SAN FRANCISCO, Aug. 1, 2019 /PRNewswire/ -- Nektar Therapeutics
(Nasdaq: NKTR) and Bristol-Myers Squibb (NYSE: BMY) today announced
that the U.S. Food and Drug Administration (FDA) has granted
Breakthrough Therapy Designation for investigational agent
bempegaldesleukin (NKTR-214) in combination with Bristol-Myers
Squibb's Opdivo® (nivolumab) for the
treatment of patients with previously untreated unresectable or
metastatic melanoma. The Breakthrough Therapy Designation is based
on clinical data which were recently reported at the 2019 American
Society of Clinical Oncology (ASCO) Annual Meeting from the cohort
of patients with metastatic melanoma that were treated with the
doublet therapy in the ongoing PIVOT-02 Phase 1/2 clinical
study.
FDA Breakthrough Therapy Designation is intended to expedite the
development and review of medicines aimed at treating a serious or
life-threatening disease where there is preliminary clinical
evidence that the investigational therapy may offer substantial
improvement over existing therapies on at least one clinically
significant endpoint.
Bempegaldesleukin, Nektar's lead immuno-oncology candidate, is
an investigational CD122-preferential IL-2 pathway agonist designed
to provide activation and proliferation of cancer-killing immune
cells, known as CD8+ effector T cells and natural killer (NK)
cells. A Phase 3 clinical trial evaluating bempegaldesleukin in
combination with nivolumab versus nivolumab in first-line advanced
melanoma patients is currently recruiting patients
(NCT03635983).
"In collaboration with our partner Bristol-Myers Squibb, we plan
to work closely with FDA as we continue to advance our development
program of bempegaldesleukin in combination with nivolumab in
advanced melanoma patients," said Dr. Stephen Doberstein, SVP,
Research and Development and Chief R&D Officer of Nektar
Therapeutics. "Our teams are encouraged by the deepening of
responses we observed in patients with previously untreated
advanced melanoma who received the doublet therapy in our PIVOT-02
study. We look forward to continuing to provide updated results at
a future medical meeting as the data mature further in this ongoing
cohort of melanoma patients."
In February 2018, Bristol-Myers
Squibb and Nektar executed a global strategic development and
commercialization collaboration for bempegaldesleukin.
About Bempegaldesleukin (NKTR-214)
Bempegaldesleukin
is designed to stimulate cancer-killing immune cells in the body by
targeting CD122 receptors found on the surface of these immune
cells. CD122, which is also known as the Interleukin-2 receptor
beta subunit, is a key signaling receptor that is known to increase
proliferation of these effector T cells.1 In clinical
and preclinical studies, treatment with bempegaldesleukin resulted
in expansion of these cells and mobilization into the tumor
micro-environment.2,3
About Nektar
Nektar Therapeutics is a research-based,
development stage biopharmaceutical company whose mission is to
discover and develop innovative medicines to address the unmet
medical needs of patients. Our R&D pipeline of new
investigational medicines includes treatments for cancer,
autoimmune disease and chronic pain. We leverage Nektar's
proprietary and proven chemistry platform in the discovery and
design of our new therapeutic candidates. Nektar is headquartered
in San Francisco, California, with
additional operations in Huntsville,
Alabama and Hyderabad,
India. Further information about the company and its drug
development programs and capabilities may be found online at
http://www.nektar.com.
Bristol-Myers Squibb:
Advancing Oncology Research
At Bristol-Myers Squibb,
patients are at the center of everything we do. The focus of our
research is to increase quality, long-term survival for patients
and make cure a possibility. Through a unique multidisciplinary
approach powered by translational science, we harness our deep
scientific experience in oncology and Immuno-Oncology (I-O)
research to identify novel treatments tailored to individual
patient needs. Our researchers are developing a diverse,
purposefully built pipeline designed to target different immune
system pathways and address the complex and specific interactions
between the tumor, its microenvironment and the immune system. We
source innovation internally, and in collaboration with academia,
government, advocacy groups and biotechnology companies, to help
make the promise of transformational medicines, like I-O, a reality
for patients.
About Opdivo
Opdivo is a programmed
death-1 (PD-1) immune checkpoint inhibitor that is designed to
uniquely harness the body's own immune system to help restore
anti-tumor immune response. By harnessing the body's own immune
system to fight cancer, Opdivo has become an
important treatment option across multiple cancers.
Opdivo's leading global development program is based on
Bristol-Myers Squibb's scientific expertise in the field of
Immuno-Oncology, and includes a broad range of clinical trials
across all phases, including Phase 3, in a variety of tumor types.
To date, the Opdivo clinical development program
has treated more than 35,000 patients.
The Opdivo trials have contributed to gaining a
deeper understanding of the potential role of biomarkers in patient
care, particularly regarding how patients may benefit
from Opdivo across the continuum of PD-L1
expression.
In July 2014, Opdivo was the first PD-1 immune
checkpoint inhibitor to receive regulatory approval anywhere in the
world. Opdivo is currently approved in more than
65 countries, including the United
States, the European Union, Japan and China. In October
2015, the Company's Opdivo and Yervoy
combination regimen was the first Immuno-Oncology combination to
receive regulatory approval for the treatment of metastatic
melanoma and is currently approved in more than 60 countries,
including the United States and
the European Union.
U.S. FDA-APPROVED INDICATIONS FOR
OPDIVO®
OPDIVO® (nivolumab) as a single agent is indicated
for the treatment of patients with unresectable or metastatic
melanoma.
OPDIVO® (nivolumab), in combination with
YERVOY® (ipilimumab), is indicated for the treatment of
patients with unresectable or metastatic melanoma.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with metastatic non-small cell lung cancer (NSCLC) with
progression on or after platinum-based chemotherapy. Patients with
EGFR or ALK genomic tumor aberrations should have disease
progression on FDA-approved therapy for these aberrations prior to
receiving OPDIVO.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with metastatic small cell lung cancer (SCLC) with
progression after platinum-based chemotherapy and at least one
other line of therapy. This indication is approved under
accelerated approval based on overall response rate and duration of
response. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with advanced renal cell carcinoma (RCC) who have received
prior anti-angiogenic therapy.
OPDIVO® (nivolumab), in combination with
YERVOY® (ipilimumab), is indicated for the treatment of
patients with intermediate or poor risk, previously untreated
advanced renal cell carcinoma (RCC).
OPDIVO® (nivolumab) is indicated for the treatment of
adult patients with classical Hodgkin lymphoma (cHL) that has
relapsed or progressed after autologous hematopoietic stem cell
transplantation (HSCT) and brentuximab vedotin or after 3 or more
lines of systemic therapy that includes autologous HSCT. This
indication is approved under accelerated approval based on overall
response rate. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with recurrent or metastatic squamous cell carcinoma of
the head and neck (SCCHN) with disease progression on or after
platinum-based therapy.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with locally advanced or metastatic urothelial carcinoma
who have disease progression during or following
platinum-containing chemotherapy or have disease progression within
12 months of neoadjuvant or adjuvant treatment with
platinum-containing chemotherapy. This indication is approved under
accelerated approval based on tumor response rate and duration of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in
confirmatory trials.
OPDIVO® (nivolumab), as a single agent, is indicated
for the treatment of adult and pediatric (12 years and older)
patients with microsatellite instability-high (MSI-H) or mismatch
repair deficient (dMMR) metastatic colorectal cancer (CRC) that has
progressed following treatment with a fluoropyrimidine,
oxaliplatin, and irinotecan. This indication is approved under
accelerated approval based on overall response rate and duration of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in
confirmatory trials.
OPDIVO® (nivolumab), in combination with
YERVOY® (ipilimumab), is indicated for the treatment of
adults and pediatric patients 12 years and older with
microsatellite instability-high (MSI-H) or mismatch repair
deficient (dMMR) metastatic colorectal cancer (CRC) that has
progressed following treatment with a fluoropyrimidine,
oxaliplatin, and irinotecan. This indication is approved under
accelerated approval based on overall response rate and duration of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in
confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with hepatocellular carcinoma (HCC) who have been
previously treated with sorafenib. This indication is approved
under accelerated approval based on tumor response rate and
durability of response. Continued approval for this indication may
be contingent upon verification and description of clinical benefit
in the confirmatory trials.
OPDIVO® (nivolumab) is indicated for the adjuvant
treatment of patients with melanoma with involvement of lymph nodes
or metastatic disease who have undergone complete resection.
IMPORTANT SAFETY INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse
reactions. These immune-mediated reactions may involve any organ
system; however, the most common severe immune-mediated adverse
reactions are enterocolitis, hepatitis, dermatitis (including toxic
epidermal necrolysis), neuropathy, and endocrinopathy. The majority
of these immune-mediated reactions initially manifested during
treatment; however, a minority occurred weeks to months after
discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis,
dermatitis, neuropathy, and endocrinopathy, and evaluate clinical
chemistries including liver function tests (LFTs),
adrenocorticotropic hormone (ACTH) level, and thyroid function
tests, at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic
high-dose corticosteroid therapy for severe immune-mediated
reactions.
Immune-Mediated Pneumonitis
OPDIVO can cause
immune-mediated pneumonitis. Fatal cases have been reported.
Monitor patients for signs with radiographic imaging and for
symptoms of pneumonitis. Administer corticosteroids for Grade 2 or
more severe pneumonitis. Permanently discontinue for Grade 3 or 4
and withhold until resolution for Grade 2. In patients
receiving OPDIVO monotherapy, fatal cases of immune-mediated
pneumonitis have occurred. Immune-mediated pneumonitis occurred in
3.1% (61/1994) of patients. In patients receiving OPDIVO 1
mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in
6% (25/407) of patients. In RCC patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in
4.4% (24/547) of patients. In MSI-H/dMMR mCRC patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated
pneumonitis occurred in 1.7% (2/119) of patients.
In Checkmate 205 and 039, pneumonitis, including interstitial
lung disease, occurred in 6.0% (16/266) of patients receiving
OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of
patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).
Immune-Mediated Colitis
OPDIVO can cause
immune-mediated colitis. Monitor patients for signs and symptoms of
colitis. Administer corticosteroids for Grade 2 (of more than 5
days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for
Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent
colitis upon re-initiation of OPDIVO. When administered with
YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently
discontinue for Grade 3 or 4 or recurrent colitis. In patients
receiving OPDIVO monotherapy, immune-mediated colitis occurred in
2.9% (58/1994) of patients. In patients receiving OPDIVO 1
mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 26%
(107/407) of patients including three fatal cases. In RCC
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
immune-mediated colitis occurred in 10% (52/547) of
patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg
with YERVOY 1 mg/kg, immune-mediated colitis occurred in 7% (8/119)
of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal (diarrhea of ≥7 stools above baseline,
fever, ileus, peritoneal signs; Grade 3-5) immune-mediated
enterocolitis occurred in 34 (7%) patients. Across all
YERVOY-treated patients in that study (n=511), 5 (1%) developed
intestinal perforation, 4 (0.8%) died as a result of complications,
and 26 (5%) were hospitalized for severe enterocolitis.
Immune-Mediated Hepatitis
OPDIVO can cause
immune-mediated hepatitis. Monitor patients for abnormal liver
tests prior to and periodically during treatment. Administer
corticosteroids for Grade 2 or greater transaminase
elevations. For patients without HCC, withhold OPDIVO for
Grade 2 and permanently discontinue OPDIVO for Grade 3 or
4. For patients with HCC, withhold OPDIVO and administer
corticosteroids if AST/ALT is within normal limits at baseline and
increases to >3 and up to 5 times the upper limit of normal
(ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and
increases to >5 and up to 10 times the ULN, and if AST/ALT is
>3 and up to 5 times ULN at baseline and increases to >8 and
up to 10 times the ULN. Permanently discontinue OPDIVO and
administer corticosteroids if AST or ALT increases to >10 times
the ULN or total bilirubin increases >3 times the ULN. In
patients receiving OPDIVO monotherapy, immune-mediated hepatitis
occurred in 1.8% (35/1994) of patients. In patients receiving
OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis
occurred in 13% (51/407) of patients. In RCC patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated
hepatitis occurred in 7% (38/547) of patients. In MSI-H/dMMR
mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
immune-mediated hepatitis occurred in 8% (10/119) of
patients.
In Checkmate 040, immune-mediated hepatitis requiring systemic
corticosteroids occurred in 5% (8/154) of patients receiving
OPDIVO.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal hepatotoxicity (AST or ALT elevations
>5x the ULN or total bilirubin elevations >3x the ULN; Grade
3-5) occurred in 8 (2%) patients, with fatal hepatic failure
in 0.2% and hospitalization in 0.4%.
Immune-Mediated Neuropathies
In a separate Phase 3
study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome
and 1 case of severe (Grade 3) peripheral motor neuropathy were
reported.
Immune-Mediated Endocrinopathies
OPDIVO can cause
immune-mediated hypophysitis, immune-mediated adrenal
insufficiency, autoimmune thyroid disorders, and Type 1 diabetes
mellitus. Monitor patients for signs and symptoms of hypophysitis,
signs and symptoms of adrenal insufficiency, thyroid function prior
to and periodically during treatment, and hyperglycemia. Administer
hormone replacement as clinically indicated and corticosteroids for
Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and
permanently discontinue for Grade 4 hypophysitis. Administer
corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold
for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal
insufficiency. Administer hormone-replacement therapy for
hypothyroidism. Initiate medical management for control of
hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently
discontinue for Grade 4 hyperglycemia.
In patients receiving OPDIVO monotherapy, hypophysitis occurred
in 0.6% (12/1994) of patients. In patients receiving OPDIVO 1
mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY
1 mg/kg, hypophysitis occurred in 4.6% (25/547) of
patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg
with YERVOY 1 mg/kg, immune-mediated hypophysitis occurred in 3.4%
(4/119) of patients. In patients receiving OPDIVO monotherapy,
adrenal insufficiency occurred in 1% (20/1994) of patients. In
patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal
insufficiency occurred in 5% (21/407) of patients. In RCC
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal
insufficiency occurred in 7% (41/547) of patients. In
MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, adrenal insufficiency occurred in 5.9% (7/119) of
patients. In patients receiving OPDIVO monotherapy,
hypothyroidism or thyroiditis resulting in hypothyroidism occurred
in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7%
(54/1994) of patients receiving OPDIVO monotherapy. In
patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg,
hypothyroidism or thyroiditis resulting in hypothyroidism occurred
in 22% (89/407) of patients. Hyperthyroidism occurred in 8%
(34/407) of patients receiving this dose of OPDIVO with
YERVOY. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism
occurred in 22% (119/547) of patients. Hyperthyroidism occurred in
12% (66/547) of patients receiving this dose of OPDIVO with
YERVOY. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg
with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 15% (18/119) of patients.
Hyperthyroidism occurred in 12% (14/119) of patients. In
patients receiving OPDIVO monotherapy, diabetes occurred in 0.9%
(17/1994) of patients. In patients receiving OPDIVO 1 mg/kg
with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY
1 mg/kg, diabetes occurred in 2.7% (15/547) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe to
life-threatening immune-mediated endocrinopathies (requiring
hospitalization, urgent medical intervention, or interfering with
activities of daily living; Grade 3-4) occurred in 9 (1.8%)
patients. All 9 patients had hypopituitarism, and some had
additional concomitant endocrinopathies such as adrenal
insufficiency, hypogonadism, and hypothyroidism. Six of the 9
patients were hospitalized for severe endocrinopathies.
Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO
can cause immune-mediated nephritis. Monitor patients for elevated
serum creatinine prior to and periodically during treatment.
Administer corticosteroids for Grades 2-4 increased serum
creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently
discontinue for Grade 4 increased serum creatinine. In
patients receiving OPDIVO monotherapy, immune-mediated nephritis
and renal dysfunction occurred in 1.2% (23/1994) of
patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg, immune-mediated nephritis and renal dysfunction occurred in
2.2% (9/407) of patients. In RCC patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal
dysfunction occurred in 4.6% (25/547) of patients. In
MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated nephritis and renal dysfunction occurred in
1.7% (2/119) of patients.
Immune-Mediated Skin Adverse Reactions and
Dermatitis
OPDIVO can cause immune-mediated rash, including
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis
(TEN), some cases with fatal outcome. Administer corticosteroids
for Grade 3 or 4 rash. Withhold for Grade 3 and permanently
discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN,
withhold OPDIVO and refer the patient for specialized care for
assessment and treatment; if confirmed, permanently
discontinue. In patients receiving OPDIVO monotherapy,
immune-mediated rash occurred in 9% (171/1994) of patients. In
patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg,
immune-mediated rash occurred in 22.6% (92/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY
1 mg/kg, immune-mediated rash occurred in 16.6% (91/547) of
patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg
with YERVOY 1 mg/kg, immune-mediated rash occurred in 14% (17/119)
of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal immune-mediated dermatitis (eg,
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash
complicated by full thickness dermal ulceration, or necrotic,
bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13
(2.5%) patients. 1 (0.2%) patient died as a result of toxic
epidermal necrolysis. 1 additional patient required hospitalization
for severe dermatitis.
Immune-Mediated Encephalitis
OPDIVO can cause
immune-mediated encephalitis. Evaluation of patients with
neurologic symptoms may include, but not be limited to,
consultation with a neurologist, brain MRI, and lumbar puncture.
Withhold OPDIVO in patients with new-onset moderate to severe
neurologic signs or symptoms and evaluate to rule out other causes.
If other etiologies are ruled out, administer corticosteroids and
permanently discontinue OPDIVO for immune-mediated
encephalitis. In patients receiving OPDIVO monotherapy,
encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic
encephalitis occurred in one patient after 7.2 months of exposure
despite discontinuation of OPDIVO and administration of
corticosteroids. Encephalitis occurred in one patient
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after
1.7 months of exposure. Encephalitis occurred in one RCC
patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after
approximately 4 months of exposure. Encephalitis occurred in
one MSI-H/dMMR mCRC patient (0.8%) receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg after 15 days of exposure.
Other Immune-Mediated Adverse Reactions
Based on the
severity of the adverse reaction, permanently discontinue or
withhold OPDIVO, administer high-dose corticosteroids, and, if
appropriate, initiate hormone-replacement therapy. Across clinical
trials of OPDIVO monotherapy or in combination with YERVOY, the
following clinically significant immune-mediated adverse reactions,
some with fatal outcome, occurred in <1.0% of patients receiving
OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis,
pancreatitis, facial and abducens nerve paresis, demyelination,
polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré
syndrome, hypopituitarism, systemic inflammatory response syndrome,
gastritis, duodenitis, sarcoidosis, histiocytic necrotizing
lymphadenitis (Kikuchi lymphadenitis), motor dysfunction,
vasculitis, aplastic anemia, pericarditis, and myasthenic
syndrome.
If uveitis occurs in combination with other immune-mediated
adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome,
which has been observed in patients receiving OPDIVO and may
require treatment with systemic steroids to reduce the risk of
permanent vision loss.
Infusion Reactions
OPDIVO can cause severe infusion
reactions, which have been reported in <1.0% of patients in
clinical trials. Discontinue OPDIVO in patients with Grade 3
or 4 infusion reactions. Interrupt or slow the rate of infusion in
patients with Grade 1 or 2. In patients receiving OPDIVO
monotherapy as a 60-minute
infusion, infusion-related reactions occurred in
6.4% (127/1994) of patients. In a separate study in which
patients received OPDIVO monotherapy as a 60-minute infusion or a
30-minute infusion, infusion-related reactions occurred in 2.2%
(8/368) and 2.7% (10/369) of patients, respectively. Additionally,
0.5% (2/368) and 1.4% (5/369) of patients, respectively,
experienced adverse reactions within 48 hours of infusion that led
to dose delay, permanent discontinuation or withholding of
OPDIVO. In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg every 3 weeks, infusion-related reactions occurred
in 2.5% (10/407) of patients. In RCC patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related
reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR
mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
infusion-related reactions occurred in 4.2% (5/119) of
patients.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation
Fatal and other serious complications can
occur in patients who receive allogeneic hematopoietic stem cell
transplantation (HSCT) before or after being treated with a PD-1
receptor blocking antibody. Transplant-related complications
include hyperacute graft-versus-host-disease (GVHD), acute GVHD,
chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced
intensity conditioning, and steroid-requiring febrile syndrome
(without an identified infectious cause). These complications may
occur despite intervening therapy between PD-1 blockade and
allogeneic HSCT.
Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risks of treatment with a PD-1 receptor blocking antibody prior to
or after an allogeneic HSCT.
Embryo-Fetal Toxicity
Based on their mechanisms of
action, OPDIVO and YERVOY can cause fetal harm when administered to
a pregnant woman. Advise pregnant women of the potential risk to a
fetus. Advise females of reproductive potential to use effective
contraception during treatment with an OPDIVO- or YERVOY-
containing regimen and for at least 5 months after the last dose of
OPDIVO.
Increased Mortality in Patients with Multiple Myeloma when
OPDIVO is Added to a Thalidomide Analogue and
Dexamethasone
In clinical trials in patients with multiple
myeloma, the addition of OPDIVO to a thalidomide analogue plus
dexamethasone resulted in increased mortality. Treatment of
patients with multiple myeloma with a PD-1 or PD-L1 blocking
antibody in combination with a thalidomide analogue plus
dexamethasone is not recommended outside of controlled clinical
trials.
Lactation
It is not known whether OPDIVO or YERVOY is
present in human milk. Because many drugs, including antibodies,
are excreted in human milk and because of the potential for serious
adverse reactions in nursing infants from an OPDIVO-containing
regimen, advise women to discontinue breastfeeding during
treatment. Advise women to discontinue breastfeeding during
treatment with YERVOY and for 3 months following the final
dose.
Serious Adverse Reactions
In Checkmate 037, serious
adverse reactions occurred in 41% of patients receiving OPDIVO
(n=268). Grade 3 and 4 adverse reactions occurred in 42% of
patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse
drug reactions reported in 2% to <5% of patients receiving
OPDIVO were abdominal pain, hyponatremia, increased aspartate
aminotransferase, and increased lipase. In Checkmate 066, serious
adverse reactions occurred in 36% of patients receiving OPDIVO
(n=206). Grade 3 and 4 adverse reactions occurred in 41% of
patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse
reactions reported in ≥2% of patients receiving OPDIVO were
gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In
Checkmate 067, serious adverse reactions (74% and 44%), adverse
reactions leading to permanent discontinuation (47% and 18%) or to
dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions
(72% and 51%) all occurred more frequently in the OPDIVO plus
YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most
frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY
arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%),
colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In
Checkmate 017 and 057, serious adverse reactions occurred in 46% of
patients receiving OPDIVO (n=418). The most frequent serious
adverse reactions reported in ≥2% of patients receiving OPDIVO were
pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion,
pneumonitis, and respiratory failure. In Checkmate 032,
serious adverse reactions occurred in 45% of patients receiving
OPDIVO (n=245). The most frequent serious adverse reactions
reported in at least 2% of patients receiving OPDIVO were
pneumonia, dyspnea, pneumonitis, pleural effusions, and
dehydration. In Checkmate 025, serious adverse reactions
occurred in 47% of patients receiving OPDIVO (n=406). The most
frequent serious adverse reactions reported in ≥2% of patients were
acute kidney injury, pleural effusion, pneumonia, diarrhea, and
hypercalcemia. In Checkmate 214, serious adverse reactions
occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43%
of patients receiving sunitinib. The most frequent serious adverse
reactions reported in ≥2% of patients were diarrhea, pyrexia,
pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea,
adrenal insufficiency, and colitis; in patients treated with
sunitinib, they were pneumonia, pleural effusion, and
dyspnea. In Checkmate 205 and 039, adverse reactions leading
to discontinuation occurred in 7% and dose delays due to adverse
reactions occurred in 34% of patients (n=266). Serious adverse
reactions occurred in 26% of patients. The most frequent serious
adverse reactions reported in ≥1% of patients were pneumonia,
infusion-related reaction, pyrexia, colitis or diarrhea, pleural
effusion, pneumonitis, and rash. Eleven patients died from causes
other than disease progression: 3 from adverse reactions within 30
days of the last OPDIVO dose, 2 from infection 8 to 9 months after
completing OPDIVO, and 6 from complications of allogeneic
HSCT. In Checkmate 141, serious adverse reactions occurred in
49% of patients receiving OPDIVO (n=236). The most frequent serious
adverse reactions reported in ≥2% of patients receiving OPDIVO were
pneumonia, dyspnea, respiratory failure, respiratory tract
infection, and sepsis. In Checkmate 275, serious adverse
reactions occurred in 54% of patients receiving OPDIVO (n=270). The
most frequent serious adverse reactions reported in ≥2% of patients
receiving OPDIVO were urinary tract infection, sepsis, diarrhea,
small intestine obstruction, and general physical health
deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients
receiving OPDIVO with YERVOY, serious adverse reactions occurred in
47% of patients. The most frequent serious adverse reactions
reported in ≥2% of patients were colitis/diarrhea, hepatic events,
abdominal pain, acute kidney injury, pyrexia, and
dehydration. In Checkmate 040, serious adverse reactions
occurred in 49% of patients (n=154). The most frequent serious
adverse reactions reported in ≥2% of patients were pyrexia,
ascites, back pain, general physical health deterioration,
abdominal pain, and pneumonia. In Checkmate 238, Grade 3 or 4
adverse reactions occurred in 25% of OPDIVO-treated patients
(n=452). The most frequent Grade 3 and 4 adverse reactions reported
in ≥2% of OPDIVO-treated patients were diarrhea and increased
lipase and amylase. Serious adverse reactions occurred in 18% of
OPDIVO-treated patients.
Common Adverse Reactions
In Checkmate 037, the most
common adverse reaction (≥20%) reported with OPDIVO (n=268) was
rash (21%). In Checkmate 066, the most common adverse reactions
(≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were
fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28%
vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most
common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm
(n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea
(44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%),
vomiting (31%), decreased appetite (29%), cough (27%), headache
(26%), dyspnea (24%), upper respiratory tract infection (23%),
arthralgia (21%), and increased transaminases (25%). In Checkmate
067, the most common (≥20%) adverse reactions in the OPDIVO arm
(n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%),
diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper
respiratory tract infection (22%), decreased appetite (22%),
headache (22%), constipation (21%), arthralgia (21%), and vomiting
(20%). In Checkmate 017 and 057, the most common adverse
reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue,
musculoskeletal pain, cough, dyspnea, and decreased
appetite. In Checkmate 032, the most common adverse reactions
(≥20%) in patients receiving OPDIVO (n=245) were fatigue (45%),
decreased appetite (27%), musculoskeletal pain (25%), dyspnea
(22%), nausea (22%), diarrhea (21%), constipation (20%), and cough
(20%). In Checkmate 025, the most common adverse reactions
(≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus
(n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28%
vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs
32%), constipation (23% vs 18%), decreased appetite (23% vs 30%),
back pain (21% vs 16%), and arthralgia (20% vs 14%). In
Checkmate 214, the most common adverse reactions (≥20%)
reported in patients treated with OPDIVO plus YERVOY (n=547)
vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs 25%),
diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus
(33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25%
vs 17%), arthralgia (23% vs 16%), decreased appetite (21% vs 29%),
dyspnea (20% vs 21%), and vomiting (20% vs 28%). In Checkmate
205 and 039, the most common adverse reactions (≥20%) reported in
patients receiving OPDIVO (n=266) were upper respiratory tract
infection (44%), fatigue (39%), cough (36%), diarrhea (33%),
pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%)
and pruritus (20%). In Checkmate 141, the most common adverse
reactions (≥10%) in patients receiving OPDIVO (n=236) were cough
and dyspnea at a higher incidence than investigator's
choice. In Checkmate 275, the most common adverse reactions
(≥20%) reported in patients receiving OPDIVO (n=270) were fatigue
(46%), musculoskeletal pain (30%), nausea (22%), and decreased
appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients
receiving OPDIVO as a single agent, the most common adverse
reactions (≥20%) were fatigue (54%), diarrhea (43%), abdominal pain
(34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%),
cough (26%), pyrexia (24%), rash (23%), constipation (20%), and
upper respiratory tract infection (20%). In Checkmate 142 in
MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, the most
common adverse reactions (≥20%) were fatigue (49%), diarrhea (45%),
pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%),
pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%),
and vomiting (20%). In Checkmate 040, the most common adverse
reactions (≥20%) in patients receiving OPDIVO (n=154) were fatigue
(38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus
(27%), diarrhea (27%), rash (26%), cough (23%), and decreased
appetite (22%). In Checkmate 238, the most common adverse
reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs
ipilimumab-treated patients (n=453) were fatigue (57% vs 55%),
diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32%
vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23%
vs 28%), upper respiratory infection (22% vs 15%), and abdominal
pain (21% vs 23%). The most common immune-mediated adverse
reactions were rash (16%), diarrhea/colitis (6%), and hepatitis
(3%).
In a separate Phase 3 study of YERVOY 3 mg/kg, the most common
adverse reactions (≥5%) in patients who received YERVOY at
3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%),
rash (29%), and colitis (8%).
Please see U.S. Full Prescribing Information
for OPDIVO and YERVOY, including Boxed
WARNING regarding immune-mediated adverse reactions for
YERVOY.
Checkmate Trials and Patient Populations
Checkmate
037–previously treated metastatic melanoma; Checkmate
066–previously untreated metastatic melanoma; Checkmate
067–previously untreated metastatic melanoma, as a single agent
or in combination with YERVOY; Checkmate 017–second-line
treatment of metastatic squamous non-small cell lung cancer;
Checkmate 057–second-line treatment of metastatic
non-squamous non-small cell lung cancer; Checkmate 032–small
cell lung cancer; Checkmate 025–previously treated renal
cell carcinoma; Checkmate 214–previously untreated renal
cell carcinoma, in combination with YERVOY; Checkmate
205/039–classical Hodgkin lymphoma; Checkmate
141–recurrent or metastatic squamous cell carcinoma of the head
and neck; Checkmate 275–urothelial carcinoma; Checkmate
142–MSI-H or dMMR metastatic colorectal cancer, as a single
agent or in combination with YERVOY; Checkmate
040–hepatocellular carcinoma; Checkmate 238–adjuvant
treatment of melanoma.
About the Bristol-Myers Squibb and Ono Pharmaceutical
Collaboration
In 2011, through a collaboration agreement
with Ono Pharmaceutical Co., Bristol-Myers Squibb expanded its
territorial rights to develop and commercialize Opdivo
globally, except in Japan,
South Korea and Taiwan, where Ono had retained all rights to
the compound at the time. On July 23,
2014, Ono and Bristol-Myers Squibb further expanded the
companies' strategic collaboration agreement to jointly develop and
commercialize multiple immunotherapies – as single agents and
combination regimens – for patients with cancer in Japan, South
Korea and Taiwan.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical
company whose mission is to discover, develop and deliver
innovative medicines that help patients prevail over serious
diseases. For more information about Bristol-Myers Squibb, visit us
at BMS.com or follow us on LinkedIn, Twitter, YouTube and
Facebook.
Bristol-Myers Squibb Cautionary Statement Regarding
Forward-Looking Statements
This press release contains
"forward-looking statements" within the meaning of the Private
Securities Litigation Reform Act of 1995 regarding, among other
things, the research, development and commercialization of
pharmaceutical products. All statements that are not statements of
historical facts are, or may be deemed to be, forward-looking
statements. Such forward-looking statements are based on historical
performance and current expectations and projections about our
future financial results, goals, plans and objectives and involve
inherent risks, assumptions and uncertainties, including internal
or external factors that could delay, divert or change any of them
in the next several years, that are difficult to predict, may be
beyond our control and could cause our future financial results,
goals, plans and objectives to differ materially from those
expressed in, or implied by, the statements. These risks,
assumptions, uncertainties and other factors include, among others,
that future study results will be consistent with the results to
date, that Opdivo, alone or in combination with bempegaldesleukin,
may not achieve their primary study endpoints or receive regulatory
approval for the additional indication described in this release in
the currently anticipated timeline or at all and, if approved,
whether such product candidate or combination treatment for such
additional indication described in this release will be
commercially successful. No forward-looking statement can be
guaranteed. It should also be noted that Breakthrough Therapy
Designation does not change the standards for FDA approval.
Forward-looking statements in this press release should be
evaluated together with the many risks and uncertainties that
affect Bristol-Myers Squibb's business and market, particularly
those identified in the cautionary statement and risk factors
discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for
the year ended December 31, 2018, as
updated by our subsequent Quarterly Reports on Form 10-Q, Current
Reports on Form 8-K and other filings with the Securities and
Exchange Commission. The forward-looking statements included in
this document are made only as of the date of this document and
except as otherwise required by applicable law, Bristol-Myers
Squibb undertakes no obligation to publicly update or revise any
forward-looking statement, whether as a result of new information,
future events, changed circumstances or otherwise.
Nektar Forward-Looking Statements
This
press release contains forward-looking statements which can be
identified by words such as: "may," "plan," "continue," "designed"
and similar references to future periods. Examples of
forward-looking statements include, among others, statements we
make regarding the therapeutic potential of bempegaldesleukin
(NKTR-214) in combination with nivolumab, the availability of
results and outcomes from clinical studies involving
bempegaldesleukin, and our future clinical development plans.
Forward-looking statements are neither historical facts nor
assurances of future performance. Instead, they are based only on
our current beliefs, expectations and assumptions regarding the
future of our business, future plans and strategies, anticipated
events and trends, and other future conditions. Because
forward-looking statements relate to the future, they are subject
to inherent uncertainties, risks and changes in circumstances that
are difficult to predict and many of which are outside of our
control. Our actual results may differ materially from those
indicated in the forward-looking statements. Therefore, you should
not rely on any of these forward-looking statements. Important
factors that could cause our actual results to differ materially
from those indicated in the forward-looking statements include,
among others: (i) our statements regarding the therapeutic
potential of bempegaldesleukin are based on preclinical and
clinical findings and observations to date from ongoing clinical
studies; (ii) bempegaldesleukin is in early stage clinical
development and the risk of failure remains high and failure can
unexpectedly occur at any stage for one or more of the cancer
indications being studied prior to regulatory approval due to lack
of sufficient efficacy, safety considerations or other factors that
negatively impact drug development; (iii) data reported from
ongoing clinical trials is necessarily interim data only and the
final results will change based on continuing observations from
patients that currently remain enrolled in the trials and/or new
observations from patients enrolling in the trials; (iv) scientific
discovery of new medical breakthroughs is an inherently uncertain
process and the future success of potential new drug candidates
(such as bempegaldesleukin) is therefore very uncertain and
unpredictable; (v) patents may not issue from our patent
applications for our drug candidates, patents that have issued may
not be enforceable, or additional intellectual property licenses
from third parties may be required; and (vi) certain other
important risks and uncertainties set forth in Nektar's Quarterly
Report on Form 10-Q filed with the Securities and Exchange
Commission on May 9, 2019. Any
forward-looking statement made by us in this press release is based
only on information currently available to us and speaks only as of
the date on which it is made. We undertake no obligation to update
any forward-looking statement, whether written or oral, that may be
made from time to time, whether as a result of new information,
future developments or otherwise.
Nektar Contacts:
For Investors:
Jennifer Ruddock of Nektar
Therapeutics
415-482-5585
For Media:
Katie Engleman of 1AB
919-333-7722
katie@1abmedia.com
Bristol-Myers Squibb Company Contacts:
Media Inquiries:
Ken Dominski
609-302-3114
ken.dominski@bms.com
Investors:
Tim Power
609-252-7509
timothy.power@bms.com
1 Boyman, J., et al., Nature Reviews Immunology, 2012, 12,
180-190.
2 Charych, D., et al., Clin Can Res; 22(3) February 1,
2016
3 Diab, A., et al., Journal for ImmunoTherapy of
Cancer 2016, 4(Suppl 1): P369
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SOURCE Nektar Therapeutics; Bristol-Myers Squibb