-
Results from two Phase II
trials, ENESTfreedom and ENESTop, support and extend previous
findings of long-term durability of molecular response after
stopping Tasigna, reducing time on drug for many CML
patients1,2
-
New Phase I data for asciminib
in combination with imatinib, nilotinib or dasatinib in heavily
pre-treated Ph+ CML-CP patients demonstrate potential molecular
response and a well-tolerated safety profile3,4
Basel, June 14, 2019 -
Long-term follow-up data from the ongoing, pivotal open-label
ENESTfreedom and ENESTop trials showed sustained treatment-free
remission (TFR) after stopping frontline and second-line Tasigna
(nilotinib) therapy in eligible adult patients with Philadelphia
chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the
chronic phase (CP). Separate data demonstrate promising results for
asciminib (ABL001), an investigational allosteric BCR-ABL
inhibitor, in combination with three different tyrosine kinase
inhibitors (TKIs) in heavily pre-treated Ph+ CML-CP patients. The
results will be presented at the 24th Congress of
the European Hematology Association (EHA) in Amsterdam1-4.
"We are pleased to report many of our Tasigna
clinical-trial patients continue to maintain treatment-free
remission for nearly four years with a low adverse event burden,"
said John Tsai, MD, Head of Global Drug Development and Chief
Medical Officer, Novartis. "Long-term trials like ENESTfreedom and
ENESTop, as well as promising Phase I data from asciminib, are
helping us to reimagine medicine and the way CML is treated."
Results from the ENESTfreedom study showed that
about 44% of patients remained in TFR (84/190) for 192 weeks after
stopping frontline Tasigna treatment. The treatment-free survival
rate at 192 weeks was nearly 49%. About 99% (90/91) and 92% (84/91)
of patients who resumed nilotinib due to loss of major molecular
response (MMR) during the TFR phase regained MMR and molecular
response4.5,
respectively. Among 91 patients who resumed nilotinib, the most
common adverse events (AEs) were nasopharyngitis (18.7%) as well as
pruritus, fatigue and increased lipase (14.3% each). The majority
of AEs were grade 1/21.
Consistent results were observed in the ENESTop
trial: About 46% of patients remained in TFR (58/126) for 192 weeks
after stopping second-line Tasigna treatment. The treatment-free
survival rate at 192 weeks was over 50%. Among 59 patients who
resumed nilotinib, the most common AEs were hypertension (20.3%)
and arthralgia (13.6%). The majority of AEs were grade
1/22.
Novartis will also present data from a Phase I
trial of asciminib in combination with ATP-competitive TKI in
heavily-pretreated patients with Ph+ CML-CP. Importantly, each
combination was evaluated in a dose finding study assessing
different asciminib dose levels, so results are not comparable
across the three treatment arms. The preliminary results
showed:
Among patients who at baseline did not achieve
BCR-ABL1 International Scale [IS] <1%, by 48 weeks3,4:
-
60% (9/15) achieved molecular response <1% in
the asciminib-plus-imatinib arm, and
-
43% (6/14) and 56% (5/9) patients achieved
molecular response <1% in the asciminib-plus-nilotinib and
asciminib-plus-dasatinib arms, respectively.
In evaluable patients without MMR at baseline, by
48 weeks3,4:
-
42% (8/19) achieved MMR with asciminib plus
imatinib with median treatment exposure of 54.6 weeks, and
-
31% (4/13) patients with asciminib plus
nilotinib and 36% (5/14) patients with asciminib plus dasatinib,
respectively, achieved MMR.
No patients with MMR at baseline lost MMR due to
either of the three combination therapies. All combinations showed
tolerable safety profile in heavily pretreated CML
patients3,4:
-
Among patients who received asciminib plus
imatinib, the most common any-grade AEs were nausea (32%),
increased lipase (20%), as well as abdominal pain, peripheral edema
and vomiting (16% each).
-
Among patients who received asciminib plus
nilotinib, most common any-grade AEs were myalgia (35%), increased
lipase (29%), and increased amylase, fatigue and pruritus (24%
each).
-
Among patients who received asciminib plus
dasatinib, most common any-grade AEs were increased lipase (35%)
and diarrhea, headache and nausea (18% each).
"While the introduction of TKIs has changed the
CML treatment paradigm, there remains a subset of patients who are
intolerant or resistant to TKI therapy," said Jorge Cortes, MD,
Deputy Chair and Professor of Medicine in the Department of
Leukemia at MD Anderson Cancer Center, Houston Texas. "These
initial results from combination therapy with currently available
TKIs and a BCR-ABL1 inhibitor like asciminib are encouraging - and
give us the potential to increase molecular response and prevent
development of mutations."
Commitment to
CML
Our ongoing research in Ph+ CML has helped transform the disease
from a fatal leukemia to a chronic condition in most patients.
Novartis maintains an unwavering commitment to scientific
innovation and access to care for patients worldwide. As an
organization committed to patients, Novartis continues to reimagine
CML care by pursuing ambitious goals with courage, passion and
commitment for the global CML community.
About Tasigna
Tasigna (nilotinib) is approved in more than 130 countries for the
treatment of adult patients with newly diagnosed Philadelphia
chromosome-positive chronic myelogenous leukemia (Ph+ CML) in
chronic phase and with chronic and accelerated phase Ph+ CML
resistant or intolerant to at least one prior therapy, including
Glivec® (imatinib).
Tasigna is also approved for the treatment of pediatric patients
with newly diagnosed Ph+ CML in the chronic phase and with
resistance or intolerance to prior TKI therapy.
About asciminib
Asciminib (ABL001) is an investigational allosteric
BCR-ABL inhibitor with a mechanism of action distinct from
currently available TKI treatments for patients with CML. There is
a broad clinical development program underway for asciminib both as
a potential monotherapy such as the Phase III ASCEMBL third-line
CML study and in combination with other therapies, such as the
Phase II ASC4MORE study investigating asciminib plus imatinib for
patients with CML-CP without deep molecular response. It is
currently being studied in patients with and without genetic
mutations that make them resistant to many targeted CML therapies.
If proven safe and effective, asciminib has the potential to be a
meaningful therapy, increasing the treatment options in CML and
addressing the treatment needs of patients.
IMPORTANT SAFETY INFORMATION for
TASIGNA® (nilotinib)
Capsules
Use with caution in patients with uncontrolled or significant
cardiac disease and in patients who have or may develop
prolongation of QTc. Low levels of potassium or magnesium must be
corrected prior to Tasigna administration. Monitor closely for an
effect on the QTc interval. Baseline ECG is recommended prior to
initiating therapy and as clinically indicated. Cases of sudden
death have been reported in clinical studies in patients with
significant risk factors. Avoid use of concomitant drugs known to
prolong the QT interval and strong CYP3A4 inhibitors. Avoid food 2
hours before and 1 hour after taking dose.
Reactivation of hepatitis B can occur in patients
who are chronic carriers of this virus after receiving TKI
treatment.
Use with caution in patients with liver
impairment, with a history of pancreatitis and with total
gastrectomy. Patients with rare hereditary problems of galactose
intolerance, severe lactase deficiency or glucose-galactose
malabsorption should not use Tasigna. Tasigna may cause fetal harm
in pregnant women. If pregnancy is planned during the
treatment-free remission phase, the patient must be informed of a
potential need to re-initiate treatment with Tasigna during
pregnancy. Women should not breastfeed while taking Tasigna and for
2 weeks after the last dose.
Cases of cardiovascular events included ischemic
heart disease-related events, peripheral arterial occlusive
disease, and ischemic cerebrovascular events have been reported.
Serious cases of hemorrhage from various sites including
gastrointestinal were reported in patients receiving Tasigna. Grade
3 or 4 fluid retention including pleural effusion, pericardial
effusion, ascites and pulmonary edema have been reported. Cases of
tumor lysis syndrome have been reported in Tasigna-treated patients
who were resistant or intolerant to prior CML therapy.
In pediatric patients the long-term effects of
prolonged treatment with Tasigna is unknown.
Eligible patients who are confirmed to express the
typical BCR-ABL transcripts, e13a2/b2a2 or e14a2/b3a2, can be
considered for treatment discontinuation. Frequent monitoring of
BCR-ABL transcript levels in patients eligible for treatment
discontinuation must be performed with a quantitative diagnostic
test validated to measure molecular response levels with a
sensitivity of at least MR4.5 (BCR-ABL/ABL
<=0.0032% IS). BCR-ABL transcript levels must be assessed prior
to and during treatment discontinuation. Loss of major molecular
response (MMR=BCR-ABL/ABL <=0.1% IS) or confirmed loss of
MR4 (two
consecutive measures separated by at least 4 weeks showing loss of
MR4(MR4=BCR-ABL/ABL
<=0.01% IS) will trigger treatment re-initiation within 4 weeks
of when loss of remission is known to have occurred. It is crucial
to perform frequent monitoring of BCR-ABL transcript levels and
complete blood count with differential in order to detect possible
loss of remission. For patients who fail to achieve MMR after three
months of treatment re-initiation, BCR-ABL kinase domain mutation
testing should be performed.
Musculoskeletal pain, myalgia, pain in extremity,
arthralgia, bone pain and spinal pain may occur upon discontinuing
treatment with Tasigna within the framework of attempting
treatment-free remission.
The most frequent Grade 3 or 4 adverse events are
hematological (neutropenia, thrombocytopenia, anemia) which are
generally reversible and usually managed by withholding Tasigna
temporarily or dose reduction. Chemistry panels, including
electrolytes, lipid profile, liver enzymes, and glucose should be
checked prior to therapy and periodically. Tasigna can cause
increases in serum lipase. The most frequent non-hematologic
adverse events were rash, pruritus, nausea, fatigue, headache,
alopecia, myalgia, constipation and diarrhea.
Please see full Prescribing Information
at http://www.tasigna.com/.
Disclaimer
This press release contains forward-looking statements within the
meaning of the United States Private Securities Litigation Reform
Act of 1995. Forward-looking statements can generally be identified
by words such as "potential," "can," "will," "plan," "expect,"
"anticipate," "look forward," "believe," "committed,"
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actual results may vary materially from those set forth in the
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References
-
David M. Ross, et al. Durability and impact on
quality of life of treatment-free remission (tfr) in patients with
chronic myeloid leukemia (cml) after stopping frontline (1l)
nilotinib: ENESTfreedom 192-wk results. Abstract# PF409.
24th Congress of
the European Hematology Association. June 13-16, Amsterdam, The
Netherlands.
-
François-Xavier Mahon, et al. ENESTop 192-wk
results: durability and impact on quality of life of treatment-free
remission (tfr) following second-line (2l) nilotinib (nil) in
patients (pts) with chronic myeloid leukemia (cml). Abstract #
PF411. 24th Congress of
the European Hematology Association. June 13-16, Amsterdam, The
Netherlands.
-
Jorge Cortes, et al. Combination therapy using
asciminib plus imatinib (ima) in patients (pts) with chronic
myeloid leukemia (cml): results from a phase 1 study. Abstract #
S883. 24th Congress of
the European Hematology Association. June 13-16, Amsterdam, The
Netherlands.
-
Michael Mauro, et al. Combination of asciminib
plus nilotinib (nil) or dasatinib (das) in patients (pts) with
chronic myeloid leukemia (cml): results from a phase 1 study.
Abstract # S884. 24th Congress of
the European Hematology Association. June 13-16, Amsterdam, The
Netherlands.
# # #
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