Bristol-Myers
Squibb Company (NYSE: BMY) and PsiOxus
Therapeutics, Ltd. (PsiOxus) today announced an exclusive clinical
collaboration agreement to evaluate the safety, tolerability, and
preliminary efficacy of PsiOxus’ enadenotucirev, a systemically
administered oncolytic adenovirus therapeutic, in combination with
Bristol-Myers Squibb’s Immuno-Oncology (I-O) agent
Opdivo
(nivolumab) to treat a range of tumor types in late-stage cancer
patients.
Enadenotucirev is designed to have immune stimulating effects while Opdivo
is designed to alleviate immune suppression. The clinical collaboration
will support Phase 1 studies to determine whether combining these two
agents can significantly improve the proportion of patients
achieving objective tumor responses, the extent of tumor shrinkage,
and/or the durability of responses.
“This collaboration continues to expand our clinical development of Opdivo
and explores how oncolytic viruses may provide a complementary mechanism
to address tumors that are resistant to I-O therapy,” said Jean Viallet,
M.D., Global Clinical Research Lead, Oncology, Bristol-Myers Squibb. “We
are excited to partner with PsiOxus to evaluate the combination of Opdivo
and enadenotucirev to accelerate our understanding of its potential as a
new therapeutic option for cancer patients.”
“We are delighted to collaborate with Bristol-Myers Squibb and to
investigate enadenotucirev with Opdivo in several tumor types,”
stated John Beadle, M.D., Chief Executive Officer, PsiOxus. “They are
our ideal partner since we share a common vision of exploring novel
combinations such as enadenotucirev and Opdivo to expand the
range of patients who potentially respond favorably to checkpoint
inhibitor therapy.”
Opdivo is a PD-1 immune checkpoint inhibitor currently approved
in 50 countries globally for the treatment of patients with metastatic
non-small cell lung cancer (NSCLC) with progression on or after
platinum-based chemotherapy, in 50 countries globally for the treatment
of patients with unresectable or metastatic melanoma as mono-or
combination therapy, in 34 countries globally for the treatment of
patients with advanced renal cell carcinoma (RCC) who have received
prior anti-angiogenic therapy and in the U.S. for the treatment of
patients with classical Hodgkin’s Lymphoma (cHL) that has relapsed or
progressed after autologous hematopoietic stem cell transplantation
(HSCT) and post-transplantation brentuximab vedotin.
PsiOxus’ enadenotucirev is an oncolytic group B adenovirus therapeutic
that is given intravenously and is currently in Phase 1 clinical studies
for multiple solid tumor types. Enadenotucirev is a virus that
selectively replicates in tumor cells but not in normal cells. Such
viruses promote anti-tumor responses through a dual mechanism of action
that is dependent on selective tumor cell killing and the induction of
systemic anti-tumor immunity. Preclinical data demonstrate that this
approach is potentially applicable to a broad range of epithelially
derived solid tumors, many of which have compelling unmet needs even
when treated with checkpoint inhibitors.
Under the terms of this agreement, Bristol-Myers Squibb will make a
one-time upfront payment of $10 million to PsiOxus, and the parties will
share development costs. PsiOxus will be responsible for conducting the
Phase 1 study with patient recruitment expected to start in the third
quarter of 2016. Additionally, the companies will work exclusively with
each other on anti-PD-1/PD-L1 antagonist antibody and enadenotucirev
combination regimens, and Bristol-Myers Squibb will have a time-limited
right of exclusive negotiation for commercial rights to enadenotucirev.
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.
U.S. 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 carcinoma (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 PsiOxus Therapeutics Ltd.
PsiOxus Therapeutics, an Oxford, UK-based development stage
biotechnology company focused upon immune-oncology, has developed a
patented platform for delivering tumor-targeted oncolytic immune
therapeutics systemically. The Tumor-Specific Immuno-Gene (T-SIGn)
therapy platform is based on the company's oncolytic virus,
enadenotucirev, which has unique properties that allow it to be
delivered systemically via intravenous administration and to replicate
only in tumor cells. The anti-cancer capability can be further enhanced
through “arming” – a process that involves the addition of new genes
into the virus. The armed T-SIGn platform makes possible creation of a
broad range of systemically delivered oncolytic immune therapeutics
including oncolytic viruses that express one or more antibodies,
cytokines, immunomodulatory proteins, or nucleotide (RNA) based
payloads. The T-SIGn platform is in preclinical stage, while phase I/II
clinical trials are ongoing with enadenotucirev in different tumor types
and with different combinations including checkpoint inhibitors and
conventional chemotherapeutics.
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 an oncolytic adenovirus therapeutic 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.
Bristol-Myers Squibb Media: Lisa McCormick Lavery, 609-252-7602 lisa.mccormicklavery@bms.com Ken Dominski, 609-252-5251 ken.dominski@bms.com or Investors: Bill Szablewski, 609-252-5894 william.szablewski@bms.com or PsiOxus Therapeutics Ltd. John Beadle, +44 1235 42 98 40 john.beadle@psioxus.com