-
Progression-free survival (PFS)
in ALKi-naïve patients is consistent with results previously
reported from Phase I ASCEND-1 study
-
Phase II study also showed
overall response rate of 63.3% in ALKi-naïve patients with brain
metastases at baseline, per blinded independent review
committee
-
Novartis' dedication to
exploring Zykadia's efficacy in ALK+ NSCLC patients continues to
grow, with first-line data from Phase III study expected in Q4
2016
Basel, October 9, 2016
- Novartis today announced updated results
from a Phase II study (ASCEND-3), which demonstrated that
anaplastic lymphoma kinase-positive (ALK+) non-small cell lung
cancer (NSCLC) patients taking Zykadia® (ceritinib)
as their first ALK inhibitor (post-chemotherapy) had a median
progression-free survival (PFS) of 18.4 months [95% CI: 10.9-26.3;
median follow-up time of 25.9 months, as measured by blinded
independent review committee (BIRC)][1].Results were
presented during an oral session at the Annual European Society for
Medical Oncology Congress (ESMO) in Copenhagen.
These results are consistent with findings from
the Phase I ASCEND-1 study, which demonstrated a median PFS of 18.4
months (95% CI: 15.2-not reached) as per BIRC assessment with a
median follow-up of 11.1 months[2]. The previous analysis by BIRC
in ASCEND-3 indicated that the median PFS had not been reached
after a median follow-up time of 8.3 months[3].
Further, in a sub-analysis of these data, patients
who entered the study with brain metastases at baseline experienced
an overall response rate (ORR) of 63.3% (95% CI: 48.3-76.6) and a
disease control rate (DCR) of 83.7% (95% CI: 70.3-92.7), both as
measured by BIRC. These results were similar to those in patients
without brain metastases, who demonstrated an ORR of 64.0% (95% CI:
52.1-74.8) and DCR of 88.0% (95% CI: 78.4-94.4), based on BIRC
assessment[1].
"The unfortunate reality of ALK+ NSCLC is that
advancement is needed to delay disease progression in these
patients," said lead investigator Dr. Enriqueta Felip, Head of the
Thoracic Tumors Group, Vall d'Hebron University Hospital. "These
data, coupled with a compelling response in the sub-analysis of
patients with baseline brain metastases, provide greater evidence
of Zykadia's potential efficacy in the ALKi-naïve population."
At the time of analysis, the estimated 18-month
overall survival (OS) rate was 73.4% (95% CI: 64.6-80.4). This
population also demonstrated an ORR of 63.7% (95% CI: 54.6-72.2)
and median duration of response of 23.9 months (95% CI: 16.6-not
estimable), according to BIRC assessment. A decrease in tumor
burden from baseline was shown in 94.7% patients (investigator
assessment only, no BIRC assessment available)[1].
"Novartis is committed to extending lives of
patients with difficult-to-treat forms of cancer, and these data
presented at ESMO affirm our desire to improve outcomes for those
with metastatic NSCLC, specifically," said Alessandro Riva, MD,
Global Head, Oncology Development and Medical Affairs, Novartis
Oncology. "With our first-line Phase III results forthcoming as
well as ongoing brain metastases studies, we look forward to
sharing further evidence of Zykadia's full potential."
Results from the randomized Phase III ASCEND-5
study were also presented for the first time, and were included as
part of a late-breaking oral session as well as in the ESMO press
program. The ASCEND-5 study assessed median PFS in patients
previously treated with crizotinib and one or two prior regimens of
cytotoxic chemotherapy (including platinum doublet), who then
received either Zykadia or standard chemotherapy. Results
demonstrated a statistically significant and clinically meaningful
improvement in median PFS by BIRC for patients taking Zykadia
versus chemotherapy (HR 0.49, 95% CI 0.36-0.67; p<0.001 one
sided). Median PFS by BIRC for Zykadia and chemotherapy were 5.4
months (95% CI: 4.1-6.9) vs. 1.6 months (95% CI: 1.4-2.8),
respectively[4].
The ALK gene arrangement, one of the three most
common biomarkers - or genetic drivers -of NSCLC, affects
approximately 2-7% of cases each year[5],[6]. More than half of
these patients are either former smokers or have never
smoked[7],[8],[9]. These patients are candidates for treatment with
a targeted ALK inhibitor[6].
About ASCEND-3
ASCEND-3 is a Phase II single-arm, open-label,
multicenter study which included 124 patients with ALK+ NSCLC who
had received up to three lines of chemotherapy and had no prior
experience with an ALK inhibitor. Brain metastases at baseline were
seen in 39.5% of patients. The most frequent adverse events were
diarrhea [85.5% (3.2% grade 3/4)], nausea [77.4% (6.5% grade 3/4)]
and vomiting [71.8% (6.5% grade 3/4)][1].
About ASCEND-5
ASCEND-5 is an open-label, randomized,
active-controlled, multicenter Phase III study to compare the
efficacy and safety of Zykadia to standard second-line chemotherapy
(pemetrexed or docetaxel) in patients with advanced ALK+ NSCLC who
progressed on prior crizotinib and one or two prior regimens of
chemotherapy. Of 231 patients, 115 were randomized to ceritinib and
116 to chemotherapy. Of patients discontinuing chemotherapy due to
disease progression, 75 crossed over to Zykadia. The most frequent
adverse events were diarrhea [72.2% (4.3% grade 3/4)], nausea
[66.1% (7.8% grade 3/4)] and vomiting [52.2% (7.8% grade 3/4)] with
ceritinib; fatigue [28.3% (4.4% grade 3/4)], nausea [23.0% (1.8%
grade 3/4)], alopecia [21.2% (0% grade 3/4)] and neutropenia [20.4%
(15.0% grade 3/4)] with chemotherapy[4].
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 "dedication," "continues,"
"expected," "potential," "committed," "desire," "forthcoming,"
"ongoing," "look forward," "conditional approval," 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 receive additional regulatory
approvals or 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] Felip, E. et al. Phase 2 study of ceritinib in previously
treated ALKi-naïve patients (pts) with ALK-rearranged (ALK+)
non-small cell lung cancer (NSCLC): whole body efficacy in all pts
and in pts with baseline brain metastases (BM). Abstract #1208O.
European Society for Medical Oncology. Annual Meeting, Copenhagen,
9 October 2016.
[2] Kim, DW. Activity and safety of ceritinib in patients with
ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated
results from the multicenter, open-label, phase 1 trial. Lancet
Oncol 2016; 17: 452-463.
[3] Felip, E. et al. ASCEND-3: A single-arm, open-label,
multicenter Phase 2 study of ceritinib in ALKi-naïve adult patients
(pts) with ALK-rearranged (ALK+) non-small cell lung cancer
(NSCLC). Abstract #8060. American Society of Clinical Oncology
Annual Meeting, Chicago, 1 June 2015.
[4] Scagliotti, G. et al. Ceritinib vs chemotherapy (CT) in
patients (pts) with advanced anaplastic lymphoma kinase
(ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC)
previously treated with CT and crizotinib (CRZ): results from the
confirmatory phase 3 ASCEND-5 study. Abstract #LBA42_PR. European
Society for Medical Oncology. Annual Meeting, Copenhagen, 9 October
2016.
[5] 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.
[6] National Comprehensive Cancer Network (NCCN). NCCN Clinical
Practice Guidelines in Oncology (NCCN Guidelines): Non-Small Cell
Lung Cancer. NCCN 2014 3:1-148.
[7] Thun MJ, et al. Lung Cancer Occurrence in Never-Smokers: An
Analysis of 13 Cohorts and 22 Cancer Registry Studies. PLOS
Medicine, 2008. 5(9): e185.
[8] Park E, Japuntich S, Rigotti N, et al. A Snapshot of Smokers
After Lung and Colorectal Cancer Diagnosis. Cancer, June 2012.
http://onlinelibrary.wiley.com/doi/10.1002/cncr.26545/abstract.
[9] Lovly C, Horn L, Pao W. 2016. Molecular Profiling of Lung
Cancer. My Cancer Genome.
https://www.mycancergenome.org/content/disease/lung-cancer/.
Updated March 2016.
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