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2014-04-29

Novartis International AG: Novartis gains FDA approval for Zykadia(TM), first therapy for patients with ALK+ NSCLC previously treated with the ALK inhibitor cr

Novartis International AG / Novartis gains FDA approval for Zykadia(TM), first
therapy for patients withALK+ NSCLC previously treated with the ALK inhibitor
crizotinib . Processed and transmitted by NASDAQ OMX Corporate Solutions.The
issuer is solely responsible for the content of this announcement.
* Zykadia (ceritinib) demonstrated an overall response rate of 54.6% in
patients with ALK+ metastatic NSCLC who have no other treatment option[1]
* Median duration of response to Zykadia was 7.4 months; patients in study
started treatment with metastases, including brain (60%), liver (42%) and
bone (42%)[1]
* ALK+ NSCLC is driven by a rearrangement of the ALK gene, which is
responsible for cancer cell growth in 2-7% of patients with NSCLC[2]
* Approval follows FDA Breakthrough Therapy designation; regulatory
application submitted in the EU and filings underway with other health
authorities worldwide

The digital press release with multimedia content can be accessed here:

Basel, April 29, 2014
-
Novartis announced today that the US Food and Drug Administration (FDA) has
approved Zykadia(TM) (ceritinib, previously known as LDK378) for the
treatment of patients with anaplastic lymphoma kinase-positive (ALK+)
metastatic non-small cell lung cancer (NSCLC) who have progressed on or are
intolerant to crizotinib[1]. The approval of Zykadia addresses an unmet
medical need for patients with this type of lung cancer who have progressed
on prior therapy.

"Zykadia represents an important treatment option for ALK+ NSCLC patients who
relapse after starting initial therapy with crizotinib," said lead
investigator Alice T. Shaw, MD, PhD, Massachusetts General Hospital Cancer
Center, Boston. "This approval will affect the way we manage and monitor
patients with this type of lung cancer, as we will now be able to offer them
the opportunity for continued treatment response with a new ALK inhibitor."

Lung cancer is the leading cause of cancer death worldwide. The most common
type of lung cancer is NSCLC, accounting for 85-90% of all cases[3]. Of
those, 2-7% are driven by a rearrangement of the ALK gene, which increases
the growth of cancer cells and can be identified by a molecular test of the
cancer tumor[2]. Despite significant treatment advances for patients with
ALK+ NSCLC, disease progression is often inevitable and more options are
needed.

The approval of Zykadia is based on a pivotal trial that included 163 patients
with metastatic ALK+ NSCLC who progressed on or were intolerant to treatment
with crizotinib. The most common sites of metastases in the patient
population studied were brain (60%), liver (42%) and bone (42%)[1].

Among previously-treated patients, Zykadia achieved an overall response rate
(ORR) of 54.6% [95% CI, 47-62%] and a median duration of response (DOR) of
7.4 months [95% CI, 5.4-10.1 months][1]. The most common adverse reactions
(incidence of at least 25%) were diarrhea, nausea, elevated transaminases,
vomiting, abdominal pain, fatigue, decreased appetite and constipation[1].

"The approval of Zykadia less than three and a half years after the first
patient entered our clinical trial exemplifies what is possible with a highly
focused approach to drug development and strong collaboration," said
Alessandro Riva, MD, President, Novartis Oncology ad interim and Global Head,
Oncology Development and Medical Affairs. "The dedication of clinical
investigators, patients, the FDA and others has enabled us to bring this
medicine to patients in need as swiftly as possible."

Zykadia is an oral, selective inhibitor of ALK, an important therapeutic
target in lung cancer. ALK is a gene that can fuse with other genes to form
an aberrant "fusion protein" that promotes the development and growth of
cancer cells[4],[5]. Zykadia is one of the first medicines to be approved
following FDA Breakthrough Therapy designation, which was received in March
2013 due to the significance of results observed in the pivotal trial and the
serious and life-threatening nature of ALK+ NSCLC. Additional regulatory
submissions for Zykadia are underway worldwide, with an application currently
filed in the European Union.

About the pivotal trial and Zykadia clinical trial program
The efficacy of Zykadia was established in a multicenter, single-arm,
open-label clinical trial. A total of 163 patients with metastatic ALK+ NSCLC
who progressed on or were intolerant to treatment with crizotinib were
enrolled and treated at a Zykadia dose of 750 mg once daily. The major
efficacy outcome measure was ORR according to RECIST v1.0 as evaluated by
both investigators and a Blinded Independent Central Review Committee (BIRC).
DOR was an additional outcome measure[1].

The study population characteristics were: median age 52 years, age less than
65 (87%), female (54%), Caucasian (66%), Asian (29%), never or former smoker
(97%), ECOG PS 0 or 1 (87%), progression on previous crizotinib (91%), number
of prior therapies 2 or more (84%), and adenocarcinoma histology (93%). Sites
of extra-thoracic metastasis included brain (60%), liver (42%) and bone
(42%). ALK-positivity was verified retrospectively by review of local test
results for 99% of patients[1].

Zykadia achieved an ORR of 54.6% [95% CI, 47-62%] and a median DOR of 7.4
months [95% CI, 5.4-10.1 months]based on investigator assessment. The
analysis by the BIRC assessment was similar to the analysis by the
investigator assessment with an ORR of 43.6% [95% CI, 36-52%] and a median
DOR of 7.1 months [95% CI, 5.6-NE months][1].

This study is part of the ongoing Novartis clinical trial program in this
patient population. Several major studies evaluating treatment with ceritinib
are being conducted in more than 300 study centers across more than 30
countries. Two Phase II single-arm clinical trials in previously-treated and
treatment-naïve ALK+ NSCLC patients, (www.clinicaltrials.govidentifiers
NCT01685060 and NCT01685138), are fully enrolled and ongoing. In addition,
two Phase III clinical trials comparing ceritinib with chemotherapy in
treatment-naïve and in previously-treated patients,
(www.clinicaltrials.govidentifiers NCT01828099 and NCT01828112), are ongoing
and actively recruiting patients worldwide[6],[7],[8],[9].

About Zykadia
Zykadia (ceritinib) is indicated for the treatment of patients with ALK+
metastatic NSCLC who have progressed on or are intolerant to crizotinib. This
indication is approved under accelerated approval based on tumor response
rate and duration of response. An improvement in survival or disease-related
symptoms has not been established. Continued approval for this indication may
be contingent upon verification and description of clinical benefit in
confirmatory trials.

Zykadia Important Safety Information
Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients
including severe cases in 14% of patients treated with Zykadia in Study 1.
Dose modification due to diarrhea, nausea, vomiting, or abdominal pain
occurred in 38% of patients. Patients should be monitored and managed using
standards of care, including anti-diarrheals, anti-emetics, or fluid
replacement, as indicated. Based on the severity of the adverse drug
reaction, withhold Zykadia with resumption at a reduced dose as described in
Table 1 of the package insert.

Drug-induced hepatotoxicity occurred in patients treated with Zykadia.
Elevations in alanine aminotransferase (ALT) greater than 5 times the upper
limit of normal (ULN) occurred in 27% of 255 patients in Study 1. One patient
(0.4%) required permanent discontinuation due to elevated transaminases and
jaundice. Patients should be monitored with liver laboratory tests including
ALT, aspartate aminotransferase (AST), and total bilirubin once a month and
as clinically indicated, with more frequent testing in patients who develop
transaminase elevations. Based on the severity of the adverse drug reaction,
withhold Zykadia with resumption at a reduced dose, or permanently
discontinue Zykadia as described in Table 1 of the package insert.

Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis
can occur in patients treated with Zykadia. In Study 1, pneumonitis was
reported in 4% of 255 patients treated with Zykadia. CTCAE Grade 3 or 4
ILD/pneumonitis was reported in 3% of patients, and fatal ILD/pneumonitis was
reported in 1 patient (0.4%) in Study 1. One percent (1%) of patients
discontinued Zykadia in Study 1 due to ILD/pneumonitis. Patients should be
monitored for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other
potential causes of ILD/pneumonitis, and permanently discontinue Zykadia in
patients diagnosed with treatment-related ILD/pneumonitis.

QTc interval prolongation occurs in patients treated with Zykadia. Three
percent (3%) of 255 patients experienced a QTc interval increase over
baseline greater than 60 msec in Study 1. Across the development program of
Zykadia, one of 304 patients (less than 1%) treated with Zykadia doses
ranging from 50 to 750 mg was found to have a QTc greater than 500 msec and
3% of patients had an increase from baseline QTc greater than 60 msec. A
pharmacokinetic analysis suggested that Zykadia causes
concentration-dependent increases in the QTc interval. When possible, avoid
use of Zykadia in patients with congenital long QT syndrome. Conduct periodic
monitoring with electrocardiograms (ECGs) and electrolytes in patients with
congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or
those who are taking medications that are known to prolong the QTc interval.
Withhold Zykadia in patients who develop a QTc interval greater than 500 msec
on at least 2 separate ECGs until the QTc interval is less than 481 msec or
recovery to baseline if the QTc interval is greater than or equal to 481
msec, then resume Zykadia at a reduced dose as described in Table 1 of the
package insert. Permanently discontinue Zykadia in patients who develop QTc
interval prolongation in combination with Torsade de pointes or polymorphic
ventricular tachycardia or signs/symptoms of serious arrhythmia.

Hyperglycemia can occur in patients receiving Zykadia. In Study 1, CTCAE Grade
3-4 hyperglycemia, based on laboratory values, occurred in 13% of 255
patients. There was a 6-fold increase in the risk of CTCAE Grade 3-4
hyperglycemia in patients with diabetes or glucose intolerance and a 2-fold
increase in patients taking corticosteroids. Monitor serum glucose levels as
clinically indicated. Initiate or optimize anti-hyperglycemic medications as
indicated. Based on the severity of the adverse drug reaction, withhold
Zykadia until hyperglycemia is adequately controlled, then resume Zykadia at
a reduced dose as described in Table 1 of the package insert. If adequate
hyperglycemic control cannot be achieved with optimal medical management,
permanently discontinue Zykadia.

Bradycardia can occur ...

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