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2019-11-21

AstraZeneca: Calquence approved in the US for adult patients with chronic lymphocytic leukaemia

Two Phase III Calquence trials demonstrated superior progression-free
survival across multiple settings while maintaining favourable
tolerability

Calquence combined with obinutuzumab and as monotherapy reduced the
risk of disease progression or death by 90% and 80%, respectively in
ELEVATE-TN

AstraZeneca today announced that the US Food and Drug Administration
(FDA) has approved Calquence (acalabrutinib) for adult patients with
chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma
(SLL).[1] The US approval was granted under the FDA's Real-Time
Oncology Review and newly established Project Orbis programmes.

The approval is based on positive results from the interim analyses of
two Phase III clinical trials, ELEVATE-TN in patients with previously
untreated CLL and ASCEND in patients with relapsed or refractory CLL.
Together, the trials showed that Calquence in combination with
obinutuzumab or as a monotherapy significantly reduced the relative
risk of disease progression or death versus the comparator arms in
both 1st-line and relapsed or refractory CLL. Across both trials, the
safety and tolerability of Calquence were consistent with its
established profile.[1]

Dave Fredrickson, Executive Vice President, Oncology Business Unit
said: "With over 20,000 new cases anticipated this year in the US
alone, today's approval of Calquence provides new hope for patients
with one of the most common types of adult leukaemia, offering
outstanding efficacy and a favourable tolerability profile. The
chronic lymphocytic leukaemia patient population is known to face
multiple comorbidities, and tolerability is a critical factor in
their treatment."

Dr Jeff Sharman, Director of Research at Willamette Valley Cancer
Institute, Medical Director of Hematology Research for The US
Oncology Network, and a lead author of the ELEVATE-TN trial, said:
"Tolerability remains an issue in the current treatment landscape of
chronic lymphocytic leukaemia, which may require ongoing therapy for
many years. In the ELEVATE-TN and ASCEND trials comparing Calquence
to commonly used treatment regimens, Calquence demonstrated a
clinically meaningful improvement in progression-free survival in
patients across multiple settings, while maintaining its favourable
tolerability and safety profile."

The results of the interim analysis of the ELEVATE-TN trial will be
presented at the upcoming American Society of Hematology congress.[2]

The trial showed a statistically significant and clinically meaningful
improvement in progression-free survival (PFS) for patients treated
with either Calquence in combination with obinutuzumab or Calquence
monotherapy versus chlorambucil chemotherapy plus obinutuzumab, a
current standard-of-care combination used in the control arm.[1]

In the Calquence combination arm, risk of disease progression or death
was reduced by 90% (HR 0.10; 95% CI, 0.06-0.17, p<0.0001) and in the
monotherapy arm it was reduced by 80% (HR 0.20; 95% CI, 0.13-0.30,
p<0.0001).[1]

The median time to disease progression for patients treated with
Calquence in combination with obinutuzumab or as a monotherapy has
not yet been reached versus 22.6 months (95% CI, 20-28) for
chlorambucil plus obinutuzumab.[1]

ELEVATE-TN safety overview (most common ARs, ?15%):[1]

[][][][][][][][][]
Adverse reaction Calquence Calquence Chlorambucil
plus monotherapy plus
obinutuzumab (n=179) obinutuzumab
(n=178) (n=169)
Any Grade ?3 Any Grade Any Grade
?3 ?3
Infection[?] 69% 22% 65% 14% 46% 13%
Neutropenia[?] 53% 37% 23% 13% 78% 50%
Anemia[?] 52% 12% 53% 10% 54% 14%
Thrombocytopenia[?] 51% 12% 32% 3.4% 61% 16%
Headache 40% 1.1% 39% 1.1% 12% 0
Diarrhoea 39% 4.5% 35% 0.6% 21% 1.8%
Musculoskeletal 37% 2.2% 32% 1.1% 16% 2.4%
pain[?]
Fatigue 34% 2.2% 23% 1.1% 24% 1.2%
Bruising[?] 31% 0 21% 0 5% 0
Rash[?] 26% 2.2% 25% 0.6% 9% 0.6%
Arthralgia 22% 1% 16% 0.6% 4.7% 1.2%
Dizziness 20% 0 12% 0 7% 0
Hemorrhage[?] 20% 1.7% 20% 1.7% 6% 0
Nausea 20% 0 22% 0 31% 0
Lymphocytosis[?] 12% 11% 16% 15% 0.6% 0.6%

[?]Includes multiple ADR terms.

In patients treated with the combination of Calquence plus
obinutuzumab, adverse reactions (ARs) led to treatment
discontinuation in 11% of patients and a dose reduction of Calquence
in 7% of patients. In the monotherapy arm, ARs led to discontinuation
in 10% and dose reduction in 4% of patients.[1] In the control arm,
ARs led to regimen discontinuation in 14% of patients with a dose
reduction of chlorambucil in 28% of patients.[3] There were no dose
reductions for obinutuzumab.[1,][3]

In 1,029 patients with haematologic malignancies who were treated with
Calquence 100mg approximately every 12 hours across multiple clinical
trials, where 88% received treatment for at least six months and 79%
received treatment for at least one year, serious or Grade ?3
infections occurred in 19%, and Grade 3 atrial fibrillation and
flutter occurred in 1.1% of patients. In the same patient
population, major haemorrhage occurred in 3.0% (serious or Grade ?3
bleeding or any central nervous system bleeding), with fatal
haemorrhage occurring in 0.1% of patients. Second primary
malignancies (all grades) including skin cancers occurred in 12% of
patients.[1]

The US approval is among the first to be granted under Project Orbis,
an initiative of the US FDA Oncology Center of Excellence, which
provides a framework for concurrent submission and review of oncology
medicines among international partners. The FDA, the Australian
Therapeutic Goods Administration, and Health Canada collaborated on
this review.[ ][4]

About Calquence

In the US, Calquence (acalabrutinib) is indicated for the treatment of
adult patients with chronic lymphocytic leukaemia (CLL)/small
lymphocytic lymphoma (SLL). In the US, Canada, Australia, Brazil,
Qatar, the United Arab Emirates, Mexico, Argentina, Singapore, Chile,
and recently India, Calquence is indicated for adult patients with
mantle cell lymphoma (MCL) who have received at least one prior
therapy. Approved under accelerated review in the US, continued
approval for previously treated MCL is contingent upon verification
and confirmation of clinical benefit in confirmatory trials.

Calquence is a next-generation selective inhibitor of Bruton's
tyrosine kinase (BTK). Calquence binds covalently to BTK, thereby
inhibiting its activity.[1,5,6,7] In B-cells, BTK signalling results
in activation of pathways necessary for B-cell proliferation,
trafficking, chemotaxis, and adhesion.[1]

As part of an extensive clinical development programme, AstraZeneca
and Acerta Pharma are currently evaluating Calquence in 23
company-sponsored clinical trials. Calquence is being developed for
the treatment of multiple B-cell blood cancers including CLL, MCL,
diffuse large B-cell lymphoma, Waldenström macroglobulinaemia and
follicular lymphoma and other haematologic malignancies. Several
Phase III clinical trials in CLL are ongoing, including ASCEND,
ELEVATE-TN, ELEVATE-RR (ACE-CL-006) evaluating Calquence versus
ibrutinib in patients with previously treated high-risk CLL, and
ACE-CL-311 evaluating Calquence in combination with venetoclax and
with/without obinutuzumab versus chemoimmunotherapy in patients with
previously untreated CLL without 17p deletion or TP53 mutation.

About ELEVATE-TN

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, a CD20 monoclonal antibody, or
Calquence alone versus chlorambucil, a chemotherapy, in combination
with obinutuzumab in previously untreated patients with CLL. In the
trial, 535 patients were randomised (1:1:1) into three arms. Patients
in the first arm received chlorambucil in combination with
obinutuzumab. Patients in the second arm received Calquence (100mg
twice daily until disease progression or unacceptable toxicity) in
combination with obinutuzumab. Patients in the third arm received
Calquence monotherapy (100mg twice daily until disease progression or
unacceptable toxicity).[1,8]

The primary endpoint is PFS in the Calquence and obinutuzumab arm
compared to the chlorambucil and obinutuzumab arm, assessed by an
independent review committee (IRC), and a key secondary endpoint is
IRC-assessed PFS in the Calquence monotherapy arm compared to the
chlorambucil and obinutuzumab arm. Other secondary endpoints include
objective response rate, time to next treatment and overall
survival.[1,8]

About ASCEND

ASCEND (ACE-CL-309) is a global, randomised, multicentre, open-label
Phase III trial evaluating the efficacy of Calquence in previously
treated patients with CLL. In the trial, 310 patients were randomised
(1:1) into two arms. Patients in the first arm received Calquence
monotherapy (100mg twice daily until disease progression or
unacceptable toxicity). Patients in the second arm received
investigator's choice of either rituximab, a CD20 monoclonal
antibody, in combination with idelalisib, a PI3K inhibitor, or
rituximab in combination with bendamustine, a chemotherapy.[1,9]

The primary endpoint is PFS assessed by an IRC, and key secondary
endpoints include physician-assessed PFS, IRC- and physician-assessed
overall response rate and duration of response, as well as overall
survival, patient-reported outcomes and time to next treatment.[1,9]

About CLL

Chronic lymphocytic leukaemia (CLL) is one of the most common types of
leukaemia in adults, with an estimated 105,000 new cases globally
each year and 20,720 new cases in the US in 2019, and the number of
people living with CLL is expected to grow with improved treatment as
patients live longer with the disease.[10,11,12,13] In CLL, too many
blood stem cells in the bone marrow become abnormal lymphocytes and
these abnormal cells have difficulty fighting infections.[10] As the
number of abnormal cells grows there is less room for healthy white
blood cells, red blood cells and platelets.[10] This could result in
anaemia, infection and bleeding.[10] B-cell receptor signalling
through B...

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