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2019-12-07

AstraZeneca: Calquence significantly prolonged the time patients lived without disease progression or death in previously u...

Full results from the Phase III ELEVATE TN trial showed 93% of
patients on Calquence combined with obinutuzumab vs. 47% of patients
on chlorambucil plus obinutuzumab remained free of disease
progression or death at 24 months

Trial also showed 87% of patients on Calquence alone remained free of
disease progression or death at 24 months

AstraZeneca today presented results from the interim analysis of the
Phase III ELEVATE TN trial, showing that Calquence (acalabrutinib)
combined with obinutuzumab or as monotherapy significantly improved
progression-free survival (PFS) compared to chlorambucil plus
obinutuzumab, a standard chemo-immunotherapy treatment, in patients
with previously untreated chronic lymphocytic leukaemia (CLL).[1]

The Independent Review Committee (IRC)-assessed results were presented
at the 2019 American Society of Hematology Annual Meeting and
Exhibition in Orlando, US. At a median follow-up of 28.3 months,
Calquence in combination with obinutuzumab or as a monotherapy
significantly reduced the risk of disease progression or death by 90%
and 80%, respectively, vs. chlorambucil plus obinutuzumab.[1]

In an exploratory analysis, Calquence in combination or alone
demonstrated consistent PFS improvements across most pre-specified
subgroups of patients with high-risk disease characteristics,
including the unmutated immunoglobulin heavy-chain variable gene
(IGHV), del(11q) and complex karyotype. Overall, the safety and
tolerability profile of Calquence observed in the ELEVATE TN trial
was consistent with its known profile.[1]

José Baselga, Executive Vice President, Oncology R&D said: "On the
heels of approvals in the US, Australia and Canada, these full
results provide further evidence that Calquence, as a new treatment
option for patients with chronic lymphocytic leukaemia, demonstrates
remarkable efficacy and a favourable tolerability profile. These
results also provide, for the first time, post-hoc analysis data
exploring the potential progression-free survival benefit of adding
obinutuzumab to a BTK inhibitor such as Calquence versus BTK
inhibitor monotherapy in a randomised trial."

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:
"In the detailed results from the ELEVATE TN trial comparing
Calquence to a commonly used chemo-immunotherapy treatment regimen,
Calquence demonstrated a clinically meaningful improvement in
progression-free survival, while maintaining its known tolerability
and safety profile. These are encouraging results for a patient
population that is known to face multiple comorbidities, and where
tolerability is a critical factor in their treatment."

Summary of key efficacy results as assessed by IRC from the ELEVATE TN
trial at a median follow-up of 28.3 months:[1]

Efficacy Calquence plus Calquence Chlorambucil plus
measure obinutuzumab N = monotherapy N obinutuzumab N =
179 = 179 177
PFS
Number of 14 (7.8) 26 (14.5) 93 (52.5)
events (%)
Median (95% NR (NE, NE) NR (34.2, NE) 22.6 (20.2, 27.6)
CI), months
HR (95% CI) 0.10 (0.06, 0.17) 0.20 (0.13, -
0.30)
p-value <0.0001 <0.0001 -
Estimated PFS 93 87 47
at 24 months,
%
ORR
ORR, n (%) 168 (93.9) (89.3, 153 (85.5) 139 (78.5) (71.9,
(95% CI) 96.5) (79.6, 89.9) 83.9)
p-value <0.0001 =0.0763 -
OS
Number of 9 (5.0) 11 (6.1) 17 (9.6)
events (%)
Median (95% NR (NE, NE) NR (NE, NE) NR (NE, NE)
CI), months
HR (95% CI) 0.47 (0.21, 1.06) 0.60 (0.28, -
1.27)
p-value =0.0577 =0.1556 -

CI, confidence interval; NR, not reached; NE, not estimable; HR,
hazard ratio; ORR, overall response rate;

OS, overall survival

Adverse events (AEs) led to treatment discontinuation in 11.2% of
patients treated with Calquence in combination with obinutuzumab and
8.9% of patients treated with Calquence monotherapy versus 14.1% of
patients treated with chlorambucil plus obinutuzumab.[1]

With over two years of follow-up, 79% of patients in both the
Calquence-containing arms remain on Calquence as a monotherapy. In
the Calquence combination arm (n=178), the most common AEs of any
grade (?30%) included headache (39.9%), diarrhoea (38.8%) and
neutropenia (31.5%). In the Calquence monotherapy arm (n=179), the
most common AEs of any grade (?30%) included headache (36.9%) and
diarrhoea (34.6%). In the chlorambucil plus obinutuzumab arm (n=169),
the most common AEs of any grade (?30%) included neutropenia (45.0%),
infusion-related reaction (39.6%) and nausea (31.4%).[1]

[]
Other AEs of Calquence Calquence Chlorambucil
clinical interest plus monotherapy plus
(%)[1] obinutuzumab N = 179 obinutuzumab
N = 178 N = 169
Any Grade ?3 Any Grade ?3 Any Grade ?3
Atrial 3.4% 0.6% 3.9% 0% 0.6% 0%
fibrillation
Major bleeding 2.8% 1.7% 1.7% 1.7% 1.2% 0%
Hypertension 7.3% 2.8% 4.5% 2.2% 3.6% 3.0%
Infection 69.1% 20.8% 65.4% 14.0% 43.8% 8.3%
SPM excluding NMSC 5.6% 3.4% 2.8% 1.1% 1.8% 1.2%

SPM, secondary primary malignancy; NMSC, non-melanoma skin cancer

These findings, along with previously reported data from the Phase III
ASCEND trial in relapsed or refractory CLL, support the recent
approvals of Calquence by the US FDA and the Australian Therapeutic
Goods Administration for the treatment of adult patients with CLL or
small lymphocytic lymphoma (SLL) and by Health Canada for CLL.[2]

About Calquence

In the US and Australia, Calquence (acalabrutinib) is approved for the
treatment of adult patients with chronic lymphocytic leukaemia (CLL)
or small lymphocytic lymphoma (SLL) and in Canada for CLL. In the US,
Canada, Australia, Brazil, Qatar, the United Arab Emirates, Mexico,
Argentina, Singapore, Chile, and recently India, Calquence is also
approved for adult patients with mantle cell lymphoma (MCL) who have
received at least one prior therapy. Calquence was approved for MCL
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). It binds covalently to BTK, thereby inhibiting
its activity.[2,3,4,5] In B-cells, BTK signalling results in
activation of pathways necessary for B-cell proliferation,
trafficking, chemotaxis, and adhesion.[2]

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,
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. Patients
65 years of age or older, or between 18 and 65 years of age with a
total Cumulative Illness Rating Scale (CIRS) >6 or creatinine
clearance of 30 to 69 mL/min, were enrolled. 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 approximately
every 12 hours until disease progression or unacceptable toxicity) in
combination with obinutuzumab. Patients in the third arm received
Calquence monotherapy (100mg approximately every 12 hours until
disease progression or unacceptable toxicity).[1,6]

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.[1,6]

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 in
2016 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.[7,8,9,10] In CLL, too many
blood stem cells in the bone marrow become abnormal lymphocytes and
these abnormal cells have difficulty fighting infections.[7] As the
number of abnormal cells grows there is less room for healthy white
blood cells, red blood cells and platelets.[7] This could result in
anaemia, infection and bleeding.[7] B-cell receptor signalling
through BTK is one of the essential growth pathways for CLL.

About AstraZeneca in haematology

Leveraging its strength in oncology, AstraZeneca has established
haematology as one of four key oncology disease areas of focus. The
Company's haematology franchise includes two US FDA-approved
medicines and a robust global development programme for a broad
portfolio of potential blood cancer treatments. Acerta Pharma serves
as AstraZeneca's haematology research and development arm.
AstraZeneca partners with like-minded science-led companies to
advance the discovery and development of therapies to address unmet
need.

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