Trodelvy® (sacituzumab govitecan-hziy)
Use in Patients with Hepatic Impairment
Gilead Sciences, Inc. is providing this document to you, a US Healthcare Professional, in response to your unsolicited request for medical information.
Gilead Sciences, Inc. is providing this document to you, a US Healthcare Professional, in response to your unsolicited request for medical information.
Trodelvy® (sacituzumab govitecan-hziy)
Use in Patients with Hepatic Impairment
This document is in response to your request for information regarding Trodelvy® (sacituzumab govitecan-hziy [SG]) use in patients with hepatic impairment, including patients with hepatic impairment due to liver metastases.
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
Warnings and Precautions: 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 SG.
Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue SG 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.
Use in Specific Populations: No adjustment to the starting dosage is required when administering SG to patients with mild hepatic impairment.
The safety of SG in patients with moderate (total bilirubin >1.5 to 3 × upper limit of normal [ULN]) or severe (total bilirubin >3 × ULN) hepatic impairment has not been established. SG has not been tested in patients with AST or ALT >3 × ULN without liver metastases, or AST or ALT >5 × ULN with liver metastases. No recommendations can be made for the starting dosage in these patients.
Pharmacokinetics in Patients With Hepatic Impairment: The exposure of SG is similar in patients with mild hepatic impairment (total bilirubin ≤ULN with AST >ULN, or bilirubin >1 to ≤1.5 × ULN with any AST; n=257) to patients with normal hepatic function (total bilirubin or AST <ULN; n=526).
SG and free SN-38 exposures are unknown in patients with moderate (total bilirubin >1.5 to 3 × ULN) or severe (total bilirubin >3 × ULN) hepatic impairment.
SG PK in Patients With Mild Hepatic Impairment
Two population pharmacokinetic (PK) analyses evaluated the exposures of SG in patients with mild hepatic impairment relative to those with normal hepatic function.2,3 One study evaluated SG exposure in ASCENT (in metastatic triple-negative breast cancer [mTNBC]), TROPiCS-02 (in hormone receptor-positive/human epidermal growth factor receptor 2-negative [HR+/HER2-] metastatic breast cancer [mBC]), and IMMU-132-01 (in metastatic epithelial cancer)2; another analysis evaluated exposure to SG, free active metabolite of irinotecan (SN-38), and total antibody (tAB), and used data from ASCENT and IMMU‑132‑01.3
- In both analyses, SG, SN-38, and tAB exposures were similar between patients with mild hepatic impairment and patients with normal hepatic function.2-4
Study of SG in Patients With Moderate Hepatic Impairment
A phase 1, open-label, multicenter, dose-escalation study (NCT04617522) is being conducted to understand the safety and dosing of SG in patients with advanced or metastatic solid tumors and moderate hepatic impairment.5
SG Clinical Studies: Inclusion of Patients With Adequate Hepatic Function
In four studies of SG (ASCENT, TROPiCS-02, TROPHY‑U‑01, and IMMU-132-01), patients, including those with liver metastases, were required to have adequate hepatic function as described below.6-9
SG PK in Patients With Mild Hepatic Impairment
SG PK in Patients With mTNBC, HR+/HER2- mBC, or Metastatic Epithelial Cancer and Mild Hepatic Impairment2
A population PK analysis using data from ASCENT (n=253), TROPiCS-02 (n=260), and IMMU-132-01 (n=276) evaluated the impact of clinical covariates on SG exposure. SG exposure was similar in patients with mild hepatic impairment compared to patients with normal hepatic function (Table 1 and Table 2).
Table 1. PK Analysis: Categorical Covariate Relationship to SG Exposure in the First Cycle Relative to Reference2
Covariate (Reference) | Covariate | Predicted SG Exposure (90% CI) | |
AUC | Cmax | ||
Hepatic impairment relative to normal (bilirubin and AST ≤ULN; n=525) | Mild hepatic impairment (bilirubin >ULN–1.5 × ULN | 0.976 | 0.983 |
Abbreviations: AUC=area under the concentration‑time curve; Cmax=maximum concentration.
Table 2. PK Analysis: Continuous Covariate Relationships to SG Exposure in First Cycle Relative to Reference2
Covariate (Reference) | Percentile | Predicted SG Exposure (90% CI) | |
AUC | Cmax | ||
AST (27.5 IU/L) | 95th (124 IU/L) | 0.951 (0.925–0.977) | 0.984 (0.965–1) |
5th (14 IU/L) | 1.01 (0.994–1.02) | 1 (0.993–1.01) | |
ALT (21.6 IU/L) | 95th (88.3 IU/L) | 0.985 (0.963–1.01) | 0.996 (0.981–1.01) |
5th (8.84 IU/L) | 1 (0.990–1.02) | 1 (0.991–1.01) | |
Albumin (39 g/L) | 95th (45 g/L) | 1.06 (1.04–1.08) | 1 (0.998–1.01) |
5th (30 g/L) | 0.912 (0.892–0.932) | 0.998 (0.983–1.01) | |
ALP (95 IU/L) | 95th (339 IU/L) | 0.959 (0.939–0.979) | 0.986 (0.971–1) |
5th (51.4 IU/L) | 1.01 (0.995–1.02) | 1 (0.994–1.01) | |
Bilirubin (0.4 mg/dL) | 95th (1 mg/dL) | 0.986 (0.965–1.01) | 1 (0.984–1.02) |
5th (0.2 mg/dL) | 1 (0.989–1.02) | 1 (0.989–1.01) | |
Abbreviation: ALP=alkaline phosphatase.
SG PK in Patients With mTNBC or Metastatic Epithelial Cancer and Mild Hepatic Impairment
A population PK analysis using data from patients in ASCENT (n=253) and patients in IMMU-132-01 who received 10 mg/kg SG (n=276) doses (in metastatic epithelial cancer) evaluated the impact of clinical covariates on exposures of SG, free SN-38, and tAB. Exposure to SG was similar between patients with mild hepatic impairment and patients with normal hepatic function (Table 3 and Table 4).3
Table 3. PK Analysis: Categorical Covariate Relationship to SG Exposure in the First Cycle Relative to Reference3
Covariate (Reference) | Covariate | Predicted SG Exposure (90% CI) | |
AUC | Cmax | ||
Hepatic impairment relative to normal (bilirubin and AST ≤ULN; n=412) | Mild hepatic impairment (bilirubin >ULN–1.5 × ULN | 0.963 | 0.981 |
Table 4. PK Analysis: Continuous Covariate Relationships to SG Exposure in First Cycle Relative to Reference3
Covariate (Reference) | Percentile | Predicted SG Exposure (90% CI) | |
AUC | Cmax | ||
AST (24.6 IU/L) | 95th (101 IU/L) | 0.961 (0.932–0.99) | 0.991 (0.97–1.01) |
5th (13 IU/L) | 1.01 (0.99–1.02) | 1 (0.99–1.01) | |
ALT (19.6 IU/L) | 95th (68.8 IU/L) | 0.983 (0.958–1.01) | 0.999 (0.981–1.02) |
5th (8 IU/L) | 1 (0.988–1.02) | 1 (0.988–1.01) | |
Albumin (38 g/L) | 95th (45 g/L) | 1.06 (1.03–1.08) | 0.996 (0.979–1.01) |
5th (29.2 g/L) | 0.928 (0.902–0.953) | 1 (0.986–1.02) | |
ALP (90 IU/L) | 95th (326 IU/L) | 0.965 (0.94–0.989) | 0.988 (0.97–1.01) |
5th (52 IU/L) | 1.01 (0.991–1.02) | 1 (0.991–1.01) | |
Bilirubin (0.4 mg/dL) | 95th (1 mg/dL) | 0.998 (0.971–1.03) | 1.01 (0.986–1.03) |
5th (0.2 mg/dL) | 1 (0.982–1.02) | 0.998 (0.984–1.01) | |
Similar results were observed for the correlation between mild hepatic impairment and exposures to free SN-38 and tAB (Table 5, Table 6, and Table 7).4
Table 5. PK Analysis: Categorical Covariate Relationship to Free SN-38 and tAB Exposure in the First Cycle Relative to Reference4
| Covariate (Reference) | Covariate | Predicted Exposure (90% CI) | |
AUC | Cmax | |||
SN-38 | Hepatic impairment relative | Mild hepatic impairment (bilirubin >ULN–1.5 × ULN or AST >ULN; n=110) | 0.884 | 0.945 |
tAB | Hepatic impairment relative | Mild hepatic impairment (bilirubin >ULN–1.5 × ULN or AST >ULN; n=113) | 0.918 | 0.943 |
Table 6. PK Analysis: Continuous Covariate Relationships to Free SN-38 Exposure in First Cycle Relative to Reference4
Covariate (Reference) | Percentile | Predicted SG Exposure (90% CI) | |
AUC | Cmax | ||
AST (24.6 IU/L) | 95th (101 IU/L) | 0.901 (0.789–1.01) | 0.963 (0.869–1.06) |
5th (13 IU/L) | 1.02 (0.955–1.08) | 1.01 (0.955–1.06) | |
ALT (19.6 IU/L) | 95th (67.8 IU/L) | 0.997 (0.901–1.09) | 1.04 (0.958–1.12) |
5th (7.94 IU/L) | 1 (0.939–1.06) | 0.991 (0.938–1.04) | |
Albumin (38 g/L) | 95th (44.4 g/L) | 1.01 (0.928–1.1) | 0.985 (0.913–1.06) |
5th (29.5 g/L) | 0.981 (0.882–1.08) | 1.02 (0.937–1.1) | |
ALP (89.4 IU/L) | 95th (326 IU/L) | 0.92 (0.822–1.02) | 0.96 (0.878–1.04) |
5th (52 IU/L) | 1.01 (0.954–1.07) | 1.01 (0.957–1.06) | |
Bilirubin (0.4 mg/dL) | 95th (1 mg/dL) | 1.03 (0.926–1.14) | 1.05 (0.963–1.14) |
5th (0.2 mg/dL) | 0.989 (0.916–1.06) | 0.982 (0.921–1.04) | |
Table 7. PK Analysis: Continuous Covariate Relationships to tAB Exposure in First Cycle Relative to Reference4
Covariate (Reference) | Percentile | Predicted SG Exposure (90% CI) | |
AUC | Cmax | ||
AST (24.6 IU/L) | 95th (99.3 IU/L) | 0.914 (0.862–0.967) | 0.95 (0.903–0.998) |
5th (13 IU/L) | 1.01 (0.985–1.04) | 1.01 (0.982–1.03) | |
ALT (19.6 IU/L) | 95th (66 IU/L) | 0.988 (0.944–1.03) | 0.996 (0.956–1.04) |
5th (8 IU/L) | 1 (0.974–1.03) | 1 (0.975–1.03) | |
Albumin (38 g/L) | 95th (45 g/L) | 1.09 (1.05–1.13) | 1.05 (1.01–1.09) |
5th (29.2 g/L) | 0.89 (0.843–0.936) | 0.938 (0.896–0.981) | |
ALP (89.4 IU/L) | 95th (325 IU/L) | 0.917 (0.872–0.961) | 0.932 (0.892–0.972) |
5th (52 IU/L) | 1.01 (0.986–1.04) | 1.01 (0.986–1.04) | |
Bilirubin (0.4 mg/dL) | 95th (1 mg/dL) | 0.989 (0.938–1.04) | 0.983 (0.937–1.03) |
5th (0.2 mg/dL) | 1 (0.969–1.04) | 1.01 (0.975–1.04) | |
Study of SG in Patients With Moderate Hepatic Impairment5
IMMU-132-15 an ongoing, phase 1, open-label, multicenter, dose-escalation study (NCT04617522) being conducted to understand the safety and dosing of SG in patients (estimated enrollment N=30) with advanced or metastatic solid tumors and moderate hepatic impairment. Moderate hepatic impairment is defined as a bilirubin level >1.5 to <3 × ULN and any AST level. SG will be administered on Days 1 and 8 at escalating doses of 5, 7.5, and 10 mg/kg, if determined by the study investigator to be tolerable. The primary outcomes of this study include percentage of patients with treatment-emergent adverse events, clinically significant laboratory abnormalities, and who develop positive anti‑SG antibodies. PK parameters will also be analyzed. Patients who had a treatment benefit will be eligible to continue SG in a rollover study, IMMU-132-14 (NCT04319198).
Please note, as this study is ongoing, results have not been reported. Please refer to ClinicalTrials.gov for additional details.
SG Clinical Studies: Inclusion of Patients With Adequate Hepatic Function
In four studies of SG (ASCENT, TROPiCS-02, TROPHY‑U‑01, and IMMU-132-01), patients, including those with liver metastases, were required to have adequate hepatic function, as described in the inclusion criteria of the studies and defined in Table 8.6-9
Table 8. SG Studies: Definitions of Adequate Hepatic Function6-9
Hepatic Function Test | Value |
Bilirubin | ≤1.5 × ULNa |
AST and ALT | ≤2.5 × ULNb |
AST and ALT in patients with known liver metastases | ≤5 × ULN |
Serum albuminc | ≥3 g/dL |
ALPd | ≤5 × ULN |
aIn TROPiCS-02, patients with documented Gilbert’s syndrome were required to have a bilirubin level ≤3 × ULN.
bIn IMMU-132-01, AST and ALT levels were required to be ≤3 × ULN.
cNot reported in IMMU-132-01.
dOnly required in TROPiCS-02 study. If a patient had known bone metastases, liver-specific ALP levels were separated from the total ALP level and were used to assess liver function instead of total ALP.
References
- TRODELVY® Gilead Sciences Inc. Trodelvy (sacituzumab govitecan-hziy) for injection, for intravenous use. U.S. Prescribing Information. Foster City, CA.
- Sathe AG, Singh I, Jones A, et al. Population pharmacokinetics of sacituzumab govitecan in patients with locally advanced or metastatic breast cancer or other solid tumors [Poster PII-082]. Presented at: American Society for Clinical Pharmacology & Therapeutics,; March 22-24, 2023; Atlanta, GA.
- Sathe AG, Singh I, Singh P, et al. Population pharmacokinetics of sacituzumab govitecan in patients with metastatic triple-negative breast cancer and other solid tumors. Clin Pharmacokinet. 2024;63(5):669-681.
- Sathe AG, Singh I, Singh P, et al. Population pharmacokinetics of sacituzumab govitecan in patients with metastatic triple-negative breast cancer and other solid tumors [Supplementary Appendix]. Clinical Pharmacokinet. 2024;63(5):669-681.
- ClinicalTrials.gov. Study of Sacituzumab Govitecan in Participants With Advanced or Metastatic Solid Tumor and Moderate Liver Impairment. ClinicalTrials.gov Identifier: NCT04617522. Available at: https://clinicaltrials.gov/ct2/show/NCT04617522.
- Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer [Supplementary Appendix]. N Engl J Med. 2021;384(16):1529-1541.
- 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. 2022;40(29):3365-3376.
- 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.
- 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 [Supplementary Appendix]. Ann Oncol. 2021;32(6):746-756.
Product Label
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:
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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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