-
At six months, 30% of patients
treated with Kymriah were in complete response, with a 74%
relapse-free rate after onset of response; median duration of
response was not reached
-
Grade 3/4 neurologic events
occurred in 12% of patients; Grade 3/4 CRS occurred in 23% of
treated patients using the Penn Grading Scale
and was managed by protocol-specific algorithm
-
More than a quarter of patients
received Kymriah in outpatient setting during JULIET
trial
-
Cost-effectiveness and societal
value of Kymriah in pediatric and young adult patients with r/r
B-cell ALL to be presented at ASH
The digital
press release with multimedia content can be accessed
here:
Basel, December 10, 2017
- Novartis today announced updated results
from the JULIET clinical trial demonstrating sustained responses
with KymriahTM
(tisagenlecleucel) suspension for intravenous infusion, formerly
CTL019, in adult patients with relapsed or refractory (r/r) diffuse
large B-cell lymphoma (DLBCL). The data from this pivotal trial,
led by researchers from the University of Pennsylvania (Penn), show
an overall response rate (ORR) of 53% (95% confidence interval
[CI], 42% - 64%; p<0.0001), with 40%
achieving a complete response (CR) and 14% achieving a partial
response (PR) among 81 infused patients with three or more months
of follow-up or earlier discontinuation. At six months from
infusion, the ORR was 37% with a CR rate of 30%. The median
duration of response was not reached. Results from this study of
Kymriah, the first-ever FDA-approved chimeric antigen receptor T
cell (CAR-T) therapy, were included in the US and EU regulatory
filings for Kymriah in r/r DLBCL and will be presented in an oral
presentation at the 59th American Society of Hematology (ASH)
annual meeting (Abstract #577; Monday, December 11, 7:00 AM
EST)[1].
"At the time of trial enrollment, these patients
with DLBCL had been through multiple rounds of chemotherapy and
many had unsuccessful stem cell transplants, leaving them with few
options and a poor prognosis," said the study's principal
investigator Stephen J. Schuster, MD, the Robert and Margarita
Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and
Lymphoma Clinical Care and Research in the University of
Pennsylvania's (Penn) Perelman School of Medicine and director of
the Lymphoma Program at the Abramson Cancer Center. "With
tisagenlecleucel, we have been able to significantly increase their
chance of achieving and maintaining a sustained response without
stem cell transplant, demonstrating the therapy's benefit in the
treatment of this lethal blood cancer."
At month three, the CR rate was 32% and the PR
rate was 6%, which remained consistent to month six (30% CR, 7%
PR). Response rates were also consistent among prognostic
subgroups, including patients who received prior autologous stem
cell transplant (ASCT) and those with a subtype of DLBCL known as
double-hit lymphoma, who historically have poor outcomes. No
patients in response following treatment with Kymriah proceeded to
stem cell transplant[1].
In the JULIET study, the relapse-free probability
at six months after first response was 74% (95% CI, 52%-87%), and
median duration of response was not reached. Median overall
survival was also not reached (95% CI: 6.5 months to NE [not
estimable]), and the median time from infusion to data cutoff was
5.6 months[1].
"While immediate response to treatment is a marker
for efficacy, patients and physicians need treatment options that
provide sustained responses over time with a consistent safety
profile," said Samit Hirawat, MD, Head, Novartis Oncology Global
Drug Development. "We look forward to continuing to work with
health authorities to bring Kymriah to patients with relapsed or
refractory DLBCL."
In the JULIET study, cytokine release syndrome
(CRS) occurred in 58% of all treated patients, with 23% of patients
experiencing grade 3/4 CRS (15% grade 3; 8% grade 4) using the Penn
Grading Scale, a rigorous scale for grading CRS. CRS is a known
complication of CAR-T therapy that may occur when the engineered
cells become activated in the patient's body. CRS was managed
globally using prior site education on implementation of the CRS
treatment algorithm[1].
Twenty one percent of patients experienced any
grade neurologic events, and 12% of patients had grade 3/4
neurologic adverse events, which were managed with supportive care.
Grade 3/4 cytopenias lasting more than 28 days, grade 3/4
infections and grade 3/4 febrile neutropenia occurred in 27%, 20%
and 13% of patients, respectively. Three patients died from disease
progression within 30 days of infusion. There were no deaths
attributed to Kymriah, CRS or neurological events. No cerebral
edema events were reported[1].
In the JULIET trial, 26 patients (26%) were
infused in the outpatient setting; of those, 20 patients (77%)
remained outpatient for three or more days after infusion.
Forty-three patients discontinued before infusion and
the majority did so due to rapid progression of their disease
or deterioration in their clinical status. This reflects the
acute and progressive nature of relapsed or refractory DLBCL. Only
9 of 147 (6.1%) enrolled patients could not be infused due to
inability to manufacture an adequate dose of CAR-T cells. Over the
course of JULIET, with continuous process improvements,
manufacturing success rate improved to 97% for the last 30
patients.
JULIET is the first multi-center global
registration study for Kymriah in adult patients with r/r DLBCL and
the second global CAR-T cell therapy trial, following the Novartis
ELIANA study of Kymriah in children and young adults with r/r
B-cell acute lymphoblastic leukemia (ALL). JULIET was conducted in
collaboration with Penn and enrolled patients from 27 sites in 10
countries across the US, Canada, Europe, Australia and Japan. In
2012, Novartis and Penn entered into a global collaboration to
further research, develop and commercialize CAR-T cell therapies,
including Kymriah, for the investigational treatment of
cancers.
The results from JULIET build upon a pilot study
of Kymriah in r/r DLBCL and follicular lymphoma published online
today in the New England Journal of Medicine,
which was led by and conducted at Penn and supported by Novartis
and grants from the National Institutes of Health, as well as
through philanthropic support. Among patients with r/r DLBCL, the
study demonstrated an ORR and safety profile similar to results
seen in JULIET. The study demonstrated sustained remissions at a
follow up of 28.6 months among patients who responded at six
months[2].
In April 2017, the US Food and Drug Administration
(FDA) granted Breakthrough Therapy designation to Kymriah based on
data from the JULIET study. In October 2017, Novartis submitted an
application to the FDA for Kymriah in adult patients with r/r DLBCL
who are ineligible for or relapse after ASCT, followed shortly by
an application to the European Medicines Agency (EMA) in November
for Kymriah for the treatment of adult patients with r/r DLBCL who
are ineligible for ASCT, and for children and young adults with r/r
B-cell ALL. Additional filings beyond the US and EU are anticipated
in 2018.
Economic and Societal Value of
Kymriah in ALL Presented at ASH
Results of a cost-effectiveness analysis of Kymriah for the
treatment of r/r B-cell ALL in the US will be presented in an oral
presentation at the meeting (Abstract #609; Monday, December 11,
7:30 AM EST).
The analysis showed that, based on the current US
list price of $475,000, Kymriah is cost-effective compared to
standard of care. The analysis compared the life years and
quality-adjusted life years gained with Kymriah compared to
clofarabine monotherapy, clofarabine combination therapy,
blinatumomab, other salvage chemotherapies and allogeneic stem cell
transplant. Quality-adjusted life years is a measure of value of
health outcomes based on disease burden, including both the quality
and quantity of life lived[3].
In addition, results of another analysis to
determine the potential societal value of Kymriah to patients with
r/r ALL in the United Kingdom were presented in a poster
presentation at the meeting (Abstract #1330; Saturday, December 9,
5:30 PM EST).
To quantify the societal value of Kymriah, the
analysis looked at the economic value of the incremental quality
adjusted life years gained along with the patient's expected
productivity using nationally representative data on employment
rates and earnings. Results show that therapies such as Kymriah
have the potential to provide benefit to patients and society,
particularly through gains in survival, contributing to
productivity[4].
About Kymriah
In August 2017, Kymriah became the first available chimeric antigen
receptor T cell (CAR-T) therapy when it received FDA approval for
children and young adults with B-cell acute lymphoblastic leukemia
(ALL) that is refractory or has relapsed at least twice. Kymriah is
a novel immunocellular therapy and a one-time treatment that uses a
patient's own T cells to fight cancer. Kymriah uses the 4-1BB
costimulatory domain in its chimeric antigen receptor to enhance
cellular expansion and persistence.
About Kymriah
Manufacturing
Kymriah will be manufactured for each individual patient using
their own cells at the Novartis Morris Plains, New Jersey facility.
Novartis has successfully demonstrated a 22-day turnaround time for
manufacturing Kymriah in the commercial setting, and this will
continue to be the target. The reliable and integrated
manufacturing and supply chain platform for Kymriah allows for an
individualized treatment approach on a global scale. The process
includes cryopreservation of a patient's harvested (or
leukapheresed) cells, giving treating physicians and centers the
flexibility to initiate therapy with Kymriah based on the
individual patient's condition. Building on the company's
experience, having manufactured CAR-T cells for over 250 patients
from 11 countries across various indications in clinical trials, it
has demonstrated a high-quality and reproducible product. Novartis
continues to advance its CAR-T manufacturing expertise and make
investments to support the anticipated demand to meet the needs of
patients.
About DLBCL
DLBCL is the most common form of non-Hodgkin lymphoma, a cancer of
the lymphatic system, with an estimated 27,650 new cases diagnosed
in 2016[5],[6]. Ten to 15% of DLBCL patients fail to respond to
initial therapy or relapse within three months of treatment, and an
additional 20% to 25% relapse after initial response to therapy[5].
Nearly 40% of patients with DLBCL will die of relapsed or
refractory disease[7].
KymriahTM
(tisagenlecleucel) Important Safety
information (for pediatric and young adult patients with B-cell
precursor acute lymphoblastic leukemia)
The full prescribing information, including Boxed WARNING, for
Kymriah can be found at:
https://www.pharma.us.novartis.com/files/kymriah.pdf
Kymriah may cause side effects that are severe or
life-threatening, such as Cytokine Release Syndrome (CRS) or
Neurological Toxicities. Patients with CRS may experience symptoms
including high fever, difficulty breathing, chills/shaking chills,
severe nausea, vomiting and diarrhea, severe muscle or joint pain,
very low blood pressure, or dizziness/lightheadedness. Patients may
be admitted to the hospital for CRS and treated with other
medications.
Patients with neurological toxicities may
experience symptoms such as altered or decreased consciousness,
headaches, delirium, confusion, agitation, anxiety, seizures,
difficulty speaking and understanding, or loss of balance. Patients
should be advised to call their health care provider or get
emergency help right away if they experience any of these signs and
symptoms of CRS or neurological toxicities.
Because of the risk of CRS and neurological
toxicities, Kymriah is only available through a restricted program
under a Risk Evaluation and Mitigation Strategy (REMS) in the US
called Kymriah REMS.
Serious allergic reactions, including anaphylaxis,
may occur after Kymriah infusion.
Kymriah can increase the risk of life-threatening infections that
may lead to death. Patients should be advised to tell their health
care provider right away if they develop fever, chills, or any
signs or symptoms of an infection.
Patients may experience prolonged low blood cell
counts (cytopenia), where one or more types of blood cells (red
blood cells, white blood cells, or platelets) are decreased. The
patient's health care provider will do blood tests to check all of
their blood cell counts after treatment with Kymriah. Patients
should be advised to tell their health care provider right away if
they get a fever, are feeling tired, or have bruising or
bleeding.
Patients may experience hypogammaglobulinemia, a
condition in which the level of immunoglobulins (antibodies) in the
blood is low and the risk of infection is increased. It is expected
that patients may develop hypogammaglobulinemia with Kymriah, and
may need to receive immunoglobulin replacement for an indefinite
amount of time following treatment with Kymriah. Patients should
tell their health care provider about their treatment with Kymriah
before receiving a live virus vaccine.
After treatment with Kymriah, patients will be
monitored life-long by their health care provider, as they may
develop secondary cancers or recurrence of their leukemia.
Patients should not drive, operate heavy
machinery, or do other dangerous activities for 8 weeks after
receiving Kymriah because the treatment can cause temporary memory
and coordination problems, including sleepiness, confusion,
weakness, dizziness, and seizures.
Some of the most common side effects of Kymriah
are difficulty breathing, fever (100.4°F/38°C or higher),
chills/shaking chills, confusion, severe nausea, vomiting and
diarrhea, severe muscle or joint pain, very low blood pressure, and
dizziness/lightheadedness. However, these are not all of the
possible side effects of Kymriah. Patients should talk to their
health care provider for medical advice about side effects.
Prior to a female patient starting treatment with
Kymriah, their health care provider may do a pregnancy test. There
is no information available for Kymriah use in pregnant or
breast-feeding women. Therefore, Kymriah is not recommended for
women who are pregnant or breast feeding. If either sex partner has
received Kymriah, patients should talk to their health care
provider about birth control and pregnancy.
Patients should tell their health care provider
about all the medicines they take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
After receiving Kymriah, patients should be
advised that some commercial HIV tests may cause a false positive
test result. Patients should also be advised not to donate blood,
organs, or tissues and cells for transplantation after receiving
Kymriah.
Disclaimer
This press release contains forward-looking statements within the
meaning of the United States Private Securities Litigation Reform
Act of 1995. Forward-looking statements can generally be identified
by words such as "potential," "can," "will," "plan," "expect,"
"anticipate," "look forward," "believe," "committed,"
"investigational," "pipeline," "launch," or similar terms, or by
express or implied discussions regarding potential marketing
approvals, new indications or labeling for Kymriah, regarding our
ability to scale and sustain commercial manufacturing for Kymriah,
regarding our ability to build and sustain a network of treatment
centers to offer Kymriah, or regarding potential future revenues
from Kymriah. You should not place undue reliance on these
statements. Such forward-looking statements are based on our
current beliefs and expectations 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 Kymriah will be
submitted or approved for sale or for any additional indications or
labeling in any market, or at any particular time. Neither can
there be any guarantee that Novartis will successfully scale and
sustain commercial manufacturing for Kymriah, or successfully build
and sustain a network of treatment centers to offer Kymriah. Nor
can there be any guarantee that Kymriah will be commercially
successful in the future. In particular, our expectations regarding
Kymriah could be affected by, among other things, our ability to
successfully scale and sustain commercial manufacturing and build
and sustain a network of treatment centers; 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;
our ability to obtain or maintain proprietary intellectual property
protection; the particular prescribing preferences of physicians
and patients; global trends toward health care cost containment,
including government, payor and general public pricing and
reimbursement pressures; general economic and industry conditions,
including the effects of the persistently weak economic and
financial environment in many countries; 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 121,000 full-time-equivalent
associates. Novartis products are sold in approximately 155
countries around the world. For more information, please visit
http://www.novartis.com.
Novartis is on Twitter. Sign up to follow
@Novartis at http://twitter.com/novartis and @NovartisCancer at
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For Novartis multimedia content, please visit
www.novartis.com/news/media-library
For questions about the site or required registration, please
contact media.relations@novartis.com
References
[1] Schuster
S., et al. Primary Analysis of Juliet: A Global, Pivotal, Phase 2
Trial of CTL019 in Adult Patients with Relapsed or Refractory
Diffuse Large B-Cell Lymphoma. 59th American
Society of Hematology Annual Meeting and Exposition. Abstract
#577.
[2] Schuster
S., et al. CAR-T cells (CTL019) in Refractory B-cell
Lymphomas. N Engl J Med. December 10, 2017. doi:
10.1056/NEJMoa1708566. [Epub ahead of print].
[3] Hao Y.,
et al. Cost-Effectiveness Analysis of CTL019 for the Treatment of
Pediatric and Young Adult Patients with Relapsed or Refractory
B-Cell Acute Lymphoblastic Leukemia in the United States.
59th American
Society of Hematology Annual Meeting and Exposition. Abstract
#609.
[4] Snider
J., et al. The Economic Value of CTL019 Therapy for Pediatric
Patients with Relapsed and Refractory Acute Lymphoblastic Leukemia
in the United Kingdom. 59th American
Society of Hematology Annual Meeting and Exposition. Abstract
#1330.
[5] American
Society of Clinical Oncology. Lymphoma - Non-Hodgkin: Subtypes
(Dec. 2016
revision). http://www.cancer.net/cancer-types/lymphoma-non-hodgkin/subtypes.
Accessed December 2017.
[6] Teras
LR., DeSantis CE., Cerhan JR., et al. 2016 US Lymphoid Malignancy
Statistics by World Health Organization Subtypes. CA CANCER J CLIN.
September 2016;66(6):443-459.
[7] Vaidya
R., Witzig T.E. Prognostic factors for diffuse large B-cell
lymphoma in the R(X)CHOP era. Ann of Onc. March 2014; Volume
25(11):2124-33.
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