First approval of Opdivo in the United
States
Bristol-Myers Squibb Company (NYSE:BMY) today announced that the
U.S. Food and Drug Administration (FDA) approved Opdivo (nivolumab)
injection, for intravenous use. Opdivo is a human programmed death
receptor-1 (PD-1) blocking antibody indicated for the treatment of
patients with unresectable or metastatic melanoma and disease
progression following Yervoy (ipilimumab) and, if BRAF V600
mutation positive, a BRAF inhibitor. This indication is approved
under accelerated approval based on tumor response rate and
durability of response. Continued approval for this indication may
be contingent upon verification and description of clinical benefit
in the confirmatory trials. Metastatic melanoma is the deadliest
form of skin cancer, and despite recent advances, there are limited
treatment options available for patients who have been previously
treated with approved agents.
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“Bristol-Myers Squibb is pleased to be able to offer an
important new option for patients who have progressed following
treatment for unresectable or metastatic melanoma, which is one of
the most aggressive forms of cancer,” said Lamberto Andreotti,
chief executive officer, Bristol-Myers Squibb. “The approval of
Opdivo, the latest breakthrough medicine from our immuno-oncology
pipeline, demonstrates our company’s commitment to meeting the
needs of these patients, and to leading advances in the science of
immuno-oncology.”
Opdivo is associated with immune-mediated: pneumonitis, colitis,
hepatitis, nephritis and renal dysfunction, hypothyroidism and
hyperthyroidism, other adverse reactions; and embryofetal toxicity.
Please see the Important Safety Information section below.
The company expects to begin shipping Opdivo within one to two
weeks of today’s approval.
Opdivo Delivered A Response Rate of 32%
Opdivo is the only PD-1 that has demonstrated efficacy in a
Phase 3, pivotal clinical trial with advanced melanoma in patients
who had been previously treated and progressed with Yervoy and, if
BRAF mutation positive, a BRAF inhibitor. The efficacy of Opdivo
was evaluated based on a single-arm, non-comparative planned
interim analysis of the first 120 patients who received Opdivo with
a minimum of 6 months follow-up in the Phase 3 CheckMate -037
trial.
Opdivo achieved a 32% (95% CI: 23, 41) response rate (38/120)
with a dosing strength and frequency of 3 mg/kg intravenously over
60 minutes every 2 weeks. 3% of patients (4/120) achieved a
complete response, and 28% (34/120) achieved a partial response. Of
38 patients with responses, 33 patients (87%) had ongoing responses
with durability of response ranging from 2.6+ to 10+ months, which
included 13 patients with ongoing responses of 6 months or longer.
Responses to Opdivo were demonstrated in both patients with and
without BRAF mutation.
The safety profile of Opdivo has been demonstrated in the
pivotal, Phase 3 CheckMate-037 trial. 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. The most common adverse reaction (≥20%) reported with
Opdivo was rash (21%). Please see the Important Safety Information
section below.
“The approval of Opdivo gives patients and physicians an
important new treatment option for a population where they were
once very limited,” said Jeffrey S. Weber, MD, Ph.D., director of
the Donald A. Adam Comprehensive Melanoma Research Center at
Moffitt Cancer Center. “For the first time, a PD-1 blocking
antibody has shown a response rate of 32% in a Phase 3 randomized
clinical trial of patients with unresectable or metastatic
melanoma, who have progressed following first line therapy.”
Efficacy was evaluated in a single-arm, non-comparative, planned
interim analysis of the first 120 patients who received Opdivo in
the CheckMate -037 trial in whom the minimum duration of follow up
was 6 months.
“The emergence of effective immuno-oncology therapies that are
capable of successfully treating metastatic melanoma has
reinvigorated the field of cancer immunology with an optimism that
immune based treatments will play a central role in therapeutic
strategies for cancer patients,” said Jill O’Donnell-Tormey, Ph.D.,
CEO and director of Scientific Affairs at the Cancer Research
Institute, a nonprofit organization dedicated to advancing the
science of cancer immunology.
About the CheckMate -037 Trial
CheckMate -037 was a randomized, Phase 3 trial evaluating Opdivo
3 mg/kg (n=268), administered every two weeks, or chemotherapy
(n=102) (investigator's choice of either single-agent dacarbazine
1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6
every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks) in patients
with advanced melanoma who had been previously treated and
progressed with Yervoy and, if BRAF mutation positive, a BRAF
inhibitor. No premedication is required with Opdivo.
The primary objective of this analysis of the CheckMate -037
trial was Objective Response Rate (ORR). CheckMate -037 included 90
participating trial sites in 14 countries, and included both
institutional and community practice centers. The clinical study is
ongoing to determine whether there is an overall survival
benefit.
In the Opdivo treated patients (n=120), 76% of patients had M1C
disease, 18% of patients had a history of brain metastases, and 56%
of patients had elevated LDH levels. The median age of patients was
58. 22% of patients were BRAF V600 mutation positive.
Distinct Immune Pathway
Opdivo is approved for use in patients previously treated with
Yervoy. Although both treatments are immunotherapies, PD-1 and
CTLA-4 are distinct pathways.
About Bristol-Myers Squibb’s Support Programs for
Opdivo
As the leader in metastatic melanoma, Bristol-Myers Squibb
remains committed to helping patients through treatment with
Opdivo. For support and assistance, patients and physicians may
call 1-855-OPDIVO-1. This number offers one-stop access to a range
of support services for patients and healthcare professionals
alike.
About Bristol-Myers Squibb’s Access Support
Bristol-Myers Squibb is committed to helping patients access
Opdivo and offers numerous programs to support patient and
providers in gaining access. BMS Access Support®, the Bristol-Myers
Squibb Reimbursement Services program, is designed to support
access to BMS medicines and expedite time to therapy through
reimbursement support including Benefit Investigations, Prior
Authorization Facilitation, Appeals Assistance, and assistance for
patient out-of-pocket costs. BMS Access Support assists patients
and providers throughout the treatment journey – whether it is at
initial diagnosis or in support of transition from a clinical
trial. More information about our reimbursement support services
can be obtained by calling 1-800-861-0048 or by visiting
www.bmsaccesssupport.com. For healthcare providers seeking Opdivo
specific reimbursement information, please visit the BMS Access
Support Product section by
visiting www.bmsaccesssupportoncology.com.
About the Opdivo Clinical Development Program
Bristol-Myers Squibb has a broad, global development program to
study Opdivo in multiple tumor types consisting of more than 50
trials – as monotherapy or in combination with other therapies – in
which more than 7,000 patients have been enrolled worldwide.
IMPORTANT SAFETY INFORMATION
Immune-Mediated Pneumonitis
- Severe pneumonitis or interstitial lung
disease, including fatal cases, occurred with OPDIVO treatment.
Across the clinical trial experience in 574 patients with solid
tumors, fatal immune-mediated pneumonitis occurred in 0.9% (5/574)
of patients receiving OPDIVO; no cases occurred in Trial 1. In
Trial 1, pneumonitis, including interstitial lung disease, occurred
in 3.4% (9/268) of patients receiving OPDIVO and none of the 102
patients receiving chemotherapy. Immune-mediated pneumonitis
occurred in 2.2% (6/268) of patients receiving OPDIVO; one with
Grade 3 and five with Grade 2. Monitor patients for signs and
symptoms of pneumonitis. Administer corticosteroids for Grade 2 or
greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or
4 and withhold OPDIVO until resolution for Grade 2.
Immune-Mediated Colitis
- In Trial 1, diarrhea or colitis
occurred in 21% (57/268) of patients receiving OPDIVO and 18%
(18/102) of patients receiving chemotherapy. Immune-mediated
colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five
with Grade 3 and one with Grade 2. Monitor patients for
immune-mediated colitis. Administer corticosteroids for Grade 2 (of
more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for
Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or
recurrent colitis upon restarting OPDIVO.
Immune-Mediated Hepatitis
- In Trial 1, there was an increased
incidence of liver test abnormalities in the OPDIVO-treated group
as compared to the chemotherapy-treated group, with increases in
AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs
5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis
occurred in 1.1% (3/268) of patients receiving OPDIVO; two with
Grade 3 and one with Grade 2. 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 immune-mediated hepatitis.
Immune-Mediated Nephritis and Renal Dysfunction
- In Trial 1, there was an increased
incidence of elevated creatinine in the OPDIVO-treated group as
compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or
3 immune-mediated nephritis or renal dysfunction occurred in 0.7%
(2/268) of patients. Monitor patients for elevated serum creatinine
prior to and periodically during treatment. For Grade 2 or 3 serum
creatinine elevation, withhold OPDIVO and administer
corticosteroids; if worsening or no improvement occurs, permanently
discontinue OPDIVO. Administer corticosteroids for Grade 4 serum
creatinine elevation and permanently discontinue OPDIVO.
Immune-Mediated Hypothyroidism and Hyperthyroidism
- In Trial 1, Grade 1 or 2 hypothyroidism
occurred in 8% (21/268) of patients receiving OPDIVO and none of
the 102 patients receiving chemotherapy. Grade 1 or 2
hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO
and 1% (1/102) of patients receiving chemotherapy. Monitor thyroid
function prior to and periodically during treatment. Administer
hormone replacement therapy for hypothyroidism. Initiate medical
management for control of hyperthyroidism.
Other Immune-Mediated Adverse Reactions
- In Trial 1, the following clinically
significant, immune-mediated adverse reactions occurred in less
than 1% of OPDIVO-treated patients: pancreatitis, uveitis,
demyelination, autoimmune neuropathy, adrenal insufficiency, and
facial and abducens nerve paresis. Across clinical trials of OPDIVO
administered at doses 3 mg/kg and 10 mg/kg, additional clinically
significant, immune-mediated adverse reactions were identified:
hypophysitis, diabetic ketoacidosis, hypopituitarism,
Guillian-Barré syndrome, and myasthenic syndrome. Based on the
severity of adverse reaction, withhold OPDIVO, administer high-dose
corticosteroids, and, if appropriate, initiate hormone- replacement
therapy.
Embryofetal Toxicity
- Based on its mechanism of action,
OPDIVO 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 OPDIVO and for at least 5 months after the
last dose of OPDIVO.
Lactation
- It is not known whether OPDIVO 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 OPDIVO, advise women to
discontinue breastfeeding during treatment.
Serious Adverse Reactions
- 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.
Common Adverse Reactions
The most common adverse reaction (≥20%) reported with OPDIVO was
rash (21%).
Please see US Full Prescribing Information for
OPDIVO.
About Metastatic Melanoma
Melanoma is a form of skin cancer characterized by the
uncontrolled growth of pigment-producing cells (melanocytes)
located in the skin. Metastatic melanoma is the deadliest form of
the disease, and occurs when cancer spreads beyond the surface of
the skin to the other organs, such as the lymph nodes, lungs, brain
or other areas of the body. The incidence of melanoma has been
increasing for at least 30 years. In 2014, an estimated 76,100
melanoma cases will be diagnosed in the U.S. Melanoma is mostly
curable when treated in its early stages. However, in its late
stages, the average survival rate is just 6 months with a 1-year
survival of 25.5%, making it one of the most aggressive forms of
cancer.
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 www.bms.com, or
follow us on Twitter at http://twitter.com/bmsnews.
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