Final results from the head-to-head ELEVATE-RR Phase III trial of AstraZeneca plc (LON:AZN) Calquence (acalabrutinib) demonstrated non-inferior progression-free survival (PFS) and statistically significantly fewer events of atrial fibrillation versus ibrutinib in adults with previously treated chronic lymphocytic leukaemia (CLL), the most common type of leukaemia in adults.1
Separately, updated results at four years of follow up from the ELEVATE-TN Phase III trial continued to show a strong PFS benefit for Calquence as combination therapy or as monotherapy in previously untreated patients with CLL.
At a median follow up of 40.9 months, the ELEVATE-RR trial met its primary endpoint of PFS non-inferiority versus ibrutinib with a median PFS of 38.4 months in both arms (based on a hazard ratio [HR] of 1.0, 95% confidence interval [CI] 0.79-1.27). Patients treated with Calquence had a statistically significantly lower incidence of all-grade atrial fibrillation compared with patients treated with ibrutinib (9.4% versus 16.0%), a key secondary endpoint.2 Atrial fibrillation is an irregular heart rate that can increase the risk of stroke, heart failure and other heart-related complications.3
John C. Byrd, MD, Distinguished University Professor, The Ohio State University, and lead investigator of the ELEVATE-RR trial, said: “Cardiac adverse events are an important consideration for treating chronic lymphocytic leukaemia patients with Bruton’s tyrosine kinase inhibitors because they can produce significant morbidity in some cases and also lead patients to discontinue treatment. These data provide compelling evidence that acalabrutinib is a more tolerable option with reduced cardiovascular toxicity and overall fewer discontinuations due to adverse events, giving clinicians further reassurance when prescribing this medicine that patients can stay on treatment while maintaining ongoing control of their disease.”
The results of both trials were presented during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting on 7 June 2021.
ELEVATE-RR: Calquence versus ibrutinib in relapsed or refractory CLL
ELEVATE-RR (ACE-CL-006) is the first Phase III trial to compare two Bruton’s tyrosine kinase (BTK) inhibitors in patients with previously treated CLL with presence of 17p deletion or presence of 11q deletion.2 The trial met the non-inferiority endpoint for PFS defined by the trial for Calquence (n=268) versus ibrutinib (n=265) in patients with previously treated CLL with certain high-risk prognostic factors.2
Patients treated with Calquence had statistically significantly lower incidence of all-grade atrial fibrillation, a key secondary endpoint, compared with patients treated with ibrutinib (9.4% [n=25/266] versus 16.0% [n=42/263]; p=0.02).2
A lower frequency of adverse events (AEs) was observed with Calquence versus ibrutinib including lower common AEs, Grade 3 or higher AEs, serious AEs, treatment discontinuations due to AEs and overall cardiac events.2 The safety and tolerability of Calquence in ELEVATE-RR was consistent with the known profile of Calquence.
Adverse events led to treatment discontinuation in 14.7% of patients on Calquence and 21.3% of patients on ibrutinib. AEs of clinical interest for Calquence versus ibrutinib included cardiac events (all grade, 24.1%, and 30.0%, respectively), bleeding events (all grade, 38.0% and 51.3%, respectively), hypertension (all grade, 9.4% and 23.2%, respectively), infections (all grade, 78.2% and 81.4%, respectively), interstitial lung disease/pneumonitis (all grade, 2.6% and 6.5%, respectively) and second primary malignancies excluding non-melanoma skin cancer (all-grade, 9.0% and 7.6%, respectively).2 Serious AEs (any grade) occurred in 53.8% of patients on Calquence versus 58.6% of patients receiving ibrutinib.2
Median overall survival (OS) was not reached in either arm, with 63 (23.5%) patients in the Calquence arm, and 73 (27.5%) patients in the ibrutinib arm experiencing an event (HR of 0.82, 95% CI 0.59-1.15).2
ELEVATE-TN: Four-year follow up for Calquence in previously untreated CLL
ELEVATE-TN (ACE-CL-007) is a randomised, multicentre, open-label Phase III trial evaluating the safety and efficacy of Calquence in combination with obinutuzumab or alone versus chlorambucil in combination with obinutuzumab in previously untreated patients with CLL.4 The trial met its primary endpoint (IRC-assessed PFS with Calquence plus obinutuzumab versus chlorambucil plus obinutuzumab) at the data cut-off for the interim analysis after a median follow up of 28.3 months.5
After a median follow up of 46.9 months, the ELEVATE-TN Phase III trial showed Calquence plus obinutuzumab reduced the risk of disease progression or death by 90% (HR 0.10, 95% CI 0.07-0.17) and as a monotherapy by 81% (HR 0.19, 95% CI 0.13-0.28) compared with chlorambucil plus obinutuzumab.4 Estimated PFS rates at 48 months for Calquence plus obinutuzumab or as monotherapy were 87% and 78%, respectively, versus 25% for chlorambucil plus obinutuzumab.4 PFS findings were consistent across high-risk subgroups.4 Median PFS was not yet reached for either Calquence arm at four years of follow up. Median OS was not reached in any treatment arm with a trend toward significance in the Calquence plus obinutuzumab group (p=0.0604).4
Summary of key efficacy results from the ELEVATE-TN trial4
Median follow up of 46.9 months (range: 0.0-59.4)
|Efficacy measure||Calquence plus obinutuzumabN=179||Calquence monotherapyN=179||Chlorambucil plus obinutuzumabN=177|
|PFS*: Overall population|
|Median (HR, 95% CI), months||NR(0.10; 0.07-0.17)||NR(0.19; 0.13-0.28)||27.8|
|Estimated PFS at 48 months, %||87||78||25|
|PFS*: Patients with del(17p) and/or mutated TP53|
|Median (HR, 95% CI), months||NR(0.17; 0.07-0.42)||NR(0.18; 0.07-0.46)||17.5|
|Estimated PFS at 48 months, %||75||76||18|
|ORR, % (95% CI)||96.1(92.1-98.1)||89.9(84.7-93.5)||82.5(76.2-87.4)|
|Median (HR, 95% CI), months||NR(0.50; 0.25-1.02)||NR(0.95; 0.52-1.74)||NR|
|Estimated OS at 48 months, %||93||88||88|
CI, confidence interval; NR, not reached; ORR, overall response rate; OS, overall survival
The safety profile remained largely unchanged from the interim analysis at 24 months, with similar treatment discontinuation rates across arms (25.1%, 30.7% and 22.6% for Calquence plus obinutuzumab, Calquence monotherapy and chlorambucil plus obinutuzumab, respectively).4 The most common reasons for treatment discontinuation were AEs (12.8%, 12.34% and 14.7%, respectively) and progressive disease (4.5%, 7.8% and 1.7%, respectively).4
Selected AEs of interest of any grade in the Calquence combination arm (n=178), Calquence monotherapy arm (n=179) and chlorambucil plus obinutuzumab arm (n=169) included cardiac events (20.8%, 19.0% and 7.7%, respectively), bleeding (47.2%, 41.9% and 11.8%, respectively), hypertension (7.9%, 7.3% and 4.1%, respectively), infections (75.3%, 73.7% and 44.4%, respectively) and second primary malignancies (15.7%, 13.4% and 4.1%, respectively).4
Calquence (acalabrutinib) is a next-generation, selective inhibitor of BTK. Calquence binds covalently to BTK, thereby inhibiting its activity.11,12 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.11
Calquence is approved for the treatment of CLL and 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.
Dave Fredrickson, Executive Vice President, AstraZeneca’s Oncology Business Unit, said: “Tolerability is a critical factor in treating patients with chronic lymphocytic leukaemia who often remain on medicines for many years and experience multiple comorbidities. The totality of the Calquence data at ASCO confirm our confidence in the favourable benefit-risk profile of this medicine, with over 40 months of follow up in each of these two trials. Together, the results provide strong evidence that Calquence is a preferred option for people living with this chronic and devastating disease.”