NORTH CHICAGO, Ill. and
NEW YORK, July 25, 2016 /PRNewswire/ -- AbbVie (NYSE:
ABBV) and Bristol-Myers Squibb Company (NYSE:BMY) today announced a
clinical trial collaboration to evaluate the safety, tolerability
and efficacy of AbbVie's investigational biomarker-specific
antibody drug conjugate Rova-T (rovalpituuzumab tesirine) in
combination with Bristol-Myers Squibb's Opdivo (nivolumab) and
Opdivo + Yervoy (ipilimumab) regimen as a treatment for relapsed
extensive-stage small cell lung cancer (SCLC).
The Phase 1/2 clinical program will explore the potential of
combining Bristol-Myers Squibb's immuno-oncology agents, which are
designed to alleviate immune suppression, in conjunction with
AbbVie's investigational antibody drug conjugate, Rova-T, to drive
improved and sustained efficacy and tolerability above the current
standard of care. Rova-T is a novel antibody drug conjugate that
targets and eliminates tumor initiating cells and other bulk tumor
cells. This collaboration will determine if the targeted cell
killing and antigen release caused by Rova-T may further enhance
the effect of immunotherapy.
"We are excited to explore the potential benefits of combining
Bristol-Myers Squibb's immunotherapies with a targeted approach
like Rova-T in small cell lung cancer where the need for new
therapies is particularly acute for this aggressive form of lung
cancer," said Jean Viallet, M.D.,
global clinical research lead, oncology, Bristol-Myers Squibb. "As
the science around cancer research continues to rapidly evolve, we
are building on our leadership in Immuno-Oncology with numerous
collaborations that may help advance new therapies for cancers in
need of better options."
"We believe the combination of these cancer-fighting agents may
offer patients a new treatment option in a disease with limited
therapies," said Scott J. Dylla,
Ph.D., vice president, research and development, AbbVie. "By
combining immune-checkpoint inhibitors that prime the body's immune
system to fight cancer cells with Rova-T's approach to target
cancer stem cells, we hope to build on our goal to develop
differentiated treatments with therapeutic benefit that elevate the
standard of care for small cell lung cancer patients."
Small cell lung cancer is a difficult-to-treat form of cancer
that accounts for approximately 15 percent of all lung cancers. The
five-year survival rate for extensive-stage SCLC is less than 5
percent and treatment options are limited for the more than 234,000
people diagnosed annually.
Rova-T is a novel biomarker-specific therapy that targets cancer
stem cells and combines a targeted antibody that delivers a
cytotoxic agent directly to cancer cells expressing a delta-like
protein 3 (DLL3). DLL3 is expressed in more than 80 percent of SCLC
patient tumors and is not present in healthy tissue. Rova-T is
currently in investigational studies as a third-line treatment for
SCLC. AbbVie will initiate a first-line clinical study for Rova-T
in SCLC and several other types of tumors in the near term.
Opdivo was the first PD-1 immune checkpoint
inhibitor to receive regulatory approval anywhere in the world in
July 2014, and currently has
regulatory approval in 54 countries including the United States, Japan, and in the European Union. Yervoy
is a CTLA-4 immune checkpoint inhibitor approved in 50 countries
globally for patients with unresectable or metastatic melanoma.
About AbbVie in Oncology
AbbVie is striving to
outsmart cancer by working with scientists, physicians, industry
peers, patient advocacy groups and most importantly, patients, to
discover, develop and provide new therapies that will have a
remarkable impact on the lives of people around the world affected
by cancer. Our goal is to provide medicines that make a
transformational improvement in cancer treatment and outcomes for
cancer patients. By exploring and investing in new pathways,
technologies and approaches, AbbVie is breaking ground in some of
the most widespread and difficult-to-treat cancers. We are also
exploring solutions to help patients obtain access to our cancer
medicines. With the acquisition of Pharmacyclics in 2015 and
Stemcentrx in 2016, and through several collaborations, AbbVie's
oncology portfolio consists of marketed medicines and a pipeline
containing multiple new molecules being evaluated worldwide in
nearly two hundred clinical trials in 20 different tumor types. For
more information about AbbVie Oncology, please visit
https://abbvieoncology.com.
About Rovalpituzumab Tesirine (Rova-T)
Rova-T is an
investigational antibody drug conjugate targeting the cancer-stem
cell-associated target delta-like protein 3 (DLL3), which is
expressed in more than 80 percent of small cell lung cancer (SCLC)
patient tumors, where it is prevalent on tumor cells, including
cancer stem cells, but not present in healthy tissue. Rova-T
combines a targeted antibody that delivers a cytotoxic agent
directly to the DLL3-expressing cancer cells while minimizing
toxicity to healthy cells. Rova-T is under investigation as a
third-line treatment in SCLC. Studies evaluating Rova-T as a
first-line SCLC regimen will be starting in the near term. The
expression of DLL3 suggests Rova-T may be useful across multiple
tumor types, including metastatic melanoma, glioblastoma multiforme
and some prostate, pancreatic and colorectal cancers.
Rova-T is an investigational compound and its efficacy and
safety have not been established by the FDA or any other health
authority.
Bristol-Myers Squibb &
Immuno-Oncology: Advancing Oncology Research
At
Bristol-Myers Squibb, we have a vision for the future of cancer
care that is focused on Immuno-Oncology, now considered a major
treatment choice alongside surgery, radiation, chemotherapy and
targeted therapies for certain types of cancer.
We have a comprehensive clinical portfolio of investigational
and approved Immuno-Oncology agents, many of which were discovered
and developed by our scientists. Our ongoing Immuno-Oncology
clinical program is looking at broad patient populations, across
multiple solid tumors and hematologic malignancies, and lines of
therapy and histologies, with the intent of powering our trials for
overall survival and other important measures like durability of
response. We pioneered the research leading to the first regulatory
approval for the combination of two Immuno-Oncology agents and
continue to study the role of combinations in cancer.
We are also investigating other immune system pathways in the
treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1,
GITR, CSF1R, IDO and LAG-3. These pathways may lead to potential
new treatment options – in combination or monotherapy – to help
patients fight different types of cancers. Our collaboration with
academia, as well as small and large biotech and pharmaceutical
companies, to research the potential of Immuno-Oncology and
non-Immuno-Oncology combinations helps achieve our goal of
providing new treatment options in clinical practice.
At Bristol-Myers Squibb, we are committed to changing survival
expectations in hard-to-treat cancers and the way patients live
with cancer.
About Opdivo
Cancer cells may exploit
"regulatory" pathways, such as checkpoint pathways, to hide from
the immune system and shield the tumor from immune attack.
Opdivo is a PD-1 immune checkpoint inhibitor that binds to
the checkpoint receptor PD-1 expressed on activated T-cells, and
blocks the binding of PD-L1 and PD-L2, preventing the PD-1
pathway's suppressive signaling on the immune system, including the
interference with an anti-tumor immune response.
Opdivo's broad global development program is based on
Bristol-Myers Squibb's understanding of the biology behind
Immuno-Oncology. Our company is at the forefront of researching the
potential of Immuno-Oncology to extend survival in hard-to-treat
cancers. This scientific expertise serves as the basis for the
Opdivo development program, which includes a broad range of
Phase 3 clinical trials evaluating overall survival as the primary
endpoint across a variety of tumor types. The Opdivo trials
have also contributed toward the clinical and scientific
understanding of the role of biomarkers and how patients may
benefit from Opdivo across the continuum of PD-L1
expression. To date, the Opdivo clinical development program
has enrolled more than 18,000 patients.
INDICATIONS & IMPORTANT SAFETY
INFORMATION
INDICATIONS
OPDIVO® (nivolumab) as a
single agent is indicated for the treatment of patients with BRAF
V600 wild-type unresectable or metastatic melanoma.
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 mutation-positive unresectable
or metastatic melanoma. This indication is approved under
accelerated approval based on progression-free survival. 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 patients with unresectable or
metastatic melanoma. This indication is approved under accelerated
approval based on progression-free survival. 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
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 advanced renal cell carcinoma (RCC) who
have received prior anti-angiogenic therapy.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with classical Hodgkin lymphoma (cHL) that has relapsed or
progressed after autologous hematopoietic stem cell transplantation
(HSCT) and post-transplantation brentuximab vedotin. 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.
Please refer to the end of the Important Safety Information
for a brief description of the patient populations studied in the
CheckMate trials.
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
Immune-mediated
pneumonitis, including fatal cases, occurred with OPDIVO treatment.
Across the clinical trial experience with solid tumors, fatal
immune-mediated pneumonitis occurred with OPDIVO. In addition, in
Checkmate 069, there were six patients who died without resolution
of abnormal respiratory findings. Monitor patients for signs with
radiographic imaging and symptoms of pneumonitis. Administer
corticosteroids for Grade 2 or greater pneumonitis. Permanently
discontinue for Grade 3 or 4 and withhold until resolution for
Grade 2. In Checkmate 069 and 067, immune-mediated pneumonitis
occurred in 6% (25/407) of patients receiving OPDIVO with YERVOY:
Fatal (n=1), Grade 3 (n=6), Grade 2 (n=17), and Grade 1 (n=1). In
Checkmate 037, 066, and 067, immune-mediated pneumonitis occurred
in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and
Grade 2 (n=12). In Checkmate 057, immune-mediated pneumonitis,
including interstitial lung disease, occurred in 3.4% (10/287) of
patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In
Checkmate 025, pneumonitis, including interstitial lung disease,
occurred in 5% (21/406) of patients receiving OPDIVO and 18%
(73/397) of patients receiving everolimus. Immune-mediated
pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO:
Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1). In
Checkmate 205 and 039, pneumonitis, including interstitial lung
disease, occurred in 4.9% (13/263) of patients receiving OPDIVO.
Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients
receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).
Immune-Mediated Colitis
Immune-mediated colitis can
occur with OPDIVO treatment. Monitor patients for signs and
symptoms of colitis. Administer corticosteroids for Grade 2 (of
more than 5 days duration), 3, or 4 colitis. As a single agent,
withhold OPDIVO for Grade 2 or 3 and permanently discontinue for
Grade 4 or recurrent colitis upon restarting OPDIVO. When
administered with YERVOY, withhold OPDIVO for Grade 2 and
permanently discontinue for Grade 3 or 4 or recurrent colitis upon
restarting OPDIVO. In Checkmate 069 and 067, diarrhea or colitis
occurred in 56% (228/407) of patients receiving OPDIVO with YERVOY.
Immune-mediated colitis occurred in 26% (107/407) of patients:
Grade 4 (n=2), Grade 3 (n=60), Grade 2 (n=32), and Grade 1 (n=13).
In Checkmate 037, 066, and 067, diarrhea or colitis occurred in 31%
(242/787) of patients receiving OPDIVO. Immune-mediated colitis
occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2
(n=10), and Grade 1 (n=2). In Checkmate 057, diarrhea or colitis
occurred in 17% (50/287) of patients receiving OPDIVO.
Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade
3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In Checkmate 025,
diarrhea or colitis occurred in 25% (100/406) of patients receiving
OPDIVO and 32% (126/397) of patients receiving everolimus.
Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of
patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade
1 (n=1). In Checkmate 205 and 039, diarrhea or colitis occurred in
30% (80/263) of patients receiving OPDIVO. Immune-mediated diarrhea
(Grade 3) occurred in 1.1% (3/263) 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
Immune-mediated hepatitis
can occur with OPDIVO treatment. Monitor patients for abnormal
liver tests prior to and periodically during treatment. Administer
corticosteroids for Grade 2 or greater transaminase elevations.
Withhold for Grade 2 and permanently discontinue for Grade 3 or 4
immune-mediated hepatitis. In Checkmate 069 and 067,
immune-mediated hepatitis occurred in 13% (51/407) of patients
receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37), Grade
2 (n=5), and Grade 1 (n=1). In Checkmate 037, 066, and 067,
immune-mediated hepatitis occurred in 2.3% (18/787) of patients
receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4).
In Checkmate 057, one patient (0.3%) developed immune-mediated
hepatitis. In Checkmate 025, there was an increased incidence of
liver test abnormalities compared to baseline in AST (33% vs 39%),
alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total
bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms,
respectively. Immune-mediated hepatitis requiring systemic
immunosuppression occurred in 1.5% (6/406) of patients receiving
OPDIVO: Grade 3 (n=5) and Grade 2 (n=1). In Checkmate 205 and 039,
hepatitis occurred in 11% (30/263) of patients receiving OPDIVO.
Immune-mediated hepatitis occurred in 3.4% (9/263): Grade 3 (n=7)
and Grade 2 (n=2).
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 Dermatitis
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 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
Hypophysitis, adrenal
insufficiency, thyroid disorders, and type 1 diabetes mellitus can
occur with OPDIVO treatment. Monitor patients for signs and
symptoms of hypophysitis, signs and symptoms of adrenal
insufficiency during and after treatment, thyroid function prior to
and periodically during treatment, and hyperglycemia. Administer
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. Administer insulin for type 1 diabetes. Withhold
OPDIVO for Grade 3 and permanently discontinue for Grade 4
hyperglycemia.
In Checkmate 069 and 067, hypophysitis occurred in 9% (36/407)
of patients receiving OPDIVO with YERVOY: Grade 3 (n=8), Grade 2
(n=25), and Grade 1 (n=3). In Checkmate 037, 066, and 067,
hypophysitis occurred in 0.9% (7/787) of patients receiving OPDIVO:
Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=2). In Checkmate 025,
hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO:
Grade 3 (n=1) and Grade 1 (n=1). In Checkmate 069 and 067, adrenal
insufficiency occurred in 5% (21/407) of patients receiving OPDIVO
with YERVOY: Grade 4 (n=1), Grade 3 (n=7), Grade 2 (n=11), and
Grade 1 (n=2). In Checkmate 037, 066, and 067, adrenal
insufficiency occurred in 1% (8/787) of patients receiving OPDIVO:
Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 057,
0.3% (1/287) of OPDIVO-treated patients developed adrenal
insufficiency. In Checkmate 025, adrenal insufficiency occurred in
2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2
(n=4), and Grade 1 (n=1). In Checkmate 205 and 039, adrenal
insufficiency (Grade 2) occurred in 0.4% (1/263) of patients
receiving OPDIVO. In Checkmate 069 and 067, hypothyroidism or
thyroiditis occurred in 22% (89/407) of patients receiving OPDIVO
with YERVOY: Grade 3 (n=6), Grade 2 (n=47), and Grade 1 (n=36).
Hyperthyroidism occurred in 8% (34/407) of patients: Grade 3 (n=4),
Grade 2 (n=17), and Grade 1 (n=13). In Checkmate 037, 066, and 067,
hypothyroidism or thyroiditis occurred in 9% (73/787) of patients
receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1 (n=35).
Hyperthyroidism occurred in 4.4% (35/787) of patients receiving
OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In
Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis,
occurred in 7% (20/287) and elevated thyroid stimulating hormone
occurred in 17% of patients receiving OPDIVO. Grade 1 or 2
hyperthyroidism occurred in 1.4% (4/287) of patients. In Checkmate
025, thyroid disease occurred in 11% (43/406) of patients receiving
OPDIVO, including one Grade 3 event, and in 3.0% (12/397) of
patients receiving everolimus. Hypothyroidism/thyroiditis occurred
in 8% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2
(n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5%
(10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1
(n=5). In Checkmate 205 and 039, hypothyroidism/thyroiditis
occurred in 12% (32/263) of patients receiving OPDIVO: Grade 2
(n=18) and Grade 1: (n=14). Hyperthyroidism occurred in 1.5%
(4/263) of patients receiving OPDIVO: Grade 2: (n=3) and Grade 1
(n=1). In Checkmate 069 and 067, diabetes mellitus or diabetic
ketoacidosis occurred in 1.5% (6/407) of patients: Grade 4 (n=3),
Grade 3 (n=1), Grade 2 (n=1), and Grade 1 (n=1). In Checkmate 037,
066, and 067, diabetes mellitus or diabetic ketoacidosis occurred
in 0.8% (6/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade
2 (n=3), and Grade 1 (n=1). In Checkmate 025, hyperglycemic adverse
events occurred in 9% (37/406) patients. Diabetes mellitus or
diabetic ketoacidosis occurred in 1.5% (6/406) of patients
receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1).
In Checkmate 205 and 039, diabetes mellitus occurred in 0.8%
(2/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1
(n=1).
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. 6 of the 9
patients were hospitalized for severe endocrinopathies.
Immune-Mediated Nephritis and Renal
Dysfunction
Immune-mediated nephritis can occur with OPDIVO
treatment. Monitor patients for elevated serum creatinine prior to
and periodically during treatment. For Grade 2 or 3 increased serum
creatinine, withhold and administer corticosteroids; if worsening
or no improvement occurs, permanently discontinue. Administer
corticosteroids for Grade 4 serum creatinine elevation and
permanently discontinue. In Checkmate 069 and 067, immune-mediated
nephritis and renal dysfunction occurred in 2.2% (9/407) of
patients: Grade 4 (n=4), Grade 3 (n=3), and Grade 2 (n=2). In
Checkmate 037, 066, and 067, nephritis and renal dysfunction of any
grade occurred in 5% (40/787) of patients receiving OPDIVO.
Immune-mediated nephritis and renal dysfunction occurred in 0.8%
(6/787) of patients: Grade 3 (n=4) and Grade 2 (n=2). In Checkmate
057, Grade 2 immune-mediated renal dysfunction occurred in 0.3%
(1/287) of patients receiving OPDIVO. In Checkmate 025, renal
injury occurred in 7% (27/406) of patients receiving OPDIVO and
3.0% (12/397) of patients receiving everolimus. Immune-mediated
nephritis and renal dysfunction occurred in 3.2% (13/406) of
patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3
(n=5), and Grade 2 (n=6). In Checkmate 205 and 039, nephritis and
renal dysfunction occurred in 4.9% (13/263) of patients treated
with OPDIVO. This included one reported case (0.3%) of Grade 3
autoimmune nephritis.
Immune-Mediated Rash
Immune-mediated rash can occur
with OPDIVO treatment. Severe rash (including rare cases of fatal
toxic epidermal necrolysis) occurred in the clinical program of
OPDIVO. Monitor patients for rash. Administer corticosteroids for
Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue
for Grade 4. In Checkmate 069 and 067, immune-mediated rash
occurred in 22.6% (92/407) of patients receiving OPDIVO with
YERVOY: Grade 3 (n=15), Grade 2 (n=31), and Grade 1 (n=46). In
Checkmate 037, 066, and 067, immune-mediated rash occurred in 9%
(72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2
(n=15), and Grade 1 (n=50). In Checkmate 057, immune-mediated rash
occurred in 6% (17/287) of patients receiving OPDIVO including four
Grade 3 cases. In Checkmate 025, rash occurred in 28% (112/406) of
patients receiving OPDIVO and 36% (143/397) of patients receiving
everolimus. Immune-mediated rash, defined as a rash treated with
systemic or topical corticosteroids, occurred in 7% (30/406) of
patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade
1 (n=19). In Checkmate 205 and 039, rash occurred in 22% (58/263)
of patients receiving OPDIVO. Immune-mediated rash occurred in 7%
(18/263) of patients on OPDIVO: Grade 3 (n=4), Grade 2 (n=3), and
Grade 1 (n=11).
Immune-Mediated Encephalitis
Immune-mediated
encephalitis can occur with OPDIVO treatment. 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 Checkmate
067, encephalitis was identified in one patient (0.2%) receiving
OPDIVO with YERVOY. In Checkmate 057, fatal limbic encephalitis
occurred in one patient (0.3%) receiving OPDIVO. In Checkmate 205
and 039, encephalitis occurred in 0.8% (2/263) of patients after
allogeneic HSCT after OPDIVO.
Other Immune-Mediated Adverse Reactions
Based on the
severity of adverse reaction, permanently discontinue or withhold
treatment, administer high-dose corticosteroids, and, if
appropriate, initiate hormone-replacement therapy. In < 1.0% of
patients receiving OPDIVO, the following clinically significant,
immune‑mediated adverse reactions occurred: uveitis, iritis,
pancreatitis, facial and abducens nerve paresis, demyelination,
polymyalgia rheumatica, autoimmune neuropathy, Guillain‑Barré
syndrome, hypopituitarism, systemic inflammatory response syndrome,
gastritis, duodenitis, and sarcoidosis. Across clinical trials of
OPDIVO as a single agent administered at doses of 3 mg/kg and
10 mg/kg, additional clinically significant, immune-mediated
adverse reactions were identified: motor dysfunction, vasculitis,
and myasthenic syndrome.
Infusion Reactions
Severe infusion reactions have been
reported in <1.0% of patients in clinical trials of OPDIVO.
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 Checkmate 069 and 067, infusion- related reactions
occurred in 2.5% (10/407) of patients receiving OPDIVO with YERVOY:
Grade 2 (n=6) and Grade 1 (n=4). In Checkmate 037, 066, and 067,
Grade 2 infusion related reactions occurred in 2.7% (21/787) of
patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade
1 (n=11). In Checkmate 057, Grade 2 infusion reactions requiring
corticosteroids occurred in 1.0% (3/287) of patients receiving
OPDIVO. In Checkmate 025, hypersensitivity/infusion-related
reactions occurred in 6% (25/406) of patients receiving OPDIVO and
1.0% (4/397) of patients receiving everolimus. In Checkmate 205 and
039, hypersensitivity/infusion-related reactions occurred in 16%
(42/263) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2
(n=24), and Grade 1 (n=16).
Complications of Allogeneic HSCT after OPDIVO
Complications, including fatal events, occurred in patients who
received allogeneic HSCT after OPDIVO. Outcomes were evaluated in
17 patients from Checkmate 205 and 039, who underwent allogeneic
HSCT after discontinuing OPDIVO (15 with reduced-intensity
conditioning, 2 with myeloablative conditioning). Thirty-five
percent (6/17) of patients died from complications of allogeneic
HSCT after OPDIVO. Five deaths occurred in the setting of severe or
refractory GVHD. Grade 3 or higher acute GVHD was reported in 29%
(5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of
patients. A steroid-requiring febrile syndrome, without an
identified infectious cause, was reported in 35% (n=6) of patients.
Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic
encephalitis without an identified infectious cause, and Grade 3
(n=1) suspected viral encephalitis. Hepatic veno-occlusive disease
(VOD) occurred in one patient, who received reduced-intensity
conditioned allogeneic SCT and died of GVHD and multi-organ
failure. Other cases of hepatic VOD after reduced-intensity
conditioned allogeneic HSCT have also been reported in patients
with lymphoma who received a PD-1 receptor blocking antibody before
transplantation. Cases of fatal hyperacute GVHD have also been
reported. These complications may occur despite intervening therapy
between PD-1 blockade and allogeneic HSCT.
Follow patients closely for early evidence of transplant-related
complications such as hyperacute GVHD, severe (Grade 3 to 4) acute
GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.
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.
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 nursing during treatment
with YERVOY and for 3 months following the final dose.
Serious Adverse Reactions
In Checkmate 067, serious
adverse reactions (73% and 37%), adverse reactions leading to
permanent discontinuation (43% and 14%) or to dosing delays (55%
and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all
occurred more frequently in the OPDIVO plus YERVOY arm relative to
the OPDIVO arm. The most frequent (≥10%) serious adverse reactions
in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively,
were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia
(10% and 0.6%). In Checkmate 037, serious adverse reactions
occurred in 41% of patients receiving OPDIVO. 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. 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 057, serious adverse reactions
occurred in 47% of patients receiving OPDIVO. The most frequent
serious adverse reactions reported in ≥2% of patients were
pneumonia, pulmonary embolism, dyspnea, pleural effusion, and
respiratory failure. In Checkmate 025, serious adverse reactions
occurred in 47% of patients receiving OPDIVO. The most frequent
serious adverse reactions reported in ≥2% of patients were acute
kidney injury, pleural effusion, pneumonia, diarrhea, and
hypercalcemia. In Checkmate 205 and 039, among all patients (safety
population [n=263]), adverse reactions leading to discontinuation
(4.2%) or to dosing delays (23%) occurred. The most frequent
serious adverse reactions reported in ≥1% of patients were
infusion-related reaction, pneumonia, pleural effusion, pyrexia,
rash and pneumonitis. Ten patients died from causes other than
disease progression, including 6 who died from complications of
allogeneic HSCT. Serious adverse reactions occurred in 21% of
patients in the safety population (n=263) and 27% of patients in
the subset of patients evaluated for efficacy (efficacy population
[n=95]).
Common Adverse Reactions
In Checkmate 067, the most
common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm were
fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia
(37%), vomiting (28%), and dyspnea (20%). The most common (≥20%)
adverse reactions in the OPDIVO arm were fatigue (53%), rash (40%),
diarrhea (31%), and nausea (28%). In Checkmate 037, the most common
adverse reaction (≥20%) reported with OPDIVO was rash (21%). In
Checkmate 066, the most common adverse reactions (≥20%) reported
with OPDIVO vs dacarbazine were fatigue (49% vs 39%),
musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus
(23% vs 12%). In Checkmate 057, the most common adverse reactions
(≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal
pain (36%), cough (30%), decreased appetite (29%), and constipation
(23%). In Checkmate 025, the most common adverse reactions (≥20%)
reported in patients receiving OPDIVO vs everolimus were asthenic
conditions (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 205
and 039, among all patients (safety population [n=263]) and the
subset of patients in the efficacy population (n=95), respectively,
the most common adverse reactions (reported in at least 20%) were
fatigue (32% and 43%), upper respiratory tract infection (28% and
48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22%
and 35%). In the subset of patients in the efficacy population
(n=95), the most common adverse reactions also included rash (31%),
musculoskeletal pain (27%), pruritus (25%), nausea (23%),
arthralgia (21%), and peripheral neuropathy (21%).
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%).
CHECKMATE Trials and Patient Populations
Checkmate
069 and 067 - advanced melanoma alone or in combination with
YERVOY; Checkmate 037 and 066 - advanced melanoma;
Checkmate 057 – non-squamous non-small cell lung cancer
(NSCLC); Checkmate 025 - renal cell carcinoma; Checkmate
205/039 - classical Hodgkin lymphoma
Please see U.S. Full Prescribing Information, including Boxed
WARNING regarding immune-mediated adverse reactions, for
YERVOY.
Please see U.S. Full Prescribing Information for OPDIVO.
About the Bristol-Myers Squibb and Ono Pharmaceutical Co.,
Ltd. Collaboration
In 2011, through a collaboration
agreement with Ono Pharmaceutical Co., Ltd (Ono), 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, Bristol-Myers Squibb
and Ono 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.
About AbbVie
AbbVie is a global, research-based
biopharmaceutical company formed in 2013 following separation from
Abbott Laboratories. The company's mission is to use its expertise,
dedicated people and unique approach to innovation to develop and
market advanced therapies that address some of the world's most
complex and serious diseases. Together with its wholly-owned
subsidiary, Pharmacyclics, AbbVie employs more than 28,000 people
worldwide and markets medicines in more than 170 countries. For
further information on the company and its people, portfolio and
commitments, please visit www.abbvie.com. Follow @abbvie on
Twitter or view careers on our Facebook or LinkedIn page.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as
that term is defined in the Private Securities Litigation Reform
Act of 1995 regarding the research, development and
commercialization of pharmaceutical products. Such forward-looking
statements are based on current expectations and involve inherent
risks and uncertainties, including factors that could delay, divert
or change any of them, and could cause actual outcomes and results
to differ materially from current expectations. No forward-looking
statement can be guaranteed. Among other risks, there can be no
guarantee that Opdivo in combination with a Live Attenuated
Double–Deleted (LADD) Listerial
monocytogenes cancer vaccine, expressing mesothelin and EGFRvIII
(ADU-214), will receive regulatory approval for the
treatment of cancer. Forward-looking statements in this press
release should be evaluated together with the many uncertainties
that affect Bristol-Myers Squibb's business, particularly those
identified in the cautionary factors discussion in Bristol-Myers
Squibb's Annual Report on Form 10-K for the year ended December 31, 2015 in our Quarterly Reports on
Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation
to publicly update any forward-looking statement, whether as a
result of new information, future events or otherwise.
AbbVie Forward-Looking Statement
Some statements in this news release may be forward-looking
statements for purposes of the Private Securities Litigation Reform
Act of 1995. The words "believe," "expect," "anticipate," "project"
and similar expressions, among others, generally identify
forward-looking statements. AbbVie cautions that these
forward-looking statements are subject to risks and uncertainties
that may cause actual results to differ materially from those
indicated in the forward-looking statements. Such risks and
uncertainties include, but are not limited to, challenges to
intellectual property, competition from other products,
difficulties inherent in the research and development process,
adverse litigation or government action, and changes to laws and
regulations applicable to our industry. Additional information
about the economic, competitive, governmental, technological and
other factors that may affect AbbVie's operations is set forth in
Item 1A, "Risk Factors," in AbbVie's 2015 Annual Report on Form
10-K, which has been filed with the Securities and Exchange
Commission. AbbVie undertakes no obligation to release publicly any
revisions to forward-looking statements as a result of subsequent
events or developments, except as required by law.
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