– Antibody-Drug Conjugate Trodelvy is First
Treatment to Show Survival Benefit versus Standard of Care in
Metastatic Triple-Negative Breast Cancer –
– Project Orbis is a Collaborative Review
Program Intended for High-Impact Oncology Products –
– Canada Joins Australia, Great Britain,
Switzerland, and the United States in Approval of Trodelvy as a
Second-Line Treatment Option for Adults with Metastatic TNBC
–
Gilead Sciences, Inc. (Nasdaq: GILD) today announced that Health
Canada has approved Trodelvy® (sacituzumab govitecan-hziy) for the
treatment of adult patients with unresectable locally advanced or
metastatic triple-negative breast cancer (TNBC) who have received
two or more prior therapies, at least one of them for metastatic
disease. Canada joins Australia, Great Britain, Switzerland, and
the United States among the countries that have approved Trodelvy
for use under Project Orbis. Project Orbis is an initiative of the
U.S. Food and Drug Administration (FDA) Oncology Center of
Excellence (OCE) with international regulatory authorities as a
global collaborative review program for high impact oncology
marketing applications across participating countries.
Trodelvy is a first-in-class Trop-2 directed antibody-drug
conjugate. Trop-2, a protein located on the surface of cells, is
overexpressed in TNBC as well as other solid tumors. Beyond the
Project Orbis regulatory approvals, the European Medicines Agency
validated a Marketing Authorization Application for Trodelvy in
March and regulatory review is also underway in Kazakhstan and
Saudi Arabia, as well as Singapore via licensing partner, Everest
Medicines.
“Because Trodelvy is the first and only targeted treatment to
show benefit in overall survival in 2L metastatic TNBC versus
chemotherapy, ensuring that it is accessible to eligible patients
is imperative,” said Merdad Parsey, MD, PhD, Chief Medical Officer,
Gilead Sciences. “We pursued innovative regulatory pathways, such
as those made possible by Project Orbis, to help make Trodelvy
available to patients as rapidly as possible.”
These approvals were supported by data from the Phase 3 ASCENT
study, in which Trodelvy showed a statistically significant and
clinically meaningful 57% reduction in the risk of disease
worsening or death (progression-free survival (PFS)) and improved
median PFS in patients regardless of brain metastasis to 4.8 months
from 1.7 months with chemotherapy (HR: 0.43; 95% CI: 0.35-0.54;
p<0.0001). Trodelvy also improved median overall survival to
11.8 months versus 6.9 months with chemotherapy (HR: 0.51; 95% CI:
0.41-0.62; p<0.0001), representing a 49% reduction in the risk
of death. In the study of 2L+ TNBC patients, the most frequent
Grade ≥3 treatment-related adverse events compared to single-agent
chemotherapy were neutropenia (52% versus 34%), diarrhea (11%
versus 1%), leukopenia (11% versus 6%) and anemia (9% versus 6%).
The Trodelvy U.S. Prescribing Information has a BOXED WARNING for
severe or life-threatening neutropenia and severe diarrhea; see
below for Important Safety Information.
About the ASCENT Study
The ASCENT study is a global, open-label, randomized Phase 3
study that enrolled more than 500 patients across 230 study
locations. The study evaluated the efficacy and safety of Trodelvy
compared with a single-agent chemotherapy of the physician’s choice
in patients with unresectable, locally advanced or metastatic TNBC
who had received at least two prior systemic treatments. Patients
were randomized to receive either Trodelvy or a chemotherapy chosen
by the patients’ treating physicians. The primary endpoint was
progression-free survival (PFS, as determined by blinded
independent central review) in patients without brain metastases.
Secondary endpoints included: PFS for full study population or
intention-to-treat (ITT) population, overall survival in both the
ITT population and in the subgroup without brain metastasis,
independently determined objective response rate, duration of
response, time to onset of response according to Response
Evaluation Criteria in Solid Tumors (RECIST 1.1), quality of life
and safety. More information about ASCENT is available at
http://clinicaltrials.gov/show/NCT02574455.
About Triple-Negative Breast Cancer
(TNBC)
TNBC is the most aggressive type of breast cancer and accounts
for approximately 15% of all breast cancers. TNBC is diagnosed more
frequently in younger and premenopausal women and is more prevalent
in Black and Hispanic women. TNBC cells do not have estrogen and
progesterone receptors and have limited human epidermal growth
factor receptor 2 (HER2). Due to the nature of TNBC, treatment
options are extremely limited compared with other breast cancer
types. TNBC has a higher chance of recurrence and metastases than
other breast cancer types. The average time to metastatic
recurrence for TNBC is approximately 2.6 years compared with 5
years for other breast cancers, and the relative five-year survival
rate is much lower. Among women with metastatic TNBC, the five-year
survival rate is 12%, compared with 28% for those with other types
of metastatic breast cancer.
About Trodelvy
Trodelvy (sacituzumab govitecan-hziy) is a first-in-class
antibody and topoisomerase inhibitor conjugate directed to the
Trop-2 receptor, a protein overexpressed in multiple types of
epithelial tumors, including metastatic TNBC and metastatic
urothelial cancer (UC), where high expression is associated with
poor survival and relapse. Beyond the approvals of Trodelvy in the
United States, it is also approved for metastatic TNBC in
Australia, Canada, Great Britain and Switzerland for adults with
metastatic TNBC. Trodelvy is also under multiple regulatory reviews
worldwide, including the EU, as well as in Singapore through our
partner Everest Medicines. Trodelvy is also being developed as an
investigational treatment for hormone receptor-positive/human
epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic
breast cancer and metastatic non-small cell lung cancer. Additional
evaluation across multiple solid tumors is also underway.
In the United States, Trodelvy is indicated for the treatment
of:
- Adult patients with unresectable locally advanced or metastatic
triple-negative breast cancer who have received two or more prior
systemic therapies, at least one of them for metastatic
disease.
- Adult patients with locally advanced or metastatic UC who have
previously received a platinum-containing chemotherapy and either
programmed death receptor-1 (PD-1) or programmed death-ligand 1
(PD-L1) inhibitor.
U.S. Important Safety Information for
Trodelvy
BOXED WARNING: NEUTROPENIA AND DIARRHEA
- Severe or life-threatening neutropenia may occur. Withhold
Trodelvy for absolute neutrophil count below 1500/mm3 or
neutropenic fever. Monitor blood cell counts periodically during
treatment. Consider G-CSF for secondary prophylaxis. Initiate
anti-infective treatment in patients with febrile neutropenia
without delay.
- Severe diarrhea may occur. Monitor patients with diarrhea
and give fluid and electrolytes as needed. Administer atropine, if
not contraindicated, for early diarrhea of any severity. At the
onset of late diarrhea, evaluate for infectious causes and, if
negative, promptly initiate loperamide. If severe diarrhea occurs,
withhold Trodelvy until resolved to ≤Grade 1 and reduce subsequent
doses.
CONTRAINDICATIONS
- Severe hypersensitivity reaction to Trodelvy.
WARNINGS AND PRECAUTIONS
Neutropenia: Severe, life-threatening, or fatal
neutropenia can occur and may require dose modification.
Neutropenia occurred in 61% of patients treated with Trodelvy.
Grade 3-4 neutropenia occurred in 47% of patients. Febrile
neutropenia occurred in 7%. Withhold Trodelvy for absolute
neutrophil count below 1500/mm3 on Day 1 of any cycle or neutrophil
count below 1000/mm3 on Day 8 of any cycle. Withhold Trodelvy for
neutropenic fever.
Diarrhea: Diarrhea occurred in 65% of all patients
treated with Trodelvy. Grade 3-4 diarrhea occurred in 12% of
patients. One patient had intestinal perforation following
diarrhea. Neutropenic colitis occurred in 0.5% of patients.
Withhold Trodelvy for Grade 3-4 diarrhea and resume when resolved
to ≤Grade 1. At onset, evaluate for infectious causes and if
negative, promptly initiate loperamide, 4 mg initially followed by
2 mg with every episode of diarrhea for a maximum of 16 mg daily.
Discontinue loperamide 12 hours after diarrhea resolves. Additional
supportive measures (e.g., fluid and electrolyte substitution) may
also be employed as clinically indicated. Patients who exhibit an
excessive cholinergic response to treatment can receive appropriate
premedication (e.g., atropine) for subsequent treatments.
Hypersensitivity and Infusion-Related Reactions: Serious
hypersensitivity reactions including life-threatening anaphylactic
reactions have occurred with Trodelvy. Severe signs and symptoms
included cardiac arrest, hypotension, wheezing, angioedema,
swelling, pneumonitis, and skin reactions. Hypersensitivity
reactions within 24 hours of dosing occurred in 37% of patients.
Grade 3-4 hypersensitivity occurred in 2% of patients. The
incidence of hypersensitivity reactions leading to permanent
discontinuation of Trodelvy was 0.3%. The incidence of anaphylactic
reactions was 0.3%. Pre-infusion medication is recommended. Observe
patients closely for hypersensitivity and infusion-related
reactions during each infusion and for at least 30 minutes after
completion of each infusion. Medication to treat such reactions, as
well as emergency equipment, should be available for immediate use.
Permanently discontinue Trodelvy for Grade 4 infusion-related
reactions.
Nausea and Vomiting: Nausea occurred in 66% of all
patients treated with Trodelvy and Grade 3 nausea occurred in 4% of
these patients. Vomiting occurred in 39% of patients and Grade 3-4
vomiting occurred in 3% of these patients. Premedicate with a two
or three drug combination regimen (e.g., dexamethasone with either
a 5-HT3 receptor antagonist or an NK1 receptor antagonist as well
as other drugs as indicated) for prevention of chemotherapy-induced
nausea and vomiting (CINV). Withhold Trodelvy doses for Grade 3
nausea or Grade 3-4 vomiting and resume with additional supportive
measures when resolved to Grade ≤1. Additional antiemetics and
other supportive measures may also be employed as clinically
indicated. All patients should be given take-home medications with
clear instructions for prevention and treatment of nausea and
vomiting.
Increased Risk of Adverse Reactions in Patients with Reduced
UGT1A1 Activity: Patients homozygous for the uridine
diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at
increased risk for neutropenia, febrile neutropenia, and anemia and
may be at increased risk for other adverse reactions with Trodelvy.
The incidence of Grade 3-4 neutropenia was 67% in patients
homozygous for the UGT1A1*28, 46% in patients heterozygous for the
UGT1A1*28 allele and 46% in patients homozygous for the wild-type
allele. The incidence of Grade 3-4 anemia was 25% in patients
homozygous for the UGT1A1*28 allele, 10% in patients heterozygous
for the UGT1A1*28 allele, and 11% in patients homozygous for the
wild-type allele. Closely monitor patients with known reduced
UGT1A1 activity for adverse reactions. Withhold or permanently
discontinue Trodelvy based on clinical assessment of the onset,
duration and severity of the observed adverse reactions in patients
with evidence of acute early-onset or unusually severe adverse
reactions, which may indicate reduced UGT1A1 function.
Embryo-Fetal Toxicity: Based on its mechanism of action,
Trodelvy can cause teratogenicity and/or embryo-fetal lethality
when administered to a pregnant woman. Trodelvy contains a
genotoxic component, SN-38, and targets rapidly dividing cells.
Advise pregnant women and females of reproductive potential of the
potential risk to a fetus. Advise females of reproductive potential
to use effective contraception during treatment with Trodelvy and
for 6 months after the last dose. Advise male patients with female
partners of reproductive potential to use effective contraception
during treatment with Trodelvy and for 3 months after the last
dose.
ADVERSE REACTIONS
In the ASCENT study (IMMU-132-05), the most common
adverse reactions (incidence ≥25%) were fatigue, neutropenia,
diarrhea, nausea, alopecia, anemia, constipation, vomiting,
abdominal pain, and decreased appetite. The most frequent serious
adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea
(4%), and pneumonia (3%). SAR were reported in 27% of patients, and
5% discontinued therapy due to adverse reactions. The most common
Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study
were reduced neutrophils, leukocytes, and lymphocytes.
In the TROPHY study (IMMU-132-06), the most common
adverse reactions (incidence ≥25%) were diarrhea, fatigue,
neutropenia, nausea, any infection, alopecia, anemia, decreased
appetite, constipation, vomiting, abdominal pain, and rash. The
most frequent serious adverse reactions (SAR) (≥5%) were infection
(18%), neutropenia (12%, including febrile neutropenia in 10%),
acute kidney injury (6%), urinary tract infection (6%), and sepsis
or bacteremia (5%). SAR were reported in 44% of patients, and 10%
discontinued due to adverse reactions. The most common Grade 3-4
lab abnormalities (incidence ≥25%) in the TROPHY study were reduced
neutrophils, leukocytes, and lymphocytes.
DRUG INTERACTIONS
UGT1A1 Inhibitors: Concomitant administration of Trodelvy
with inhibitors of UGT1A1 may increase the incidence of adverse
reactions due to potential increase in systemic exposure to SN-38.
Avoid administering UGT1A1 inhibitors with Trodelvy.
UGT1A1 Inducers: Exposure to SN-38 may be
substantially reduced in patients concomitantly receiving UGT1A1
enzyme inducers. Avoid administering UGT1A1 inducers with
Trodelvy.
Please see full Prescribing Information, including BOXED
WARNING.
About Gilead Sciences
Gilead Sciences, Inc. is a biopharmaceutical company that has
pursued and achieved breakthroughs in medicine for more than three
decades, with the goal of creating a healthier world for all
people. The company is committed to advancing innovative medicines
to prevent and treat life-threatening diseases, including HIV,
viral hepatitis and cancer. Gilead operates in more than 35
countries worldwide, with headquarters in Foster City,
California.
Forward-Looking
Statements
This press release includes forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of 1995
that are subject to risks, uncertainties and other factors,
including Gilead’s ability to initiate, progress or complete
clinical trials within currently anticipated timelines or at all,
including those involving Trodelvy; the possibility of unfavorable
results from ongoing or additional trials, including those
involving Trodelvy; Gilead’s ability to receive regulatory
approvals in a timely manner or at all, including additional
regulatory approvals of Trodelvy for the treatment of metastatic
TNBC, metastatic breast cancer, metastatic UC, metastatic non-small
cell lung cancer and other solid tumors, and the risk that
physicians may not see the benefits of prescribing Trodelvy; and
any such approvals may be subject to significant limitations on
use; the risk that physicians and any assumptions underlying any of
the foregoing. These and other risks, uncertainties and other
factors are described in detail in Gilead’s Quarterly Report on
Form 10-Q for the quarter ended June 30, 2021, as filed with the
U.S. Securities and Exchange Commission. These risks, uncertainties
and other factors could cause actual results to differ materially
from those referred to in the forward-looking statements. All
statements other than statements of historical fact are statements
that could be deemed forward-looking statements. Investors are
cautioned that any such forward-looking statements are not
guarantees of future performance and involve risks and
uncertainties and are cautioned not to place undue reliance on
these forward-looking statements. All forward-looking statements
are based on information currently available to Gilead, and Gilead
assumes no obligation and disclaims any intent to update any such
forward-looking statements.
U.S. Prescribing Information for Trodelvy
including BOXED WARNING, is available at www.gilead.com.
Trodelvy, Gilead and the Gilead logo are
trademarks of Gilead Sciences, Inc., or its related companies.
For more information about Gilead, please visit
the company’s website at www.gilead.com, follow Gilead on Twitter
(@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5
or 1-650-574-3000.
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Jacquie Ross, Investors (650) 358-1054
Karley Ura, Media (416) 858-0537
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