Trodelvy® (sacituzumab govitecan-hziy)

Incidence and Management of Diarrhea

This document is in response to your request for information regarding Trodelvy® (sacituzumab govitecan-hziy [SG]) and the incidence and management of diarrhea.

Gilead continually assesses safety data from all sources for unidentified drug reactions and updates the product label information accordingly to reflect the safety profile of SG. Because case reports of potential adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. For this reason, Gilead does not provide information from post-marketing spontaneous reports.

Information summarized in this document includes data for SG monotherapy (10 mg/kg IV on Days 1 and 8 of a 21-day treatment cycle) from Phase 2 and 3 clinical studies that constitute the largest pooled safety populations of SG.

Some data may be outside of the US FDA-approved Prescribing Information. In providing this data, Gilead Sciences, Inc. is not making any representation as to its clinical relevance or to the use of any Gilead product(s). For information about the approved conditions of use of any Gilead drug product, please consult the FDA approved prescribing information.

The full indication, important safety information, and boxed warnings for neutropenia and diarrhea are available at:
www.gilead.com/-/media/files/pdfs/medicines/oncology/trodelvy/trodelvy_pi.

Summary

Relevant Product Labeling1

SG 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 SG until resolved to ≤ Grade 1 and reduce subsequent doses.

Management of adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of SG as described in Tables 1 and 2 of the Prescribing Information. Do not re-escalate the SG dose after a dose reduction for adverse reactions has been made.

A Pooled Safety Analysis of SG in Multiple Epithelial Tumors

A total of 1063 patients from four studies of multiple epithelial tumors (ASCENT,2 TROPiCS‑02,3 TROPHY-U-01,4,5 and IMMU-132-016) were included in this analysis.7 These studies included patients with metastatic triple-negative breast cancer (mTNBC), hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (HR+/HER2- mBC), and metastatic urothelial cancer (mUC). The median treatment duration of SG was 4.1 (range: 0–63) mo.8

• Treatment-emergent any-grade diarrhea, Grade ≥3 diarrhea, and diarrhea that led to treatment discontinuation, was reported by 64%, 11% and 1% of patients treated with SG, respectively.7
• Grade ≥3 diarrhea was more common in patients with uridine diphosphate glucuronosyl transferase family 1 member A1 (UGT1A1) *28/*28 genotype (15%) than in those with other genotypes (*1/*1, 8%; and *1/*28, 12%).7 UGT1A1 testing is not required as per the product label.1
• Median onset of any-grade and Grade ≥3 diarrhea occurred at approximately 2 wk from treatment initiation and resolved in approximately 1 wk.7

• Antidiarrheal treatment was administered to 477 patients (70%); loperamide ± other antidiarrheals were used by 90% of these patients. Loperamide was advised for non-infectious diarrhea at onset.9-12 For unresolved diarrhea after 24 h, opium tincture12 and diphenoxylate/atropine10,12 were recommended. Subcutaneous octreotide was recommended for persistent diarrhea and premedication with atropine was recommended for patients who experienced a cholinergic response, including diarrhea, to SG.9-12 Additional supportive measures and dietary modifications were recommended.7,9,10,12

A Pooled Safety Analysis of SG in mBC

A total of 969 patients, with either with mTNBC or HR+/HER2- mBC, were included in an analysis of six clinical studies (ASCENT,2 TROPiCS-02,3 IMMU-132-01,6 EVER-132-001,13 EVER-132-002,14 and ASCENT-J0215).16 Treatment-emergent adverse events (TEAEs) were analyzed by region, North America/Europe (NA/EU [n=688]) and Asia (n=281).

• Patients in NA/EU had higher rates of any-grade and Grade ≥3 diarrhea compared to Asia (absolute incidence not reported), these rates remained generally stable over time (through to approximately weeks 68 and 72 in NA/EU and Asia, respectively). Of the patients who received an antidiarrheal during SG treatment, a higher percentage in NA/EU received loperamide and atropine than patients in Asia; 89% and 20% vs 49% and 5%, respectively. A higher percentage of patients in Asia received other antidiarrheal treatment vs patients in NA/EU; 73% vs 23%, respectively.16

PRIMED Study in mTNBC and HR+/HER2- mBC

PRIMED, a phase 2 study in 50 patients with unresectable locally advanced mTNBC or HR+/HER2- mBC, is evaluating the impact of primary prophylactic granulocyte colony‑stimulating factor (G-CSF) as management of neutropenia and primary prophylactic loperamide as management of diarrhea.17

• At the primary safety analysis (median follow-up 4.3 mo) incidence of any-grade diarrhea after 2 cycles of SG was 34% (n=17); Grade ≥2 diarrhea was 16% (n=8) and Grade 3 diarrhea was 4% (n=2).17 At the extended safety analysis (median follow-up 9 mo) incidence of any-grade diarrhea was 44% (n=22); nine patients (18%) had Grade ≥2 diarrhea; there was no Grade 4 diarrhea. Two patients discontinued due to treatment-related adverse events (TRAEs) of Grade 2 enteritis and Grade 3 diarrhea.18

Real-World Safety of SG and Prophylactic Atropine Use19

In 3 Spanish centers, 17 female patients with unresectable locally advanced mTNBC and HR+/HER2- mBC were given atropine as a premedication to each SG infusion, according to the approved indications in Spain. Incidence of treatment-emergent any-grade, Grade 1, and Grade 2 diarrhea was 41% (n=7), 35% (n=6), and 6% (n=1), respectively. Three patients required an SG dose reduction.  No discontinuations were due TEAEs.

Pooled SG Safety Analyses

Safety Analysis in Patients With Multiple Epithelial Tumors

A pooled safety analysis examined exposure to SG 10 mg/kg IV as monotherapy in 1063 patients from four studies of multiple epithelial tumors (ASCENT,2 TROPiCS-02,3 TROPHY-U-01,4,5  and IMMU-132-016).7 These studies included patients with mTNBC, HR+/HER2- mBC, and mUC (Figure 1). The median treatment duration of SG was 4.1 (range: 0–63) mo.8

Figure 1. Pooled Clinical Studies in Patients With Multiple Epithelial Tumors7

Abbreviations: CKD4/6i=cyclin-dependent 4/6 inhibitor; CPI=checkpoint inhibitor; PLT=platinum; TNBC=triple-negative breast cancer.

Baseline demographics and disease characteristics are summarized in Table 1. 

Table 1. Pooled Safety in Multiple Epithelial Tumors: Baseline Demographics and Disease Characteristics7

Abbreviation: ECOG PS=Eastern Cooperative Oncology Group Performance Status.

Diarrhea Incidence, Onset, and Duration

Treatment-emergent any-grade diarrhea, Grade ≥3 diarrhea, and diarrhea that led to treatment discontinuation, was reported by 64%, 11% and 1% of patients treated with SG, respectively.7

Grade ≥3 diarrhea was more common in patients with UGT1A1 *28/*28 genotype (15%) than in those with other genotypes (*1/*1, 8%; and *1/*28, 12%).7 UGT1A1 testing is not required as per the product label.1

Median any-grade and Grade ≥3 diarrhea occurred approximately 2 wk after treatment initiation and resolved in approximately 1 wk (Table 2).7

Table 2. Pooled Safety in Multiple Epithelial Tumors: Time to Onset and Resolution of Diarrhea (N=1063)7

Diarrhea Management

SG-associated toxicities were assessed and managed in accordance with standard clinical/institutional practices and accepted treatment guidelines.9-11,20

Antidiarrheal medication

At the onset of non-infectious diarrhea, prompt initiation of loperamide 4 mg was advised, followed by 2 mg per episode (up to a dose of 16 mg/d). According to the ASCENT and IMMU-132-01 protocols, loperamide was to be discontinued 12 h after diarrhea had resolved and normal diet resumed; this was not required in TROPiCS-02 or TROPHY-U-01.9-12

If diarrhea did not resolve after 24 h, the TROPHY-U-01 and TROPiCS-02 protocols recommended that diphenoxylate/atropine be considered.10,12 In addition, the TROPiCS-02 protocol also recommended opium tincture after 24 h.12 For persistent diarrhea, subcutaneous octreotide (100–150 mcg three times daily) could be considered.9-12

Additional supportive measures included fluid and electrolyte substitution and oral antibiotics,9-12 such as ciprofloxacin (for diarrhea that persisted >24 h, or in patients who exhibited an absolute neutrophil count <500/mm3 or fever with diarrhea). The ASCENT and IMMU-132-01 protocols specified a ciprofloxacin dose of 250 to 750 mg/12 h for 7 d.9,11 In the study protocols for TROPHY-U-01 and TROPiCS-02, several dietary modifications were recommended, including a bland diet, small frequent meals, adequate intake of clear liquids to maintain hydration, and discontinuation of lactose-containing foods/drinks and alcohol.10,12

Anticholinergic medication

It was recommended that patients who experienced a cholinergic response to SG, including diarrhea, should receive premedications (eg, atropine) for future treatments.9-12

Incidence of patients receiving any antidiarrheal medication7

Of the 681 patients who experienced any-grade diarrhea, 477 (70%) received antidiarrheal medication (Table 3); loperamide ± other antidiarrheals were used by 90% of these patients.

Table 3. Pooled Safety in Multiple Epithelial Tumors: Treatment of Diarrhea7

aAntidiarrheals with the same start or overlapping treatment dates were considered an antidiarrheal regimen.

Pooled Safety Analysis in Patients With mBC

A pooled safety analysis of six clinical studies16 (ASCENT,2 TROPiCS-02,3 IMMU-132-01,6 EVER-132-001,13 EVER-132-002,14 and ASCENT-J0215) examined exposure to SG 10 mg/kg IV as monotherapy in 969 patients with mTNBC or HR+/HER2- mBC; TEAEs were analyzed by region, NA/EU and Asia. Except for race (Table 4), baseline characteristics, including age, sex and body mass index, were comparable between the NA/EU and Asia groups.

Table 4. Pooled Safety in mBC: Baseline Race by Region16

Diarrhea incidence and management16

Patients in the NA/EU region had higher rates of any-grade and Grade ≥3 diarrhea compared to patients in Asia (Figure 2), these rates remained generally stable over time (through to approximately weeks 68 and 72 in NA/EU and Asia, respectively). Diarrhea was identified as one of the most common reasons for discontinuation in the NA/EU region with an incidence of <1%.

Figure 2. Pooled Safety in mBC:
Incidence of Any-Grade (≥20%) and Grade ≥3 (≥10%) Treatment-Emergent Diarrhea16

Of the patients who received an antidiarrheal during SG treatment, a higher percentage in the NA/EU region received loperamide and atropine than patients in Asia, while a higher percentage of patients in Asia received other antidiarrheal treatment vs patients in NA/EU (Table 5).

Table 5. Pooled Safety in mBC: Treatment of Diarrhea16

PRIMED Study in mTNBC and HR+/HER2- mBC

Study Design and Patient Demographics17

PRIMED is an open-label, single-arm, phase 2 study evaluating the impact of 1) primary prophylactic G-CSF as management of neutropenia and 2) primary prophylactic loperamide as management of diarrhea in 50 patients with unresectable locally advanced mTNBC (n=32) or HR+/HER2- mBC (n=18). Patients received primary prophylactic loperamide (2 mg twice-daily or 4 mg once-daily on Days 2, 3, 4, 9, 10, and 11). Patient baseline characteristics and prior treatments are summarized in Table 6.

Table 6. Baseline Characteristics and Prior Treatments17

aSystemic treatment in the curative setting was considered as a line of therapy if development of unresectable locally advanced or metastatic disease occurred within 12 mo of chemotherapy or immunotherapy completion.

Safety

Primary Safety Analysis17

The primary safety analysis had a median follow-up time of 4.3 (range: 0.2-8.6) mo. At data cut-off, October 18, 2023, 31 patients (62%) remained on treatment. Disease progression was the primary reason for treatment discontinuation in 16 patients (32%). Results were reported for 50 patients after the first 2 cycles of SG with the incidence of any Grade diarrhea (34%) and Grade ≥2 diarrhea was reported in 8 patients (16%) (P=0.084) (Table 7).

Extended Safety Analysis18

The extended safety analysis had a median follow-up of 9 (range; 0.2-13.5) mo. At data cut-off, May 5, 2024, the incidence of any Grade diarrhea was 44.0% (Table 7). A total of 9 patients (18.0%) had Grade ≥2 diarrhea (no Grade 4). The overall rate of AEs associated with dose reductions and treatment interruptions was 22% and 50%, respectively. Four patients discontinued due to AEs, two of which were SG-related (Grade 2 enteritis and Grade 3 diarrhea; Table 8). Other TEAEs can be found in Table 9. 

Table 7. Diarrhea During First 2 Cycles and Until Data Cut-Off17,18

Table 8. Dose Reductions, Treatment Interruptions, and Discontinuations
due to AEs17,18

Table 9. Any Grade and Grade ≥3 TEAEs Occurring in Patients Until Data Cut-Off18

Real-World Safety of SG and Prophylactic Atropine Use19

In 3 Spanish centers, 17 female patients with unresectable locally advanced mTNBC (n=13) and HR+/HER2- mBC (n=4) received atropine (0.5 mg subcutaneous) as a premedication to each SG infusion, according to the approved indications in Spain. Patient baseline characteristics are summarized in Table 10.

Table 10. Baseline Characteristics19

Of the 17 patients that received prophylactic atropine, 7 patients developed any Grade diarrhea, 6 patients Grade 1 diarrhea, and 1 patient Grade 2 diarrhea. Constipation was not reported as a common TEAE. Three patients required an SG dose reduction and there were no discontinuations due to TEAEs.   

References

1. TRODELVY® Gilead Sciences Inc. Trodelvy (sacituzumab govitecan-hziy) for injection, for intravenous use. U.S. Prescribing Information. Foster City, CA.

2. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. Apr 22 2021;384(16):1529-1541.

3. Rugo HS, Bardia A, Marme F, et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2022;40(29):3365-3376.

4. Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: A phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021;39(22):2474-2485. doi:10.1200/JCO.20.03489

5. Petrylak DP, Tagawa ST, Jain RK, et al. Early results of TROPHY-U-01 cohort 2: sacituzumab govitecan in platinum-ineligible patients with metastatic urothelial cancer who progressed after prior checkpoint inhibitor therapy [Poster]. presented at: American Society of Clinical Oncology (ASCO) Meeting; 29 May-2 June 2020; Chicago, IL.

6. Bardia A, Messersmith WA, Kio EA, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol. Jun 2021;32(6):746-756.

7. Rugo HS, Tolaney SM, Bardia A, et al. Pooled safety analysis of sacituzumab govitecan in multiple solid tumor types [Poster 3029]. presented at: American Society of Clinical Oncology (ASCO); May 31-June 4 2024; Chicago, IL.

8. TRODELVY® Gilead Sciences Inc. Trodelvy (sacituzumab govitecan-hziy) for injection, for intravenous use. U.S. Prescribing Information. Foster City, CA.

9. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer [Protocol]. N Engl J Med. 2021;384(16):1529-1541.

10. Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: A phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors [Protocol]. J Clin Oncol. 2021;39(22):2474-2485.

11. Immunomedics Inc. IMMU-132-01. A phase I/II study of IMMU-132 (hRS7-SN38 antibody drug conjugate) in patients with epithelial cancer [Protocol]. 2020. Available at: https://www.clinicaltrials.gov/ProvidedDocs/52/NCT01631552/Prot_000.pdf.

12. Rugo HS, Bardia A, Marme F, et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer [Supplementary Appendix]. J Clin Oncol. 2022;40(29):3365-3376.

13. Ma F, Wang S, Tong Z, et al. Overall survival results from EVER-132-001, a phase 2b single-arm study of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer [Poster PO1-06-10]. presented at: San Antonio Breast Cancer Symposium (SABCS); December 5-9 2023; San Antonio, TX.

14. Xu B, Wang S, Yan M, et al. Sacituzumab govitecan in HR+/HER2- metastatic breast cancer: the randomized phase 3 EVER-132-002 trial. Nat Med. 2024;30(12):3709-3716

15. Naito Y, Nakamura S, Kawaguchi-Sakita N, et al. Preliminary results from ASCENT-J02: a phase 1/2 study of sacituzumab govitecan in Japanese patients with advanced solid tumors. Int J Clin Oncol. 2024;29(11):1684-1695.

16. Rugo HS, Tolaney SM, Cortés J, et al. Pooled safety analysis of sacituzumab govitecan in metastatic breast cancer, including data from patients treated in North America/Europe and Asia [Poster FPN 345P]. Presented at: European Society for Medical Oncology Breast Cancer (ESMO BC); 14-17 May, 2025; Munich, Germany.

17. Perez-Garcia JM, Gion M, Ruiz-Borrego M, et al. Prevention of sacituzumab govitecan-related neutropenia and diarrhea in patients with triple-negative or HR[+]/HER2[-] advanced breast cancer (PRIMED): a phase 2 trial [Poster 1101]. Poster presented at: American Society of Clinical Oncology (ASCO); 31May-04Jun, 2024.

18. Perez-Garcia JM, Gion M, Ruiz-Borrego M, et al. Efficacy analysis and updated safety from the phase 2 PRIMED study of prophylactic granulocyte-colony stimulating factor (G-CSF) and loperamide for patients with HER2-negative advanced breast cancer treated with sacituzumab govitecan [Poster  P1-02-06]. presented at: San Antonio Breast Cancer Symposium (SABCS); December 10-13 2024; San Antonio, TX.

19. Echarri MA, Santisteban M, Cardenas JD. Efficacy and safety of sacituzumab govitecan treatment with the addition of prophylactic atropine to prevent diarrhea to patients with metastatic breast cancer treated: a Spanish multicenter real-world study [Poster P1-06-12]. presented at: San Antonio Breast Cancer Symposium (SABCS); December 10-13 San Antonio, TX.

20. Rugo HS, Bardia A, Marme F, et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer [Protocol]. J Clin Oncol. Oct 10 2022;40(29):3365-3376.

For the full indication, important safety information, and boxed warning(s), please refer to the Trodelvy US Prescribing Information available at:
www.gilead.com/-/media/files/pdfs/medicines/oncology/trodelvy/trodelvy_pi.

Follow-Up

For any additional questions, please contact Trodelvy Medical Information at:

☎ 1‐888-983-4668 or   www.askgileadmedical.com

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Please report all adverse events to:

Gilead Global Patient Safety ☎ 1-800-445-3235, option 3 or
 www.gilead.com/utility/contact/report-an-adverse-event

FDA MedWatch Program by ☎ 1-800-FDA-1088 or MedWatch, FDA, 5600 Fishers Ln, Rockville, MD 20852 or   www.accessdata.fda.gov/scripts/medwatch

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