Sacituzumab

1 INDICATIONS AND USAGE 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.

12.1 Mechanism of Action 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.

2 DOSAGE AND ADMINISTRATION Do NOT substitute TRODELVY for or use with other drugs containing irinotecan or its active metabolite SN-38. ( 2 ) Premedication for prevention of infusion reactions and of chemotherapy-induced nausea and vomiting is recommended. ( 2.1 ) The recommended dosage as a single agent or in combination with pembrolizumab is 10 mg/kg on Days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. ( 2.3 ) Monitor patients during the infusion and for at least 30 minutes after completion of infusion. Treatment interruption and/or dose reduction may be needed to manage adverse reactions. ( 2.4 , 2.5 ) See Full Prescribing Information for preparation and administration instructions. ( 2.4 ) 2.1 Important Use Information and Premedication Do NOT substitute TRODELVY for or use with other drugs containing irinotecan or its active metabolite SN-38. Premedication Prior to each dose of TRODELVY, premedication for prevention of infusion reactions and of chemotherapy-induced nausea and vomiting (CINV) is recommended. Premedicate with antipyretics, H1 and H2 blockers prior to infusion, and corticosteroids may be used for patients who had prior infusion reactions. Premedicate with a 2 or 3 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). Prophylaxis for Neutropenia Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is recommended starting in the first cycle for all patients at increased risk of febrile neutropenia [see Warnings and Precautions (5.1) ] . 2.2 Patient Selection for Combination Therapy Select patients for treatment of unresectable locally advanced or metastatic TNBC with TRODELVY in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, based on the tumor expression of PD-L1 as confirmed by an FDA-authorized test [see Clinical Studies (14.1) ] . Information on FDA-authorized tests is available at http://www.fda.gov/companiondiagnostics . 2.3 Recommended Dosage The recommended dosage of TRODELVY as a single agent or in combination with pembrolizumab is 10 mg/kg administered as an intravenous infusion on Days 1 and 8 of each 21-day cycle. Continue TRODELVY until disease progression or unacceptable toxicity. Do not administer TRODELVY at doses greater than 10 mg/kg. When TRODELVY is administered in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, discontinue pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, after approximately 24 months. Refer to the Prescribing Information for pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph for the recommended dosing information. 2.4 Dosage Modifications for Adverse Reactions Management of adverse reactions may require temporary interruption, dose reduction, or permanent discontinuation of TRODELVY as described in Tables 1 and 2. Do not re-escalate the TRODELVY dose after a dose reduction for adverse reactions has been made. Table 1: Dosage Reduction Levels Dose Reduction Permanently discontinue TRODELVY in patients unable to tolerate 5 mg/kg. Dosage and Schedule First Reduce to 7.5 mg/kg Second Reduce to 5 mg/kg The recommended dosage modifications for adverse reactions are provided in Table 2. Table 2: Dosage Modifications for Adverse Reactions Adverse reactions Severity Dose Modification Neutropenia [see Warnings and Precautions (5.1) ] Grade 3-4 neutropenia (Absolute Neutrophil Count [ANC] <1,000/mm 3 ) or febrile neutropenia Withhold TRODELVY until ANC ≥1500/mm 3 for Day 1 dose or ANC ≥1000/mm 3 for Day 8 Dose Administer G-CSF during treatment as clinically indicated. Reduce one dose level for each occurrence of febrile neutropenia or prolonged Grade 3-4 neutropenia, or permanently discontinue according to Table 1. Nausea/Vomiting/ Diarrhea [see Warnings and Precautions (5.2 , 5.4) ] Grade 3-4 nausea, vomiting or diarrhea that is not controll

6 ADVERSE REACTIONS 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 C

5 WARNINGS AND PRECAUTIONS 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 react

4 CONTRAINDICATIONS 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 )

10 OVERDOSAGE In a clinical trial, planned doses of up to 18 mg/kg (approximately 1.8 times the maximum recommended dose of 10 mg/kg) of TRODELVY were administered. In these patients, a higher incidence of severe neutropenia was observed.