Novartis International AG / NEJM publishes full analysis of Rydapt(R)
(midostaurin) Phase III RATIFY trial in newly diagnosed FLT3-mutated
acute myeloid leukemia (AML) . Processed and transmitted by Nasdaq
Corporate Solutions. The issuer is solely responsible for the content of
this announcement.
-- Significant overall survival benefit observed for FLT3+ AML patients
consistent across FLT3 mutation subgroups, including ITD and TKD
-- Detailed data show Rydapt plus standard chemotherapy improved event-free
survival in FLT3-mutated AML versus chemotherapy alone
-- First publication of RATIFY data following ASH 2015 presentation; result
of over a decade's collaboration with Alliance for Clinical Trials in
Oncology/CALGB
Basel, June 23, 2017 - Novartis today announced that full results from
the Rydapt [(R)] (midostaurin) Phase III RATIFY (CALGB 10603 [Alliance])
clinical trial were published in The New England Journal of Medicine
(NEJM) [1]. Top-line data from this study were previously presented
during the plenary session at the American Society of Hematology (ASH)
Annual Meeting in 2015 [2]. New data include disease-free survival (DFS),
further analysis of patients undergoing transplant and expanded safety
information.
"The data from the CALGB 10603/RATIFY trial reinforce the efficacy and
safety of Rydapt in patients with FLT3-mutated AML and set the stage for
a shift in the way the medical community can approach this
difficult-to-treat disease," said Richard M. Stone, MD, Chief of Staff
and Director of the Adult Leukemia Program at Dana-Farber Cancer
Institute, and Alliance for Clinical Trials in Oncology study chair for
the RATIFY trial. "This study has provided critical insights for the AML
community and shows the potential of clinical research carried out by
international investigators with support from both public and private
sources."
Study Results Published in NEJM
In RATIFY, patients aged 18-59 years treated with Rydapt in combination
with standard cytarabine and daunorubicin induction and cytarabine
consolidation chemotherapy experienced significant improvement in
overall survival (OS) with a 22% reduction in the risk of death compared
with chemotherapy plus placebo. In patients in the Rydapt arm, OS was
74.7 months [95% CI, 31.5-not reached] vs. 25.6 months [95% CI,
18.6-42.9] in the placebo arm (one-sided stratified log-rank p=0.009,
HR=0.78). At four years, OS was 51.4% in the Rydapt arm, compared with
44.3% in the placebo arm [1].
The median event-free survival (EFS) was 8.2 months (95% CI, 5.4-10.7)
in the Rydapt arm and 3.0 months (95% CI, 1.9-5.9) in the placebo arm
(one-sided stratified log-rank p=0.002, HR=0.78). Median DFS was greater
with the addition of Rydapt versus the placebo arm (26.7 months [95% CI,
19.4-not reached] vs. 15.5 months [95% CI, 11.3-23.5], respectively;
p=0.01). The complete remission (CR) rate, defined as CR reported within
60 days of protocol therapy initiation, was 58.9% in the Rydapt arm and
53.5% in the placebo arm (p=0.15). The benefit of Rydapt on OS and EFS
was consistent across all FMS-like tyrosine kinase 3 (FLT3) mutation
subgroups, including internal tandem duplication (ITD) and tyrosine
kinase domain (TKD) FLT3 mutations [1].
"The Rydapt RATIFY trial is a testament to Novartis' dedication to
exploring opportunities to create therapies for patients with difficult
to treat diseases," said Vasant Narasimhan, Global Head of Drug
Development and Chief Medical Officer, Novartis. "These results
represent the culmination of years of work and dedication from
investigators around the world who were driven to find a targeted
treatment for these patients."
More patients in the Rydapt arm were able to undergo allogenic
hematopoietic stem cell transplantation (HCT) during their first
complete response versus placebo (28.1% vs. 22.7%, respectively;
p=0.10). When censoring patients at the time of transplant (when
protocol therapy was discontinued), OS was numerically better for those
in the Rydapt arm versus placebo arm, with a 24.3% reduction in the risk
of death at four years (63.7% vs. 55.7% respectively, p=0.08) [1].
The most frequent Grade 3 to 5 non-hematologic adverse events (AEs)
(incidence greater than or equal to 20%) in the Rydapt arm were febrile
neutropenia and infection. In the placebo arm, the most common AEs were
febrile neutropenia, infection and lymphopenia. There were few
significant differences (greater than 5%) observed in the overall rate
of Grade 3 to 5 AEs between the treatment arms - patients receiving
Rydapt experienced higher rates of anemia and rash [1]. Please see below
for additional important US safety information [3].
RATIFY, the largest clinical trial in FLT3-mutated AML to date, included
3,277 patients screened and 717 study participants from around the
world. The full data from the randomized Phase III trial have now been
published and include data outside the parameters of the US Prescribing
Information and Swiss Product Information. Based on data from the RATIFY
clinical trial, The National Comprehensive Cancer Network Clinical
Practice Guidelines in Oncology (NCCN Guidelines [(R)]) for AML now
include use of midostaurin in FLT3-mutated AML [4].
About AML
AML, a rare and aggressive cancer of the blood and bone marrow, is the
most common acute leukemia in adults. It accounts for approximately 25%
of all adult leukemias worldwide, with the highest incidence rates
occurring in the US, Europe and Australia [5]. It also has the lowest
survival rate of all adult leukemias [5].
AML prevents white blood cells from maturing, causing an accumulation of
"blasts," which do not allow room for the normal blood cells [6].
Mutations in specific genes are found in many cases of AML [7], and
genetic testing for mutations in newly diagnosed AML patients can help
to determine prognosis and potential treatment strategies [8].
Approximately one-third of AML patients will have a FLT3 gene mutation
[7]. FLT3 is a type of cell-surface receptor which plays a role in
increasing the number of certain blood cells [9]. The FLT3 gene mutation
can result in faster disease progression, higher relapse rates and lower
rates of survival than other forms of AML [7,9,10].
About Rydapt [(R)] (midostaurin)
Rydapt [(R)] (midostaurin) is an oral, multi-targeted inhibitor of
multiple kinases, including FLT3 and KIT, which help regulate many
essential cell processes, interrupting cancer cells' ability to grow and
multiply [3].
In the US, Rydapt is Food and Drug Administration (FDA)-approved for the
treatment of adults with newly diagnosed AML who are FLT3
mutation-positive (FLT3+) as detected by an FDA-approved test, in
combination with standard cytarabine and daunorubicin induction and
cytarabine consolidation [3]. Rydapt is not indicated in the US as a
single-agent induction therapy for the treatment of patients with AML.
For a description of the experience with single-agent treatment beyond
induction and consolidation, healthcare professionals in the US should
refer to the Clinical Studies section of the US Prescribing Information
(14.1) [3].
The full US Prescribing Information for Rydapt can be found at:
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/rydapt.pdf
Rydapt is also approved in Switzerland for use in combination with
standard induction and consolidation chemotherapy, followed by
maintenance monotherapy for treatment of newly diagnosed adult AML
patients who have an FLT3 mutation. Novartis has submitted a regulatory
application for Rydapt to the European Medicines Agency (EMA) and this
application is currently under review.
Indications vary by country and not all indications are available in
every country. The safety and efficacy profile of Rydapt has not yet
been established outside the approved indications. Because of the
uncertainty of clinical trials, there is no guarantee that Rydapt will
become commercially available for additional indications anywhere else
in the world.
Rydapt Important Safety Information
Patients who are allergic to midostaurin or any of the ingredients in
Rydapt should not take Rydapt. If a patient taking Rydapt develops signs
of an allergic reaction, they should seek medical help immediately.
Signs of an allergic reaction include trouble breathing, flushing, chest
pain, throat tightness, and swelling of lips, mouth or throat.
Rydapt should be not be used during pregnancy since Rydapt may harm an
unborn baby. Pregnancy testing should be conducted for women who might
become pregnant. Effective birth control should be used during treatment
and for at least four months after stopping Rydapt. If a patient becomes
pregnant or thinks she may be, the patient should tell their doctor
right away. Women should not breastfeed during treatment with Rydapt and
for at least four months after the final dose. Men taking Rydapt who
have female partners that are able to become pregnant should use
effective birth control during his treatment with Rydapt and for at
least four months after the last Rydapt dose. Rydapt may cause fertility
problems in women and men, which may affect their ability to have
children.
Rydapt may cause lung problems that may lead to death. Patients on
Rydapt who develop a new or worsening cough, shortness of breath, or
chest discomfort should get medical help right away. These may be signs
of serious lung problems.
Common sides effects reported during Rydapt treatment for AML included
low level of white blood cells with fever (febrile neutropenia); nausea;
redness, pain or ulcers inside the mouth (mucositis); vomiting;
headache; bruising; muscle or bone pain; nose bleeds; device-related
infection; high blood sugar levels (hyperglycemia) and upper respiratory
infections.
If side effects including nausea, vomiting, and diarrhea occur, get
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