U.S. Food and Drug Administration Approves Opdivo® (nivolumab) + Yervoy® (ipilimumab) Combination as First-Line Treatment for Patients with Intermediate- and Poor-Risk Advanced Renal Cell Carcinoma

  • The Opdivo + low-dose Yervoy combination is
    the first and only treatment to show significantly superior overall
    survival versus sunitinib in intermediate- and poor-risk advanced
    renal cell carcinoma, including a survival benefit regardless of PD-L1
    expression
    1,2
  • Treatment with Opdivo + Yervoy delivered higher
    objective response rates, including more complete responses, than
    sunitinib
    1,2
  • In the CheckMate -214 trial, which used dosing optimized for
    advanced renal cell carcinoma,
    Opdivo + Yervoy was associated
    with fewer overall Grade 3 or 4 adverse reactions than sunitinib
    1,2

PRINCETON, N.J.–(BUSINESS WIRE)–$BMY #BMSBristol-Myers
Squibb Company
(NYSE: BMY) today announced that Opdivo (nivolumab)
3 mg/kg plus Yervoy (ipilimumab) 1 mg/kg (injections for
intravenous use) was approved by the U.S. Food and Drug Administration
(FDA) as the first Immuno-Oncology combination therapy for previously
untreated patients with intermediate- and poor-risk advanced renal cell
carcinoma (RCC).1,2 In the Phase 3 CheckMate -214 clinical
trial, the Opdivo + Yervoy combination demonstrated a
significant and unprecedented increase in overall survival (OS) in this
patient population compared to a current standard of care, sunitinib. An
OS benefit was observed regardless of PD-L1 expression level.1,2,3Opdivo + Yervoy also delivered durable responses, with a
higher objective response rate (ORR) compared to sunitinib.1,2
Patients in the CheckMate -214 trial received four cycles of the Opdivo
+ low-dose Yervoy combination, followed by Opdivo
maintenance therapy.1,2 In the combination arm of the trial,
79% of patients received all four doses of Opdivo + Yervoy and
went on to the Opdivo monotherapy phase.4 Flexible
dosing options are available during the Opdivo maintenance phase
(480 mg infused every four weeks or 240 mg infused every two weeks).


“Our goal is to provide cancer patients with medicines that have the
potential to extend their lives. As the first treatment option to
increase overall survival for subgroups of patients with advanced RCC
compared to sunitinib, the Opdivo plus low-dose Yervoy
combination helps deliver on that promise,” said Johanna Mercier, head,
U.S. Commercial, Bristol-Myers Squibb. “This approval demonstrates our
commitment to bringing Immuno-Oncology treatments that may improve
outcomes to a broader range of RCC patients.”

Opdivo is associated with the following Warnings and Precautions:
immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies,
nephritis and renal dysfunction, skin adverse reactions, encephalitis,
other adverse reactions; infusion reactions; and embryo-fetal toxicity.
Please see the Important Safety Information section below, including
Boxed WARNING for Yervoy regarding immune-mediated adverse
reactions.1,2

Results from the CheckMate -214 trial in patients with previously
untreated intermediate- and poor-risk advanced RCC include:

  • Overall Survival: Opdivo + Yervoy reduced the
    risk of death by 37% versus sunitinib (hazard ratio [HR] 0.63; 99.8%
    confidence interval [CI]: 0.44 to 0.89; p<0.0001).1,2
    The median OS was not yet reached for Opdivo + Yervoy (95% CI:
    28.2 to not estimable [NE]) and was 25.9 months for sunitinib (95% CI:
    22.1 to NE).1,2,3
  • Objective Response Rate: Opdivo + Yervoy was
    associated with a 41.6% ORR (95% CI: 36.9 to 46.5; p<0.0001; n=177/425) versus 26.5% for sunitinib (95% CI: 22.4 to 31.0; n=112/422).1,2

    • Complete and Partial Response Rates: The complete response
      (CR) rate was 9.4% for Opdivo + Yervoy (n=40/425)
      and 1.2% for sunitinib (n=5/422), and the partial response (PR)
      rate was 32.2% for Opdivo + Yervoy (n=137/425) and 25.4%
      for sunitinib (n=107/422).1,2
    • Duration of Response: Among patients who responded, median
      duration of response (durability) for Opdivo + Yervoy
      was not yet reached (95% CI: 21.8 to NE), compared to 18.2 months
      for sunitinib (95% CI: 14.8 to NE).1,2
  • Progression-Free Survival: Progression-free survival (PFS) was
    11.6 months for the Opdivo + Yervoy combination, compared to
    8.4 months for sunitinib (HR 0.82; 99.1% CI: 0.64 to 1.05; p=not
    significant), which did not reach statistical significance.1,2

Among those with advanced RCC, 75% to 80% have one or more risk factors
and are considered intermediate- and poor-risk patients according to
International Metastatic Renal Cell Carcinoma Database Consortium
criteria.5,6 These patients historically had a poor
prognosis, and although there have been a number of treatment advances
over the past decade, additional options to improve overall survival are
still needed.7,8 Currently, only 36% of patients with
advanced RCC survive beyond one year, and only 8% will live past five
years.7,9

“Physicians treating advanced RCC have had few options to help achieve
the goal of improved survival,” said Robert J. Motzer, M.D., medical
oncologist, Jack and Dorothy Byrne chair in clinical oncology, Memorial
Sloan Kettering Cancer Center. “Data from the CheckMate -214 trial
demonstrated superior overall survival with Opdivo + Yervoy,
showing the potential for the combination to become a new standard of
care for patients with intermediate- and poor-risk advanced RCC. What’s
more, the combination resulted in fewer overall Grade 3 and 4 adverse
reactions compared to sunitinib. Because of these encouraging results,
we now have a new treatment option for newly diagnosed advanced RCC
patients across PD-L1 expression levels.”

In CheckMate -214, the combination was associated with fewer overall
Grade 3 or 4 adverse events than sunitinib (65% versus 76%).1,2
Treatment discontinuation due to adverse events occurred in 31% of
patients in the Opdivo + Yervoy arm, compared to 21% in
the sunitinib arm. Fifty-four percent (54%) of patients receiving Opdivo
+ Yervoy and 43% of patients receiving sunitinib had a dose delay
for an adverse reaction. In the sunitinib group, 53% of patients
required a dose reduction, which was not permitted for patients treated
with the Opdivo + Yervoy combination. Serious adverse reactions
occurred in 59% of patients receiving Opdivo + Yervoy and
in 43% of patients receiving sunitinib.1,2

“Kidney cancer is the deadliest of all urological cancers, and too many
patients are faced with this grim diagnosis,” said Dena Battle,
president, KCCure. “Today’s approval of Opdivo + Yervoy for
advanced RCC has the potential to transform the first-line treatment
landscape for kidney cancer. But for patients, it is more than just a
new therapy option – it represents hope for a longer life.”

Approval Based on CheckMate -214 Trial:
Demonstrating Superior Overall Survival and Objective Response Rate vs.
Sunitinib

CheckMate -214 is a Phase 3, randomized, open-label study evaluating the
combination of Opdivo + Yervoy versus sunitinib in
patients with previously untreated advanced RCC. In the intermediate-
and poor-risk study population, 425 patients received Opdivo 3
mg/kg plus Yervoy 1 mg/kg every three weeks for four doses,
followed by Opdivo 3 mg/kg every two weeks, and 422 patients
received sunitinib 50 mg once daily for four weeks, followed by two
weeks off every cycle.1,2 The recommended dosing for the Opdivo
+ Yervoy
combination is Opdivo 3 mg/kg followed by Yervoy 1
mg/kg each infused intravenously over 30 minutes on the same day every
three weeks for four doses. After completing four doses of the
combination, Opdivo should be administered intravenously 240 mg
every two weeks or 480 mg every four weeks over 30 minutes until disease
progression or unacceptable toxicity.1,2

The primary efficacy outcome measures of the trial were OS, ORR (CR+PR)
and PFS as determined by an independent radiographic review committee
(IRRC) in intermediate- and poor-risk patients. Patients were included
regardless of their PD-L1 status.1,2 Data from CheckMate -214
were presented at the European Society for Medical Oncology Congress in
September 2017 and the Society for Immunotherapy of Cancer Annual
Meeting in November 2017 and were published in the New England
Journal of Medicine
in March 2018.3,10,11

Select Safety Profile for the CheckMate -214
Trial

The most frequent serious adverse reactions reported in at least 2% of
patients receiving Opdivo + Yervoy were diarrhea, pyrexia,
pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea,
adrenal insufficiency and colitis. The most common adverse reactions
(≥20%) reported in patients receiving Opdivo + Yervoy were
fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%),
pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia
(23%), decreased appetite (21%), dyspnea (20%) and vomiting (20%).1,2

About Renal Cell Carcinoma

Renal cell carcinoma is the most common type of kidney cancer in adults,
accounting for nearly 15,000 deaths in the United States each year.12,13
Clear-cell RCC is the most prevalent type of RCC and constitutes 70% to
80% of all patients.14 Renal cell carcinoma is approximately
twice as common in men as in women.15 In the United States,
the five-year survival rate for those diagnosed with metastatic, or
advanced, kidney cancer is 8%.7

INDICATION

OPDIVO® (nivolumab), in combination with YERVOY®
(ipilimumab), is indicated for the treatment of patients with
intermediate or poor-risk, previously untreated advanced renal cell
carcinoma (RCC).

OPDIVO (10 mg/mL) and YERVOY (5 mg/mL) are injections for intravenous
use.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse
reactions. These immune-mediated reactions may involve any organ system;
however, the most common severe immune-mediated adverse reactions are
enterocolitis, hepatitis, dermatitis (including toxic epidermal
necrolysis), neuropathy, and endocrinopathy. The majority of these
immune-mediated reactions initially manifested during treatment;
however, a minority occurred weeks to months after discontinuation of
YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis,
neuropathy, and endocrinopathy and evaluate clinical chemistries
including liver function tests (LFTs), adrenocorticotropic hormone
(ACTH) level, and thyroid function tests at baseline and before each
dose.

Permanently discontinue YERVOY and initiate systemic high-dose
corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been
reported. Monitor patients for signs with radiographic imaging and for
symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more
severe pneumonitis. Permanently discontinue for Grade 3 or 4 and
withhold until resolution for Grade 2. In patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4%
(24/547) of patients.

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and
symptoms of colitis. Administer corticosteroids for Grade 2 (of more
than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for
Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent
colitis upon re-initiation of OPDIVO. When administered with YERVOY,
withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for
Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO 3 mg/kg
with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of
patients.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for
abnormal liver tests prior to and periodically during treatment.
Administer corticosteroids for Grade 2 or greater transaminase
elevations. Withhold OPDIVO for Grade 2 and permanently discontinue
OPDIVO for Grade 3 or 4. In patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of
patients.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal
insufficiency, autoimmune thyroid disorders, and Type 1 diabetes
mellitus. Monitor patients for signs and symptoms of hypophysitis, signs
and symptoms of adrenal insufficiency, thyroid function prior to and
periodically during treatment, and hyperglycemia. Administer hormone
replacement as clinically indicated and corticosteroids for Grade 2 or
greater hypophysitis. Withhold for Grade 2 or 3 and permanently
discontinue for Grade 4 hypophysitis. Administer corticosteroids for
Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently
discontinue for Grade 3 or 4 adrenal insufficiency. Administer
hormone-replacement therapy for hypothyroidism. Initiate medical
management for control of hyperthyroidism. Withhold OPDIVO for Grade 3
and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis
occurred in 4.6% (25/547) of patients. In patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547)
of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
hypothyroidism or thyroiditis resulting in hypothyroidism occurred in
22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of
patients receiving this dose of OPDIVO with YERVOY. In patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7%
(15/547) of patients.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for
elevated serum creatinine prior to and periodically during treatment.
Administer corticosteroids for Grades 2-4 increased serum creatinine.
Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4
increased serum creatinine. In patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred
in 4.6% (25/547) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with
fatal outcome. Administer corticosteroids for Grade 3 or 4 rash.
Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For
symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient
for specialized care for assessment and treatment; if confirmed,
permanently discontinue. In patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6% (91/547) of
patients.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients
with neurologic symptoms may include, but not be limited to,
consultation with a neurologist, brain MRI, and lumbar puncture.
Withhold OPDIVO in patients with new-onset moderate to severe neurologic
signs or symptoms and evaluate to rule out other causes. If other
etiologies are ruled out, administer corticosteroids and permanently
discontinue OPDIVO for immune-mediated encephalitis. Encephalitis
occurred in one patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg
(0.2%) after approximately 4 months of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue
or withhold OPDIVO, administer high-dose corticosteroids, and, if
appropriate, initiate hormone-replacement therapy. Across clinical
trials of OPDIVO monotherapy or in combination with YERVOY, the
following clinically significant immune-mediated adverse reactions, some
with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.

If uveitis occurs in combination with other immune-mediated adverse
reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been
observed in patients receiving OPDIVO and may require treatment with
systemic steroids to reduce the risk of permanent vision loss.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in
<1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients.

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
breastfeeding during treatment with YERVOY and for 3 months following
the final dose.

Serious Adverse Reactions

In Checkmate 214, serious adverse reactions occurred in 59% of patients
receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib.
The most frequent serious adverse reactions reported in at least 2% of
patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis,
acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in
patients treated with sunitinib, they were pneumonia, pleural effusion,
and dyspnea.

Common Adverse Reactions

In Checkmate 214, the most common adverse reactions reported in at least
20% of patients treated with OPDIVO plus YERVOY (n=547) vs sunitinib
(n=535) were fatigue (58% vs 69%), rash (39% vs 25%), diarrhea (38% vs
58%), musculoskeletal pain (37% vs 40%), pruritus (33% vs 11%), nausea
(30% vs 43%), cough (28% vs 25%), pyrexia (25% vs 17%), arthralgia (23%
vs 16%), and decreased appetite (21% vs 29%).

Please see U.S. Full Prescribing Information for OPDIVO
and YERVOY,
including Boxed WARNING regarding immune-mediated adverse reactions
for YERVOY.

Bristol-Myers Squibb & Immuno-Oncology:
Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do.
Our vision for the future of cancer care is focused on researching and
developing transformational Immuno-Oncology (I-O) medicines for
hard-to-treat cancers that could potentially improve outcomes for these
patients.

We are advancing the scientific understanding of I-O through our
extensive portfolio of investigational compounds and approved agents.
Our differentiated clinical development program is studying broad
patient populations across more than 50 types of cancers with 24
clinical-stage molecules designed to target different immune system
pathways. Our deep expertise and innovative clinical trial designs
position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies
and I-O/radiation therapies across multiple tumors and potentially
deliver the next wave of therapies with a sense of urgency. Through our
leading translational capabilities, we are pioneering immune biology
research and identifying a number of potentially predictive biomarkers,
including PD-L1, TMB, MSI-H/dMMR and LAG-3, advancing the possibility of
precision medicine for more patients with cancer.

We understand making the promise of I-O a reality for the many patients
who may benefit from these therapies requires not only innovation on our
part but also close collaboration with leading experts in the field. Our
partnerships with academia, government, advocacy and biotech companies
support our collective goal of providing new treatment options to
advance the standards of clinical practice.

About Bristol-Myers Squibb’s Patient Access
Support

Bristol-Myers Squibb remains committed to providing assistance so that
cancer patients who need our medicines can access them and expedite time
to therapy.

BMS Access Support®, the Bristol-Myers Squibb patient access
and reimbursement program, is designed to help appropriate patients
initiate and maintain access to BMS medicines during their treatment
journey. BMS Access Support offers benefit investigation, prior
authorization assistance and co-pay assistance for eligible,
commercially insured patients. More information about our access and
reimbursement support can be obtained by calling BMS Access Support®
at 1-800-861-0048 or by visiting www.bmsaccesssupport.com.

About the Bristol-Myers Squibb and Ono
Pharmaceutical Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co.,
Bristol-Myers Squibb expanded its territorial rights to develop and
commercialize Opdivo globally except in Japan, South
Korea and Taiwan, where Ono had retained all rights to the compound at
the time. On July 23, 2014, Ono and Bristol-Myers Squibb further
expanded the companies’ strategic collaboration agreement to jointly
develop and commercialize multiple immunotherapies – as single agents
and combination regimens – for patients with cancer in Japan, South
Korea and Taiwan.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission
is to discover, develop and deliver innovative medicines that help
patients prevail over serious diseases. For more information about
Bristol-Myers Squibb, visit us at BMS.com
or follow us on LinkedIn,
Twitter,
YouTube
and Facebook.

Bristol-Myers Squibb 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, 2017 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.

References

1. Opdivo Prescribing Information.

Contacts

Bristol-Myers Squibb Company
Media Inquiries:
Laurel
Sacks, 609-302-5456
laurel.sacks@bms.com
or
Investors:
Tim
Power, 609-252-7509
timothy.power@bms.com
or
Bill
Szablewski, 609-252-5894
william.szablewski@bms.com

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