Results from the global, Phase 3 RATIONALE 302
trial showed TEVIMBRA prolonged the survival of patients who
received prior systemic treatment compared to chemotherapy
Approval represents the first indication in the
U.S. for TEVIMBRA
BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global
oncology company, today announced that the U.S. Food and Drug
Administration (FDA) has approved TEVIMBRA® (tislelizumab-jsgr) as
monotherapy for the treatment of adult patients with unresectable
or metastatic esophageal squamous cell carcinoma (ESCC) after prior
systemic chemotherapy that did not include a PD-(L)1 inhibitor.
TEVIMBRA will be available in the U.S. in the second half of
2024.
“Today’s FDA approval of TEVIMBRA for patients with ESCC who
have previously received chemotherapy, along with its ongoing
review of our BLA for first-line ESCC patients, represents a
significant step in our commitment to bringing this therapy to more
patients around the world,” said Mark Lanasa, M.D., Ph.D., Chief
Medical Officer, Solid Tumors at BeiGene. “As BeiGene’s first drug
candidate produced through our immuno-oncology program and second
approved medicine in the U.S., TEVIMBRA is poised to be a critical
pillar of our solid tumor development program, which spans more
than 17 registration-enabling clinical trials in more than 30
countries across regions globally.”
The approval is based on the RATIONALE 302 trial, which met its
primary endpoint in the intention-to-treat (ITT) population with a
statistically significant and clinically meaningful survival
benefit for TEVIMBRA compared with chemotherapy. In the ITT
population, the median overall survival (OS) in the TEVIMBRA arm
was 8.6 months (95% CI: 7.5, 10.4) compared to 6.3 months (95% CI:
5.3, 7.0) in the chemotherapy arm (p=0.0001; hazard ratio [HR]=0.70
[95% CI: 0.57, 0.85]). The safety profile of TEVIMBRA was favorable
over chemotherapy.i The most common (≥20%) adverse reactions for
TEVIMBRA, 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.i
“Patients diagnosed with advanced or metastasized ESCC, the most
common histologic subtype of esophageal cancer, often progress
following initial therapy and are in need of new options,” Syma
Iqbal, M.D., Associate Professor of Clinical Medicine, Section
Chief Gastrointestinal Oncology, Division of Medical Oncology and
Cancer Physician in Chief, Norris Comprehensive Cancer Center, Keck
School of Medicine, University of Southern California. “The
RATIONALE 302 trial showed that patients with previously treated
ESCC who received TEVIMBRA saw a clinically meaningful survival
benefit, highlighting its potential as an important treatment
option for these patients.”
Tislelizumab received approval by the European Commission for
advanced or metastatic ESCC after prior chemotherapy in 2023 and a
positive opinion by the Committee for Medicinal Products for Human
Use of the European Medicines Agency (EMA) in February 2024 as a
treatment for non-small cell lung cancer across three
indications.
The FDA is also reviewing Biologics License Applications (BLAs)
for tislelizumab as a first-line treatment for patients with
unresectable, recurrent, locally advanced, or metastatic ESCC and
patients with locally advanced unresectable or metastatic gastric
or gastroesophageal junction (G/GEJ) adenocarcinoma. The target
action dates are July and December 2024, respectively.
BeiGene has launched more than 17 potentially
registration-enabling trials with TEVIMBRA, of which 11 Phase 3
randomized trials and four Phase 2 trials have already had positive
readouts. Through these trials, TEVIMBRA has demonstrated its
potential to deliver clinically meaningful improvements in survival
benefits and quality of life for hundreds of thousands of cancer
patients across a range of tumor types – in many cases, regardless
of PD-(L)1 status – both as monotherapy and in combination with
other regimens. More than 900,000 patients have been prescribed
TEVIMBRA globally to date.
About RATIONALE 302
RATIONALE 302 is a global, randomized, open-label, Phase 3 study
(NCT03430843) designed to investigate the efficacy and safety of
TEVIMBRA when compared with investigator’s choice of chemotherapy
as a second-line treatment for patients with unresectable, locally
advanced or metastatic ESCC. The study randomized 512 patients from
132 research sites in 11 countries in Europe, Asia and North
America.
About ESCC
Globally, esophageal cancer (EC) is the sixth most common cause
of cancer-related deaths, and ESCC is the most common histologic
subtype, accounting for nearly 90% of ECs.ii An estimated 957,000
new EC cases are projected in 2040, an increase of nearly 60% from
2020, underscoring the need for additional effective treatments.ii
EC is a rapidly fatal disease, and more than two-thirds of patients
have advanced or metastatic disease at the time of diagnosis, with
an expected five-year survival rate of less than 6% for those with
distant metastases.iii
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, with administrative
offices in Basel, Beijing, and Cambridge, U.S. To learn more about
BeiGene, please visit www.beigene.com and follow us on LinkedIn and
X (formerly known as Twitter).
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 more patients around the
world; the future significance of TEVIMBRA in BeiGene’s solid tumor
development program; the potential of TEVIMBRA to be an important
treatment for ESCC; 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
and its 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.
To access BeiGene media resources, please visit our News
& Media site.
___________________________ i Shen, L., Kato, K., Kim, S. B.,
Ajani, J. A., Zhao, K., He, Z., ... & Van Cutsem, E. (2022).
Tislelizumab versus chemotherapy as second-line treatment for
advanced or metastatic esophageal squamous cell carcinoma
(RATIONALE-302): A randomized phase III study. Journal of Clinical
Oncology. 40(26), 3065-3076. DOI: 10.1200/JCO.21.01926 ii Morgan E,
et al. The Global Landscape of Esophageal Squamous Cell Carcinoma
and Esophageal Adenocarcinoma Incidence and Mortality in 2020 and
Projections to 2040: New Estimates From GLOBOCAN 2020.
Gastroenterology. 2022 Sep;163(3):649-658.e2. doi:
10.1053/j.gastro.2022.05.054. Epub 2022 Jun 4. PMID: 35671803. iii
National Cancer Institute. Cancer stat facts: esophageal cancer.
https://seer.cancer.gov/statfacts/html/esoph.html.
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Investor Contact: Liza Heapes +1 857-302-5663
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