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)]

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 in 1063 patients from four studies, IMMU-132-01, ASCENT, TROPiCS-02, and TROPHY which included 366 patients with mTNBC, 322 patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and 180 patients with mUC. 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 1063 patients treated with TRODELVY, the median duration of treatment was 4.1 months (range: 0 to 63 months). In this 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%).

Locally Advanced or Metastatic Triple-Negative Breast Cancer

ASCENT Study

The safety of TRODELVY was evaluated in a randomized, active-controlled, open-label study (ASCENT) in patients with mTNBC who had previously received a taxane and at least two prior chemotherapies. Patients were randomized (1:1) to receive either TRODELVY (n=258) or single agent chemotherapy (n=224) and were treated until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. For patients treated with TRODELVY, the median duration of treatment was 4.4 months (range: 0 to 23 months).

Serious adverse reactions occurred in 27% of patients receiving TRODELVY. Serious adverse reactions in > 1% of patients receiving TRODELVY included neutropenia (7%), diarrhea (4%), and pneumonia (3%). Fatal adverse reactions occurred in 1.2% of patients who received TRODELVY, including respiratory failure (0.8%) and pneumonia (0.4%). TRODELVY was permanently discontinued for adverse reactions in 5% of patients. Adverse reactions leading to permanent discontinuation in ≥ 1 % of patients who received TRODELVY were pneumonia (1%) and fatigue (1%).

Adverse reactions leading to a treatment interruption of TRODELVY occurred in 63% of patients. The most frequent (≥5%) adverse reactions leading to a treatment interruption were neutropenia (47%), diarrhea (5%), respiratory infection (5%), and leukopenia (5%).

Adverse reactions leading to a dose reduction of TRODELVY occurred in 22% of patients. The most frequent (>4%) adverse reactions leading to a dose reduction were neutropenia (11%) and diarrhea (5%).

Granulocyte-colony stimulating factor (G-CSF) was used in 44% of patients who received TRODELVY.

Tables 2 and 3 summarize adverse reactions and laboratory abnormalities, respectively, in the ASCENT study.

Table 2: Adverse Reactions in ≥ 10% of Patients with mTNBC in ASCENT
	TRODELVY (n=258)		Single Agent Chemotherapy (n=224)
Adverse Reaction	All Grades %	Grade 3 – 4 %	All Grades %	Grade 3 – 4 %
*Single agent chemotherapy included one of the following single-agents: eribulin (n=139), capecitabine (n=33), gemcitabine (n=38), or vinorelbine (except if patient had ≥ Grade 2 neuropathy, n=52).
Graded per NCI CTCAE v.5.0.
* Including stomatitis, glossitis, mouth ulceration, and mucosal inflammation † Including fatigue and asthenia
Gastrointestinal disorders
Diarrhea	59	11	17	1
Nausea	57	3	26	0.4
Vomiting	33	2	16	1
Constipation	37	0.4	23	0
Abdominal Pain	30	3	12	1
Stomatitis*	17	2	13	1
General disorders and administration site conditions
Fatigue†	65	6	50	9
Pyrexia	15	0.4	14	2
Infections and infestation
Urinary tract infection	13	0.4	8	0.4
Upper respiratory tract infection	12	0	3	0
Metabolism and nutrition disorders
Decreased appetite	28	2	21	1
Musculoskeletal and connective tissue disorders
Back pain	16	1	14	2
Arthralgia	12	0.4	7	0
Nervous system disorders
Headache	18	0.8	13	0.4
Dizziness	10	0	7	0
Psychiatric disorders
Insomnia	11	0	5	0
Respiratory, thoracic and mediastinal disorders
Cough	24	0	18	0.4
Skin and subcutaneous tissue disorders
Alopecia	47	0	16	0
Rash	12	0.4	5	0.4
Pruritus	10	0	3	0

Table 3: Laboratory Abnormalities in > 10% of Patients with mTNBC in ASCENT
Laboratory Abnormality	TRODELVY (n=258)		Single Agent Chemotherapy (n=224)
	All Grades (%)	Grade 3 – 4 (%)	All Grades (%)	Grade 3 – 4 (%)
Hematology
Decreased hemoglobin	94	9	57	6
Decreased lymphocyte count	88	31	40	24
Decreased leukocyte count	86	41	53	25
Decreased neutrophil count	78	49	48	36
Decreased platelet count	23	1.2	25	2.7
Chemistry
Increased glucose	49	2.3	43	2.8
Decreased calcium	36	1.6	21	1.4
Decreased magnesium	33	0.4	20	0
Decreased potassium	33	4.3	28	0.9
Increased albumin	32	0.8	25	1.4
Increased aspartate aminotransferase	27	1.2	32	1.4
Increased alanine aminotransferase	26	1.2	26	1.8
Increased alkaline phosphatase	26	0	17	0.5
Decreased phosphate	26	7.8	20	3.3
Decreased sodium	22	0.4	17	0.5
Increased lactate dehydrogenase	18	0	22	0
Decreased glucose	10	0	3.2	0

Study IMMU-132-01

The safety of TRODELVY was evaluated in a single-arm, open-label study (IMMU-132-01) in patients with mTNBC and other malignancies, which included 108 patients with mTNBC who had received at least two prior anticancer therapies for metastatic disease [see Clinical Studies (14.1)]. TRODELVY was administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles at doses up to 10 mg/kg until disease progression or unacceptable toxicity. The median treatment duration in these 108 patients was 5.1 months (range: 0 to 51 months).

Serious adverse reactions occurred in 31% of the patients. Serious adverse reactions in > 1% of patients receiving TRODELVY included febrile neutropenia (6%) vomiting (5%), nausea (3%), dyspnea (3%), diarrhea (4%), anemia (2%), pleural effusion, neutropenia, pneumonia, dehydration (each 2%).

TRODELVY was permanently discontinued for adverse reactions in 2% of patients. Adverse reactions leading to permanent discontinuation were anaphylaxis, anorexia/fatigue, headache (each 0.9%). Forty- five percent (45%) of patients experienced an adverse reaction leading to treatment interruption. The most common adverse reaction leading to treatment interruption was neutropenia (33%). Adverse reactions leading to dose reduction occurred in 33% of patients treated with TRODELVY, with 24% having one dose reduction, and 9% with two dose reductions. The most common adverse reaction leading to dose reductions was neutropenia/febrile neutropenia.

Tables 4 and 5 summarize adverse reactions and laboratory abnormalities occurring in ≥10% of patients with mTNBC in the IMMU-132-01 study.

Table 4: Adverse Reactions in ≥ 10% of Patients with mTNBC in IMMU-132-01
Adverse Reaction	TRODELVY (n=108)
Adverse Reaction	Grade 1–4 (%)	Grade 3–4 (%)
Graded per NCI CTCAE v. 4.0
* Including abdominal pain, distention, pain (upper), discomfort, tenderness. † Including stomatitis, esophagitis, and mucosal inflammation ‡ Including fatigue and asthenia. § Including edema; and peripheral, localized, and periorbital edema ¶ Including rash; maculopapular, erythematous, generalized rash; dermatitis acneiform; skin disorder, irritation, and exfoliation # Including gait disturbance, hypoesthesia, muscular weakness, paresthesia, peripheral and sensory neuropathy Þ Including lower and upper respiratory tract infection, pneumonia, influenza, viral upper respiratory infection, bronchitis and respiratory syncytial virus infection ß Includes cough and productive cough à Includes dyspnea and exertional dyspnea
Any adverse reaction	100	71
Gastrointestinal disorders	95	21
Nausea	69	6
Diarrhea	63	9
Vomiting	49	6
Constipation	34	1
Abdominal pain*	26	1
Mucositis†	14	1
General disorders and administration site conditions	77	9
Fatigue‡	57	8
Edema§	19	0
Pyrexia	14	0
Metabolism and nutrition disorders	68	22
Decreased appetite	30	1
Dehydration	13	5
Skin and subcutaneous tissue disorders	63	4
Alopecia	38	0
Rash¶	31	3
Pruritus	17	0
Dry Skin	15	0
Nervous system disorders	56	4
Headache	23	1
Dizziness	22	0
Neuropathy#	24	0
Dysgeusia	11	0
Infections and infestations	55	12
Urinary Tract Infection	21	3
Respiratory InfectionÞ	26	3
Musculoskeletal and connective tissue disorders	54	1
Back pain	23	0
Arthralgia	17	0
Pain in extremity	11	0
Respiratory, thoracic and mediastinal disorders	54	5
Coughß	22	0
Dyspneaà	21	3
Psychiatric disorders	26	1
Insomnia	13	0

Table 5: Laboratory Abnormalities observed in ≥ 10% of Patients while receiving TRODELVY in IMMU-132-01
Laboratory Abnormality	TRODELVY (n=108)
Laboratory Abnormality	All Grades (%)	Grade 3–4 (%)
Hematology
Decreased hemoglobin	93	6
Decreased leukocyte count	91	26
Decreased neutrophil count	82	32
Increased activated partial thromboplastin time	60	12
Decreased platelet count	30	3
Chemistry
Increased alkaline phosphatase	57	2
Decreased magnesium	51	3
Decreased calcium	49	3
Increased aspartate aminotransferase	45	3
Decreased albumin	39	1
Increased alanine aminotransferase	35	2
Increased glucose	31	2.8
Decreased phosphate	29	5
Decrease magnesium	27	1.9
Decreased phosphate	27	6.5
Decreased sodium	25	4.7
Decreased potassium	24	3.7
Decreased glucose	19	2

Locally Advanced or Metastatic HR-Positive, HER2-Negative Breast Cancer

TROPiCS-02 Study

The safety of TRODELVY was evaluated in a randomized, active-controlled, open-label, study (TROPiCS-02) in patients with unresectable locally advanced or metastatic HR-positive, HER2-negative breast cancer whose disease has progressed after the following in any setting: a CDK 4/6 inhibitor, endocrine therapy, and a taxane; patients received at least two prior chemotherapies in the metastatic setting (one of which could be in the neoadjuvant or adjuvant setting if progression occurred within 12 months). Patients were randomized (1:1) to receive either TRODELVY (n=268) or single agent chemotherapy (n=249) and were treated until disease progression or unacceptable toxicity [see Clinical Studies (14.2)].For patients treated with TRODELVY, the median duration of treatment was 4.1 months (range: 0 to 63 months).

Serious adverse reactions occurred in 28% of patients receiving TRODELVY. Serious adverse reactions in >1% of patients receiving TRODELVY included diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting (each 2%). Fatal adverse reactions occurred in 2% of patients who received TRODELVY including arrhythmia, COVID-19, nervous system disorder, pulmonary embolism, and septic shock (each 0.4%). TRODELVY was permanently discontinued for adverse reactions in 6% of patients. The most frequent (≥0.5%) adverse reactions leading to permanent discontinuation in patients who received TRODELVY were asthenia, general physical health deterioration, and neutropenia (each 0.7%).

Adverse reactions leading to a treatment interruptions of TRODELVY occurred in 66% of patients. The most frequent (≥5%) adverse reaction leading to treatment interruption was neutropenia (50%).

Adverse reaction leading to a dose reduction of TRODELVY occurred in 33% of patients. The most frequent (>5%) adverse reaction leading to dose reduction were neutropenia (16%) and diarrhea (8%). G-CSF was used in 54% of patients who received TRODELVY.

Tables 6 and 7 summarize adverse reactions and laboratory abnormalities in the TROPiCS-02 study.

Table 6: Adverse Reactions in ≥ 10% of Patients with HR+/HER2- mBC in TROPiCS-02
	TRODELVY (n=268)		Single Agent Chemotherapy (n=249)
Adverse Reaction	All Grades %	Grade 3 – 4 %	All Grades %	Grade 3 – 4 %
*Single agent chemotherapy included one of the following single-agents: eribulin (n=130), vinorelbine (n=63), gemcitabine (n=56), or capecitabine (n=22).
Graded per NCI CTCAE v.5.0.
* Including dyspepsia, gastroesophageal reflux disease. † Including fatigue, asthenia. ‡ Including dyspnea; exertional dyspnea
Gastrointestinal disorders
Diarrhea	62	10	23	1
Nausea	59	1	35	3
Constipation	34	1	25	0
Vomiting	23	1	16	2
Abdominal Pain	20	0	14	0
Dyspepsia*	11	0	6	0
General disorders and administration site conditions
Fatigue†	60	8	51	4
Metabolism and nutrition disorders
Decreased appetite	21	2	21	0
Hypokalemia	10	2	4	0
Musculoskeletal and connective tissue disorders
Arthralgia	15	0	12	0
Nervous system disorders
Headache	16	1	15	1
Respiratory, thoracic and mediastinal disorders
Dyspnea ‡	20	0	17	0
Cough	12	0	7	0
Skin and subcutaneous tissue disorders
Alopecia	48	0	19	0
Pruritus	12	0	2	0

Other clinically significant adverse reactions in TROPiCS-02 (≤ 10%) include: hypotension (5%), pain (5%), rhinorrhea (5%), hypocalcemia (3%), nasal congestion (3%), skin hyperpigmentation, (3%), colitis or neutropenic colitis (2%), hyponatremia (2%), pneumonia (2%), proteinuria (1%), enteritis (0.4%).

Table 7: Laboratory Abnormalities in > 10% of Patients with HR+/HER2- mBC in TROPiCS-02
Laboratory Abnormality	TRODELVY (n=268)		Single Agent Chemotherapy (n=249)
	All Grades (%)	Grade 3 – 4 (%)	All Grades (%)	Grade 3 – 4 (%)
Hematology
Decreased leukocyte count	88	38	73	26
Decreased neutrophil count	83	53	67	40
Decreased hemoglobin	73	8	59	5
Decreased lymphocyte count	65	21	47	14
Decreased platelet count	21	1	30	4
Eosinophilia	13	0	4	0
Chemistry
Increased glucose	37	0	31	0
Decreased albumin	32	0	27	0.4
Decreased creatinine clearance	24	2	19	1
Increased alkaline phosphatase	23	0	23	1
Decreased potassium	22	3	12	0.4
Increased alanine aminotransferase	21	1	31	2
Decreased sodium	19	1	17	0.4
Decreased magnesium	18	0	15	0
Decreased phosphate	17	0	10	0
Increased phosphate	16	0	16	0
Increased lactate dehydrogenase	16	0	28	0
Increased aspartate aminotransferase	15	2	25	1
Increased potassium	14	2	9	0

Locally Advanced or Metastatic Urothelial Cancer

TROPHY Study

The safety of TRODELVY was evaluated in a single-arm, open-label study in patients (n=113) with mUC who had received previous platinum-based and anti-PD-1/PD-L1 therapy. 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. (see Clinical Studies 14.3)

Serious adverse reactions occurred in 44% of patients. Serious adverse reactions in >1% of patients receiving TRODELVY included infection (18%), neutropenia (12%, including febrile neutropenia in 10%), acute kidney injury (6%), urinary tract infection (6%), sepsis or bacteremia (5%), diarrhea (4%), anemia, venous thromboembolism, and small intestinal obstruction (3% each), pneumonia, abdominal pain, pyrexia, and thrombocytopenia (2% each). Fatal adverse reactions occurred in 3.6% of patients, including sepsis, respiratory failure, epistaxis, and completed suicide.

TRODELVY was permanently discontinued for adverse reactions in 10% of patients. The most frequent adverse reaction leading to permanent discontinuation of study drug was neutropenia (4%, including febrile neutropenia in 2%). Adverse reactions leading to dose interruption occurred in 52% of patients. The most common adverse reactions leading to dose interruption were neutropenia (27%, including febrile neutropenia in 2%), infection (12%), and acute kidney injury (8%). Adverse reactions leading to a dose reduction of TRODELVY occurred in 42% of patients. The most common (> 4%) adverse reactions leading to a dose reduction were neutropenia (13%, including febrile neutropenia in 3%), diarrhea (11%), fatigue (8%), and infection (4%). Granulocyte-colony stimulating factor (G-CSF) was used in 47% of patients who received TRODELVY.

The most common (≥ 25%) adverse reactions including laboratory abnormalities were decreased leukocyte count (78%), diarrhea (72%), decreased hemoglobin (71%), decreased lymphocyte count (71%), decreased neutrophil count (67%), nausea (66%), increased glucose (59%), fatigue (56%), decreased albumin (51%), alopecia (49%), decreased calcium (46%), decreased sodium (43%), decreased appetite (41%), decreased phosphate (41%), increased alkaline phosphatase (36%), constipation (34%), vomiting (34%), increased activated partial thromboplastin time (33%), increased creatinine (32%), decreased magnesium (31%), increased alanine aminotransferase (28%), increased lactate dehydrogenase (28%), abdominal pain (27%), decreased potassium (27%), increased aspartate aminotransferase (26%), and decreased platelet count (25%).

Tables 8 and 9 summarize adverse reactions and laboratory abnormalities occurring in ≥10% of patients with mUC in the TROPHY study.

Table 8: Adverse Reactions Reported in ≥ 15% (Grade 1–4) or ≥ 5% (Grade ≥ 3) of Patients Treated with TRODELVY in TROPHY
Adverse Reaction	TRODELVY n=113
Adverse Reaction	Grade 1–4 %	Grade 3–4 %
Graded per NCI CTCAE v.5.0.
* Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain † Includes fatigue and asthenia ‡ Includes edema genital, edema peripheral, peripheral swelling § Includes dermatitis acneiform, dermatitis bullous, erythema, lichen planus, photosensitivity reaction, pruritus, pruritus generalised, rash, rash macular, rash maculo-papular, rash pruritic, skin papilloma, skin toxicity ¶ Includes failure to thrive and weight decreased # Includes acute kidney injury, blood creatinine increased, nephropathy toxic, renal failure, renal impairment Þ Includes bacteremia, body tinea, bronchitis, candida infection, cellulitis, clostridium difficile infection, corona virus infection, device related infection, diverticulitis, escherichia bacteremia, escherichia pyelonephritis, folliculitis, gastroenteritis, gastroenteritis escherichia coli, herpes zoster, kidney infection, klebsiella sepsis, lung infection, nasopharyngitis, oral candidiasis, oral herpes, pneumonia, pyelonephritis, pyelonephritis acute, respiratory tract infection, rhinitis, sepsis, sinusitis, skin infection, tooth abscess, upper respiratory tract infection, urinary tract infection, urosepsis, vascular device infection, viral infection, viral pharyngitis, vulvovaginal mycotic infection ß Includes cough, productive cough, upper-airway cough syndrome à Includes deep vein thrombosis, embolism, and pulmonary embolism
Any adverse reaction	94	80
Gastrointestinal disorders
Diarrhea	72	12
Nausea	66	4
Constipation	34	1
Vomiting	34	1
Abdominal pain*	31	2
General disorders and administration site conditions
Fatigue†	68	5
Pyrexia	19	0
Edema‡	17	2
Skin and subcutaneous tissue disorders
Alopecia	49	0
Rash§	32	2
Metabolism and nutrition disorders
Decreased appetite	41	3
Weight loss¶	17	2
Renal and urinary disorders
Acute kidney injury#	24	7
Hematuria	16	1
Infections and infestations
Any infectionÞ	50	25
Urinary tract infection	19	12
Respiratory, thoracic and mediastinal disorders
Coughß	17	0
Dyspnea	16	0
Musculoskeletal disorders
Back pain	16	0
Vascular disorders
Venous thromboembolismà	9	6

Other clinically significant adverse reactions in TROPHY (≤ 15%) include: peripheral neuropathy (12%), sepsis or bacteremia (9%), and pneumonia (4%).

Table 9: Laboratory Abnormalities Reported in ≥ 20% (Any Grade) or ≥ 5% (Grade 3–4) of Patients Treated with TRODELVY in TROPHY
Adverse Reaction	TRODELVY n = 113
Adverse Reaction	Any Grade* %	Grade 3–4* %
* Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available (range: 66 to 111 patients).
Hematology
Decreased leukocyte count	78	38
Decreased lymphocyte count	71	35
Decreased hemoglobin	71	18
Decreased neutrophil count	67	43
Decreased platelet count	25	2
Chemistry
Increased glucose	59	8
Decreased albumin	51	4
Decreased calcium	46	9
Decreased sodium	43	1
Decreased phosphate	41	15
Increased alkaline phosphatase	36	0
Increased creatinine	32	5
Decreased magnesium	31	2
Increased alanine aminotransferase	28	2
Increased lactate dehydrogenase	28	0
Decreased potassium	27	0
Increased aspartate aminotransferase	26	2
Coagulation
Increased activated partial thromboplastin time	33	6