Opdivo demonstrated superior overall
survival vs. dacarbazine with a one-year survival rate of 73% vs.
42% and a 58% decrease in the risk of death (Hazard Ratio [HR] =
0.42, P<0.0001)
Objective response rate was significantly
higher for Opdivo than dacarbazine (40% vs.14%), including a higher
percentage of complete responses (7.6% vs. 1%)
Safety and tolerability were well
characterized with fewer treatment-related Grade 3/4 adverse events
observed with Opdivo than dacarbazine (11.7% vs. 17.6%)
Bristol-Myers Squibb Company (NYSE:BMY) today announced results
from CheckMate -066, a Phase 3 randomized double blind study,
comparing Opdivo, an investigational PD-1 immune checkpoint
inhibitor, to the chemotherapy dacarbazine (DTIC) in patients with
treatment naïve BRAF wild-type advanced melanoma (n=418). The study
met the primary endpoint of overall survival (OS) with the median
OS not reached for Opdivo vs. 10.8 months for DTIC. The one-year
survival rate was 73% for Opdivo vs. 42% for DTIC and there was a
58% decrease in the risk of death for patients treated with Opdivo
(Hazard Ratio for death [HR]: 0.42, P<0.0001). This survival
advantage was also observed in Opdivo-treated patients in both
PD-L1 positive and PD-L1 negative patients. Findings from CheckMate
-066 were published today in The New England Journal of Medicine
and presented during an oral session at the Society for Melanoma
Research 2014 International Congress in Zurich, Switzerland.
“The results from CheckMate -066 are significant as they
represent the first time a PD-1 immune checkpoint inhibitor has
shown a survival benefit in a randomized Phase 3 trial,” said Prof.
Caroline Robert, Professor of Dermatology, Head of the Dermatology
Unit, Institute Gustave Roussy and lead author of the New England
Journal of Medicine manuscript. “This represents a major milestone
in the study of treatment naïve patients with wild-type BRAF
advanced melanoma.”
Safety was reported in all patients treated in the Opdivo and
DTIC arms. Fewer discontinuations were observed with Opdivo than
DTIC (6.8% vs. 11.7%) as well as for treatment-related Grade 3/4
adverse events (AEs) (11.7% vs. 17.6%), which were managed using
established safety algorithms. The most common Opdivo
treatment-related AEs were fatigue (20%), pruritus (17%), and
nausea (16.5%). Common adverse events in the DTIC arm were
consistent with those in previous reports and included nausea
(41.5%), vomiting (21%), fatigue (15%), diarrhea (15%) and
hematological toxicities. No deaths were attributed to study drug
toxicity in either arm.
“Treatment naïve advanced melanoma patients who received
nivolumab in this study had clinically important improvements in
both overall survival and objective response rates compared to
DTIC,” said Georgina V. Long, M.D., Ph.D., Melanoma Institute
Australia & the University of Sydney and Mater Hospital and
presenter of the results. “This study also confirms our hypothesis
on the role of PD-L1 expression in advanced melanoma. In CheckMate
-066, both PD-L1 positive and negative patients treated with
nivolumab had a clear survival benefit.”
“Results from this Phase 3 Opdivo trial with a survival endpoint
build upon the pioneering science that led to the introduction of
Yervoy in 2011 and underscore our strategic commitment to provide
more patients with the potential opportunity for long-term
survival,” said Michael Giordano, senior vice president, head of
Development, Oncology, Bristol-Myers Squibb. “And, we continue to
develop our immuno-oncology portfolio across the continuum of
melanoma and multiple other cancers as single agents and as part of
combination regimens.”
Bristol-Myers Squibb has proposed the
name Opdivo (pronounced op-dee-voh), which, if approved
by health authorities, will serve as the trademark for
nivolumab.
About the CheckMate -066 Trial
Design
CheckMate -066 is a Phase 3 randomized, double-blind study of
patients with treatment naïve BRAF wild-type unresectable Stage III
and IV melanoma. The trial enrolled 418 patients who were
randomized to receive either Opdivo 3 mg/kg every two weeks (n=210)
or DTIC 1000 mg/m2 every three weeks (n=208). Treatment continued
until there was disease progression or an unacceptable level of
toxicity. Thirty-eight percent of patients in the DTIC arm received
Yervoy (ipilimumab) after stopping study treatment. All randomized
patients were followed for up to 16.7 months at the time of
database lock. The primary endpoint was OS. Secondary endpoints
included progression free survival (PFS), objective response rate
(ORR) by RECIST v1.1 criteria and PD-L1 expression as a predictive
biomarker of OS. PD-L1 positivity was defined as at least 5% of
tumor cells showing cell-surface PD-L1 staining. The study, which
was designed in consultation with the Committee for Medicinal
Products for Human Use (CHMP), was primarily conducted in countries
where DTIC is a commonly-used treatment in the first-line setting,
including Canada, Europe and Australia, but not at U.S. trial
sites. On June 24, 2014, Bristol-Myers Squibb announced that
CheckMate -066 was stopped early because an analysis conducted by
the independent Data Monitoring Committee showed evidence of
superior OS in patients receiving Opdivo compared to the control
arm, DTIC. As a result, patients in the trial were unblinded and
allowed to receive Opdivo. However, the results reported today are
from the double-blind portion of the study before the
amendment.
Detailed Study Results
Median OS was not reached for patients treated with Opdivo and
was 10.8 months for DTIC (95% CI 9.3–12.1). The one-year survival
rate was 73% for Opdivo (95% CI = 66-79) vs. 42% for DTIC (95% CI =
33-51). There was a 58% decrease in the risk of death for patients
treated with Opdivo (Hazard Ratio for death [HR]: 0.42; 99.79% CI =
0.25-0.73; P<0.0001). Median PFS was 5.1 months and 2.2 months,
respectively (HR: 0.43; 95% CI = 0.34–0.56; P < 0.0001).
ORR was also significantly higher for Opdivo than DTIC (40% vs.
14%, p<0.0001). Complete responses were observed in 7.6% of
Opdivo-treated patients vs. 1% for DTIC. Median duration of
response was not reached for Opdivo responders and was six months
for DTIC (95% CI, 3.0–not estimable). Responses were ongoing in 86%
of Opdivo responders compared to 51% for DTIC responders.
In both the PD-L1 positive and PD-L1 negative/indeterminate
subgroups, Opdivo-treated patients had improved OS vs. DTIC
(unstratified HR 0.30, 95% CI, 0.15-0.60 in PD-L1 positive
patients; 0.48, 95% CI 0.32-0.71 in PD-L1 negative/indeterminate
patients). Median OS was not reached in either PD-L1 subgroup in
the Opdivo arm. In the DTIC arm, mOS was slightly longer in the
PD-L1 positive subgroup (12 vs. 10 months).
Safety was reported in all patients treated in the Opdivo and
DTIC arms. The incidence of any-grade treatment-related AEs was
similar between the Opdivo and DTIC groups (74.3% and 75.6%,
respectively). However, fewer treatment-related Grade 3/4 AEs were
observed with Opdivo than DTIC (11.7% vs. 17.6%), which were
managed using established safety algorithms, and there were fewer
treatment discontinuations (6.8% vs. 11.7%). The frequency of Grade
3/4 treatment-related serious AEs was similar between the Opdivo
and DTIC group (5.8% and 5.9%, respectively). The most common
Opdivo treatment-related AEs were fatigue (20%), pruritus (17%),
and nausea (16.5%). Common AEs in the DTIC arm were consistent with
those in previous reports and included nausea (41.5%), vomiting
(21%), fatigue (15%), diarrhea (15%) and hematological toxicities.
No deaths were attributed to study drug toxicity in either arm.
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 an investigational, fully-human
PD-1 immune checkpoint inhibitor that binds to the checkpoint
receptor PD-1 (programmed death-1) expressed on activated
T-cells.
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. Among
these are several potentially registrational trials in non-small
cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC),
head and neck cancer, glioblastoma and non-Hodgkin lymphoma.
In 2012, the FDA granted Fast Track designation for Opdivo in
NSCLC, melanoma and RCC. In April 2014, the company initiated a
rolling submission with the FDA for Opdivo in third-line
pre-treated squamous cell NSCLC and expects to complete the
submission by year-end. The FDA granted Opdivo Breakthrough Therapy
Designation in May 2014 for the treatment of patients with Hodgkin
lymphoma after failure of autologous stem cell transplant and
brentuximab. On July 4, Ono Pharmaceutical Co. announced that
Opdivo received manufacturing and marketing approval in Japan for
the treatment of patients with unresectable melanoma, making Opdivo
the first PD-1 immune checkpoint inhibitor to receive regulatory
approval anywhere in the world. On September 26, Bristol-Myers
Squibb announced that the FDA accepted for priority review the
Biologics License Application for previously treated advanced
melanoma, and the Prescription Drug User Fee Act goal date for a
decision is March 30, 2015. The FDA also granted Opdivo
Breakthrough Therapy status for this indication. In the European
Union, the European Medicines Agency (EMA) has validated for review
the Marketing Authorization Application for Opdivo in advanced
melanoma. The application has also been granted accelerated
assessment by the EMA’s CHMP. The EMA also validated for review the
MAA for nivolumab in NSCLC.
About Advanced 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 2012, an estimated 232,130
melanoma cases were diagnosed globally. Melanoma is mostly curable
when treated in its early stages. However, in its late stages, the
average survival rate has historically been just six months with a
one-year mortality rate of 75 percent, making it one of the most
aggressive forms of cancer.
Immuno-Oncology at Bristol-Myers
Squibb
Surgery, radiation, cytotoxic or targeted therapies have
represented the mainstay of cancer treatment over the last several
decades, but long-term survival and a positive quality of life have
remained elusive for many patients with advanced disease.
To address this unmet medical need, Bristol-Myers Squibb is
leading advances in the innovative field of immuno-oncology, which
involves agents whose primary mechanism is to work directly with
the body’s immune system to fight cancer. The company is exploring
a variety of compounds and immunotherapeutic approaches for
patients with different types of cancer, including researching the
potential of combining immuno-oncology agents that target different
and complementary pathways in the treatment of cancer.
Bristol-Myers Squibb is committed to advancing the science of
immuno-oncology, with the goal of changing survival expectations
and the way patients live with cancer.
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, Bristol-Myers Squibb
and ONO PHARMACEUTICAL CO 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 pharmaceutical 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.
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 will receive regulatory approval in the U.S. or, if
approved, that it will become a commercially successful product.
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, 2013 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 CompanyMedia:Sarah Koenig,
609-252-4145sarah.koenig@bms.comorChrissy Trank,
609-419-5497Christina.trank@bms.comorInvestors:Ranya Dajani,
609-252-5330ranya.dajani@bms.comorRyan Asay,
609-252-5020ryan.asay@bms.com
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