- 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 [®]
(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 [®]) 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 [®] (midostaurin)
Rydapt [®] (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 worse or do not go away during treatment with
Rydapt, patients should contact their doctor. Depending on the side
effect and/or severity of the side effect that occur, their doctor
may decrease their dose, temporarily stop, or completely stop
treatment with Rydapt.
Patients should tell their doctor about all the
medicines they take, including prescription and over-the-counter
medicines, vitamins and herbal supplements. Rydapt may affect how
these medicines work or these other medicines may affect how Rydapt
works.
Disclaimer
The foregoing release contains forward-looking statements that can
be identified by words such as "set the stage," "can," "potential,"
"dedication," "under review," "yet," "will," or similar terms, or
by express or implied discussions regarding potential additional
marketing approvals for Rydapt, potential new indications or
labeling for Rydapt, or regarding potential future revenues from
Rydapt. You should not place undue reliance on these statements.
Such forward-looking statements are based on the current beliefs
and expectations of management regarding future events, and are
subject to significant known and unknown risks and uncertainties.
Should one or more of these risks or uncertainties materialize, or
should underlying assumptions prove incorrect, actual results may
vary materially from those set forth in the forward-looking
statements. There can be no guarantee that Rydapt will be submitted
or approved for any additional indications or labeling in any
market, or at any particular time. Neither can there be any
guarantee that Rydapt will be submitted or approved for sale in any
additional markets, or at any particular time. Nor can there be any
guarantee that Rydapt will be commercially successful in the
future. In particular, management's expectations regarding Rydapt
could be affected by, among other things, the uncertainties
inherent in research and development, including clinical trial
results and additional analysis of existing clinical data;
regulatory actions or delays or government regulation generally;
the company's ability to obtain or maintain proprietary
intellectual property protection; general economic and industry
conditions; global trends toward health care cost containment,
including ongoing pricing and reimbursement pressures; safety,
quality or manufacturing issues, and other risks and factors
referred to in Novartis AG's current Form 20-F on file with
the US Securities and Exchange Commission. Novartis is providing
the information in this press release as of this date and does not
undertake any obligation to update any forward-looking statements
contained in this press release as a result of new information,
future events or otherwise.
About Novartis
Novartis provides innovative healthcare solutions that address the
evolving needs of patients and societies. Headquartered in Basel,
Switzerland, Novartis offers a diversified portfolio to best meet
these needs: innovative medicines, cost-saving generic and
biosimilar pharmaceuticals and eye care. Novartis has leading
positions globally in each of these areas. In 2016, the Group
achieved net sales of USD 48.5 billion, while R&D throughout
the Group amounted to approximately USD 9.0 billion. Novartis Group
companies employ approximately 118,000 full-time-equivalent
associates. Novartis products are sold in approximately 155
countries around the world. For more information, please visit
http://www.novartis.com.
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References
[1] |
Stone RM,
Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for
Acute Myeloid Leukemia with a FLT3 Mutation. N
Engl J Med. 2017 June 23. doi: 10.1056/NEJMoa1614359. [Epub
ahead of print]. |
[2] |
Stone RM,
Mandrekar SJ, Sanford BL, et al. The Multi-Kinase Inhibitor
Midostaurin (M) Prolongs Survival Compared with Placebo (P) in
Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind),
High-Dose C Consolidation (consol), and As Maintenance (maint)
Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients
(pts) Age 18-60 with FLT3 Mutations (muts): An International
Prospective Randomized (rand) P-Controlled Double-Blind Trial
(CALGB 10603/RATIFY [Alliance]). Presented at the 57th Annual
Meeting of the American Society of Hematology. Abstract 6. |
[3] |
Rydapt
[prescribing information]. East Hanover, NJ: Novartis
Pharmaceuticals Corp, 2017. |
[4] |
NCCN
Clinical Practice Guidelines In Oncology (NCCN Guidelines [®]) for
Acute Myeloid Leukemia. V.3.2017. © National Comprehensive
Cancer Network, Inc. 2017.
https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf.
Accessed June 20, 2017. |
[5] |
Deschler
B, Lübbert M. Acute myeloid leukemia: epidemiology and etiology.
Cancer. 2006;107(9):2009-2107. |
[6] |
National
Institutes of Health (NIH) National Cancer Institute (NCI). Adult
Acute Myeloid Leukemia Treatment (PDQ®)
http://www.cancer.gov/types/leukemia/patient/adult-aml-treatment-pdq.
Accessed June 20, 2017. |
[7] |
Patel JP,
Gönen M, Figueroa ME, et al. Prognostic relevance of integrated
genetic profiling in acute myeloid leukemia. N
Engl J Med. 2012; 22;366(12):1079-1089. |
[8] |
Arber DA,
Borowitz MJ, Cessna M, et al. Initial Diagnostic Workup of Acute
Leukemia: Guideline from the College of American Pathologists and
the American Society of Hematology. Arch Pathol
Lab Med. 2017 Feb 22. doi: 10.5858/arpa.2016-0504-CP. [Epub
ahead of print]. |
[9] |
Gilliland
DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia.
Blood. 2002;100(5):1532-1542. |
[10] |
Yanada M,
Matsuo K, Suzuki T, et al. Prognostic significance of FLT3 internal
tandem duplication and tyrosine kinase domain mutations for acute
myeloid leukemia: a meta-analysis. Leukemia.
2005;19(8):1345-1349. |
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