Five-year follow-up analysis from Phase 1 CA209-004 study provides
evidence of long-term survival following discontinuation of treatment in
patients with advanced melanoma
Analyses from Phase 3 CheckMate -067 study provide new long-term
quality of life data on Opdivo alone and in combination
with Yervoy
PRINCETON, N.J.–(BUSINESS WIRE)–$BMY #ASCO19—Bristol-Myers
Squibb Company (NYSE: BMY) today announced updated results from
studies evaluating Opdivo (nivolumab) and Yervoy (ipilimumab),
alone or in combination, in patients with advanced or metastatic
melanoma. These analyses (Abstracts #9533, #9568 and #9551) will be
featured on Monday, June 3 from 1:15-4:15 PM CDT at the American Society
of Clinical Oncology 2019 Annual Meeting in Chicago.
Five-Year Analysis from Phase 1 CA209-004 Study
A five-year analysis of the Phase 1 CA209-004 study, the longest
follow-up for the Opdivo plus Yervoy combination in
patients with previously treated or untreated advanced melanoma to date,
showed that with a median follow-up of 43.1 months (range: 0.9-76.7) in
all patients, at four years or longer, overall survival (OS) rates were
stable at 57% (95% Confidence Internal [CI]: 47, 67). The three-year OS
rate following discontinuation of therapy was 56% (95% CI: 46, 66). The
study also showed long-term survival outcomes with Opdivo plus Yervoy,
regardless of BRAF or lactate dehydrogenase (LDH) status, with
four-year OS rates of 62% (95% CI: 48, 74) versus 49% (95% CI: 32, 65)
for patients with normal and elevated LDH, respectively, and four-year
OS rates of 54% (95% CI: 41, 65) and 61% (95% CI: 38, 77) for patients
with wild-type and mutant BRAF tumors, respectively. The overall
safety of the combination was consistent with previously reported
studies of these medicines in patients with advanced melanoma.
New Analyses from Phase 3 CheckMate -067 Study
An analysis exploring long-term quality of life (QoL) and symptom burden
in the Phase 3 CheckMate -067 study found that QoL was maintained during
the treatment-free interval (TFI) – the period where a patient is off
study treatment and free of subsequent therapy – in patients with
previously untreated unresectable or metastatic melanoma following
discontinuation of therapy with Opdivo or Opdivo plus Yervoy.
Patient reported outcome (PRO) scores were maintained from last
on-treatment visit to follow-up 1 (30 days after the last dose) or
follow-up 2 (84 days after follow-up 1) for patients who discontinued
treatment. PRO scores remained stable beyond follow-up 2 for the
EQ-5D-3L (measures of mobility, self-care, usual activities,
pain/discomfort and anxiety/depression), which were collected at
survival follow-up visits every three months in the first year and then
every six months.
Finally, a four-year analysis from the CheckMate -067 study of Opdivo and
Yervoy, alone or in combination, in patients with previously
untreated unresectable or metastatic melanoma, showed that
patient-reported QoL and symptoms were maintained from baseline during
extended treatment. Of 813 patients included in the PRO analysis
population, QoL – including an assessment of functioning and symptom
burden – was maintained for the duration of treatment and in follow-up,
with no sustained clinically meaningful deterioration in any treatment
arm.
“These latest results provide further support for the long-term
scientific rationale for combining Opdivo and Yervoy for
the treatment of advanced melanoma,” said Arvin Yang, M.D., Ph.D.,
development lead, melanoma and genitourinary cancers, Bristol-Myers
Squibb. “We will continue to evaluate the combination in these patients,
as it also provides us with a wealth of valuable scientific information
on the impact of immuno-oncology therapy in this population.”
“Given the significant impact of treatment with Opdivo, alone or
in combination with Yervoy, we’re able to gain new insights into
the quality of life benefits of these immuno-oncology therapies,” said
John O’Donnell, MPP, Ph.D., Vice President, Worldwide Health Economics
and Outcomes Research, Bristol-Myers Squibb. “What we saw in multiple
analyses of CheckMate -067 is that quality of life was maintained
throughout the course of treatment and follow-up and, as important,
these benefits were maintained when the patients were off therapy.”
About CA209-004
CA209-004 is a Phase 1b, open-label, multicenter, multidose,
dose-finding study of Opdivo in combination with Yervoy in
patients with previously treated or untreated advanced malignant
melanoma. The trial evaluated different dosing schedules for the Opdivo
plus Yervoy regimen, including Opdivo plus
Yervoy every three weeks (Q3W) for four doses, followed by Opdivo Q3W
for four doses (Cohorts 1, 2, 2a, and 3) (n=53), or Opdivo 1
mg/kg and Yervoy 3 mg/kg Q3W for four doses followed by Opdivo 3
mg/kg every two weeks for up to 96 weeks (Cohort 8) (n=41). Forty
percent of patients in Cohorts 1-3 and 51% of patients in Cohort 8 were
previously treated. Patients were followed for the primary endpoint of
safety (based on adverse event reports and the results of clinical
laboratory tests, immune safety tests, physical examinations, vital sign
measurements, Eastern Cooperative Oncology Group [ECOG] performance
status, and electrocardiogram evaluations) and the secondary endpoints
of response and progression-free survival (PFS) for up to 2.5 years,
then for the survival exploratory endpoint for up to an additional 3
years, for a maximum study participation of 5.5 years.
About CheckMate -067
CheckMate -067 is a Phase 3, double-blind, randomized trial that
evaluated the combination of Opdivo plus Yervoy or Opdivo
monotherapy versus Yervoy monotherapy in 945 patients with
previously untreated advanced melanoma. Patients in the combination
group (n=314) received Opdivo 1 mg/kg plus Yervoy 3 mg/kg
(Q3W) for four doses followed by Opdivo 3 mg/kg every two weeks
(Q2W). Patients in the Opdivo monotherapy group (n=316) received Opdivo
3 mg/kg Q2W plus placebo. Patients in the Yervoy monotherapy
group (n=315) received Yervoy 3 mg/kg every three weeks for four
doses plus placebo. Patients were treated until progression or
unacceptable toxic effects. Overall survival (OS) and progression-free
survival (PFS) were co-primary endpoints of the trial. Secondary
endpoints included objective response rates (ORR), efficacy by tumor
PD-L1 expression level and safety.
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 other organs. The
incidence of melanoma has been increasing steadily for the last 30
years. In the United States, 91,270 new diagnoses of melanoma and more
than 9,320 related deaths are estimated for 2018. Globally, the World
Health Organization estimates that by 2035, melanoma incidence will
reach 424,102, with 94,308 related deaths. Melanoma is mostly curable
when treated in its very early stages; however, survival rates are
roughly halved if regional lymph nodes are involved. Patients in the
United States diagnosed with advanced melanoma classified as Stage IV
historically have a five-year survival rate of 15% to 20% and 10-year
survival of about 10% to 15%.
Bristol-Myers Squibb: Advancing Oncology
Research
At Bristol-Myers Squibb, patients are at the center of everything we do.
The focus of our research is to increase quality, long-term survival for
patients and make cure a possibility. Through a unique multidisciplinary
approach powered by translational science, we harness our deep
scientific experience in oncology and Immuno-Oncology (I-O) research to
identify novel treatments tailored to individual patient needs. Our
researchers are developing a diverse, purposefully built pipeline
designed to target different immune system pathways and address the
complex and specific interactions between the tumor, its
microenvironment and the immune system. We source innovation internally,
and in collaboration with academia, government, advocacy groups and
biotechnology companies, to help make the promise of transformational
medicines, like I-O, a reality for patients.
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 treated more than 35,000
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 65 countries, including the United
States, the European Union, Japan and China. 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.
U.S. FDA-APPROVED INDICATIONS FOR OPDIVO®
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with unresectable or metastatic melanoma.
OPDIVO® (nivolumab), in combination with YERVOY®
(ipilimumab), is indicated for the treatment of patients with
unresectable or metastatic melanoma.
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 metastatic small cell lung cancer (SCLC) with progression
after platinum-based chemotherapy and at least one other line of
therapy. This indication is approved under accelerated approval based on
overall response rate and duration of response. 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 advanced renal cell carcinoma (RCC) who have received
prior anti-angiogenic therapy.
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® (nivolumab) is indicated for the treatment of adult
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.
OPDIVO® (nivolumab), as a single agent, is indicated for the
treatment of adult and pediatric (12 years and older) patients with
microsatellite instability-high (MSI-H) or mismatch repair deficient
(dMMR) metastatic colorectal cancer (CRC) that has progressed following
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This
indication is approved under accelerated approval based on overall
response rate and duration of response. 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 adults and pediatric
patients 12 years and older with microsatellite instability-high (MSI-H)
or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC)
that has progressed following treatment with a fluoropyrimidine,
oxaliplatin, and irinotecan. This indication is approved under
accelerated approval based on overall response rate and duration of
response. 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 hepatocellular carcinoma (HCC) who have been previously
treated with sorafenib. 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.
OPDIVO® (nivolumab) is indicated for the adjuvant treatment
of patients with melanoma with involvement of lymph nodes or metastatic
disease who have undergone complete resection.
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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated
pneumonitis occurred in 6% (25/407) of patients. In RCC patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated
pneumonitis occurred in 4.4% (24/547) of patients. In MSI-H/dMMR mCRC
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated
pneumonitis occurred in 1.7% (2/119) 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 1 mg/kg with YERVOY 3 mg/kg,
immune-mediated colitis occurred in 26% (107/407) of patients including
three fatal cases. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY
1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of
patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated colitis occurred in 7% (8/119) 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
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. For patients without HCC, withhold OPDIVO for Grade 2 and
permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC,
withhold OPDIVO and administer corticosteroids if AST/ALT is within
normal limits at baseline and increases to >3 and up to 5 times the
upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at
baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT
is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10
times the ULN. Permanently discontinue OPDIVO and administer
corticosteroids if AST or ALT increases to >10 times the ULN or total
bilirubin increases >3 times the ULN. In patients receiving OPDIVO
monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of
patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg,
immune-mediated hepatitis occurred in 13% (51/407) of patients. In RCC
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated
hepatitis occurred in 7% (38/547) of patients. In MSI-H/dMMR mCRC
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated
hepatitis occurred in 8% (10/119) of patients.
In Checkmate 040, immune-mediated hepatitis requiring systemic
corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.
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 1 mg/kg with YERVOY
3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In RCC
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis
occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated
hypophysitis occurred in 3.4% (4/119) of patients. In patients receiving
OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of
patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg,
adrenal insufficiency occurred in 5% (21/407) of patients. In RCC
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal
insufficiency occurred in 7% (41/547) of patients. In MSI-H/dMMR mCRC
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal
insufficiency occurred in 5.9% (7/119) 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 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or
thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of
patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving
this dose of OPDIVO with YERVOY. In RCC 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 MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY
1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism
occurred in 15% (18/119) of patients. Hyperthyroidism occurred in 12%
(14/119) of patients. In patients receiving OPDIVO monotherapy, diabetes
occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO 1
mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
diabetes occurred in 2.7% (15/547) 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. Six of the 9 patients were hospitalized for severe
endocrinopathies.
Immune-Mediated Nephritis and Renal Dy
Contacts
Bristol-Myers Squibb Company
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Van Zanten
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Investors:
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Power
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timothy.power@bms.com