Gilead Sciences, Inc. (Nasdaq: GILD) today announced topline
results from the confirmatory Phase 3 TROPiCS-04 study in locally
advanced or metastatic urothelial cancer (mUC). The TROPiCS-04
study evaluated Trodelvy® (sacituzumab govitecan-hziy; SG) vs.
single-agent chemotherapy (treatment of physicians’ choice, TPC) in
patients with mUC who have previously received platinum-containing
chemotherapy and anti-PD-(L)1 therapy.
The study did not meet the primary endpoint of overall survival
(OS) in the intention-to-treat (ITT) population. A numerical
improvement in OS favoring Trodelvy was observed, and trends in
improvement for select pre-specified subgroups and secondary
endpoints of progression-free survival (PFS) and overall response
rate (ORR) were also shown. The pre-specified subgroup analyses
were not alpha-controlled for formal statistical testing. These
data will be presented at an upcoming medical meeting.
In the overall study population, there was a higher number of
deaths due to adverse events with Trodelvy compared to TPC, which
were primarily observed early in treatment and related to
neutropenic complications, including infection. Gilead will further
investigate these data, and is working to reiterate to treating
physicians the importance of granulocyte-colony stimulating factor
(G-CSF) use for the prevention of neutropenic complications.
Trodelvy has a Boxed Warning for severe or life-threatening
neutropenia; please see below for Important Safety Information.
There are no changes to the known safety profile of Trodelvy for
the approved breast cancer indications or other investigational
uses. To date, the Trodelvy safety profile is generally
well-tolerated and consistent with use in over 40,000 patients
across Trodelvy’s approved indications and in clinical trials.
Gilead is continuing to analyze the data and will discuss the
results and next steps with the FDA. In the U.S., Trodelvy has an
accelerated approval indication for patients with locally advanced
or metastatic urothelial cancer (mUC) who have previously received
a platinum-containing chemotherapy and anti-PD-(L)1 therapy. 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, including the TROPiCS-04
study.
Metastatic UC is an aggressive disease which most commonly
affects older patients with concurrent medical morbidities and
additional changes related to the aging process. Despite recent
advances, survival rates remain poor with only 8% of patients
living beyond five years after diagnosis. These results may in part
reflect the difficulty of treating patients with mUC who have
previously received platinum-containing chemotherapy and checkpoint
inhibitor therapy. There is an urgent need for new treatment
options to help improve long-term outcomes.
Gilead would like to thank the patients, families,
investigators, and advocates who contributed to this important
research. We remain committed to advancing care to address the
unmet needs for the bladder cancer community.
Trodelvy is the first approved Trop-2-directed antibody-drug
conjugate (ADC), which has demonstrated meaningful survival
advantages in two different types of metastatic breast cancers.
There are more than 20 ongoing clinical trials for Trodelvy.
Please see below for the approved U.S. Indication and additional
Important Safety Information.
About Metastatic Urothelial
Cancer
Bladder cancer is one of the most common cancers worldwide, with
more than 1.6 million people living with the disease and urothelial
cancer (UC) accounting for 90% of these cases. Metastatic bladder
cancer is an aggressive disease and survival rates remain poor,
with only 8% of patients living beyond five years after diagnosis.
Despite recent advances, less than 20% of patients with metastatic
bladder cancer go on to receive second-line therapy. There is an
urgent need for new treatment options for patients with mUC who
have progressed on available therapies to help improve long-term
outcomes.
About the TROPiCS-04
Study
The TROPiCS-04 study is an open-label, global, multi-center,
randomized Phase 3 study that evaluated Trodelvy vs. single-agent
chemotherapy (treatment of physicians’ choice, TPC) in patients
with locally advanced or mUC who received platinum-containing
chemotherapy and checkpoint inhibitor therapy. The study enrolled
711 patients randomized 1:1 to receive either Trodelvy or one of
three TPC chemotherapeutic standard of care (SOC) options:
paclitaxel, docetaxel, or vinflunine. The primary endpoint was OS.
Secondary endpoints included progression-free survival (PFS),
objective response rate (ORR), clinical benefit rate (CBR) and
duration of objective tumor response (DoR) as assessed by
investigator per Response Evaluation Criteria in Solid Tumors
(RECIST 1.1) and blinded independent central review (BICR). Further
study details are available on clinicaltrials.gov
(NCT04527991).
About Trodelvy
Trodelvy® (sacituzumab govitecan-hziy) is a first-in-class
Trop-2-directed antibody-drug conjugate. Trop-2 is a cell surface
antigen highly expressed in multiple tumor types, including in more
than 90% of breast, bladder and lung cancers. Trodelvy is
intentionally designed with a proprietary hydrolyzable linker
attached to SN-38, a topoisomerase I inhibitor payload. This unique
combination delivers potent activity to both Trop-2 expressing
cells and the tumor microenvironment through a bystander
effect.
Trodelvy is approved in almost 50 countries, with multiple
additional regulatory reviews underway worldwide, for the treatment
of adult patients with unresectable locally advanced or metastatic
triple-negative breast cancer (TNBC) who have received two or more
prior systemic therapies, at least one of them for metastatic
disease.
Trodelvy also has multiple global approvals for certain patients
with pre-treated HR+/HER2- metastatic breast cancer, including in
Australia, Brazil, Canada, the European Union, Israel, United Arab
Emirates and the United States. In the U.S., Trodelvy has an
accelerated approval for treatment of certain patients with
second-line or later metastatic urothelial cancer; see below for
full indication statements.
Trodelvy is being explored for potential investigational use in
other TNBC, HR+/HER2- and metastatic UC populations, as well as a
range of tumor types where Trop-2 is highly expressed, including
metastatic non-small cell lung cancer (NSCLC), head and neck
cancer, gynecological cancer, and gastrointestinal cancers.
U.S. Indications for
Trodelvy
In the United States, Trodelvy is indicated for the treatment of
adult patients with:
- Unresectable locally advanced or metastatic triple-negative
breast cancer (mTNBC) who have received two or more prior systemic
therapies, at least one of them for metastatic disease.
- Unresectable locally advanced or metastatic hormone receptor
(HR)-positive, human epidermal growth factor receptor 2
(HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who
have received endocrine-based therapy and at least two additional
systemic therapies in the metastatic setting.
- Locally advanced or metastatic urothelial cancer (mUC) who have
previously received a platinum-containing chemotherapy and either
programmed death receptor-1 (PD-1) or programmed death-ligand 1
(PD-L1) inhibitor. 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.
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. At the onset of
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 64% of patients treated with Trodelvy.
Grade 3-4 neutropenia occurred in 49% of patients. Febrile
neutropenia occurred in 6%. Neutropenic colitis occurred in 1.4%.
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. Administer
G-CSF as clinically indicated or indicated in Table 1 of USPI.
Diarrhea: Diarrhea occurred in 64% of all patients
treated with Trodelvy. Grade 3-4 diarrhea occurred in 11% of
patients. One patient had intestinal perforation following
diarrhea. Diarrhea that led to dehydration and subsequent acute
kidney injury occurred in 0.7% of all 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 35% of patients.
Grade 3-4 hypersensitivity occurred in 2% of patients. The
incidence of hypersensitivity reactions leading to permanent
discontinuation of Trodelvy was 0.2%. The incidence of anaphylactic
reactions was 0.2%. Pre-infusion medication is recommended. Have
medications and emergency equipment to treat such reactions
available for immediate use. Observe patients closely for
hypersensitivity and infusion-related reactions during each
infusion and for at least 30 minutes after completion of each
infusion. Permanently discontinue Trodelvy for Grade 4
infusion-related reactions.
Nausea and Vomiting: Nausea occurred in 64% of all
patients treated with Trodelvy and Grade 3-4 nausea occurred in 3%
of these patients. Vomiting occurred in 35% of patients and Grade
3-4 vomiting occurred in 2% 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 58% in patients
homozygous for the UGT1A1*28, 49% in patients heterozygous for the
UGT1A1*28 allele, and 43% in patients homozygous for the wild-type
allele. The incidence of Grade 3-4 anemia was 21% in patients
homozygous for the UGT1A1*28 allele, 10% in patients heterozygous
for the UGT1A1*28 allele, and 9% 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 pooled safety population, the most common (≥ 25%) adverse
reactions including laboratory abnormalities were decreased
leukocyte count (84%), decreased neutrophil count (75%), decreased
hemoglobin (69%), diarrhea (64%), nausea (64%), decreased
lymphocyte count (63%), fatigue (51%), alopecia (45%), constipation
(37%), increased glucose (37%), decreased albumin (35%), vomiting
(35%), decreased appetite (30%), decreased creatinine clearance
(28%), increased alkaline phosphatase (28%), decreased magnesium
(27%), decreased potassium (26%), and decreased sodium (26%).
In the ASCENT study (locally advanced or metastatic
triple-negative breast cancer), the most common adverse reactions
(incidence ≥25%) were fatigue, diarrhea, nausea, alopecia,
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 TROPiCS-02 study (locally advanced or metastatic
HR-positive, HER2-negative breast cancer), the most common adverse
reactions (incidence ≥25%) were diarrhea, fatigue, nausea,
alopecia, and constipation. The most frequent serious adverse
reactions (SAR) (>1%) were diarrhea (5%), febrile neutropenia
(4%), neutropenia (3%), abdominal pain, colitis, neutropenic
colitis, pneumonia, and vomiting (each 2%). SAR were reported in
28% of patients, and 6% discontinued therapy due to adverse
reactions. The most common Grade 3-4 lab abnormalities (incidence
≥25%) in the TROPiCS-02 study were reduced neutrophils and
leukocytes.
In the TROPHY study (locally advanced or metastatic
urothelial cancer), the most common adverse reactions (incidence
≥25%) were diarrhea, fatigue, nausea, any infection, alopecia,
decreased appetite, constipation, vomiting, rash, and abdominal
pain. 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 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, COVID-19, 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,
and the possibility of unfavorable results from ongoing or
additional clinical trials, including those involving Trodelvy;
uncertainties relating to regulatory applications and related
filing and approval timelines, including pending or potential
applications for Trodelvy for the treatment of metastatic and other
TNBC, HR+/HER2- metastatic breast cancer, mUC, metastatic NSCLC,
head and neck cancer, gynecological cancer and gastrointestinal
cancer; Gilead’s ability to receive regulatory approvals for
programs and/or indications that are currently under evaluation in
a timely manner or at all, including the risk that the FDA may not
grant full approval or may withdraw its accelerated approval for
Trodelvy for the treatment of locally advanced or metastatic
urothelial cancer (mUC), and the risk that any such approvals may
be subject to significant limitations on use and is subject to,
withdrawal or other adverse actions by the applicable regulatory
authority; the possibility that Gilead may make a strategic
decision to discontinue development of programs for indications
that are currently under evaluation, including Trodelvy for
treatment of mUC, and as a result, these programs may never be or
cease to be commercialized for such indications; 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 March 31, 2024,
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. The
reader is cautioned that any such forward-looking statements are
not guarantees of future performance and involve risks and
uncertainties, and is 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 or call Gilead Public
Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
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version on businesswire.com: https://www.businesswire.com/news/home/20240530516266/en/
Jacquie Ross, Investors investor_relations@gilead.com
Ashleigh Koss, Media public_affairs@gilead.com
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