NEJM publishes full analysis of Rydapt® (midostaurin) Phase III RATIFY trial in newly diagnosed FLT3-mutated acute myeloid leukemia (AML)
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Novartis International AG /
NEJM publishes full analysis of Rydapt® (midostaurin) Phase III RATIFY trial in
newly diagnosed FLT3-mutated acute myeloid leukemia (AML)
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* 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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Datum: 23.06.2017 - 18:00 Uhr
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