Novartis announces Zykadia® first-line study results showing 16.6 month progression-free survival in patients with ALK+ advanced NSCLC
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Novartis International AG /
Novartis announces Zykadia® first-line study results showing 16.6 month
progression-free survival in patients with ALK+ advanced NSCLC
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The issuer is solely responsible for the content of this announcement.
* Patients without brain metastases at diagnosis experienced median
progression-free survival of 26.3 months, the longest seen in a global Phase
III study in ALK+ NSCLC[1]
* Patients with measurable brain metastases in the Zykadia arm experienced an
intracranial response rate of more than 70%[1]
* Data will be used to support global regulatory submissions for first-line
use of Zykadia in ALK+ advanced NSCLC patients
Basel, December 6, 2016 - Novartis today announced results from its Phase III
open-label, randomized, active-controlled, multi-center ASCEND-4 study, which
found that patients with anaplastic lymphoma kinase-positive (ALK+) advanced
non-small cell lung cancer (NSCLC) treated with first-line Zykadia(®)
(ceritinib) had a median progression-free survival (PFS) of 16.6 months (95%
confidence interval [CI]: 12.6, 27.2), compared to 8.1 months (95% CI:
5.8, 11.1) in patients treated with standard first-line chemotherapy with
maintenance. This equated to a 45% reduction in the risk of disease progression
(hazard ratio [HR] = 0.55, P<0.001)[1]. Results were presented during the
Presidential Symposium at the 17(th) World Conference on Lung Cancer (WCLC),
hosted by the International Association for the Study of Lung Cancer (IASLC), in
Vienna. These late-breaking results were also featured in an official conference
press briefing.
"These data demonstrate the potential to more than double a patient's
progression-free survival when they take Zykadia as their first ALK inhibitor
rather than undergoing treatment with chemotherapy," said lead investigator Dr.
Gilberto de Castro Jr., head of Thoracic Oncology and Head and Neck Cancer
clinic in the Clinical Oncology Service of the Institute of Cancer of São Paulo
(ICESP), in São Paulo, Brazil. "For clinicians, who are constantly working to
extend a patient's response to treatment in the first-line setting, the ASCEND-
4 results are very compelling."
Overall survival data, a key secondary endpoint of the study, are immature;
however, a positive trend in favor of Zykadia was observed, despite 72.4% of
patients in the chemotherapy arm receiving an ALK inhibitor as their first
treatment after discontinuing chemotherapy. Pre-specified secondary endpoints
demonstrating the efficacy of Zykadia in ALK+ advanced NSCLC patients included
overall response rate (ORR), overall intracranial response rate (OIRR), disease
control rate (DCR) and duration of response (DoR).
Patients taking Zykadia had an ORR of 72.5% (95% CI: 65.5, 78.7) compared to
26.7% (95% CI: 20.5, 33.7) in patients treated with standard chemotherapy.
Further, patients with measurable brain metastases experienced an OIRR of 72.7%
(95% CI: 49.8, 89.3, n=22) with Zykadia compared to 27.3% (95% CI: 10.7, 50.2,
n=22) with standard chemotherapy. Patients without brain metastases at screening
experienced a median PFS of 26.3 months (95% CI: 15.4, 27.7, n=130) with Zykadia
compared to 8.3 months (95% CI: 6.0, 13.7, n=125) with standard chemotherapy.
Additionally, patients taking Zykadia demonstrated a DCR of 84.7% (95% CI:
78.7, 89.5) and DoR of 23.9 months (95% CI: 16.6, not estimable)[1]. Study
results were measured by a blinded independent review committee (BIRC). Patients
treated with Zykadia also reported better overall general health status and
improvement in lung cancer-specific symptoms compared to patients treated with
standard chemotherapy[2].
"The patient response to treatment is high and durable in the first-line
setting," said Bruno Strigini, CEO, Novartis Oncology. "Based on these results,
Novartis is initiating discussions with regulatory authorities worldwide
regarding this potential use of Zykadia to further improve outcomes for patients
with ALK+ advanced NSCLC."
The safety profile of Zykadia in the ASCEND-4 study was consistent with the
previously known safety profile in patients with ALK+ advanced NSCLC. The most
common adverse events (AEs) occurring in more than 50% of Zykadia patients were
diarrhea (84.7%), nausea (68.8%), vomiting (66.1%), ALT increase (60.3%) and AST
increase (52.9%), which were mostly grade 1 and 2 and managed with dose
interruption, dose reduction and concomitant medication. No new or unexpected
safety concerns were observed[1].
Novartis also presented an initial investigation of the pharmacokinetic (PK)
profile of Zykadia 450 mg or 600 mg taken with a low-fat meal versus Zykadia
750 mg taken after fasting, as currently indicated. This Phase I prospective,
open-label, multicenter, randomized study found (in Part 1) that relative to the
750 mg fasted arm, the 450 mg fed arm demonstrated comparable steady-state PK,
while the 600 mg fed arm showed approximately 25% higher steady-state PK.
Further, preliminary safety data found the overall frequency of AEs were
comparable between groups; however, incidences of gastrointestinal-related AEs
(diarrhea, nausea or vomiting) were lowest in the Zykadia 450 mg group that ate
a low-fat meal, with no grade 3/4 AEs reported[3]. This study is ongoing and
continues to enroll treatment-naïve patients into Part 2, assessing efficacy
across the three treatment arms and evaluating safety follow-up.
One of 12 known genetic drivers of NSCLC, the ALK gene arrangement affects
approximately 2-7% of people with NSCLC[4],[5]. These patients are candidates
for treatment with a targeted ALK inhibitor[5]. To determine a personalized
treatment plan, medical organizations recommend genetic testing for patients
with lung cancer[6].
About ASCEND-4
ASCEND-4 was a Phase III randomized, open-label, multicenter, global clinical
trial to evaluate the safety and efficacy of Zykadia compared to standard
chemotherapy, including maintenance, in adult patients with Stage IIIB or IV
ALK+ advanced NSCLC who received no prior therapy for their advanced disease.
Patients received Zykadia orally at 750 mg/daily or standard pemetrexed-based
platinum doublet chemotherapy per label (pemetrexed 500 mg/m2 plus cisplatin 75
mg/m2 or carboplatin AUC 5-6) for 4 cycles followed by pemetrexed maintenance.
Of 376 patients, 189 (59 with brain metastases) were randomized to Zykadia and
187 (62 with brain metastases) to chemotherapy. Among patients randomized to the
chemotherapy arm, 105 (60%) received an ALK inhibitor as their first treatment
after chemotherapy.
About Zykadia
Zykadia is an oral, selective inhibitor of anaplastic lymphoma kinase (ALK), a
gene that can fuse with others to form an abnormal "fusion protein" that
promotes the development and growth of certain tumors in cancers including non-
small cell lung cancer (NSCLC). Zykadia was granted conditional approval in the
EU for the treatment of adult patients with ALK-positive advanced NSCLC
previously treated with crizotinib. In the US, Zykadia was granted accelerated
approval for the treatment of patients with ALK-positive metastatic NSCLC who
have progressed on or are intolerant to crizotinib.
Zykadia is currently approved in over 55 countries worldwide. Please visit
www.NovartisOncology.com/news/product-portfolio/zykadia for additional
information.
Zykadia Important Safety Information
Zykadia may cause serious side effects.
Zykadia may cause stomach upset and intestinal problems in most patients,
including diarrhea, nausea, vomiting and stomach-area pain. These problems can
be severe. Patients should follow their doctor's instructions about taking
medicines to help these symptoms, and should call their doctor for advice if
symptoms are severe or do not go away.
Zykadia may cause severe liver injury. Patients should have blood tests prior to
the start of treatment with Zykadia, every two weeks for the first month of
treatment and monthly thereafter, and should talk to their doctor right away if
they experience any of the following symptoms: tiredness (fatigue), itchy skin,
yellowing of the skin or the whites of the eyes, nausea or vomiting, decreased
appetite, pain on the right side of the abdomen, urine turns dark or brown, or
bleeding or bruising more easily than normal.
Zykadia may cause severe or life-threatening swelling (inflammation) of the
lungs during treatment that can lead to death. Symptoms may be similar to those
symptoms from lung cancer. Patients should tell their doctor right away about
any new or worsening symptoms, including trouble breathing or shortness of
breath, fever, cough, with or without mucous, or chest pain.
Zykadia may cause very slow, very fast, or abnormal heartbeats. Doctors should
check their patient's heart during treatment with Zykadia. Patients should tell
their doctor right away if they feel new chest pain or discomfort, dizziness or
lightheadedness, faint, or have abnormal heartbeats, blue discoloration of lips,
shortness of breath, swelling of lower limbs or skin, or if they start to take
or have any changes in heart or blood pressure medicines.
Zykadia may cause high levels of glucose in the blood. People who have diabetes
or glucose intolerance, or who take a corticosteroid medicine have an increased
risk of high blood sugar with Zykadia. Patients should have glucose blood tests
prior to the start of treatment with Zykadia and during treatment. Patients
should follow their doctor's instructions about blood sugar monitoring and call
their doctor right away with any symptoms of high blood sugar, including
increased thirst and/or urinating often.
Zykadia may cause high levels of pancreatic enzymes in the blood and may cause
pancreatitis. Patients should have blood tests prior to the start of treatment
with Zykadia and as needed during their treatment with Zykadia. Patients should
talk to their doctor if they experience signs and symptoms of pancreatitis which
including upper abdominal pain that may spread to the back and get worse with
eating.
Before patients take Zykadia, they should tell their doctor about all medical
conditions, including liver problems; diabetes or high blood sugar; heart
problems, including a condition called long QT syndrome; if they are pregnant,
if they think they may be pregnant, or if they plan to become pregnant; are
breastfeeding or plan to breastfeed.
Zykadia may harm unborn babies. Women who are able to become pregnant must use a
highly effective method of birth control (contraception) during treatment with
Zykadia and up to 3 months after stopping Zykadia. It is not known if Zykadia
passes into breast milk. Patients and their doctor should decide whether to take
Zykadia or breastfeed, but should not do both.
Patients should tell their doctor about medicines they take, including
prescription medicines, over-the-counter medicines, vitamins and herbal
supplements. If they take Zykadia while using oral contraceptives, the oral
contraceptives may become ineffective.
The most common adverse reactions with an incidence of >=10% were diarrhea,
nausea, vomiting, tiredness (fatigue), liver laboratory test abnormalities
(requires blood test monitoring), abdominal pain, decreased appetite,
constipation, rash, kidney laboratory test abnormalities (requires blood test
monitoring), heartburn and anemia. Grade 3-4 adverse reactions with an incidence
of >=5% were liver laboratory test abnormalities, tiredness (fatigue), diarrhea,
nausea and hyperglycemia (requires blood test monitoring).
Patients should stop taking Zykadia and seek medical help immediately if they
experience any of the following, which may be signs of an allergic reaction:
* Difficulty in breathing or swallowing
* Swelling of the face, lips, tongue or throat
* Severe itching of the skin, with a red rash or raised bumps
Patients should tell their doctor of any side effect that bothers them or does
not go away. These are not all of the possible side effects of Zykadia. For more
information, patients should ask their doctor or pharmacist.
Patients should take Zykadia exactly as their health care provider tells them.
Patients should not change their dose or stop taking Zykadia unless their health
care provider advises them to. Zykadia should be taken once a day on an empty
stomach. Patients should not eat for at least 2 hours before and 2 hours after
taking Zykadia. If a dose of Zykadia is missed, they should take it as soon as
they remember. If their next dose is due within the next 12 hours, they should
skip the missed dose and take the next dose at their regular time. They should
not take a double dose to make up for a forgotten dose. Patients should not
drink grapefruit juice or eat grapefruit during treatment with Zykadia, as it
may make the amount of Zykadia in their blood increase to a harmful level. If
patients have to vomit after swallowing Zykadia capsules, they should not take
more capsules until their next scheduled dose.
Please see full Prescribing Information for Zykadia.
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by words such as "will," "potential," "compelling," "initiating," "initial,"
"ongoing," or similar terms, or by express or implied discussions regarding
potential new indications or labeling for Zykadia, or regarding potential future
revenues from Zykadia. 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 Zykadia will be
submitted or approved for any additional indications or labeling in any market,
or at any particular time. Nor can there be any guarantee that Zykadia will be
commercially successful in the future. In particular, management's expectations
regarding Zykadia could be affected by, among other things, the uncertainties
inherent in research and development, including unexpected clinical trial
results and additional analysis of existing clinical data; unexpected 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 pressures; unexpected 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,
eye care and cost-saving generic pharmaceuticals. Novartis is the only global
company with leading positions in these areas. In 2015, the Group achieved net
sales of USD 49.4 billion, while R&D throughout the Group amounted to
approximately USD 8.9 billion (USD 8.7 billion excluding impairment and
amortization charges). Novartis Group companies employ approximately 118,000
full-time-equivalent associates. Novartis products are available in more than
180 countries around the world. For more information, please visit
http://www.novartis.com.
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References
[1] De Castro, G Jr., et al. First-line Ceritinib Versus Chemotherapy in
Patients With ALK-rearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-
4). Abstract # PL03.07. IASLC World Conference on Lung Cancer. Vienna, 6
December 2016.
[2] Tan, D.S., et al. PROs With Ceritinib Versus Chemotherapy in Patients With
Previously Untreated ALK-rearranged Nonsquamous NSCLC (ASCEND-4). Abstract
P3.02a-025. IASLC World Conference on Lung Cancer. Vienna, 7 December 2016.
[3] Dziadziuszko, R., et al. Phase 1 Study of Ceritinib 450 mg or 600 mg Taken
with a Low-Fat Meal versus 750 mg in Fasted State in ALK+ Metastatic NSCLC.
Abstract P3.02a-036. IASLC World Conference on Lung Cancer. Vienna, 7 December
2016.
[4] International Cancer Control: Global Cancer Statistics. Centers for Disease
Control and Prevention Website.
http://www.cdc.gov/cancer/international/statistics.htm. Last updated February
2015.
[5] National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines): Non-Small Cell Lung Cancer.
2014: 3: 1-148.
[6] Lindeman, N.I., et al. Molecular Testing Guideline for Selection of Lung
Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors. Arch Pathol Lab
Med. 2013; 137: 828-1174.
# # #
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Source: Novartis International AG via GlobeNewswire
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Datum: 06.12.2016 - 09:45 Uhr
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News-ID 511026
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