reinforce the positive experience that this medicine can deliver for patients with chronic lymphocytic leukaemia.”

Notes

ASCEND: Three-year follow-up data for Calquence in relapsed or refractory CLL (abstract #393)
ASCEND is a global, randomised, multicentre, open-label, Phase III trial that evaluated the efficacy and safety of Calquence (100mg twice-daily until disease progression or unacceptable toxicity) versus investigator’s choice of IdR or BR in patients with relapsed or refractory CLL.1,5 ASCEND is the first randomised trial to directly compare a BTK inhibitor as monotherapy with standard chemoimmunotherapy or idelalisib and rituximab combinations.

Summary of ASCEND results1

CI, confidence interval; NR, not reached; OS, overall survival; ORR, overall response rate
*Investigator-assessed

AEs led to treatment discontinuation in 21% of patients on Calquence, 65% of patients on IdR and 17% of patients on BR. Events of clinical interest for Calquence versus comparators included atrial fibrillation/flutter (all grade, 6% and 3%, respectively), hypertension (all grade, 7% and 4%), major haemorrhage (all grade, 3% in both arms), infections (Grade ≥3, 25% and 27%, respectively) and second primary malignancies excluding non-melanoma skin cancer (all grade, 7% and 3%, respectively). Serious AEs (any-grade) occurred in 38% of patients treated with Calquence, 63% of IdR patients and 26% of BR patients.1

ELEVATE-RR: Additional safety analyses of Calquence versus ibrutinib in relapsed or refractory CLL (abstract #3721)
Results from the ELEVATE-RR Phase III trial were first presented on 7 June 2021 at the American Society of Clinical Oncology (ASCO) Annual Meeting and published in the Journal of Clinical Oncology on 26 July 2021.

Additional safety data were used to characterise BTK inhibitor-related AEs, using measures of frequency, duration and drug exposure (versus incidence alone) to measure AE burden. Median treatment exposures were 38.3 months in the Calquence arm and 35.5 months in the ibrutinib arm.3

For any-grade hypertension, median time to onset was similar for Calquence and ibrutinib (8.1 months versus 7.0), but cumulative incidence was lower for Calquence at 6 months (5% versus 12%), 12 months (6% versus 16%), 18 months (8% versus 20%) and 24 months (8% versus 23%).

Hypertension also occurred less frequently with Calquence versus ibrutinib in subgroups of age, prior line of therapy and among patients without prior history.3

Among cardiovascular AEs of clinical interest, incidences of any-grade atrial fibrillation/flutter, hypertension and bleeding were statistically higher with ibrutinib versus Calquence, with higher exposure-adjusted incidence (2.0-, 2.8-, and 1.6-fold, respectively) and exposure-adjusted time with event (2.8-, 3.7-, and 1.8-fold).3

CLL
CLL is the most common type of leukaemia in adults, with an estimated 114,000 new cases globally in 2017, and the number of people living with CLL is expected to grow with improved treatment as patients live longer with the disease.2,6-8

In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections. As the number of abnormal cells grows, there is less room for healthy white blood cells, red blood cells and platelets. This could result in anaemia, infection and bleeding.6 B-cell receptor signalling through BTK is one of the essential growth pathways for CLL.

ASCEND
ASCEND (ACE-CL-309) is a global, randomised, multicentre, open-label Phase III trial evaluating the efficacy of Calquence in patients with relapsed or refractory CLL.5,9

In the trial, 310 patients were randomised (1:1) into two treatment arms. Patients in the first arm received Calquence monotherapy (100mg twice-daily until disease progression or unacceptable toxicity). Patients in the second arm received physician’s choice of either rituximab, a CD20 monoclonal antibody, in combination with idelalisib, a PI3-kinase inhibitor, or rituximab in combination with bendamustine, a chemotherapy.9

The primary endpoint at the interim analysis was PFS assessed by an Independent Review Committee (IRC), and key secondary endpoints included investigator-assessed PFS, IRC- and investigator-assessed overall response rate and duration of response, as well as overall survival, patient-reported outcomes and time to next treatment.

ASCEND is the first randomised Phase III trial to directly compare a BTK inhibitor as monotherapy to these combinations in relapsed or refractory CLL.5,9

ELEVATE-RR
ELEVATE-RR (ACE-CL-006) is a randomised, multicentre, open-label Phase III non-inferiority trial of Calquence versus ibrutinib in patients with relapsed or refractory CLL after at least one prior therapy, and at least one of the following prognostic factors: presence of 17p deletion, or presence of 11q deletion.10,11

In the trial, 533 patients were randomised (1:1) into two arms. Patients in the first arm received Calquence (100mg orally twice-daily until disease progression or unacceptable toxicity). Patients in the second arm received ibrutinib (420mg orally once-daily until disease progression or unacceptable toxicity).11

The primary endpoint for the trial was IRC-assessed PFS (non-inferiority; tested after 250 events, upper margin of 95% CI for HR<1.429). Secondary endpoints included incidence of atrial fibrillation, incidence of Grade 3 or higher infections, incidence of Richter’s transformation (a condition in which CLL changes into an aggressive form of lymphoma12) and OS.11

ELEVATE-RR is the first randomised Phase III trial to directly compare two BTK inhibitors as monotherapy in relapsed or refractory CLL.

Calquence
Calquence (acalabrutinib) is a next-generation, selective inhibitor of BTK. Calquence binds covalently to BTK, thereby inhibiting its activity.13,14 In B cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.13

Calquence is approved for the treatment of CLL and small lymphocytic lymphoma (SLL) in the US, approved for CLL in the EU and several other countries worldwide and approved in Japan for relapsed or refractory CLL and SLL. A Phase I trial is currently underway in Japan for the treatment of front-line CLL.

In the US and several other countries, Calquence is also approved for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. The US MCL indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Calquence is not currently approved for the treatment of MCL in Europe or Japan.

As part of an extensive clinical development programme, AstraZeneca and Acerta Pharma are currently evaluating Calquence in more than 20 company-sponsored clinical trials. Calquence is being evaluated for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström’s macroglobulinaemia, follicular lymphoma and other haematologic malignancies.

AstraZeneca in haematology
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By addressing blood cancers with high unmet medical needs, our aim is to deliver innovative medicines and approaches to healthcare services that have a meaningful impact on patients and caregivers, transforming the haematologic cancer care experience.

AstraZeneca in oncology
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The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca
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References

1. Jurczak W, Pluta A, Wach M, et al. Three-Year Follow-Up of the ASCEND Trial: Acalabrutinib vs Rituximab Plus Idelalisib or Bendamustine in Relapsed/Refractory Chronic Lymphocytic Leukemia. Oral presentation at: American Society of Hematology (ASH) Annual Meeting and Exposition; December 11-14, 2021; virtual. Abs: 393.

2. American Cancer Society. What is Chronic Lymphocytic Leukemia. Available online. Accessed December 2021.

3. Seymour JF, Byrd J, Hillmen P, et al. Characterization of Bruton Tyrosine Kinase Inhibitor (BTKi)-Related Adverse Events in a Head-to-Head Trial of Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia (CLL). Poster presentation at: American Society of Hematology (ASH) Annual Meeting and Exposition; December 11-14, 2021; virtual. Abs: 3721.

4. Mayo Clinic. Patient Care & Health Information, Diseases & Conditions - Atrial Fibrillation. Available online. Accessed December 2021.

5. ClinicalTrials.gov. A Study of Acalabrutinib vs Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL. NCT identifier: NCT02970318. Available online. Accessed December 2021.

6. National Cancer Institute. Chronic Lymphocytic Leukemia Treatment (PDQ®)–Patient Version. Available online. Accessed December 2021.

7. Global Burden of Disease Cancer Collaboration. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017. JAMA Oncol. 2019;5(12):1749-1768.

8. Jain N, Chen Q, Ayer T, et al. Prevalence and Economic Burden of Chronic Lymphocytic Leukemia (CLL) in the Era of Oral Targeted Therapies. Blood. 2015;126:871.

9. Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia [published online ahead of print, 2020 May 27]. J Clin Oncol. 2020;38(25):2849-2861.

10. ClinicalTrials.gov. Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Subjects With High Risk CLL. NCT identifier: NCT02477696. Available online. Accessed December 2021.

11. Byrd JC, et al. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol. 2021;39(31):3441-3452.

12. Leukaemia Foundation. Richter’s Syndrome. Available online. Accessed December 2021.

13. CALQUENCE (acalabrutinib) [U.S. prescribing information]. Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2019.

14. Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).