Sacituzumab Govitecan

TRODELVY is a Trop-2-directed antibody and topoisomerase inhibitor conjugate indicated: Locally Advanced or Metastatic Triple-Negative Breast Cancer First Line As a single agent for the first-line treatment of adult patients with unresectable locally advanced or metastatic triple negative breast cancer (TNBC) who are not candidates for PD-1 or PD-L1 inhibitor-based therapy. ( 1.1 , 14.1 ) In combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph for the first-line treatment of adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (CPS ≥ 10) as determined by an FDA-authorized test. ( 1.1 , 14.1 ) Second Line or Later For the treatment of adult patients with unresectable locally advanced or mTNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease. ( 1.1 , 14.1 ) Locally Advanced or Metastatic HR-Positive, HER2-Negative Breast Cancer 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. ( 1.1 , 14.2 )

1.1 Locally Advanced or Metastatic Triple-Negative Breast Cancer First Line TRODELVY as a single agent is indicated for the first-line treatment of adult patients with unresectable locally advanced or metastatic triple negative breast cancer (TNBC) who are not candidates for PD-1 or PD-L1 inhibitor based therapy. TRODELVY, in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, is indicated for the first-line treatment of adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 [Combined Positive Score (CPS ≥ 10)] as determined by an FDA-authorized test [see Dosage and Administration (2.1) ] . Second Line or Later TRODELVY is indicated for the treatment of adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease.

1.2 Locally Advanced or Metastatic HR-positive, HER2-negative Breast Cancer TRODELVY is indicated 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.

For injection: 180 mg off-white to yellowish lyophilized powder in a single-dose vial. For injection: 180 mg lyophilized powder in single-dose vials for reconstitution. ( 3 )

TRODELVY is contraindicated in patients who have experienced a severe hypersensitivity reaction to TRODELVY [see Warnings and Precautions (5.3) ] . Severe hypersensitivity reaction to TRODELVY. ( 4 , 5.3 )

Hypersensitivity and Infusion-Related Reactions : Hypersensitivity reactions including severe anaphylactic reactions have been observed. Monitor patients for infusion-related reactions. Permanently discontinue TRODELVY if severe or life-threatening reactions occur. ( 5.3 ) Nausea/Vomiting : Use antiemetic preventive treatment and withhold TRODELVY for patients with Grade 3 nausea or Grade 3-4 vomiting at the time of scheduled treatment. ( 5.4 ) Patients with Reduced UGT1A1 Activity : Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia following initiation of TRODELVY. ( 5.5 ) Embryo-Fetal Toxicity : TRODELVY can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 )

5.1 Neutropenia TRODELVY can cause severe, life-threatening, or fatal neutropenia as early as the first cycle of treatment. Neutropenia occurred in 64% of patients treated with TRODELVY. Grade 3-4 neutropenia occurred in 48% of patients. Febrile neutropenia occurred in 6% of patients. The median time to first onset of neutropenia (including febrile neutropenia) was 19 days (range: 1 to 1022 days). Neutropenia occurred earlier in patients with reduced UGT1A1 activity [see Warnings and Precautions (5.5) ] . Neutropenic colitis occurred in 1.4% of patients. 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 [see Dosage and Administration (2.1) ] . Monitor absolute neutrophil count (ANC) during treatment. Withheld TRODELVY for ANC below 1500/mm 3 on Day 1 of any cycle or below 1000/mm 3 on Day 8 of any cycle. Withhold TRODELVY for neutropenic fever. Dose modifications may be required due to neutropenia. Treat neutropenia with G-CSF and administer prophylaxis in subsequent cycles as clinically indicated or indicated in Table 2 [see Dosage and Administration (2.4) ] .

5.2 Diarrhea TRODELVY can cause severe diarrhea. Diarrhea occurred in 62% of all patients treated with TRODELVY. Grade 3-4 diarrhea occurred in 10% of all patients treated with TRODELVY. One patient had intestinal perforation following diarrhea. Diarrhea that led to dehydration and subsequent acute kidney injury occurred in 0.6% of all patients. Withhold TRODELVY for Grade 3-4 diarrhea at the time of scheduled treatment administration and resume when resolved to ≤ Grade 1 [see Dosage and Administration (2.4) ]. At the onset of diarrhea, 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 replacement) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment with TRODELVY (e.g., abdominal cramping, diarrhea, salivation, etc.) can receive appropriate premedication (e.g., atropine) for subsequent treatments.

5.3 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, and skin reactions [see Contraindications (4) ] . Hypersensitivity reactions occurred in 28% of patients treated with TRODELVY with 13% occurring within 24 hours of dosage. Grade 3-4 hypersensitivity occurred in 1.5% of patients treated with TRODELVY with 0.4% of these occurring within 24 hours of dosage. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.4%. The incidence of anaphylactic reaction was <0.1%. Premedication for infusion reactions in patients receiving TRODELVY is recommended . Have medications and emergency equipment to treat infusion-related reactions, including anaphylaxis, available for immediate use when administering TRODELVY [see Dosage and Administration (2.1) ]. Closely monitor patients for hypersensitivity and infusion-related reactions during each TRODELVY infusion and for at least 30 minutes after completion of each infusion [see Dosage and Administration (2.3) ] . Permanently discontinue TRODELVY for Grade 4 infusion-related reactions [see Dosage and Administration (2.4) ] .

5.4 Nausea and Vomiting TRODELVY is emetogenic and can cause severe nausea and vomiting. Nausea occurred in 63% of all patients treated with TRODELVY. Grade 3-4 nausea occurred in 3% of patients. Vomiting occurred in 33% of all patients treated with TRODELVY. 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 NK 1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV) [ see Dosage and Administration (2.1) ]. Withhold TRODELVY doses for Grade 3 nausea or Grade 3-4 vomiting at the time of scheduled treatment administration and resume with additional supportive measures when resolved to ≤Grade 1 [see Dosage and Administration (2.4) ]. 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.

5.5 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 when treated with TRODELVY. The incidence of neutropenia and anemia was analyzed in 1202 patients who received TRODELVY and had UGT1A1 genotype results. In patients homozygous for the UGT1A1 *28 allele (n=138), the incidence of Grade 3-4 neutropenia was 57%. In patients heterozygous for the UGT1A1*28 allele (n=531), the incidence of Grade 3-4 neutropenia was 48%. In patients homozygous for the wild-type allele (n=533), the incidence of Grade 3-4 neutropenia was 41% [see Clinical Pharmacology (12.5) ] . In patients homozygous for the UGT1A1 *28 allele, the incidence of Grade 3-4 anemia was 17%. In patients heterozygous for the UGT1A1*28 allele, the incidence of Grade 3-4 anemia was 9%. In patients homozygous for the wild-type allele, the incidence of Grade 3-4 anemia was 8%. The median time to first neutropenia including febrile neutropenia was 9 days in patients homozygous for the UGT1A1*28 allele, 19 days in patients heterozygous for the UGT1A1*28 allele, and 21 days in patients homozygous for the wild-type allele. The median time to first anemia was 22 days in patients homozygous for the UGT1A1*28 allele, 29 days in patients heterozygous for the UGT1A1*28 allele, and 29 days 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 enzyme activity [see Dosage and Administration (2.4) ].

5.6 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 [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1) ]. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. […]

The following adverse reactions are discussed in greater detail in other sections of the label: Neutropenia [see Warnings and Precautions (5.1) ] Diarrhea [see Warnings and Precautions (5.2) ] Hypersensitivity and Infusion-Related Reactions [see Warnings and Precautions (5.3) ] Nausea and Vomiting [see Warnings and Precautions (5.4) ] The most common adverse reactions including laboratory abnormalities: TRODELVY as a single agent (incidence ≥ 25%) were decreased leukocyte count, decreased neutrophil count, decreased hemoglobin, nausea, diarrhea, decreased lymphocyte count, fatigue, alopecia, increased glucose, constipation, vomiting, decreased albumin, increased alkaline phosphatase, decreased appetite, abdominal pain, decreased creatinine clearance, decreased magnesium, and decreased potassium. ( 6.1 ) TRODELVY in combination with pembrolizumab (incidence ≥25%) were decreased neutrophil count, decreased hemoglobin, decreased leukocyte count, diarrhea, nausea, decreased lymphocyte count, fatigue, alopecia, increased alkaline phosphatase, increased glucose, increased alanine aminotransferase, constipation, increased aspartate aminotransferase, rash, decreased potassium, increased lactate dehydrogenase, vomiting, abdominal pain, headache, increased eosinophils, and decreased albumin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-888-983-4668 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The pooled safety population described in the Warnings and Precautions section reflect exposure to TRODELVY as a single agent in 1354 patients, which included 641 patients with mTNBC and 322 patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer from ASCENT-03, IMMU-132-01, ASCENT, and TROPiCS-02; and 391 patients with other tumor types. TRODELVY was administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles at doses of 10 mg/kg until disease progression or unacceptable toxicity. Among the 1354 patients treated with TRODELVY, the median duration of treatment was 4.9 months (range: 0 to 63 months). In this pooled safety population, the most common (> 25%) adverse reactions including laboratory abnormalities were decreased leukocyte count (83%), decreased neutrophil count (77%), decreased hemoglobin (71%), nausea (63%), diarrhea (62%), decreased lymphocyte count (60%), fatigue (59%), alopecia (47%), increased glucose (40%), constipation (37%), vomiting (33%), decreased albumin (32%), increased alkaline phosphatase (30%) decreased appetite (28%), abdominal pain (27%), decreased creatinine clearance (27%), decreased magnesium (26%), and decreased potassium (26%). The data described in the following section reflects exposure to TRODELVY in combination with intravenous pembrolizumab in 221 patients with PD-L1 positive TNBC from ASCENT-04. Among the 221 patients who received TRODELVY in combination with intravenous pembrolizumab, the most common (≥ 25%) adverse reactions including laboratory abnormalities were decreased neutrophil count and decreased hemoglobin (86% each), decreased leukocyte count (84%), diarrhea (72%), nausea (68%), decreased lymphocyte count (61%), fatigue (58%), alopecia (52%), increased alkaline phosphatase and increased glucose (50% each), increased alanine aminotransferase (47%), constipation (41%), increased aspartate aminotransferase (40%), rash (37%), decreased potassium (35%), increased lactate dehydrogenase (34%), vomiting (29%), abdominal pain, headache, increased eosinophils (26% each) and decreased albumin (25%). Locally Advanced or Metastatic Triple-Negative Breast Cancer (TNBC) Single-Agent in Previously Untreated Unresectable Locally Advanced or Metastatic TNBC (ASCENT-03) The safety of TRODELVY was evaluated in 275 patients with unresectable locally advanced or metastatic TNBC who had not received previous systemic therapy for advanced disease and who were not candidates for PD-1 or PD-L1 inhibitor therapy who had received at least one dose of TRODELVY 10 mg/kg in ASCENT-03. [see Clinical Studies (14.1) ] . The median duration of treatment was 8.3 months (range: 0 to 29 months). Serious adverse reactions occurred in 26% of patients receiving TRODELVY. Serious adverse reactions in > 2% of patients included diarrhea, febrile neutropenia, and neutropenia (3.6% each) and pneumonia (2.9%). Fatal adverse reactions occurred in 2.5% of patients who received TRODELVY including sepsis (1.1%) and acute respiratory failure , neutropenic colitis, pneumonia, and septic shock (0.4% each). Permanent discontinuation of TRODELVY due to adverse reactions occurred in 3.6% of patients, of which interstitial lung disease accounted for 1.1%. Dosage interruptions of TRODELVY occurred in 66% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients were decreased neutrophil count (43%), diarrhea (6%), decreased leukocyte count and COVID-19 (5% each). Dose reductions of TRODELVY due to an adverse reaction occurred in 37% of patients. Adverse reaction which required dose reductions in >2% of patients included decreased neutrophil count (18%), diarrhea (6%), fatigue (4.7%), febrile neutropenia (2.5%), and weight decreased (2.2%). The most common (≥25%) adverse reactions, including laboratory abnormalities, were decreased neutrophil count (84%), decreased leukocyte count (80%), decreased hemoglobin (78%), nausea (61%), diarrhea and alopecia (55% each), increased glucose (52%), decreased lymphocyte count and fatigue (47% each), increased alanine aminotransferase (39%), increased alkaline phosphatase and constipation (38% each), increased lactate dehydrogenase (35%), increased aspartate aminotransferase (31%), decreased potassium (28%) and vomiting (25%). Tables 3 and 4 summarize the adverse reactions and laboratory abnormalities in ASCENT-03. Table 3: Adverse Reactions in ≥ 10% of Patients with Metastatic TNBC in ASCENT-03 TRODELVY (n=275) Treatment of Physician’s Choice Treatment of Physician’s Choice included gemcitabine/carboplatin (n=122), nab-paclitaxel (n=110), and paclitaxel (n=44) (n=276) Adverse Reaction Graded per NCI CTCAE v.5.0. […]

UGT1A1 Inhibitors or Inducers : Avoid concomitant use. ( 7 )

7.1 Effect of Other Drugs on TRODELVY UGT1A1 Inhibitors Avoid administering UGT1A1 inhibitors with TRODELVY. SN-38 is a UGT1A1 substrate. 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 [see Warnings and Precaution (5.5) and Clinical Pharmacology (12.3 , 12.5) ] . UGT1A1 Inducers Avoid administering UGT1A1 inducers with TRODELVY. SN-38 is a UGT1A1 substrate. Concomitant administration of TRODELVY with inducers of UGT1A1may reduce exposure to SN-38 [see Warnings and Precaution (5.5) and Clinical Pharmacology (12.3 , 12.5) ] .

Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. TRODELVY contains a genotoxic component, SN-38, and is toxic to rapidly dividing cells [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1) ] . Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively. Data Animal data There were no reproductive and developmental toxicology studies conducted with sacituzumab govitecan-hziy.

8.2 Lactation Risk Summary There is no information regarding the presence of sacituzumab govitecan-hziy or SN-38 in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment and for 1 month after the last dose of TRODELVY.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of TRODELVY. Contraception Females TRODELVY can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Males Because of the potential for genotoxicity, 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. Infertility Females Based on findings in animals, TRODELVY may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1) ] .

8.4 Pediatric Use Safety and effectiveness of TRODELVY have not been established in pediatric patients.

8.5 Geriatric Use As a Single Agent Of the 641 patients with TNBC who were treated with TRODELVY in clinical studies, 20% of patients were 65 years and older and 5% were 75 years and older. No overall differences in effectiveness were observed between patients ≥ 65 years of age and younger adult patients. Patients 65 and older had an increased incidence of neutropenia with fatal outcomes. Of the 322 patients with HR+/HER2- breast cancer who were treated with TRODELVY, 26% of patients were 65 years and older and 6% were 75 years and older. No overall differences in effectiveness were observed between patients ≥ 65 years of age and younger patients. There was a higher discontinuation rate due to adverse reactions in patients aged 65 years or older (14%) compared with younger patients (3%). In Combination with Pembrolizumab Of the 221 patients with TNBC who were treated with TRODELVY in combination with pembrolizumab in ASCENT-04, 26% of patients were 65 years and older and 5% were 75 years and older. No overall differences in effectiveness were observed between patients ≥ 65 years of age and younger adult patients. There was a higher rate of serious adverse reactions in patients aged 65 years or older (31%) compared with younger adult patients (26%).

8.6 Hepatic Impairment The safety of TRODELVY in patients with moderate (total bilirubin > 1.5 to 3 × ULN) or severe (total bilirubin > 3 × ULN) hepatic impairment has not been established. TRODELVY has not been evaluated in patients with AST or ALT > 3 ULN without liver metastases, or AST or ALT > 5 ULN with liver metastases.

Sacituzumab govitecan-hziy is a Trop-2-directed antibody-drug conjugate. Sacituzumab is a humanized antibody that recognizes Trop-2. The small molecule, SN-38, is a topoisomerase I inhibitor, which is covalently attached to the antibody by a linker. Pharmacology data suggest that sacituzumab govitecan-hziy binds to Trop-2-expressing cancer cells and is internalized with the subsequent release of SN-38 via hydrolysis of the linker. SN-38 interacts with topoisomerase I and prevents re-ligation of topoisomerase I-induced single strand breaks. The resulting DNA damage leads to apoptosis and cell death. Sacituzumab govitecan-hziy decreased tumor growth in mouse xenograft models of triple-negative breast cancer.