Pivotal Phase 3 Trials Planned for 2017 will
Evaluate Rubraca in Combination with Opdivo, Rubraca as
Monotherapy, and Opdivo as Monotherapy in First Line Maintenance
Treatment for Advanced Ovarian and Advanced Triple-Negative Breast
Cancers
Phase 2 Trial will Evaluate Opdivo in
Combination with Rubraca and Other Compounds in Metastatic
Castration-Resistant Prostate Cancer
Bristol-Myers Squibb Company (NYSE:BMY) and Clovis Oncology,
Inc. (Nasdaq:CLVS) announced the companies have entered into a
clinical collaboration agreement to evaluate the combination of
Bristol-Myers Squibb’s immunotherapy Opdivo and Clovis Oncology’s
poly (ADP-ribose) polymerase (PARP) inhibitor Rubraca in pivotal
phase 3 clinical trials in:
- Advanced ovarian
cancer: First-line maintenance treatment study to evaluate
Rubraca + Opdivo, Rubraca, Opdivo and placebo in newly diagnosed
patients with stage III/IV high-grade ovarian, fallopian tube, or
primary peritoneal cancer who have completed platinum-based
chemotherapy.
- Advanced
triple-negative breast cancers (TNBC): First-line
maintenance treatment study to evaluate Rubraca + Opdivo, Rubraca,
Opdivo and chemotherapy in patients with stage IV or recurrent
locally advanced inoperable TNBC associated with a homologous
recombination deficiency (HRD).
The collaboration will also include a Phase 2 study to evaluate
the safety and efficacy of Opdivo in combination with Rubraca in
patients with metastatic castration-resistant prostate cancer
(mCRPC). The Opdivo + Rubraca combination in mCRPC will be
conducted as an arm of a larger Bristol-Myers Squibb-sponsored
study.
Rubraca is an oral, small molecule inhibitor of PARP enzymes,
including PARP-1, PARP-2, and PARP-3, being developed for the
treatment of solid tumors associated with homologous recombination
deficiency (HRD), defined as the presence of a deleterious BRCA1 or
BRCA2 mutation, a deleterious mutation in another gene involved in
DNA damage repair, and/or a high percentage of tumor genome with
LOH, a phenotypic consequence of HRD. Opdivo is a human programmed
death receptor-1 (PD-1) blocking antibody that binds to the PD-1
receptor expressed on activated T-cells and other immune cells. The
overlap in immuno-biology linked to these agents supports the
potential for synergy of PARP inhibition and PD-1 blockade.
Preclinical evidence has demonstrated that PARP inhibition can
trigger inflammation, cell death and increase T-cell infiltration
within tumors.
“We are very enthusiastic about studying Rubraca and Opdivo in
combination, and the potential to create new treatment options for
patients with multiple tumor types, as well as for patients beyond
those with BRCA mutations,” said Patrick J. Mahaffy, President, and
CEO of Clovis Oncology. “This substantial clinical collaboration in
ovarian, triple-negative breast and prostate cancers represents a
significant effort by Clovis and Bristol-Myers Squibb to realize
that potential.”
“This clinical collaboration addresses areas of unmet medical
need where the combination of Opdivo and Rubraca may lead to an
additional treatment option for patients with difficult to treat
cancers,” said Fouad Namouni, M.D., head of Oncology Development,
Bristol-Myers Squibb. “We are committed to investigating a wide
range of oncology therapies and look forward to studying the
combination of Clovis’ PARP inhibitor and our immunotherapy.”
The planned multi-arm clinical trials will be conducted in the
U.S., Europe, and possibly additional countries. Clovis will be the
study sponsor and conducting party for the ovarian cancer study and
Bristol-Myers Squibb will be the study sponsor and conducting party
for the breast and prostate cancer studies. Specific terms of the
agreement were not disclosed. All three studies are expected to
begin before the end of 2017.
About Ovarian Cancer
According to the World Cancer Research Fund International,
ovarian cancer is the seventh most common cancer in women worldwide
(18th most common cancer overall), with 239,000 new cases diagnosed
in 2012. There are often no specific initial symptoms, and in an
estimated 80 to 85% of ovarian cancer cases, the cancer has spread
to other parts of the body before a person is diagnosed and can be
treated. Ovarian cancer ranks fifth in cancer deaths in the U.S.
and causes more deaths than any other cancer of the female
reproductive system.
About Triple-Negative Breast Cancer
Breast cancer is the most frequently diagnosed cancer in women
worldwide with nearly 1.7 million new cases diagnosed in 2012,
accounting for 25% of all new cancer cases in women according to
the International Agency for the Research of Cancer (IARC) of the
World Health Organization. More than one out of every 10 breast
cancers are found to be triple-negative, meaning the cancer does
not have the biomarkers that predict response to hormonal therapy
or therapies that target HER2 receptors. Triple negative tumors are
often aggressive and have a poorer prognosis compared
to hormone receptor-positive breast cancers.
About Castration-Resistant Prostate Cancer
Prostate cancer is the second most frequently diagnosed cancer
in men, with 1.1 million new cases diagnosed worldwide in 2012.
Unlike many early-stage prostate cancers that need normal levels of
testosterone to grow, castration-resistant prostate cancer (CRPC)
continues to grow even when the amount of testosterone in the body
is reduced to castrate levels. CRPC patients have a very high
likelihood of having or developing metastases, meaning the cancer
has spread to other areas of the body. While the 5-year survival
rate for most stages of prostate cancer is almost 100%; the 5-year
survival rate for prostate cancer that has spread to distant lymph
nodes, bones, or other organs is approximately 29%.
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 leading 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
14 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. We also continue to pioneer research that will
help facilitate a deeper understanding of the role of immune
biomarkers and how patients’ individual tumor biology can be used
as a guide for treatment decisions throughout their journey.
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 Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint
inhibitor that is designed to uniquely harness the body’s own
immune system to help restore anti-tumor immune response. By
harnessing the body’s own immune system to fight
cancer, Opdivo has become an important treatment option
across multiple cancers.
Opdivo’s leading global development program is based on
Bristol-Myers Squibb’s scientific expertise in the field of
Immuno-Oncology and includes a broad range of clinical trials
across all phases, including Phase 3, in a variety of tumor types.
To date, the Opdivo clinical development program has
enrolled more than 25,000 patients. The Opdivo trials
have contributed to gaining a deeper understanding of the potential
role of biomarkers in patient care, particularly regarding how
patients may benefit from Opdivo across the continuum of
PD-L1 expression.
In July 2014, Opdivo was the first PD-1 immune
checkpoint inhibitor to receive regulatory approval anywhere in the
world. Opdivo is currently approved in more than 60
countries, including the United States, the European Union, and
Japan. In October 2015, the
company’s Opdivo and Yervoy combination regimen was
the first Immuno-Oncology combination to receive regulatory
approval for the treatment of metastatic melanoma and is currently
approved in more than 50 countries, including the United States and
the European Union.
About Rubraca
Rubraca is an oral, small molecule inhibitor of PARP1, PARP2 and
PARP3 being developed in ovarian cancer as well as several
additional solid tumor indications. In December 2016, Rubraca
(rucaparib) tablets became the first PARP inhibitor approved by the
U.S. Food and Drug Administration (FDA) as monotherapy for
treatment of patients with deleterious BRCA mutation (germline
and/or somatic) associated advanced ovarian cancer who have been
treated with two or more prior chemotherapies.
During the fourth quarter of 2016, the Marketing Authorization
Application (MAA) submission in Europe for Rubraca in the same
ovarian cancer treatment indication was submitted and accepted for
review. By the end of October 2017, Clovis Oncology intends to
submit a supplemental New Drug Application (sNDA) in the U.S. for a
second line or later maintenance treatment indication in ovarian
cancer based on the ARIEL3 data, and in early 2018, plans to file
an MAA in Europe for the maintenance treatment indication upon
receipt of a potential approval for the treatment indication.
Studies open for enrollment or under consideration include ovarian,
prostate, breast, pancreatic, gastroesophageal, bladder, lung, and
urothelial cancers. Clovis is also developing Rubraca in patients
with mutant BRCA tumors and other DNA repair deficiencies beyond
BRCA – commonly referred to as homologous recombination
deficiencies, or HRD. Clovis holds worldwide rights for
Rubraca.
OPDIVO AND YERVOY INDICATIONS &
IMPORTANT SAFETY INFORMATION
INDICATIONS
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 the confirmatory trials.
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 wild-type unresectable or
metastatic melanoma.
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 brentuximab vedotin or after 3 or more lines of systemic
therapy that includes autologous HSCT. 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.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with recurrent or metastatic squamous cell carcinoma of the head
and neck (SCCHN) with disease progression on or after
platinum-based therapy.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with locally advanced or metastatic urothelial carcinoma who have
disease progression during or following platinum-containing
chemotherapy or have disease progression within 12 months of
neoadjuvant or adjuvant treatment with platinum-containing
chemotherapy. This indication is approved under accelerated
approval based on tumor response rate and duration of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
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
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 monotherapy, fatal cases of immune-mediated
pneumonitis have occurred. Immune-mediated pneumonitis occurred in
3.1% (61/1994) of patients. In patients receiving OPDIVO with
YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of
patients.
In Checkmate 205 and 039, pneumonitis, including interstitial
lung disease, occurred in 6.0% (16/266) of patients receiving
OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of
patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).
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 monotherapy, immune-mediated colitis
occurred in 2.9% (58/1994) of patients. In patients receiving
OPDIVO with YERVOY, immune-mediated colitis occurred in 26%
(107/407) of patients including three fatal cases.
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
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 for Grade 2 and permanently discontinue for
Grade 3 or 4 immune-mediated hepatitis. In patients receiving
OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8%
(35/1994) of patients. In patients receiving OPDIVO with YERVOY,
immune-mediated hepatitis occurred in 13% (51/407) of patients.
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 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
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 monotherapy, hypophysitis occurred
in 0.6% (12/1994) of patients. In patients receiving OPDIVO with
YERVOY, hypophysitis occurred in 9% (36/407) of patients. In
patients receiving OPDIVO monotherapy, adrenal insufficiency
occurred in 1% (20/1994) of patients. In patients receiving OPDIVO
with YERVOY, adrenal insufficiency occurred in 5% (21/407) of
patients. In patients receiving OPDIVO monotherapy, hypothyroidism
or thyroiditis resulting in hypothyroidism occurred in 9%
(171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994)
of patients receiving OPDIVO monotherapy. In patients receiving
OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 22% (89/407) of patients.
Hyperthyroidism occurred in 8% (34/407) of patients receiving
OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy,
diabetes occurred in 0.9% (17/1994) of patients. In patients
receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of
patients.
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
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 monotherapy, immune-mediated nephritis and renal
dysfunction occurred in 1.2% (23/1994) of patients. In patients
receiving OPDIVO with YERVOY, immune-mediated nephritis and renal
dysfunction occurred in 2.2% (9/407) 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 monotherapy, immune-mediated rash occurred in 9%
(171/1994) of patients. In patients receiving OPDIVO with YERVOY,
immune-mediated rash occurred in 22.6% (92/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal immune-mediated dermatitis (e.g.,
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 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. In patients receiving OPDIVO
monotherapy, encephalitis occurred in 0.2% (3/1994) of patients.
Fatal limbic encephalitis occurred in one patient after 7.2 months
of exposure despite discontinuation of OPDIVO and administration of
corticosteroids. Encephalitis occurred in one patient receiving
OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.
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. Across clinical trials of OPDIVO the following clinically
significant immune-mediated adverse reactions occurred in <1.0%
of patients receiving OPDIVO: 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), myositis, myocarditis, rhabdomyolysis, motor
dysfunction, vasculitis, and myasthenic syndrome.
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
patients receiving OPDIVO monotherapy, infusion-related reactions
occurred in 6.4% (127/1994) of patients. In patients receiving
OPDIVO with YERVOY, infusion-related reactions occurred in 2.5%
(10/407) of patients.
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 HSCT 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 037, serious adverse reactions occurred in 41% of
patients receiving OPDIVO (n=268). 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 (n=206). 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 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 (n=313) relative to the OPDIVO arm (n=313).
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 017 and 057, serious adverse reactions occurred in 46%
of patients receiving OPDIVO (n=418). The most frequent serious
adverse reactions reported in at least 2% of patients receiving
OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia,
pleural effusion, pneumonitis, and respiratory failure. In
Checkmate 025, serious adverse reactions occurred in 47% of
patients receiving OPDIVO (n=406). 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, adverse reactions leading to
discontinuation occurred in 7% and dose delays due to adverse
reactions occurred in 34% of patients (n=266). Serious adverse
reactions occurred in 26% of patients. The most frequent serious
adverse reactions reported in ≥1% of patients were pneumonia,
infusion-related reaction, pyrexia, colitis or diarrhea, pleural
effusion, pneumonitis, and rash. Eleven patients died from causes
other than disease progression: 3 from adverse reactions within 30
days of the last OPDIVO dose, 2 from infection 8 to 9 months after
completing OPDIVO, and 6 from complications of allogeneic HSCT.
In Checkmate 141, serious adverse reactions occurred in 49% of
patients receiving OPDIVO. The most frequent serious adverse
reactions reported in at least 2% of patients receiving OPDIVO were
pneumonia, dyspnea, respiratory failure, respiratory tract
infections, and sepsis. In Checkmate 275, serious adverse reactions
occurred in 54% of patients receiving OPDIVO (n=270). The most
frequent serious adverse reactions reported in at least 2% of
patients receiving OPDIVO were urinary tract infection, sepsis,
diarrhea, small intestine obstruction, and general physical health
deterioration.
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%)
reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the
most common adverse reactions (≥20%) reported with OPDIVO (n=206)
vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal
pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In
Checkmate 067, the most common (≥20%) adverse reactions in the
OPDIVO plus YERVOY arm (n=313) 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 (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%),
and nausea (28%). In Checkmate 017 and 057, the most common adverse
reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue,
musculoskeletal pain, cough, dyspnea, and decreased appetite. In
Checkmate 025, the most common adverse reactions (≥20%) reported in
patients receiving OPDIVO (n=406) vs everolimus (n=397) 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, the most common adverse reactions (≥20%) reported in
patients receiving OPDIVO (n=266) were upper respiratory tract
infection (44%), fatigue (39%), cough (36%), diarrhea (33%),
pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%)
and pruritus (20%). In Checkmate 141, the most common adverse
reactions (≥10%) in patients receiving OPDIVO were cough and
dyspnea at a higher incidence than investigator’s choice. In
Checkmate 275, the most common adverse reactions (≥ 20%) reported
in patients receiving OPDIVO (n=270) were fatigue (46%),
musculoskeletal pain (30%), nausea (22%), and decreased appetite
(22%).
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 067 - advanced melanoma alone or in combination
with YERVOY; Checkmate 037 and 066 - advanced melanoma;
Checkmate 017 - squamous non-small cell lung cancer (NSCLC);
Checkmate 057 - non-squamous NSCLC; Checkmate 025 -
renal cell carcinoma; Checkmate 205/039 - classical Hodgkin
lymphoma; Checkmate 141 – squamous cell carcinoma of the
head and neck; Checkmate 275 - urothelial carcinoma.
Please see U.S. Full Prescribing Information for OPDIVO and
YERVOY, including Boxed WARNING regarding immune-mediated
adverse reactions for YERVOY.
RUBRACA INDICATION AND IMPORTANT SAFETY
INFORMATION
Rubraca® (rucaparib) is indicated as monotherapy for the
treatment of patients with deleterious BRCA mutation (germline
and/or somatic) associated advanced ovarian cancer who have been
treated with two or more chemotherapies. Select patients for
therapy based on an FDA-approved companion diagnostic for
Rubraca.
This indication is approved under accelerated approval based on
objective response rate and duration of response. Continued
approval for this indication may be contingent upon verification
and description of clinical benefit in confirmatory trials.
Select Important Safety Information
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) was
reported in 2 of 377 (0.5%) patients with ovarian cancer treated
with Rubraca. The duration of Rubraca treatment prior to the
diagnosis of MDS/AML was 57 days and 539 days. Both patients
received prior treatment with platinum and other DNA damaging
agents.
AML was reported in 2 (<1%) patients with ovarian cancer
enrolled in a blinded, randomized trial evaluating Rubraca versus
placebo. One case of AML was fatal. The duration of treatment prior
to the diagnosis of AML was 107 days and 427 days. Both patients
had received prior treatment with platinum and other DNA damaging
agents.
Do not start Rubraca until patients have recovered from
hematological toxicity caused by previous chemotherapy
(≤ Grade 1).
Monitor complete blood count testing at baseline and monthly
thereafter. For prolonged hematological toxicities, interrupt
Rubraca and monitor blood counts weekly until recovery. If the
levels have not recovered to Grade 1 or less after 4 weeks, refer
the patient to a hematologist for further investigations, including
bone marrow analysis and blood sample for cytogenetics. If MDS/AML
is confirmed, discontinue Rubraca.
Based on its mechanism of action and findings from animal
studies, Rubraca can cause fetal harm when administered to a
pregnant woman. Apprise pregnant women of the potential risk to a
fetus. Advise females of reproductive potential to use effective
contraception during treatment and for 6 months following the
last dose of Rubraca.
Most common adverse reactions (≥ 20%; Grade 1-4) were nausea
(77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%),
constipation (40%), dysgeusia (39%), decreased appetite (39%),
diarrhea (34%), abdominal pain (32%), dyspnea (21%), and
thrombocytopenia (21%).
Most common laboratory abnormalities (≥ 35%; Grade 1-4) were
increase in creatinine (92%), increase in alanine aminotransferase
(ALT) (74%), increase in aspartate aminotransferase (AST) (73%),
decrease in hemoglobin (67%), decrease in lymphocytes (45%),
increase in cholesterol (40%), decrease in platelets (39%), and
decrease in absolute neutrophil count (35%).
Because of the potential for serious adverse reactions in
breast-fed infants from Rubraca, advise lactating women not to
breastfeed during treatment with Rubraca and for 2 weeks after the
final dose.
You may report side effects to the FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch. You may also report side effects to Clovis
Oncology, Inc. at 1-844-258-7662.
Please see RUBRACA full Prescribing Information for
additional Important Safety Information.
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 Clovis Oncology
Clovis Oncology, Inc. is a biopharmaceutical company
focused on acquiring, developing and commercializing innovative
anti-cancer agents in the U.S., Europe and additional
international markets. Clovis Oncology targets
development programs at specific subsets of cancer populations, and
simultaneously develops, with partners, diagnostic tools intended
to direct a compound in development to the population that is most
likely to benefit from its use. Clovis Oncology is
headquartered in Boulder, Colorado, and has additional offices
in San Francisco, California and Cambridge, UK.
Please visit clovisoncology.com for more information.
Clovis Oncology Forward-Looking Statement
To the extent that statements contained in this press release
are not descriptions of historical facts regarding Clovis Oncology,
they are forward-looking statements reflecting the current beliefs
and expectations of management made pursuant to the safe harbor
provisions of the Private Securities Litigation Reform Act of 1995.
Examples of forward-looking statements contained in this press
release include, among others, statements regarding our expectation
of timing for submission of the sNDA for Rubraca, filing of an MAA
for Rubraca in Europe and future development plans. Such
forward-looking statements involve substantial risks and
uncertainties that could cause our future results, performance, or
achievements to differ significantly from that expressed or implied
by the forward-looking statements. Such risks and uncertainties
include, among others, the uncertainties inherent in the clinical
development program for Rubraca in combination with Opdivo,
including the result of clinical trials, whether future study
results will be consistent with study findings to-date, the
corresponding development pathways of our companion diagnostics,
the timing of availability of data from our clinical trials and the
results of our clinical trials, the initiation, enrollment and
timing of our planned clinical trials, actions by the FDA, the
EMA or other regulatory authorities regarding whether to approve
drug applications that may be filed, as well as their decisions
that may affect drug labeling, pricing and reimbursement, and other
matters that could affect the availability or commercial potential
of our drug candidates or companion diagnostics. Clovis
Oncology does not undertake to update or revise any forward-looking
statements. A further description of risks and uncertainties can be
found in Clovis Oncology’s filings with the Securities and Exchange
Commission, including its Annual Report on Form 10-K and its
reports on Form 10-Q and Form 8-K.
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 Rubraca in combination with Opdivo, will be
successfully developed or approved for any of the indications
described in this release. 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, 2016 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.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20170731005284/en/
Bristol-Myers SquibbMedia:Lisa McCormick Lavery,
609-252-7602lisa.mccormicklavery@bms.comorKen Dominski,
609-252-5251ken.dominski@bms.comorInvestors:Tim Power,
609-252-7509timothy.power@bms.comorBill Szablewski,
609-252-5894william.szablewski@bms.comorClovis
OncologyInvestors:Anna Sussman,
303-625-5022asussman@clovisoncology.comorBreanna Burkart,
303-625-5023bburkart@clovisoncology.comorMedia:Lisa
Guiterman, 301-217-9353clovismedia@sambrown.comorChristy Curran,
615-414-8668clovismedia@sambrown.com
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