Long-Term Survival and Improvement in Quality of Life Observed with Opdivo® (nivolumab) in Advanced
Renal Cell Carcinoma Patients Based on New Data Presented at the 2016 ASCO Annual Meeting
More than one-third (34%) of previously treated advanced renal cell carcinoma patients who
received Opdivo were alive at five years, in the Phase 1 study, CA209-003
In the Phase 2 study, CA209-010, 29% of previously treated advanced renal cell carcinoma patients
who received Opdivo were alive at four years
Improved health-related quality of life observed with Opdivo versus everolimus, based
on pivotal Phase 3 study, CheckMate -025
Bristol-Myers Squibb Company (NYSE:BMY) announced today new long-term overall survival (OS) results from two
dose-ranging studies, the Phase 1 CA209-003 study and the Phase 2 CA209-010 study, evaluating Opdivo in patients with
previously treated advanced renal cell carcinoma (RCC). Findings include the first report of four- and five-year survival data from
the advanced RCC cohort (n=34) of study -003, in which OS was an exploratory endpoint. In study -003, 38% of patients were alive at
four years, and 34% of patients were alive at five years. In study -010 (n=167), in which OS was a secondary endpoint, 29% of
patients were alive at four years. The long-term safety profile of Opdivo in studies -003 and -010 was consistent
with previously reported studies, with no new safety signals identified after more than four years of follow-up.
Bristol-Myers Squibb is also presenting additional analyses of health-related quality of life data, a secondary endpoint, from
the pivotal, Phase 3 study, CheckMate -025, which evaluated Opdivo versus everolimus in patients with advanced RCC who
received prior anti-angiogenic therapy. In this study, 55.4% of patients treated with Opdivo experienced a clinically
meaningful improvement in disease-related symptoms, as defined in the study, versus 36.7% of patients treated with everolimus
(HR=1.66 [95% CI: 1.33-2.08; p<0.001]).
Dr. Bernard Escudier, Chair of the Genitourinary Oncology Committee, Institut Gustave Roussy in Villejuif, France, commented,
“Historically, five-year survival rates for patients diagnosed with advanced kidney cancer have been less than 12%. Building on the
survival results seen in the Phase 3 study, CheckMate -025, research evaluating whether Opdivo may provide long-term
survival has been of interest to physicians. Data from studies -003 and -010 report, for the first time, longer than four-year
survival with Opdivo in previously treated advanced renal cell carcinoma. These findings offer additional important
information about the role of Opdivo as a treatment option for these patients.”
The results from studies -003 and -010 will be presented today, Sunday, June 5, at the 52nd Annual Meeting of the
American Society of Clinical Oncology (ASCO) during an oral presentation from 10:24 AM – 10:36 AM CDT (Abstract #4507). Data from
CheckMate -025 will be presented during a poster session on Monday, June 6, from 1:00 PM – 4:30 PM CDT (Abstract #4549).
“We are excited to share the overall survival results from studies -010 and -003, as these data provide new insights into the
long-term efficacy and safety of Opdivo in previously treated advanced renal cell carcinoma,” said Vicki Goodman, M.D.,
Development Lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb. “Additionally, with Opdivo, a meaningful
improvement in health-related quality of life, an important factor in cancer care and patient well-being, was observed compared to
everolimus, based on new data from CheckMate -025. We look forward to further evaluating our Immuno-Oncology agents across
different tumor types, including the Opdivo and Yervoy combination, with the goal of improving long-term survival and
quality of life for RCC patients.”
About CA209-003
Study -003, is a Phase 1b open-label, multicenter, multidose, dose-escalation study evaluating Opdivo in 306
patients with select advanced or recurrent malignancies. The primary endpoint was safety and tolerability. Secondary endpoints
included objective response rate (ORR). Overall survival (OS) was an exploratory endpoint.
The results from study -003 presented at the 2016 ASCO Annual Meeting focus on the cohort of patients with advanced renal cell
carcinoma (RCC, n=34) who had received one to five prior systemic therapies, and were treated with Opdivo 1 mg/kg or 10
mg/kg intravenously every two weeks.
At four years, the OS rate for patients treated with Opdivo was 38%, with a median OS of 22.4 months (95% CI: 12.5-NE),
and the five-year survival rate was 34%, with a minimum follow-up of 50.5 months. The long-term safety profile of Opdivo in
study -003 was consistent with previous studies, with no new safety signals identified after more than four years of follow-up.
Grade 3-4 treatment-related adverse events (AEs) occurred in 17.6% of patients. Any grade treatment-related AEs leading to
discontinuation occurred in 8.8% of patients.
About CA209-010
Study -010 is a Phase 2, randomized, dose-ranging study evaluating Opdivo in 167 patients with previously treated
advanced renal cell carcinoma (RCC). In the study, patients with advanced RCC who had received prior treatment with one to three
therapies (at least one being an anti-angiogenic agent) were treated with Opdivo (0.3, 2 or 10 mg/kg) every three weeks
administered intravenously. The primary endpoint was dose-response by progression-free survival (PFS). Secondary endpoints included
objective response rate (ORR), overall survival (OS) and safety.
At four years, the OS rate for patients treated with Opdivo was 29%, with a median OS of 23.4 months (95% CI: 17.7-26.9),
at a minimum follow-up of 49.2 months. In the study, the ORR was 21.6% (95% CI: 15.6-28.6) with a median duration of response
lasting 23 months. Median time to response was 2.8 months (1.2-10.0).
The long-term safety profile of Opdivo in study -010 was consistent with previous studies, with no new safety signals
identified after approximately four years of follow-up. Grade 3-4 treatment-related adverse events (AEs) occurred in 14.4% of
patients in study -010. Any grade treatment-related AEs leading to discontinuation occurred in 9.6% of patients.
About CheckMate -025
CheckMate -025 is an open-label, randomized Phase 3 study of Opdivo versus everolimus in previously treated patients with
advanced clear-cell renal cell carcinoma (RCC) after prior anti-angiogenic therapy. Patients were randomized to receive
Opdivo (n=410) 3 mg/kg administered intravenously every two weeks or everolimus (n=411) 10 mg administered orally once
daily. The primary endpoint of the study was overall survival (OS). Secondary endpoints include objective response rate (ORR),
progression-free survival (PFS), quality of life (QoL) and safety. Patient-reported QoL was measured using the kidney specific,
Functional Assessment of Cancer Therapy–Kidney Symptom Index–Disease Related Symptoms (FKSI-DRS) scale, and European Quality of
Life (EuroQol)-5 Dimensions (EQ-5D) questionnaire. Quality of life was measured at baseline among approximately 361 patients
randomized for treatment with Opdivo and 343 patients randomized for treatment with everolimus.
A higher proportion of patients treated with Opdivo experienced a clinically meaningful improvement in health-related QoL
(defined as a 2-point increase from baseline using FKSI-DRS) compared to patients treated with everolimus (200 [55.4%] of 361 vs.
126 [36.7%] of 343, respectively; (HR=1.66 [95% CI: 1.33-2.08; p<0.001]). Median time to improvement in disease-related
symptoms occurred at 4.7 months (95% CI: 3.7-7.5) with Opdivo and was not estimable with everolimus due to a limited number
of patients who experienced improvement.
About Renal Cell Carcinoma
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 100,000 deaths worldwide
each year. Clear-cell RCC is the most prevalent type of RCC and constitutes 80% to 90% of all cases. RCC is approximately twice as
common in men as it is in women, with the highest rates of the disease found in North America and Europe. Globally,
the five-year survival rate for those diagnosed with advanced kidney cancer is 12%.
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 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.
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 51 countries including the United States, Japan, and in the European Union.
U.S. FDA APPROVED INDICATIONS FOR OPDIVO®
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
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.
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. 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:
Audrey Abernathy, 609-419-5375
Cell: 919-605-4521
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or
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or
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william.szablewski@bms.com
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