Opdivo Plus Low-Dose Yervoy Combination Reduces the Risk of Progression or Death by 42% Versus Chemotherapy in First-Line Lung Cancer Patients with High Tumor Mutational Burden (TMB)

In the Phase 3 CheckMate -227 trial, the one-year
progression-free survival rate was more than triple with the combination

versus chemotherapy (43% vs. 13%) in first-line non-small cell lung
cancer patients with high TMB ≥10 mut/Mb

Near doubling of overall response rate with the combination
(45.3%) versus chemotherapy (26.9%); 68% of responders had ongoing
responses at one year (25% with chemotherapy)

Grade 3-4 treatment-related adverse event rate with the Opdivo
plus low-dose
Yervoy combination was 31% versus 36% with
chemotherapy

PRINCETON, N.J.–(BUSINESS WIRE)–$BMY #AACR18Bristol-Myers
Squibb Company
(NYSE: BMY) today announced initial results from the
pivotal Phase 3 study, CheckMate -227, evaluating the Opdivo (nivolumab)
3 mg/kg plus low-dose Yervoy (ipilimumab, 1 mg/kg)
combination in first-line advanced non-small cell lung cancer (NSCLC)
patients with high tumor mutational burden (TMB) ≥10 mutations/megabase
(mut/Mb). In the study, the combination demonstrated a superior benefit
for the co-primary endpoint of progression-free survival (PFS) versus
chemotherapy (HR 0.58; 97.5% CI: 0.41 to 0.81; p=0.0002). The PFS
benefit was observed regardless of PD-L1 expression levels and in both
squamous and non-squamous tumor histology. Additionally, based on an
early descriptive analysis, encouraging overall survival was observed
with the combination versus chemotherapy in patients with high TMB ≥10
mut/Mb (HR 0.79; 95% CI: 0.56 to 1.10).

“CheckMate -227 is the first Phase 3 study to demonstrate the important
clinical benefit of combining two immunotherapy agents to treat
first-line NSCLC patients with high TMB,” said Matthew D. Hellmann,
M.D., study investigator and medical oncologist at Memorial Sloan
Kettering Cancer Center. “Results demonstrated that first-line nivolumab
plus ipilimumab can provide frequent, deep and durable responses
compared with chemotherapy in patients with NSCLC who have TMB ≥10
mut/Mb. The trial also supports the rationale for molecular testing to
determine potential biomarkers in patients with lung cancer.”

These data were featured today during the official press program at the
American Association for Cancer Research (AACR) Annual Meeting 2018 in
Chicago (Abstract #CT077). Findings will be presented at 11:35-11:55 AM
CDT during the Clinical Trials Plenary Session, Immunotherapy
Combinations: The New Frontier in Lung Cancer, and simultaneously
published in The New England Journal of Medicine.

“Lung cancer is a highly complex disease, defined by multiple subtypes,
making it increasingly important to define a more precise treatment
approach for this disease,” said Sabine Maier, development lead,
thoracic cancers, Bristol-Myers Squibb. “We are excited to have advanced
the science by establishing in this study that TMB was an important
biomarker that predicted which first-line lung patients experienced a
clinically meaningful progression-free survival benefit with a
chemotherapy-sparing option, Opdivo plus low-dose Yervoy combination.
These results are an example of our goal to understand each patient type
through our leading translational research capabilities.”

Grade 3-4 treatment-related adverse events (AEs) with the combination were
skin reactions (34%), endocrine (23%), gastrointestinal (18%), hepatic
(15%), pulmonary (8%), hypersensitivity (4%) and renal (4%) events.
Overall, treatment-related deaths occurred in 1% of patients treated in
both the combination and chemotherapy arms.

Additional Data from CheckMate -227 Presented
at AACR 2018

Additional data from CheckMate -227 presented at AACR 2018 include
subgroup analyses by tumor PD-L1 expression in patients with TMB ≥10
mut/Mb. In these analyses, PFS was significantly improved with the
combination versus chemotherapy in patients with PD-L1 ≥1% (HR 0.62; 95%
CI: 0.44 to 0.88) and PD-L1 <1% (HR 0.48; 95% CI: 0.27 to 0.85). Increased benefit with Opdivo plus low-dose Yervoy versus
chemotherapy was also observed in patients with squamous histology (HR
0.63; 95% CI: 0.39 to 1.04) and non-squamous histology (HR 0.55; 95% CI:
0.38 to 0.80).

In the study, PFS also was evaluated with Opdivo versus
chemotherapy among patients with TMB ≥13 mut/Mb and ≥1% PD-L1 expression
as a secondary endpoint. An improvement in PFS with Opdivo
monotherapy was not observed (HR 0.95; 97.5% CI: 0.61 to 1.48; p=0.7776).

About CheckMate -227

CheckMate -227 is an open-label Phase 3 trial evaluating Opdivo-based
regimens versus platinum-doublet chemotherapy in patients with
first-line advanced non-small cell lung cancer (NSCLC) across
non-squamous and squamous tumor histologies. This program is comprised
of three parts:

  • Part 1a: Opdivo plus low-dose Yervoy or Opdivo
    monotherapy versus chemotherapy in patients whose tumors express PD-L1
  • Part 1b: Opdivo plus low-dose Yervoy or Opdivo
    plus chemotherapy versus chemotherapy in patients whose tumors do not
    express PD-L1
  • Part 2: Opdivo plus chemotherapy versus chemotherapy in a broad
    population, regardless of PD-L1 or TMB status

There are two co-primary endpoints in Part 1 for the Opdivo plus Yervoy
combination (versus chemotherapy): overall survival (OS) in patients
whose tumors express PD-L1 (assessed in patients enrolled in Part 1a)
and progression-free survival (PFS) in patients with high tumor
mutational burden (TMB) ≥10 mut/Mb across the PD-L1 spectrum (assessed
in patients enrolled across Parts 1a and 1b). The primary endpoint in
Part 2 is OS.

Secondary endpoints in TMB-selected patient populations were analyzed
hierarchically: PFS with Opdivo monotherapy versus chemotherapy
in patients with TMB ≥13 mut/Mb and ≥1% PD-L1 expression, and OS with Opdivo
plus Yervoy versus chemotherapy in patients with TMB ≥10 mut/Mb.
Based on this statistical hierarchy, OS in patients with TMB ≥10 mut/Mb
with Opdivo plus Yervoy versus chemotherapy was a
descriptive analysis.

In Part 1 of this study, patients were randomized 1:1:1 to Opdivo 3
mg/kg every two weeks plus low-dose Yervoy 1 mg/kg every six
weeks; histology-based platinum-doublet chemotherapy every three weeks
for up to four cycles; and Opdivo 240 mg every two weeks (Part
1a) or Opdivo 360 mg plus histology-based platinum-doublet
chemotherapy every three weeks for up to four cycles, followed by Opdivo
monotherapy (Part 1b).

Of all randomized patients in Part 1 (N=1,739), 1,004 (58%) were
evaluable for TMB analyses. Of all TMB-evaluable patients, 444 (44%) had
TMB ≥10 mut/Mb, including 139 patients randomized to Opdivo plus
Yervoy
and 160 patients randomized to chemotherapy. In the trial,
TMB was assessed using the validated assay, FoundationOne CDx.

About Tumor Mutational Burden (TMB)

Over time, cancer cells accumulate mutations that are not seen in normal
cells of the body. Tumor mutational burden, or TMB, is a quantitative
biomarker that reflects the total number of mutations carried by tumor
cells. Tumor cells with high TMB have higher levels of neoantigens,
which is thought to help the immune system recognize tumors and incite
an increase in cancer-fighting T cells and an anti-tumor response. TMB
is one type of biomarker that may help predict the likelihood a patient
responds to immunotherapies.

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 advancing 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 24
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. Through our
leading translational capabilities, we are pioneering immune biology
research and identifying a number of potentially predictive biomarkers,
including PD-L1, TMB, MSI-H/dMMR and LAG-3, advancing the possibility of
precision medicine for more patients with cancer.

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.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO®

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 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) 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) 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.

OPDIVO® (10 mg/mL) is an injection for intravenous (IV)
use.

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. 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 with YERVOY, immune-mediated
hepatitis occurred in 13% (51/407) 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 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.

Contacts

Bristol-Myers Squibb
Media:
Audrey Abernathy,
919-605-4521
audrey.abernathy@bms.com
or
Investor:
Tim
Power, 609-252-7509
timothy.power@bms.com
or
Bill
Szablewski, 609-252-5894
william.szablewski@bms.com

Read full story here