Bristol-Myers Squibb Announces First Presentation of Results for Opdivo (nivolumab) Plus Yervoy (ipilimumab) Combination in Advanced Hepatocellular Carcinoma at ASCO 2019
June 3, 2019
Opdivo plus Yervoy yielded objective response rate of 31%
and median duration of response of 17.5 months
Data demonstrate potential of Immuno-Oncology combination in
fourth most common cause of cancer death worldwide
PRINCETON, N.J.–(BUSINESS WIRE)–$BMY #ASCO19—Bristol-Myers
Squibb Company (NYSE: BMY) today announced first results from the Opdivo
(nivolumab) plus Yervoy (ipilimumab) cohort of the Phase 1/2
CheckMate -040 study, evaluating the Immuno-Oncology combination in
patients with advanced hepatocellular carcinoma (HCC) previously treated
with sorafenib. With a minimum follow-up of 28 months, the blinded
independent central review (BICR) objective response rate (ORR) was 31%
per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST
v1.1). At the time of data cutoff, the median duration of response (DoR)
was 17.5 months (95% CI: 11.1, N/A). These data (Abstract #4012) will be
featured at the American Society of Clinical Oncology (ASCO) Annual
Meeting 2019 in Chicago in a poster display on Monday, June 3 from 8-11
AM CDT, and in a poster discussion from 3-4:30 PM CDT.
The study randomized patients into three arms evaluating three different
dosing schedules of the Opdivo plus Yervoy combination: Opdivo 1
mg/kg and Yervoy 3 mg/kg every three weeks (Q3W) for
four cycles, followed by Opdivo 240 mg every two weeks
(Q2W) (Arm A); Opdivo 3 mg/kg and Yervoy 1
mg/kg Q3W for four cycles, followed by Opdivo 240 mg Q2W (Arm B);
or Opdivo 3 mg/kg Q2W and Yervoy 1 mg/kg
every six weeks (Q6W) (Arm C).
Meaningful responses were observed across treatment arms. Patients in
Arm A experienced the longest median overall survival (OS) of the cohort
at 22.8 months (95% CI: 9.4, N/A) and a 30-month OS rate of 44%
(95% CI: 29.5, 57). Opdivo and Yervoy demonstrated a
disease control rate (DCR) of 54%, 43% and 49% per BICR using RECIST
v1.1 across treatment arms A, B and C, respectively. Across the cohort,
5% of patients experienced a complete response and 26% experienced a
partial response. Patient responses were achieved regardless of baseline
tumor PD-L1 status. Opdivo plus Yervoy showed an
acceptable safety profile and the addition of Yervoy yielded no
new safety signals in any treatment arm.
“Hepatocellular carcinoma continues to represent a significant unmet
need, as it is often diagnosed in the advanced stage where treatment
options are limited and do not currently include the potential of an
Immuno-Oncology combination,” said Thomas Yau, M.D., Clinical Associate
Professor, Department of Medicine, The University of Hong Kong. “These
results indicate the addition of Yervoy to Opdivo elicits
promising clinical responses in patients with advanced HCC, reiterating
the important potential impact of this combination research.”
“Opdivo has been an important treatment option for patients with
advanced HCC since 2017, when it became the first Immuno-Oncology agent
FDA approved for this aggressive cancer,” said Ian M. Waxman, M.D.,
development lead, Gastrointestinal Cancers, Bristol-Myers Squibb. “We
are encouraged by the efficacy observed with the Opdivo plus Yervoy
combination in this cohort of CheckMate -040 and are grateful to the
patients and investigators for their participation in this study,
without whom this progress would not be possible.”
About CheckMate -040
CheckMate -040 (NCT01658878) is an ongoing Phase 1/2, open-label,
multi-cohort study investigating Opdivo or Opdivo-based
combinations in patients with advanced HCC with and without chronic
viral hepatitis who are naïve, intolerant to or who have progressed
during sorafenib therapy.
The Opdivo plus Yervoy cohort of CheckMate -040 is an
exploratory cohort evaluating the safety and efficacy of the combination
in three different dosing regimens. Primary endpoints include safety
and tolerability and ORR based on investigator assessment using RECIST
v1.1, which was consistent with the exploratory endpoint of
BICR-assessed ORR at 28 months follow-up (29% vs. 31%). Secondary
endpoints include DCR, DoR, OS, time to response, time to progression
and progression-free survival.
Rates of any grade treatment-related adverse events (TRAEs) were 94%,
71% and 79% in Arms A, B and C, respectively. The most commonly
occurring grade 3-4 TRAEs included pruritus (4%, N/A, N/A), rash (4%,
4%, N/A), diarrhea (4%, 2%, 2%), aspartate aminotransferase (AST)
increase (16%, 8%, 4%) and lipase increase (12% 6%, 8%). While grade 3-4
TRAEs were most common among patients in Arm A (53%) compared to Arms B
and C (29%, 31%), events were considered manageable. Thirteen patients
in the cohort (8.9%) had any grade TRAEs leading to discontinuation,
eight of whom (5.5%) discontinued due to grade 3-4 TRAEs.
About Hepatocellular Carcinoma
Liver cancer is the fourth most frequent cause of cancer death worldwide
and hepatocellular carcinoma (HCC), the most common type of liver
cancer, is the fastest rising cause of cancer-related death in the
United States. HCC is often diagnosed in the advanced stage, where
effective treatment options are limited and the survival benefit
provided by the first-line standard of care is less than three months
over placebo. While most cases of HCC are caused by hepatitis B virus
(HBV) or hepatitis C virus (HCV) infections, metabolic syndrome and
nonalcoholic steatohepatitis (NASH) are rising in prevalence and
expected to contribute to increased rates of HCC.
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 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 1 mg/kg with YERVOY
3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in
2.2% (9/407) of patients. In RCC 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. In MSI-H/dMMR mCRC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal
dysfunction occurred in 1.7% (2/119) 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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash
occurred in 22.6% (92/407) of patients. In RCC patients receiving OPDIVO
3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6%
(91/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 14% (17/119)
of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening,
or fatal immune-mediated dermatitis (eg, 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.
Contacts
Bristol-Myers Squibb Company
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Investors:
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