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U.S. FDA Approves
Trodelvy
® in Pre-treated
HR+/HER2- Metastatic Breast Cancer
HR+/HER2
- Metastatic Breast Cancer
2023-02-03
·
BioSpace
临床结果
上市批准
临床3期
ASCO会议
优先审批
-- First
Trop-2
Directed
ADC
to Demonstrate Overall Survival Benefit in
HR+/HER2- Metastatic Breast Cancer
HR+/HER2
- Metastatic Breast Cancer Patients who had Received Prior Endocrine-based Therapy and at Least Two Chemotherapies -- --
Trodelvy
has Now Improved Survival in both Pre-Treated
HR+/HER2- Metastatic Breast Cancer
HR+/HER2
- Metastatic Breast Cancer and in Second-Line
Metastatic Triple-Negative Breast Cancer
-- FOSTER CITY, Calif.--(BUSINESS WIRE)--
Gilead Sciences, Inc.
, (Nasdaq: GILD) today announced the U.S.
Food and Drug Administration (FDA)
has approved
Trodelvy
® (
sacituzumab
govitecan-hziy
) for the treatment of adult patients with 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. The approval is based on statistically significant and clinically meaningful progression-free survival and overall survival data from the Phase 3 TROPiCS-02 study.
Trodelvy
is now also recommended as a Category 1, preferred treatment for metastatic
HR+/HER2- breast cancer
HR+/HER2
- breast cancer by the National Comprehensive Cancer Network® (NCCN®) as defined in the Clinical Practice Guidelines in Oncology (NCCN Guidelines®)i. This press release features multimedia. View the full release here: (Graphic: Business Wire) “Despite decades of advances, people living with pre-treated
HR+/HER2- metastatic breast cancer
HR+/HER2
- metastatic breast cancer need new treatment options. Nearly all people with this type of
breast cancer
will eventually develop resistance to endocrine-based therapies and progress on available chemotherapies,” said Hope S. Rugo, MD, Professor of Medicine and Director, Breast Oncology and Clinical Trials Education at the
UCSF Helen Diller Family Comprehensive Cancer Center
, U.S. and principal investigator of the TROPiCS-02 study. “This approval is significant for the
breast cancer
community. We have had limited options to offer patients after endocrine-based therapy and chemotherapy, and to see a clinically meaningful survival benefit of more than three months with a quality of life benefit for these women is exceptional.” In the TROPiCS-02 study,
Trodelvy
demonstrated a statistically significant and clinically meaningful overall survival (OS) benefit of 3.2 months versus comparator single-agent chemotherapy (treatment of physician’s choice; TPC) (median OS: 14.4 months vs. 11.2 months; hazard ratio [HR]=0.79; 95% CI: 0.65-0.96; p=0.02).
Trodelvy
also demonstrated a 34% reduction in risk of disease progression or death (median PFS: 5.5 versus 4.0 months; HR: 0.66; 95% CI: 0.53-0.83; p=0.0003). Three times as many people treated with
Trodelvy
were progression free at one year versus those treated with chemotherapy (21% versus 7%). In a post-hoc analysis, data demonstrated
Trodelvy
’s efficacy across
HER2-low
and IHC0 status in pre-treated
metastatic breast cancer
patients in the TROPiCS-02 trial.
Trodelvy
also significantly improved additional secondary endpoint measures, including objective response rate and time to deterioration (TTD) assessed by the Global Health Status/Quality of Life and
Fatigue
scale per EORTC-QLQ-C30. No statistically significant difference in TTD in
Pain
Scale was observed. “The FDA approval is an important step forward for both women and men living with
metastatic breast cancer
, especially for those individuals whose
tumor
is no longer responding to endocrine-based therapies and who are facing a poor prognosis,” said Laura Carfang, Executive Director, SurvivingBreastCancer.org. “We need to combat this terrible disease, and all options that potentially slow its progress and extend life for those living with
metastatic breast cancer
are welcomed.” “We are pleased that
Trodelvy
could now provide new hope for people living with pre-treated
HR+/HER2- metastatic breast cancer
HR+/HER2
- metastatic breast cancer, building on the transformative role that
Trodelvy
is already playing for people with
metastatic triple-negative breast cancer
,” said Daniel O'Day, Chairman and Chief Executive Officer,
Gilead Sciences
. “We thank the physicians, patients and their families who put their trust in the TROPiCS-02 study and helped make this milestone possible.” The safety pro
Trodelvy
was consistent with prior studies, with no new safety signals identified in this patient population. In TROPiCS-02 the most frequent serious adverse reactions (>1%) were
diarrhea
(5%),
febrile neutropenia
(4%),
neutropenia
(3%),
abdominal pain
,
colitis
,
neutropenic colitis
,
pneumonia
, and
vomiting
(each 2%). The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPiCS-02 study were reduced neutrophils and leukocytes. No patients treated with
Trodelvy
experienced
interstitial lung disease
. This review by the FDA was conducted under Project Orbis and granted Priority Review. The
European Medicines Agency
has also validated a Type II Variation Marketing Authorization Application for
Trodelvy
in
HR+/HER2- metastatic breast cancer
HR+/HER2
- metastatic breast cancer.
Trodelvy
has a Boxed Warning for severe or life-threatening
neutropenia
and severe
diarrhea
; please see below for additional Important Safety Information. About
HR+/HER2- Metastatic Breast Cancer
HR+/HER2
- Metastatic Breast Cancer
Hormone receptor-positive/human epidermal growth factor receptor
2-negative
(HR+/HER2-) breast cancer
HR+/HER2
-) breast cancer is the most common type of
breast cancer
and accounts for approximately 70% of all new cases. Almost one in three cases of
early-stage breast cancer
eventually become metastatic, and among patients with
HR+/HER2- metastatic disease
HR+/HER2
- metastatic disease, the five-year relative survival rate is 30%. As patients with
HR+/HER2- metastatic breast cancer
HR+/HER2
- metastatic breast cancer become resistant to endocrine-based therapy, their primary treatment option is limited to single-agent chemotherapy. In this setting, it is common to receive multiple lines of chemotherapy regimens over the course of treatment, and the prognosis remains poor. About the TROPiCS-02 Study The TROPiCS-02 study is a global, multicenter, open-label, Phase 3 study, randomized 1:1 to evaluate
Trodelvy
versus physicians’ choice of chemotherapy (
eribulin
,
capecitabine
,
gemcitabine
, or
vinorelbine
) in 543 patients with
HR+/HER2- metastatic breast cancer
HR+/HER2
- metastatic breast cancer who were previously treated with endocrine therapy,
CDK4/6 inhibitor
CDK4/6
inhibitor and two to four lines of chemotherapy for metastatic disease. The primary endpoint is progression-free survival per Response Evaluation Criteria in
Solid Tumors
(RECIST 1.1) as assessed by blinded independent central review (BICR) for participants treated with
Trodelvy
compared to those treated with chemotherapy. Secondary endpoints include overall survival, overall response rate, clinical benefit rate and duration of response, as well as assessment of safety and tolerability and quality of life measures. In the study,
HER2
negativity was defined per American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) criteria as immunohistochemistry (IHC) score of 0, IHC 1+ or IHC 2+ with a negative in-situ hybridization (ISH) test. More information about TROPiCS-02 is available at . 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 and bladder 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 microenvironment.
Trodelvy
is approved in more than 40 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
is also approved in the U.S. to treat certain patients with pre-treated
HR+/HER2- metastatic breast cancer
HR+/HER2
- metastatic breast cancer and has an accelerated approval for treatment of certain patients with second-line
metastatic urothelial cancer
; see below for full indication statements.
Trodelvy
is also being developed 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)
,
metastatic small cell lung cancer (SCLC)
,
head and neck cancer
, and
endometrial cancer
. 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
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
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
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 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 for Trodelvy and related filing and approval timelines, including the risk that the
European Commission
may not approve the pending marketing authorization application for Trodelvy in HR+/HER2- metastatic breast cancer, and pending or potential applications for the treatment of metastatic TNBC, mUC, HR+/HER2- breast cancer, NSCLC, SCLC, head and neck cancer, endometrial cancer and other cancers, in the currently anticipated timelines or at all;
Gilead
’s ability to receive regulatory approvals for such indications in a timely manner or at all, and the risk that any such approvals may be subject to significant limitations on use; the possibility that
Gilead
may make a strategic decision to discontinue development of Trodelvy for such indications and as a result, Trodelvy may never be commercialized for these indications; the risk that physicians may not see the benefits of prescribing Trodelvy for treatment of HR+/HER2- metastatic breast cancer; 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 September 30, 2022, 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 . 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 , follow
Gilead
on Twitter (@GileadSciences) or call
Gilead
Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000. UC Disclaimer The information stated above was prepared by
Gilead Sciences, Inc.
, and reflects solely the opinion of the corporation. Nothing in this statement shall be construed to imply any support or endorsement of
Gilead
, or any of its products, by The Regents of the
University of California
, its officers, agents and employees. i Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for
Breast Cancer
Version 1.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed January 2023. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
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机构
ADC Therapeutics SA
Gilead Sciences, Inc.
US Food & Drug Administration
[+4]
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EGFR
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