– The First Pivotal Phase 3 Trial to Demonstrate Superiority of a TROP-2 Antibody-Drug Conjugate, Trodelvy, Plus Keytruda Versus Standard of Care Keytruda plus Chemotherapy in 1L mTNBC –
– Trodelvy Plus Keytruda Shows an Early Trend in Improvement for Overall Survival Versus Standard of Care in Patients with Previously Untreated PD-L1+ (CPS ≥10) mTNBC –
FOSTER CITY, Calif.--(BUSINESS WIRE)-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced positive topline results from the Phase 3 ASCENT-04/KEYNOTE-D19 study, demonstrating that Trodelvy® (sacituzumab govitecan-hziy) plus Keytruda® (pembrolizumab) significantly improved progression-free survival (PFS) compared to Keytruda and chemotherapy in patients with inoperable (unresectable) locally advanced or metastatic triple-negative breast cancer (mTNBC) whose tumors express PD-L1 (CPS ≥ 10). The study met its primary endpoint, showing a statistically significant and clinically meaningful improvement in PFS.
The safety profile of Trodelvy plus Keytruda in the ASCENT-04 study was consistent with the known safety profile of each agent. No new safety signals were identified with the combination.
“These findings are the first to show the transformative potential of an antibody-drug conjugate combined with an immuno-oncology agent in early treatment lines of metastatic breast cancer,” said Dietmar Berger, MD, PhD, Chief Medical Officer, Gilead Sciences. “For patients with this difficult to treat type of breast cancer, these results potentially offer a new pathway that may redefine their treatment options.”
“For patients with metastatic triple-negative breast cancer, there is a critical need for more effective treatment options,” said Dr. Sara Tolaney, MD, MPH, Dana-Farber Cancer Institute and primary investigator of the ASCENT-04 study. “These data suggest that the combination of sacituzumab govitecan-hziy and pembrolizumab may offer a new treatment approach—bringing together a potent antibody drug conjugate with immunotherapy to improve outcomes for patients.”
Overall survival (OS) is a key secondary endpoint and was not mature at the time of the PFS primary analysis. However, in the ASCENT-04 study, there was an early trend in improvement for OS with Trodelvy plus Keytruda. Gilead will continue to monitor OS outcomes, with ongoing patient follow-up and further analyses planned.
Detailed results from the study will be presented at a future medical meeting and discussed with regulatory authorities. The use of Trodelvy plus Keytruda in patients with previously untreated PD-L1+ metastatic TNBC is investigational, and the safety and efficacy of this use have not been established.
The significant and meaningful improvement in PFS demonstrated in ASCENT-04 further reinforces the potential of Trodelvy plus Keytruda as a much-needed new treatment option for patients with previously untreated inoperable (unresectable) PD-L1+ locally advanced or mTNBC.
Trodelvy is the only approved Trop-2-directed antibody-drug conjugate (ADC) that has demonstrated meaningful survival advantages in two different types of metastatic breast cancers: 2L+ mTNBC and pre-treated HR+/HER2- mBC. It is a Category 1 preferred treatment for both indications per the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelinesi) and the only ADC with an ESMO Magnitude of Clinical Benefit Scale (MCBS) rating of 5 for mTNBC. Trodelvy also has an MCBS rating of 4 for women with HR+/HER2- mBC.
With established healthcare professional experience, Trodelvy has shown consistent outcomes across clinical trials and real-world studies in 50,000+ patients across ~50 countries over ~5 years. It has now demonstrated improved outcomes in three Phase 3 breast cancer trials and is being studied in several ongoing clinical trials, aiming to extend survival across diverse tumor types and disease stages.
Currently, Gilead has three ongoing Phase 3 studies investigating Trodelvy across HER2- (IHC 0, IHC 1+ or IHC 2+/ISH–) mBC, including the upcoming ASCENT-03 pivotal trial in 1L mTNBC patients who are not candidates for PD-L1 based therapy, the ASCENT-05 pivotal trial in patients with early-stage TNBC (eTNBC), and the ASCENT-07 pivotal trial in patients with HR+/HER2- mBC who have received endocrine therapy. Trodelvy is also being investigated in additional Phase 3 studies in other disease settings, including in lung and gynecological cancers.
Gilead would like to thank the patients, families, investigators and advocates who have contributed and continue to contribute to this important research. We remain committed to advancing care to address the unmet needs for the breast cancer community.
KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
About Triple-Negative Breast Cancer with PD-L1+ Tumors
TNBC is the most aggressive type of breast cancer and has historically been difficult to treat, accounting 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 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 mTNBC, the five-year survival rate is 12%, compared with 28% for those with other types of mBC.
Despite progress in treatment, first-line mTNBC has seen limited new approvals in recent years for tumors that express PD-L1+, and additional options are urgently needed. Despite recent advances, over 50% of patients do not receive treatment beyond first-line, reinforcing the urgent need for new options to help improve patient outcomes. Breast cancers expressing PD-L1 are overall more aggressive and associated with reduced survival time.
About the ASCENT-04/KEYNOTE-D19 Study
In 2021, Gilead entered a collaboration with Merck & Co. to investigate sacituzumab govitecan in combination with pembrolizumab in the Phase 3 trial, ASCENT-04/KEYNOTE-D19. The ASCENT-04/KEYNOTE-D19 study is a global, open-label, randomized Phase 3 trial evaluating the efficacy and safety of sacituzumab govitecan in combination with pembrolizumab compared with treatment of chemotherapy plus pembrolizumab in patients with previously untreated, inoperable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1. The study enrolled 443 patients across multiple study sites.
Patients were randomized in a 1:1 ratio to receive either sacituzumab govitecan (10 mg/kg intravenously on Days 1 and 8 of a 21-day cycle) plus pembrolizumab (200 mg intravenously on Day 1 of a 21-day cycle) or chemotherapy plus pembrolizumab. The chemotherapy regimen included gemcitabine plus carboplatin, paclitaxel, or nab-paclitaxel. Treatment continued until blinded independent central review (BICR)-verified disease progression or unacceptable toxicity. Patients randomized to chemotherapy were allowed to crossover and receive sacituzumab govitecan upon disease progression.
The primary endpoint of the study is progression-free survival (PFS) as determined by BICR using RECIST v1.1. Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), time to onset of response (TTR), patient-reported outcomes (PROs), and safety.
More information about ASCENT-04/KEYNOTE-D19 is available at ClinicalTrials.gov: NCT05382286.
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 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 currently approved in more than 50 countries for second-line or later metastatic triple-negative breast cancer (TNBC) patients and in more than 40 countries for certain patients with pre-treated HR+/HER2- metastatic breast cancer.
Trodelvy is being investigated for use in other TNBC and HR+/HER2- breast cancer populations, as well as a range of tumor types where Trop-2 is highly expressed, including extensive-stage small cell lung cancer and first-line metastatic non-small cell lung cancer where Trodelvy has shown clinical activity through the TROPiCS-03 proof-of-concept study and the EVOKE-02 proof-of-concept study, respectively.
INDICATIONS
TRODELVY® (sacituzumab govitecan-hziy) is a Trop-2-directed antibody and topoisomerase inhibitor conjugate 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.
IMPORTANT SAFETY INFORMATION
BOXED WARNING: NEUTROPENIA AND DIARRHEA
TRODELVY can cause severe, life-threatening, or fatal neutropenia. Withhold TRODELVY for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Primary prophylaxis with G-CSF is recommended for all patients at increased risk of febrile neutropenia. Initiate anti-infective treatment in patients with febrile neutropenia without delay.
TRODELVY can cause severe diarrhea. 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 as early as the first cycle of treatment 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%. Primary prophylaxis with G-CSF is recommended starting in the first cycle of treatment in all patients at increased risk of febrile neutropenia, including older patients, patients with previous neutropenia, poor performance status, organ dysfunction, or multiple comorbidities. Monitor absolute neutrophil count (ANC) during treatment. Withhold TRODELVY for ANC below 1500/mm3 on Day 1 of any cycle or below 1000/mm3 on Day 8 of any cycle. Withhold TRODELVY for neutropenic fever. Treat neutropenia with G-CSF and administer prophylaxis in subsequent cycles as clinically indicated or indicated in Table 2 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: TRODELVY can cause serious hypersensitivity reactions including life-threatening anaphylactic reactions. 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: TRODELVY is emetogenic and can cause severe 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.
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 or studies within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing and additional clinical trials or studies, including those involving Trodelvy (such as ASCENT-03, ASCENT-04 and ASCENT-05); uncertainties relating to regulatory applications and related filing and approval timelines, including potential applications for programs and/or indications currently under evaluation; the possibility that Gilead may make a strategic decision to discontinue development of these programs and, as a result, these programs may never be successfully commercialized for the indications currently under evaluation; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and factors are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 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.
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