Lilly, Bristol-Myers Squibb Restructure Erbitux® (cetuximab) Collaboration in North America
April 16 2015 - 12:15PM
Business Wire
Full Commercialization Rights Transferred to
Lilly
Eli Lilly and Company (NYSE:LLY) and Bristol-Myers Squibb
Company (NYSE:BMY) today announced that the companies have agreed
to transfer rights to Erbitux® (cetuximab) in North America,
including the U.S., Canada, and Puerto Rico, from Bristol-Myers
Squibb to Lilly. Rights include, but are not limited to, full
commercialization and manufacturing operational responsibilities.
The companies’ decision comes after a 14-year successful
collaboration, which includes Lilly’s wholly-owned subsidiary
ImClone LLC. Bristol-Myers Squibb and Lilly will work closely to
ensure a smooth transition on this important product for patients
with certain advanced colorectal and head and neck cancers.
“Fully bringing Erbitux into the Lilly Oncology portfolio
accelerates Lilly’s commitment and leadership in gastrointestinal
cancers to include an effective treatment for advanced colorectal
cancer as well as head and neck cancer,” said Sue Mahony, Ph.D.,
senior vice president and president of Lilly Oncology. “Our good
work on Erbitux began with its development at ImClone and has
continued with Bristol-Myers Squibb. We look forward to carrying on
these efforts for people battling select advanced colorectal and
head and neck cancers.”
“Bristol-Myers Squibb is incredibly proud to have built Erbitux
into a major brand and an important therapy for so many patients
with certain colorectal and head and neck cancers,” said Murdo
Gordon, head of worldwide markets, Bristol-Myers Squibb. “This
agreement further aligns our Oncology organization with our
prioritized opportunities in immuno-oncology, across both solid
tumors and hematologic malignancies.”
The transition is expected to be completed in the fourth quarter
of 2015. Bristol-Myers Squibb will receive tiered royalties based
on net product sales in North America after the completion of the
transition through September 2018.
About Erbitux
Erbitux is an epidermal growth factor receptor (EGFR) antagonist
indicated for treatment of:
Head and Neck Cancer
- Erbitux, in combination with radiation
therapy, is indicated for the initial treatment of locally or
regionally advanced squamous cell carcinoma of the head and neck
(SCCHN)
- Erbitux is indicated in combination
with platinum-based therapy with 5-FU for the first-line treatment
of patients with recurrent locoregional disease or metastatic
squamous cell carcinoma of the head and neck
- Erbitux, as a single agent, is
indicated for the treatment of patients with recurrent or
metastatic squamous cell carcinoma of the head and neck for whom
prior platinum-based therapy has failed
Colorectal Cancer
Erbitux is indicated for the treatment of KRAS (wild-type),
epidermal growth factor receptor (EGFR)-expressing, metastatic
colorectal cancer (mCRC) as determined by FDA-approved tests for
this use:
- in combination with FOLFIRI
(irinotecan, 5-fluorouracil, leucovorin) for first-line
treatment
- in combination with irinotecan in
patients who are refractory to irinotecan-based chemotherapy
- as a single agent in patients who have
failed oxaliplatin- and irinotecan-based chemotherapy or who are
intolerant to irinotecan
Limitation of Use: Erbitux is not indicated for treatment of
Ras-mutant colorectal cancer or when the results of the Ras
mutation tests are unknown.
IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNINGS
Infusion Reactions
- Grade 3/4 infusion reactions
occurred in approximately 3% of patients receiving ERBITUX®
(cetuximab) in clinical trials, with fatal outcome reported in less
than 1 in 1000
- Serious infusion reactions,
requiring medical intervention and immediate, permanent
discontinuation of ERBITUX, included rapid onset of airway
obstruction (bronchospasm, stridor, hoarseness), hypotension,
shock, loss of consciousness, myocardial infarction, and/or cardiac
arrest
- Immediately interrupt and
permanently discontinue ERBITUX infusion for serious infusion
reactions
- Approximately 90% of the severe
infusion reactions were associated with the first infusion of
ERBITUX despite premedication with antihistamines
- Caution must be exercised with every
ERBITUX infusion, as there were patients who experienced their
first severe infusion reaction during later infusions
- Monitor patients for 1 hour
following ERBITUX infusions in a setting with resuscitation
equipment and other agents necessary to treat anaphylaxis (eg,
epinephrine, corticosteroids, intravenous antihistamines,
bronchodilators, and oxygen). Longer observation periods may be
required in patients who require treatment for infusion
reactions
Cardiopulmonary Arrest
- Cardiopulmonary arrest and/or sudden
death occurred in 4 (2%) of 208 patients with squamous cell
carcinoma of the head and neck treated with radiation therapy and
ERBITUX, as compared to none of 212 patients treated with radiation
therapy alone. In 3 patients with prior history of coronary
artery disease, death occurred 27, 32, and 43 days after the last
dose of ERBITUX. One patient with no prior history of coronary
artery disease died one day after the last dose of ERBITUX. Fatal
cardiac disorders and/or sudden death occurred in 7 (3%) of the 219
patients with squamous cell carcinoma of the head and neck treated
with platinum-based therapy with 5-fluorouracil (5-FU) and
European Union (EU)-approved cetuximab as compared to 4 (2%) of the
215 patients treated with chemotherapy alone. Five of these
7 patients in the chemotherapy plus cetuximab arm received
concomitant cisplatin and 2 patients received concomitant
carboplatin. All 4 patients in the chemotherapy-alone arm received
cisplatin
- Carefully consider the use of ERBITUX in combination with
radiation therapy or platinum-based therapy with 5-FU in head and
neck cancer patients with a history of coronary artery disease,
congestive heart failure, or arrhythmias in light of these
risks
- Closely monitor serum electrolytes, including serum
magnesium, potassium, and calcium during and after ERBITUX
therapy
Pulmonary Toxicity
- Interstitial lung disease (ILD), which was fatal in one case,
occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in
Studies 1, 3, and 6, as well as other studies, in colorectal cancer
and head and neck cancer. Interrupt ERBITUX for acute onset or
worsening of pulmonary symptoms. Permanently discontinue ERBITUX
for confirmed ILD
Dermatologic Toxicities
- In clinical studies of ERBITUX,
dermatologic toxicities, including acneiform rash, skin drying and
fissuring, paronychial inflammation, infectious sequelae (eg, S.
aureus sepsis, abscess formation, cellulitis, blepharitis,
conjunctivitis, keratitis/ulcerative keratitis with decreased
visual acuity, cheilitis), and hypertrichosis, occurred in patients
receiving ERBITUX therapy.
- Acneiform rash occurred in 76-88% of
1373 patients receiving ERBITUX in Studies 1, 3, 5, and 6. Severe
acneiform rash occurred in 1-17% of patients. Acneiform rash
usually developed within the first 2 weeks of therapy and resolved
in a majority of the patients after cessation of treatment,
although in nearly half, the event continued beyond 28 days
- Life-threatening and fatal bullous
mucocutaneous disease with blisters, erosions, and skin sloughing
has also been observed in patients treated with Erbitux. It could
not be determined whether these mucocutaneous adverse reactions
were directly related to EGFR inhibition or to idiosyncratic
immune-related effects (eg, Stevens Johnson syndrome or toxic
epidermal necrolysis)
- Monitor patients receiving ERBITUX for
dermatologic toxicities and infectious sequelae
- Sun exposure may exacerbate these
effects
ERBITUX Plus Radiation Therapy and Cisplatin
- In a controlled study, 940 patients
with locally advanced SCCHN were randomized 1:1 to receive either
ERBITUX in combination with radiation therapy and cisplatin or
radiation therapy and cisplatin alone. The addition of ERBITUX
resulted in an increase in the incidence of Grade 3-4 mucositis,
radiation recall syndrome, acneiform rash, cardiac events, and
electrolyte disturbances compared to radiation and cisplatin
alone
- Adverse reactions with fatal outcome
were reported in 20 patients (4.4%) in the ERBITUX combination arm
and 14 patients (3.0%) in the control arm
- Nine patients in the ERBITUX arm (2.0%)
experienced myocardial ischemia compared to 4 patients (0.9%) in
the control arm
- The addition of ERBITUX to radiation
and cisplatin did not improve progression-free survival (the
primary endpoint)
Electrolyte Depletion
- Hypomagnesemia occurred in 55% of 365
patients receiving ERBITUX in Study 5 and two other clinical trials
in colorectal cancer and head and neck cancer, respectively, and
was severe (NCI CTC grades 3 & 4) in 6-17%. In Study 2 the
addition of EU-approved cetuximab to cisplatin and 5-FU resulted in
an increased incidence of hypomagnesemia (14% vs 6%) and of grade
3–4 hypomagnesemia (7% vs 2%) compared to cisplatin and 5-FU alone.
In contrast, the incidences of hypomagnesemia were similar for
those who received cetuximab, carboplatin, and 5-FU compared to
carboplatin and 5-FU (4% vs 4%). No patient experienced grade 3–4
hypomagnesemia in either arm in the carboplatin subgroup. The onset
of hypomagnesemia and accompanying electrolyte abnormalities
occurred days to months after initiation of ERBITUX therapy
- Monitor patients periodically for
hypomagnesemia, hypocalcemia, and hypokalemia, during, and for at
least 8 weeks following the completion of, ERBITUX therapy
- Replete electrolytes as necessary
Increased Tumor Progression, Increased Mortality, or Lack of
Benefit in Patients with Ras-Mutant mCRC
- Erbitux is not indicated for the
treatment of patients with colorectal cancer that harbor somatic
mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61),
and exon 4 (codons 117 and 146) of either K-Ras or N-Ras
- Based on retrospective subset analyses
of Ras-mutant and wild-type populations across several randomized
clinical trials of anti-EGFR-directed monoclonal antibodies,
including Study 4, use of cetuximab in patients with Ras mutations
resulted in no clinical benefit with treatment related
toxicity
Late Radiation Toxicities
- The overall incidence of late radiation
toxicities (any grade) was higher with ERBITUX in combination with
radiation therapy compared with radiation therapy alone. The
following sites were affected: salivary glands (65% vs 56%), larynx
(52% vs 36%), subcutaneous tissue (49% vs 45%), mucous membranes
(48% vs 39%), esophagus (44% vs 35%), and skin (42% vs 33%) in the
ERBITUX and radiation versus radiation-alone arms, respectively
- The incidence of grade 3 or 4 late
radiation toxicities was similar between the radiation therapy
alone and the ERBITUX plus radiation therapy arms
Pregnancy and Nursing
- In women of childbearing potential and
men, appropriate contraceptive measures must be used during
treatment with ERBITUX and for 6 months following the last dose of
ERBITUX. ERBITUX may be transmitted from the mother to the
developing fetus, and has the potential to cause fetal harm when
administered to pregnant women. ERBITUX should only be used during
pregnancy if the potential benefit justifies the potential risk to
the fetus
- It is not known whether ERBITUX is
secreted in human milk. IgG antibodies, such as ERBITUX, can be
excreted in human milk. Because of the potential for serious
adverse reactions in nursing infants from ERBITUX, a decision
should be made whether to discontinue nursing or to discontinue
ERBITUX, taking into account the importance of ERBITUX to the
mother. If nursing is interrupted, based on the mean half-life of
cetuximab, nursing should not be resumed earlier than 60 days
following the last dose of ERBITUX
Adverse Reactions
- The most serious adverse
reactions associated with ERBITUX are infusion reactions,
cardiopulmonary arrest, dermatologic toxicity and radiation
dermatitis, sepsis, renal failure, interstitial lung disease, and
pulmonary embolus
- The most common adverse reactions
associated with ERBITUX (incidence ≥25%) across all studies were
cutaneous adverse reactions (including rash, pruritus, and nail
changes), headache, diarrhea, and infection
- The most frequent adverse reactions
seen in patients with carcinomas of the head and neck receiving
ERBITUX in combination with radiation therapy (n=208) versus
radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%
vs 10%), radiation dermatitis (86% vs 90%), weight loss (84% vs
72%), and asthenia (56% vs 49%). The most common grade 3/4 adverse
reactions for ERBITUX in combination with radiation therapy (≥10%)
versus radiation alone included: radiation dermatitis (23% vs 18%),
acneiform rash (17% vs 1%), and weight loss (11% vs 7%)
- The most frequent adverse reactions
seen in patients with carcinomas of the head and neck receiving
EU-approved cetuximab in combination with platinum-based therapy
with 5-FU (CT) (n=219) versus CT alone (n=215) (incidence ≥40%)
were acneiform rash (70% vs 2%), nausea (54% vs 47%), and infection
(44% vs 27%). The most common grade 3/4 adverse reactions for
cetuximab in combination with CT (≥10%) versus CT alone included:
infection (11% vs 8%). Since U.S.-licensed ERBITUX provides
approximately 22% higher exposure relative to the EU-approved
cetuximab, the data provided above may underestimate the incidence
and severity of adverse reactions anticipated with ERBITUX for this
indication. However, the tolerability of the recommended dose is
supported by safety data from additional studies of ERBITUX
- The most frequent adverse reactions
seen in patients with KRAS mutation-negative (wild-type),
EGFR-expressing metastatic colorectal cancer treated with
EU-approved cetuximab + FOLFIRI (n=317) versus FOLFIRI alone
(n=350) (incidence ≥50%) were acne-like rash (86% vs 13%) and
diarrhea (66% vs 60%). The most common grade 3/4 adverse reactions
(≥10%) included: neutropenia (31% vs 24%), acne-like rash (18% vs
<1%), and diarrhea (16% vs 10%). U.S.-licensed ERBITUX provides
approximately 22% higher exposure to cetuximab relative to the
EU-approved cetuximab. The data provided above are consistent in
incidence and severity of adverse reactions with those seen for
ERBITUX in this indication. The tolerability of the recommended
dose is supported by safety data from additional studies of
ERBITUX
- The most frequent adverse reactions
seen in patients with KRAS mutation-negative (wild-type),
EGFR-expressing metastatic colorectal cancer treated with ERBITUX +
best supportive care (BSC) (n=118) versus BSC alone (n=124)
(incidence ≥50%) were rash/desquamation (95% vs 21%), fatigue (91%
vs 79%), nausea (64% vs 50%), dry skin (57% vs 15%), pain-other
(59% vs 37%), and constipation (53% vs 38%). The most common grade
3/4 adverse reactions (≥10%) included: fatigue (31% vs 29%),
pain-other (18% vs 10%), rash/desquamation (16% vs 1%), dyspnea
(16% vs 13%), other-gastrointestinal (12% vs 5%), and infection
without neutropenia (11% vs 5%)
- The most frequent adverse reactions
seen in patients with EGFR-expressing metastatic colorectal cancer
(n=354) treated with ERBITUX plus irinotecan in clinical trials
(incidence ≥50%) were acneiform rash (88%), asthenia/malaise (73%),
diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse
reactions (≥10%) included: diarrhea (22%), leukopenia (17%),
asthenia/malaise (16%), and acneiform rash (14%)
Please read the U.S. Full Prescribing Information including
Boxed WARNINGS.
About Eli Lilly and Company
Lilly is a global healthcare leader that unites caring with
discovery to make life better for people around the world. We were
founded more than a century ago by a man committed to creating
high-quality medicines that meet real needs, and today we remain
true to that mission in all our work. Across the globe, Lilly
employees work to discover and bring life-changing medicines to
those who need them, improve the understanding and management of
disease, and give back to communities through philanthropy and
volunteerism. To learn more about Lilly, please visit us at
www.lilly.com and http://newsroom.lilly.com/social-channels.
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, please visit www.bms.com or follow us on Twitter at
http://twitter.com/bmsnews.
Erbitux is a trademark owned by or licensed to Eli Lilly and
Company, its subsidiaries, or affiliates.
Bristol-Myers Squibb and Eli Lilly and Company
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 parties’ North American collaboration
for ERBITUX. 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. Among other risks, there can be no
guarantee that the transition will be completed in the timeframe
described in this release. In addition, the amount of royalties
paid to Bristol-Myers Squibb through September 2018 may differ from
current expectations. Forward-looking statements in this press
release should be evaluated together with the many uncertainties
that affect Bristol-Myers Squibb's and Lilly’s businesses,
particularly those identified in the cautionary statement and risk
factors discussion in Bristol-Myers Squibb's and Lilly’s Annual
Reports on Form 10-K for the year ended December 31, 2014, in their
Quarterly Reports on Form 10-Q and their Current Reports on Form
8-K. Neither Bristol-Myers Squibb nor Lilly undertakes any
obligation to publicly update any forward-looking statement,
whether as a result of new information, future events or
otherwise.
MediaBristol-Myers SquibbKen Dominski,
609-252-5251ken.dominski@bms.comorSarah Koenig,
609-252-4145sarah.koenig@bms.comorEli Lilly and CompanyCrystal
Livers-Powers,
317-476-4160livers_powers_crystal@lilly.comorInvestorsBristol-Myers
SquibbRanya Dajani, 609-252-5330ranya.dajani@bms.comorEli Lilly and
CompanyPhil Johnson, 317-655-6874johnson_philip_l@lilly.com
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