# AstraZeneca’s Calquence head-to-head results versus ibrutinib

- Link: https://www.directorstalkinterviews.com/astrazenecas-calquence-head-to-head-results-versus-ibrutinib/412997702
- Published: 2021-06-07T07:18:47+01:00
- Author: Amilia Stone

Final results from the head-to-head ELEVATE-RR Phase III trial of **[AstraZeneca plc](https://www.directorstalkinterviews.com/ftse-company/astrazeneca/azn.l)**(
[LON:AZN](https://www.directorstalkinterviews.com/ftse-company/astrazeneca/azn.l))
_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 trial^(4)**

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 | 
| p-value | <0.0001 | <0.0001 | – | 
| 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 | 
| p-value | <0.0001 | <0.0001 |   | 
| Estimated PFS at 48 months, % | 75 | 76 | 18 | 
| **ORR\*** | 
| ORR, % (95% CI) | 96.1(92.1-98.1) | 89.9(84.7-93.5) | 82.5(76.2-87.4) | 
| p-value | <0.0001 | 0.035 | – | 
| **OS** | 
| Median (HR, 95% CI), months | NR(0.50; 0.25-1.02) | NR(0.95; 0.52-1.74) | NR | 
| p-value | 0.0604 | 0.9164 | – | 
| Estimated OS at 48 months, % | 93 | 88 | 88 |

CI, confidence interval; NR, not reached; ORR, overall response rate; OS, overall
survival

*Investigator-assessed.

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**

_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.”

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