Vote recommends a class-wide PD-L1 expression
level cut-off across PD-1 inhibitors in advanced esophageal
squamous cell carcinoma and gastric/gastroesophageal junction
cancers
Biologics License Applications for TEVIMBRA in
these indications are under review with the FDA
BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global
oncology company, announced the U.S. Food and Drug Administration
(FDA) Oncologic Drugs Advisory Committee (ODAC) recognizes the
favorable benefit-risk profile of PD-1 inhibitors, including
TEVIMBRA® (tislelizumab-jsgr), for the first-line treatment of
patients with locally advanced unresectable or metastatic
esophageal squamous cell carcinoma (ESCC) expressing PD-L1 (>1%)
and gastric/gastroesophageal junction (G/GEJ) cancers expressing
PD-L1 >1%.
The committee reviewed efficacy and safety data from the Phase 3
RATIONALE-305 (G/GEJ) and RATIONALE-306 (ESCC) studies, as well as
other pivotal studies from the two other PD-1 inhibitors approved
in these indications. The Advisory Committee voted 10 to 2, with
one abstaining, that the risk benefit assessment was not favorable
for the use of PD-1 inhibitors in G/GEJ with PD-L1 expression less
than 1%. The ODAC members voted 11 to 1, with one abstaining, that
the risk benefit profile was not favorable for ESCC patients with a
PD-L1 expression less than 1%. The vote represents a recommended
class-wide PD-L1 expression level cut-off across PD-1 inhibitors
reviewed during the meeting for these patient populations.
“The survival rates for gastric and esophageal cancer remain
strikingly low for the majority of patients who are diagnosed with
late-stage disease and there is a need for additional treatments
that can extend life,” said Sally Werner, RN, BSN, MSHA, CEO at
Cancer Support Community. “We appreciate the FDA's recognition of
the need for safe and effective treatments for these cancers.
Additional treatment options offer physicians and their patients
choices on the treatment that is right for them.”
“The vote by ODAC members to recommend a class-level cut-off of
PD-L1 expression for PD-1 inhibitors used in the treatment of
gastric/GEJ cancers and ESCC will help to establish a standard for
clinicians and the patients they treat,” said Mark Lanasa, M.D.,
Ph.D., Chief Medical Officer, Solid Tumors at BeiGene. “We look
forward to working with the FDA as it completes its review of our
BLAs for TEVIMBRA, and we strive to bring this therapy to
applicable patients in the U.S.”
Both the RATIONALE-305 and RATIONALE-306 studies met their
endpoints of overall survival (OS), demonstrating a statistically
significant reduction in the risk of death across both indications.
The safety profile for TEVIMBRA in combination with chemotherapy is
consistent with the known safety profile of anti-PD-1 antibodies,
and no new safety signals were identified.
The Biologics License Applications (BLAs) for TEVIMBRA in these
indications remain under review with the FDA. TEVIMBRA is currently
approved in the U.S. for the treatment of adult patients with
unresectable or metastatic ESCC after prior systemic chemotherapy
that did not include a PD-L1 inhibitor.
About RATIONALE-305
RATIONALE-305 (NCT03777657) is a randomized, double-blind,
placebo-controlled, global Phase 3 that enrolled 997 patients with
advanced unresectable or metastatic G/GEJ adenocarcinoma. The
primary endpoint was OS, with prespecified hierarchy testing for
the PD-L1 high population followed by the intent-to-treat (ITT)
population. Results of the final analysis of the ITT population
were presented as a late-breaking oral presentation during the
European Society for Medical Oncology (ESMO) Congress 2023.
About RATIONALE-306
RATIONALE-306 (NCT03783442) is a randomized, placebo-controlled,
double-blind, global Phase 3 study to evaluate the efficacy and
safety of tislelizumab in combination with chemotherapy as a
first-line treatment in patients with advanced or metastatic ESCC.
The primary endpoint of the trial is overall survival. Secondary
endpoints include progression free survival, overall response rate,
and duration of response per RECIST v1.1, as well as health-related
quality of life measures and safety. The trial enrolled 649
patients at research centers across Asia-Pacific, Europe, and North
America. Patients were randomized 1:1 to receive either
tislelizumab plus chemotherapy or placebo plus chemotherapy.
About TEVIMBRA® (tislelizumab-jsgr)
Tislelizumab is a uniquely designed humanized immunoglobulin G4
(IgG4) anti-programmed cell death protein 1 (PD-1) monoclonal
antibody with high affinity and binding specificity against PD-1.
It is designed to minimize binding to Fc-gamma (Fcγ) receptors on
macrophages, helping to aid the body’s immune cells to detect and
fight tumors.
U.S. Indication and Important Safety Information for TEVIMBRA
(tislelizumab-jsgr)
INDICATION
TEVIMBRA (tislelizumab-jsgr), as a single agent, is indicated
for the treatment of adult patients with unresectable or metastatic
esophageal squamous cell carcinoma after prior systemic
chemotherapy that did not include a PD-(L)1 inhibitor.
WARNINGS AND PRECAUTIONS
Severe and Fatal Immune-Mediated Adverse Reactions
TEVIMBRA is a monoclonal antibody that belongs to a class of
drugs that bind to either the programmed death receptor-1 (PD-1) or
PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby
removing inhibition of the immune response, potentially breaking
peripheral tolerance and inducing immune-mediated adverse
reactions.
Immune-mediated adverse reactions, which may be severe or fatal,
can occur in any organ system or tissue. Immune-mediated adverse
reactions can occur at any time after starting treatment with a
PD-1/PD-L1 blocking antibody. While immune-mediated adverse
reactions usually manifest during treatment with PD-1/PD-L1
blocking antibodies, immune-mediated adverse reactions can also
manifest after discontinuation of PD-1/PD-L1 blocking antibodies.
Important immune-mediated adverse reactions listed here may not
include all possible severe and fatal immune-mediated
reactions.
Early identification and management of immune-mediated adverse
reactions are essential to ensure safe use of PD-1/PD-L1 blocking
antibodies. Monitor patients closely for symptoms and signs that
may be clinical manifestations of underlying immune-mediated
adverse reactions. Evaluate liver enzymes, creatinine, and thyroid
function at baseline and periodically during treatment. In cases of
suspected immune-mediated adverse reactions, initiate appropriate
workup to exclude alternative etiologies, including infection.
Institute medical management promptly, including specialty
consultation as appropriate.
Withhold or permanently discontinue TEVIMBRA depending on
severity. In general, if TEVIMBRA requires interruption or
discontinuation, administer systemic corticosteroid therapy (1 to 2
mg/kg/day prednisone or equivalent) until improvement to Grade 1 or
less. Upon improvement to Grade 1 or less, initiate corticosteroid
taper and continue to taper over at least 1 month. Consider
administration of other systemic immunosuppressants in patients
whose immune-mediated adverse reactions are not controlled with
corticosteroids.
Immune-Mediated Pneumonitis
TEVIMBRA can cause immune-mediated pneumonitis, which can be
fatal. In patients treated with other PD-1/PD-L1 blocking
antibodies, the incidence of pneumonitis is higher in patients who
have received prior thoracic radiation.
Immune-mediated pneumonitis occurred in 3.8% (75/1972) of
patients receiving TEVIMBRA, including fatal (0.2%), Grade 4
(0.3%), Grade 3 (1.4%), and Grade 2 (1.7%) adverse reactions.
Pneumonitis led to permanent discontinuation of TEVIMBRA in 35
(1.8%) patients and withholding of TEVIMBRA in 27 (1.4%)
patients.
Systemic corticosteroids were required in all patients with
pneumonitis. Immune-mediated pneumonitis resolved in 47% of the 75
patients. Of the 27 patients in whom TEVIMBRA was withheld for
pneumonitis, 18 reinitiated TEVIMBRA after symptom improvement; of
these, 3 (17%) patients had recurrence of pneumonitis.
Immune-Mediated Colitis
TEVIMBRA can cause immune-mediated colitis, which can be fatal.
Cytomegalovirus (CMV) infection/reactivation has been reported in
patients with corticosteroid-refractory immune-mediated colitis
treated with PD-1/PD-L1 blocking antibodies. In cases of
corticosteroid-refractory colitis, consider repeating infectious
workup to exclude alternative etiologies.
Immune-mediated colitis occurred in 0.9% (17/1972) of patients
receiving TEVIMBRA, including Grade 3 (0.4%), and Grade 2 (0.5%)
adverse reactions. Colitis led to permanent discontinuation of
TEVIMBRA in 2 (0.1%) patients and withholding of TEVIMBRA in 10
(0.5%) patients. All 17 patients received systemic corticosteroids.
Twelve (71%) of the 17 patients received high-dose systemic
corticosteroids. Two (12%) of the 17 patients received
immunosuppressive treatment. Immune-mediated colitis resolved in
88% of the 17 patients. Of the 10 patients in whom TEVIMBRA was
withheld for colitis, 8 reinitiated TEVIMBRA after symptom
improvement; of these, 1 (13%) patient had recurrence of
colitis.
Immune-Mediated Hepatitis
TEVIMBRA can cause immune-mediated hepatitis, which can be
fatal.
Immune-mediated hepatitis occurred in 1.7% (34/1972) of patients
receiving TEVIMBRA, including fatal (0.1%), Grade 4 (0.1%), Grade 3
(1%), and Grade 2 (0.6%) adverse reactions. Immune-mediated
hepatitis led to permanent discontinuation in 9 (0.5%) patients and
withholding of TEVIMBRA in 20 (1%) patients. All patients received
systemic corticosteroids. Twenty-nine (85%) of the 34 patients
received high-dose systemic corticosteroids. One patient (2.9%) of
the 34 patients received immunosuppressive treatment.
Immune-mediated hepatitis resolved in 59% of the 34 patients. Of
the 20 patients in whom TEVIMBRA was withheld for hepatitis, 12
reinitiated TEVIMBRA after symptom improvement; of these, 2 (17%)
patients had recurrence of hepatitis.
Immune-Mediated
Endocrinopathies
Adrenal Insufficiency
TEVIMBRA can cause immune-mediated adrenal insufficiency. For
Grade 2 or higher adrenal insufficiency, initiate symptomatic
treatment, including hormone replacement as clinically indicated.
Withhold TEVIMBRA depending on severity.
Immune-mediated adrenal insufficiency occurred in 0.3% (6/1972)
of patients receiving TEVIMBRA, including Grade 4 (0.1%), Grade 3
(0.1%), and Grade 2 (0.2%) adverse reactions. Adrenal insufficiency
did not lead to permanent discontinuation of TEVIMBRA. TEVIMBRA was
withheld in 5 out of the 6 patients. All 6 patients received
systemic corticosteroids. Two (33%) of the 6 patients received
high-dose systemic corticosteroids. Adrenal insufficiency resolved
in 17% of the 6 patients.
Hypophysitis
TEVIMBRA can cause immune-mediated hypophysitis. Hypophysitis
can present with acute symptoms associated with mass effect such as
headache, photophobia, or visual field defects. Hypophysitis can
cause hypopituitarism. Initiate hormone replacement as clinically
indicated. Withhold or permanently discontinue TEVIMBRA depending
on severity.
Hypophysitis/hypopituitarism occurred in 0.1% (1/1972) of
patients receiving TEVIMBRA, including a Grade 2 (0.1%) adverse
reaction. No TEVIMBRA treatment discontinuation or withholding was
required.
Thyroid Disorders
TEVIMBRA can cause immune-mediated thyroid disorders.
Thyroiditis can present with or without endocrinopathy.
Hypothyroidism can follow hyperthyroidism. Initiate hormone
replacement for hypothyroidism or institute medical management of
hyperthyroidism as clinically indicated. Withhold or permanently
discontinue TEVIMBRA depending on severity.
Thyroiditis: Immune-mediated thyroiditis occurred in 0.4%
(7/1972) of patients receiving TEVIMBRA, including Grade 2 (0.3%)
adverse reactions. Thyroiditis did not lead to permanent
discontinuation of TEVIMBRA. TEVIMBRA was withheld in 1 (0.1%)
patient. One (14%) of the 7 patients received systemic
corticosteroids. Thyroiditis resolved in 29% of the 7 patients.
Hyperthyroidism: Immune-mediated hyperthyroidism occurred in
0.6% (12/1972) of patients receiving TEVIMBRA, including Grade 3
(0.1%), and Grade 2 (0.5%) adverse reactions. Hyperthyroidism led
to the permanent discontinuation of TEVIMBRA in 1 (0.1%) patient
and withholding of TEVIMBRA in 1 (0.1%) patient. One (8%) of the 12
patients received systemic corticosteroids. Hyperthyroidism
resolved in 92% of the 12 patients.
Hypothyroidism: Immune-mediated hypothyroidism occurred in 7%
(132/1972) of patients receiving TEVIMBRA, including Grade 4 (0.1%)
and Grade 2 (5%) adverse reactions. TEVIMBRA was not permanently
discontinued in any patient, while treatment was withheld in 6
(0.3%) patients. Two (1.5%) of the 132 patients received systemic
corticosteroids. All 132 patients received hormone replacement
therapy. Hypothyroidism resolved in 27% of the 132 patients. The
majority (86%) of patients with hypothyroidism required long-term
thyroid hormone replacement.
Type 1 Diabetes Mellitus, which can present with Diabetic
Ketoacidosis
Type 1 diabetes mellitus has been reported with PD-1/PD-L1
blocking antibodies. Monitor patients for hyperglycemia or other
signs and symptoms of diabetes. Initiate treatment with insulin as
clinically indicated. Withhold or permanently discontinue TEVIMBRA
depending on severity.
Immune-Mediated Nephritis with Renal
Dysfunction
TEVIMBRA can cause immune-mediated nephritis, which can be
fatal.
Immune-mediated nephritis with renal dysfunction occurred in
0.4% (7/1972) of patients receiving TEVIMBRA, including Grade 4
(0.1%), Grade 3 (0.1%), and Grade 2 (0.2%) adverse reactions.
TEVIMBRA was permanently discontinued in 3 (0.2%) patients and
treatment was withheld in 3 (0.2%) patients. All patients received
systemic corticosteroids. Nephritis with renal dysfunction resolved
in 57% of the 7 patients. Of the 3 patients in whom TEVIMBRA was
withheld for nephritis, 2 reinitiated TEVIMBRA after symptom
improvement and one patient had recurrence of nephritis.
Immune-Mediated Dermatologic Adverse
Reactions
TEVIMBRA can cause immune-mediated rash or dermatitis. Cases of
severe cutaneous adverse reactions (SCARs), including exfoliative
dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal
necrolysis (TEN), have been reported, some with fatal outcome.
Topical emollients and/or topical corticosteroids may be adequate
to treat mild to moderate non-exfoliative rashes. Withhold or
permanently discontinue TEVIMBRA depending on severity.
Immune-mediated dermatologic adverse reactions occurred in 1.2%
(24/1972) of patients receiving TEVIMBRA, including Grade 4 (0.2%),
Grade 3 (0.4%), and Grade 2 (0.4%) adverse reactions. Dermatologic
adverse reactions led to permanent discontinuation of TEVIMBRA in 3
(0.2%) patients and withholding of TEVIMBRA in 9 (0.5%) patients.
Twenty-three (96%) of the 24 patients received systemic
corticosteroids. Immune-mediated skin reactions resolved in 58% of
the 24 patients. Of the 9 patients in whom TEVIMBRA was withheld
for dermatologic adverse reactions, 8 reinitiated TEVIMBRA after
symptom improvement; of these, 2 (25%) patients had recurrence of
immune-mediated rash.
Other Immune-Mediated Adverse
Reactions
The following clinically significant immune-mediated adverse
reactions occurred at an incidence of less than 1% each in 1972
patients who received TEVIMBRA: myositis, myocarditis, arthritis,
polymyalgia rheumatica, and pericarditis.
The following additional clinically significant immune-mediated
adverse reactions have been reported with other PD-1/PD-L1 blocking
antibodies, including severe or fatal cases.
Cardiac/Vascular: Vasculitis
Nervous System: Meningitis, encephalitis, myelitis and
demyelination, myasthenic syndrome/myasthenia gravis (including
exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune
neuropathy.
Ocular: Uveitis, iritis, and other ocular inflammatory
toxicities can occur. Some cases can be associated with retinal
detachment. Various grades of visual impairment, including
blindness, can occur. If uveitis occurs in combination with other
immune-mediated adverse reactions, consider a
Vogt-Koyanagi-Harada-like syndrome, as this may require treatment
with systemic steroids to reduce the risk of permanent vision
loss.
Gastrointestinal: Pancreatitis including increases in serum
amylase and lipase levels, gastritis, duodenitis
Musculoskeletal and Connective Tissue: Polymyositis,
rhabdomyolysis and associated sequelae including renal failure
Endocrine: Hypoparathyroidism
Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia,
hemophagocytic lymphohistiocytosis, systemic inflammatory response
syndrome, histiocytic necrotizing lymphadenitis (Kikuchi
lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid
organ transplant rejection, other transplant (including corneal
graft) rejection.
Infusion-Related Reactions
TEVIMBRA can cause severe or life-threatening infusion-related
reactions. Infusion-related reactions occurred in 4.2% (83/1972)
patients receiving TEVIMBRA, including Grade 3 or higher (0.3%)
reactions. Monitor patients for signs and symptoms of
infusion-related reactions.
Slow the rate of infusion for mild (Grade 1) and interrupt the
infusion for moderate (Grade 2) infusion-related reactions. For
severe (Grade 3) or life-threatening (Grade 4) infusion-related
reactions, stop infusion and permanently discontinue TEVIMBRA.
Complications of Allogeneic HSCT
Fatal and other serious complications can occur in patients who
receive allogeneic hematopoietic stem cell transplantation (HSCT)
before or after being treated with a PD-1/PD-L1 blocking antibody.
Transplant-related complications include hyperacute
graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic
veno-occlusive disease after reduced intensity conditioning, and
steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between PD-1/PD-L1 blockade and allogeneic
HSCT.
Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risks of treatment with a PD-1/PD-L1 blocking antibody prior to or
after an allogeneic HSCT.
Embryo-Fetal Toxicity
Based on its mechanism of action, TEVIMBRA can cause fetal harm
when administered to a pregnant woman. Animal studies have
demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to
increased risk of immune-mediated rejection of the developing fetus
resulting in fetal death. Advise women of the potential risk to a
fetus. Advise females of reproductive potential to use effective
contraception during treatment with TEVIMBRA and for 4 months after
the last dose.
ADVERSE REACTIONS
Permanent discontinuation of TEVIMBRA due to an adverse reaction
occurred in 19% of patients. Adverse reactions which resulted in
permanent discontinuation in ≥ 1% of patients were hemorrhage,
pneumonitis (including pneumonitis and immune-mediated
pneumonitis), and pneumonia.
Dosage interruptions of TEVIMBRA due to an adverse reaction
occurred in 23% of patients. Adverse reactions which required
dosage interruptions in ≥ 2% of patients were pneumonia,
pneumonitis, and fatigue.
The most common (≥ 20%) adverse reactions, including laboratory
abnormalities, were increased glucose, decreased hemoglobin,
decreased lymphocytes, decreased sodium, decreased albumin,
increased alkaline phosphatase, anemia, fatigue, increased AST,
musculoskeletal pain, decreased weight, increased ALT, and
cough.
Please see full U.S. Prescribing Information
including Medication Guide.
About BeiGene
BeiGene is a global oncology company that is discovering and
developing innovative treatments that are more affordable and
accessible to cancer patients worldwide. With a broad portfolio, we
are expediting development of our diverse pipeline of novel
therapeutics through our internal capabilities and collaborations.
We are committed to radically improving access to medicines for far
more patients who need them. Our growing global team of more than
10,000 colleagues spans five continents. To learn more about
BeiGene, please visit www.beigene.com and follow us on LinkedIn, X
(formerly known as Twitter), Facebook and Instagram.
Forward-Looking Statements
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of 1995
and other federal securities laws, including statements regarding
BeiGene’s ability to bring TEVIMBRA to additional patients in the
U.S.; and BeiGene’s plans, commitments, aspirations, and goals
under the heading “About BeiGene.” Actual results may differ
materially from those indicated in the forward-looking statements
as a result of various important factors, including BeiGene’s
ability to demonstrate the efficacy and safety of its drug
candidates; the clinical results for its drug candidates, which may
not support further development or marketing approval; actions of
regulatory agencies, which may affect the initiation, timing, and
progress of clinical trials and marketing approval; BeiGene’s
ability to achieve commercial success for its marketed medicines
and drug candidates, if approved; BeiGene’s ability to obtain and
maintain protection of intellectual property for its medicines and
technology; BeiGene’s reliance on third parties to conduct drug
development, manufacturing, commercialization, and other services;
BeiGene’s limited experience in obtaining regulatory approvals and
commercializing pharmaceutical products; BeiGene’s ability to
obtain additional funding for operations and to complete the
development of its drug candidates and achieve and maintain
profitability; and those risks more fully discussed in the section
entitled “Risk Factors” in BeiGene’s most recent quarterly report
on Form 10-Q, as well as discussions of potential risks,
uncertainties, and other important factors in BeiGene’s subsequent
filings with the U.S. Securities and Exchange Commission. All
information in this press release is as of the date of this press
release, and BeiGene undertakes no duty to update such information
unless required by law.
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