-
Phase III trial, first-line
treatment with Zykadia resulted in improved progression-free
survival (PFS) over SOC chemotherapy with maintenance, including in
patients with brain metastases[1]
-
Zykadia is currently approved
in the European Union (EU) for the treatment of adult patients with
ALK-positive advanced NSCLC previously treated with
crizotinib
Basel, May 19, 2017 - Novartis today announced the Committee for Medicinal
Products for Human Use (CHMP) of the European Medicines Agency
(EMA) has recommended approval of expanding the use of Zykadia®
(ceritinib) to include the first-line treatment of patients with
advanced non-small cell lung cancer (NSCLC) whose tumors are
anaplastic lymphoma kinase (ALK)-positive. If approved, Zykadia
will provide a new treatment option for previously untreated and
newly diagnosed patients with ALK-positive advanced NSCLC.
"Novartis is committed to bringing targeted
treatment options to more patients living with lung cancer who may
benefit from them," said Bruno Strigini, CEO, Novartis Oncology.
"Today, we've taken an important step towards fulfilling that
commitment with the potential approval of Zykadia as a first-line
treatment option for those in the EU diagnosed with ALK-positive
advanced NSCLC."
The positive CHMP opinion was based on results
from the ASCEND-4 study, a randomized, open-label, global Phase III
trial. The study showed that patients treated with first-line
Zykadia experienced a 45% reduction in the risk of disease
progression compared to patients treated with standard first-line
pemetrexed-platinum chemotherapy with pemetrexed maintenance
(hazard ratio [HR] = 0.55 [95% CI: 0.42, 0.73])[1]. The median
progression-free survival (PFS) was 16.6 months (95% confidence
interval [CI]: 12.6, 27.2) for patients receiving Zykadia compared
to 8.1 months (95% CI: 5.8, 11.1) for patients in the chemotherapy
arm of the study[1].
Additionally, patients receiving Zykadia without
brain metastases at baseline experienced a median PFS of 26.3
months (95% CI: 15.4, 27.7), compared with 8.3 months (95% CI: 6.0,
13.7) among patients treated in the chemotherapy arm (HR = 0.48
[95% CI: 0.33, 0.69])[1]. Among patients with brain metastases at
baseline, the median PFS was 10.7 months (95% CI: 8.1, 16.4) in the
Zykadia group versus 6.7 months (95% CI: 4.1, 10.6) in the
chemotherapy group (HR = 0.70 [95% CI: 0.44, 1.12])[1]. Of these
patients, 59% did not receive prior brain radiotherapy[1]. The high
intracranial overall response rate (ORR) (72.7% [95% CI: 49.8,
89.3]) was consistent with whole body ORR (72.5% [95% CI: 65.5,
78.7])[1].
The CHMP recommendation will now be reviewed by
the European Commission (EC), which holds the authority to approve
medicines for the European Union (EU). The EC typically follows the
CHMP recommendation and typically issues an approval decision
within two months, applicable to all 28 European Union member
states plus Iceland, Lichtenstein, and Norway. Earlier this year,
the US Food and Drug Administration (FDA) granted Zykadia
Breakthrough Therapy designation for first-line treatment of
patients with ALK-positive NSCLC with metastases to the brain. The
application for first-line use of Zykadia is under Priority Review
by the FDA.
Novartis Commitment to Lung
Cancer
Worldwide, lung cancer causes more deaths than colon, breast and
prostate cancer combined, and an estimated 1.8 million new cases of
lung cancer are diagnosed each year[3],[4]. Among patients with
NSCLC, roughly 25% have an actionable mutation that may be targeted
with available therapies[5]-[8]. To determine that treatment,
medical organizations recommend biomarker testing for patients with
lung cancer[9].
Over the past decade, Novartis Oncology's research
has supported the evolution of treatment approaches for patients
living with mutation-driven types of lung cancer. The company
continues its commitment to the global lung cancer community
through ongoing studies, as well as the exploration of
investigational compounds that target genomic biomarkers in
NSCLC.
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-positive 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 (pemetrexed 500
mg/m2 plus cisplatin 75 mg/m2 or carboplatin AUC 5-6) for four
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. Approximately 60% of patients with baseline brain
metastases treated with Zykadia did not have prior radiation
therapy, the current standard of treatment for baseline brain
metastases.
The most common adverse events (AEs) occurring in
more than 25% of Zykadia patients were diarrhea (85% vs. 11% with
chemotherapy), nausea (69% vs. 55% with chemotherapy), vomiting
(66% vs. 36% with chemotherapy), ALT increase (60% vs. 22% with
chemotherapy), AST increase (53% vs. 19% with chemotherapy), GGT
increase (37% vs. 10% in chemotherapy), decreased appetite (34% vs.
31% with chemotherapy), blood alkaline phosphate increase (29% vs.
5% with chemotherapy) and fatigue (29% vs. 30% with
chemotherapy)[1].
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 is currently approved in over 69 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 three months 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, liver
laboratory test abnormalities (requires blood test monitoring),
tiredness (fatigue), abdominal pain, decreased appetite,
weight decreased, constipation, kidney laboratory test
abnormalities (requires blood test monitoring), rash, anemia and
heartburn. Grade 3-4 adverse reactions with an incidence of >=5%
were liver laboratory test abnormalities, tiredness (fatigue),
vomiting, hyperglycemia (requires blood test monitoring), nausea
and diarrhea.
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 1
hour 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.
Disclaimer
The foregoing release contains forward-looking statements that can
be identified by words such as "positive CHMP opinion,"
"recommended," "will," "committed," "may," "step towards,"
"commitment," "potential," "recommendation," "Breakthrough Therapy
designation," "Priority Review," "ongoing," "investigational," 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
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] Soria JC, et al. First-line ceritinib versus platinum-based
chemotherapy in advanced ALK-rearranged non-small-cell lung cancer
(ASCEND-4): A randomized, open-label Phase 3 study. The Lancet. 2017.
[2] Lovly, C., L. Horn, W. Pao. 2016. Molecular Profiling of Lung
Cancer. My Cancer Genome
https://www.mycancergenome.org/content/disease/lung-cancer/
(Updated March 28). Accessed March 22, 2017.
[3] World Health Organization. International Agency for Research on
Cancer. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and
Prevalence Worldwide in 2012. Lung Cancer. Available at
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx?cancer=lung.
Accessed March 22, 2017.
[4] World Health Organization. Estimated number of deaths, both
sexes, worldwide in 2012. World Health Organization.
http://gco.iarc.fr/today/online-analysis-pie?mode=cancer&mode_population=continents&
population=900&sex=0&cancer=11&type=1&statistic=0&prevalence=0&
color_palette=default. Accessed March 22, 2017.
[5] Riess JW, Wakelee, HA. Metastatic Non-Small Cell Lung Cancer
Management: Novel Targets and Recent Clinical Advances. Clinical Advances in Hematology & Oncology. 2012;
10: 226-224.
[6] Pao W, Girard N. New driver mutations in non-small-cell lung
cancer. Lancet Oncol. 2011;12:175-180.
[7] Paik PK, Arcila ME, Fara M, et al. Clinical Characteristics of
Patients With Lung Adenocarcinomas Harboring BRAF Mutations. J Clin
Oncol. 2011;29:2046-2051.
[8] Takeuchi, K, Soda M, Togashi Y, et al. RET, ROS1 and ALK
fusions in lung cancer. Nature. 2012;378-381.
[9] 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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