Trodelvy® (sacituzumab govitecan-hziy)

Second-Line Use as Monotherapy in Platinum-Eligible mUC

This document is in response to your request for information regarding the use of Trodelvy® (sacituzumab govitecan-hziy [SG]) as monotherapy in the second-line (2L) setting in patients with locally advanced or metastatic urothelial cancer (mUC) who are eligible for platinum (PLT)‑based therapy.

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.

Trodelvy is not indicated for use in patients with mUC. 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

Clinical Studies on the Use of SG Monotherapy as 2L in PLT-Eligible Patients With mUC

TROPiCS-04, an open-label, global, multicenter, randomized controlled phase 3 study, compared the efficacy and safety of SG vs TPC in patients with locally advanced and unresectable or mUC who progressed after prior PLT-based chemotherapy and CPI therapies.1

• In the ITT population (SG, n=355; TPC, n=356), the median OS with SG vs TPC was 10.3 vs 9 months, respectively (HR, 0.86; 95% CI: 0.73–1.02; P=0.087).
• By BICR, the median PFS was 4.2 (95% CI: 3.8–4.5) months with SG and 3.6 (95% CI: 2.9–‍4.2) months with TPC (HR, 0.86; 95% CI: 0.72–1.03); ORR was 23% (95% CI: 18–‍27%) for SG and 14% (95% CI: 10–‍18%) for TPC.
• The most common Grade ≥3 TRAEs with SG vs TPC were neutropenia (35% vs 10%), diarrhea (15% vs 3%), anemia (13% vs 7%), fatigue (12% vs 5%), febrile neutropenia (12% vs 4%), and leukopenia (10% vs 3%).
• TEAEs that led to death occurred in 25 (7%) vs 7 (2%) patients in the SG vs TPC groups, respectively; of the Grade 5 TEAEs in the SG group, 16 (5%) were infections in the setting of neutropenia, and 14 of those occurred within the first month of treatment.

TROPHY-U-01 is an ongoing, global, phase 2, multicohort, open-label study of SG in patients with unresectable and locally advanced or mUC. Approximately 827 patients are anticipated to be enrolled.2 Cohort 1 investigated the efficacy and safety of SG in 113 patients with mUC after progression on PLT-based chemotherapy + CPIs.2,3

• Treatment with SG resulted in an ORR of 28% (32/113; 95% CI: 20.2–37.6), a median DOR of 8.2 (95% CI: 4.7–13.7) months, a median PFS of 5.4 (95% CI: 3.5–‍6.9) months, and a median OS of 10.9 (95% CI: 8.9–13.8) months.3
• The most common Grade ≥3 TRAEs included neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%).3,4

The phase 1/2 basket study (IMMU-132-01) evaluated the use of SG in adult patients with various advanced epithelial cancers, including patients with mUC (n=49), who were refractory to or relapsed after ≥1 prior treatment.5-7

• Among patients with mUC who received SG 10 mg/kg (n=45), the ORR was 28.9% (95% CI: 16.4–44.3), and the median PFS and OS were 6.8 and 16.8 months, respectively.5
• In an analysis of patients in the mUC cohort who received SG 10 mg/kg (n=45), the most common (≥5% of patients) Grade ≥3 AEs were neutropenia/decreased neutrophil count, anemia, hypophosphatemia, diarrhea, fatigue, and febrile neutropenia.8

Clinical Studies on the Use of SG Monotherapy as 2L in PLT-Eligible Patients With mUC

TROPiCS-04 Study of SG vs TPC in Patients With mUC

Study design and patient population1

TROPiCS-04, an open-label, global, multicenter, randomized, phase 3 study, compared the efficacy and safety of SG vs single-agent chemotherapy TPC in patients with locally advanced and unresectable or mUC who progressed after prior PLT-based and CPI therapies (Figure 1).

Figure 1. TROPiCS-04: Study Design1,9

aPatients who received prior EV were eligible for the study, as were patients who were ineligible for or unable to tolerate EV.

In both arms, 83% of patients received their most recent PLT-based therapy in the locally advanced unresectable/metastatic setting, with 17% having received this therapy in the (neo)adjuvant setting. Additional demographics and characteristics are in Table 1.

Table 1. TROPiCS-04: Baseline Demographics and Disease Characteristics1

aOther regions not listed included Australia, China, Hong Kong, Korea, Singapore, and Taiwan.

bECOG PS of 2, n=3; ECOG PS of 3, n=1.

cBellmunt risk scores range from 0 to 3; scores are assigned by the following risk factors: Hgb level of <10 g/dL, ECOG PS score >0, and liver metastases.

dMissing data: SG, n=1; TPC, n=4.

Exposure and disposition1

In total, 711 patients underwent randomization (ITT population; SG, n=355; TPC, n=356); 349 patients and 337 patients received ≥1 dose of SG and TPC, respectively (safety population). Within the TPC group, patients received the following treatments: paclitaxel, n=164 (157 received treatment); docetaxel, n=143 (137 received treatment); and vinflunine, n=48 (43 received treatment). At the data cutoff on March 8, 2024, the median treatment duration was 3 months of SG and 2.1 months of TPC, the median (range) follow‑up duration was 9.2 (0–‍33.7) months; 674 patients (95%) discontinued treatment. Reasons for treatment discontinuation were as follows: disease progression, 67%; AEs, 15%; withdrawal of consent, 6%; and other reasons, 7%. Approximately half of the patients in the SG and TPC groups (50% and 49%, respectively) received subsequent chemotherapy after study discontinuation; EV was the most commonly used therapy (SG, 19%; TPC, 21%).

Efficacy1

The primary endpoint of improved OS with SG vs TPC was not met; there was no significant difference between groups in OS (P=0.087; Table 2). Additional efficacy data are shown in Table 2.

Table 2. TROPiCS-04: OS and PFS Data (ITT Population)1

aUsing a 2-sided α of 0.05, a hierarchical testing strategy was performed for the primary endpoint (OS) and key secondary endpoint (PFS per BICR). As the P-value for OS was not significant, PFS was not tested.

bPFS per investigator assessment was similar to these results.

In a prespecified subgroup analysis of OS, SG was numerically favored vs TPC in most subgroups based on demographics, disease characteristics, prognostic factors, and prior treatments at baseline.

ORR, BOR, DOR, and CBR outcomes by BICR are provided in Table 3.

Table 3. TROPiCS-04: Secondary Efficacy Endpoints by BICR (ITT Population)1

aResponses were confirmed ≥4 weeks later.

Safety

Most patients experienced any-grade TEAEs; Grade ≥3 TEAEs occurred more frequently in the SG group (77%) than in the TPC group (51%; Table 4).1

Thirty-two TEAEs that led to death were reported in 25 patients (7%) in the SG group and 7 patients (2%) in the TPC group. Of these TEAEs in the SG group, 16 (5%) were infections in the setting of neutropenia (7 of which were considered treatment related, and 7 more were possibly treatment related); 14 deaths occurred within the first month of treatment. Eleven of the patients in the SG group who died had also received G-CSF (primary prophylaxis, n=2; therapeutic, n=9). Patients in the SG group who experienced fatal infections in the setting of neutropenia had a greater number of risk factors for medical complications than did the overall SG group: 81% were aged ≥65 years; 81% had a prior major urinary tract procedure; 56% had a prior cystectomy; 50% had prior radiotherapy; and 50% had received ≥3 prior anticancer regimens. In the TPC group, 4 patients died due to infections in the setting of neutropenia.1,9

Table 4. TROPiCS-04: Safety Summary (Safety Population)1,9

The most common Grade ≥3 TRAE was neutropenia (SG, 35%; TPC, 10%); additional any‑grade and Grade ≥3 TRAEs are shown in Table 5.1

Table 5. TROPiCS-04: Most Common Any Grade (≥15%) and Grade ≥3 (≥5%)TRAEs (Safety Population)1

aIncluded fatigue and asthenia.

bIncluded neutropenia and neutrophil count decreased.

cIncluded anemia, Hgb decreased, and red blood cell count decreased.

dIncluded leukopenia and white blood cell count decreased.

Note: Included AEs that occurred after the first dose of study drug until 30 days after the last dose of study drug

G-CSF use1

G-CSF primary prophylactic use for neutropenia was not required per study protocol, but investigators were encouraged to consider primary prophylaxis in patients with risk factors for febrile neutropenia, per ASCO guidelines for use of growth factors. G-CSF use in SG and TPC groups for primary, secondary, and therapeutic prophylaxis are as follows: 21% vs 22%, 15% vs 4%, and 30% vs 10%, respectively. Relative to those who received SG and primary prophylactic G-CSF, numerically more SG-treated patients who did not receive primary prophylactic G-CSF had Grade ≥3 neutropenia (48% vs 32%, respectively), febrile neutropenia (12% vs 9%), and a fatal infection secondary to neutropenia (5% vs 3%).

TROPHY-U-01 Cohort 1 Study in PLT-Eligible Patients

TROPHY-U-01, an ongoing, multicohort, global, phase 2, open-label study, is evaluating the efficacy and safety of SG in approximately 827 patients with unresectable and locally advanced or mUC. Results from Cohort 1 are summarized below.2

Cohort 1: study design and baseline demographics3

Cohort 1 investigated the role of SG in patients with mUC who were previously treated with PLT-based therapy ± CPIs (eg, PD‑[L]1 therapy; Figure 2).

Figure 2. TROPHY-U-01 Cohort 1: Study Design3,10

aDefined as the rate of the BOR of CR + PR.

Updated efficacy and safety data for 113 patients were included in this analysis. At the time of data cutoff (July 26, 2022), 79% of patients had discontinued treatment due to death, 4% completed 2-year follow-up, 3% were lost to follow-up, and 3% withdrew consent. See
Table 6 for key baseline demographics and disease characteristics.

Table 6. TROPHY-U-01 Cohort 1:
Baseline Demographics and Disease Characteristics3,10

aSites included target and non-target lesions that were reviewed by BICR and investigator assessments at baseline.

bRisk factors included ECOG PS >0, presence of liver metastases, and Hgb level <10 g/dL.

Cohort 1: efficacy results

The median (range) follow-up duration was 10.5 (0.3–40.9) months, with a median time to response of 1.6 months and an ORR of 28%. See Table 7 for further results. Most responders to SG, and some non-responders, maintained the reduction from baseline in target lesion size.3

Table 7. TROPHY-U-01 Cohort 1: Efficacy Endpoints3,11

aPatients did not have tumor assessments after their baseline imaging.

bDefined as patients who achieved CR + PR + SD for ≥6 months.

cn=51.

dn=47.

There were 32 responders (CR or PR) to treatment, and 3 were experiencing ongoing response while still receiving treatment. Efficacy of SG was observed in all evaluated subgroups, including patients who received ≥2 prior lines of therapy, those with visceral and liver metastases at baseline, those with Bellmunt risk factors, and according to UGT1A1 status. Among the 10 patients who received prior EV, the ORR was 30%, and 4 patients had a BOR of SD. A comparison of treatment efficacy according to prior EV treatment can be found in Table 8.3,4

Table 8. TROPHY-U-01 Cohort 1: Efficacy According to Prior EV Treatment4

In patients who received prior PLT (n=39) in the (neo)adjuvant setting, the ORR was 38%. In patients with visceral metastases and those with liver metastases, the ORRs were 28% and 32%, respectively.3

Cohort 1: safety results

The most commonly reported TRAEs of any grade were diarrhea (65%), nausea (60%), and fatigue (52%). Grade ≥3 TRAEs occurred in 65% of patients; see Table 9 for the most commonly reported (≥5% of patients) Grade ≥3 TRAEs. Forty percent of patients required SG dose reduction due to TRAEs, 47% required SG dose interruption, and 7% discontinued SG due to TRAEs. G-CSF was given as primary prophylaxis in 22% of patients and as secondary prophylaxis in 23% of patients.3

Table 9. TROPHY-U-01 Cohort 1: Most Commonly (≥5%) Reported Grade ≥3 TRAEs3

A treatment-related death occurred in a 65-year‑old man (history of Stage 3 chronic kidney disease and lung cancer; genotype homozygous for the wild-type UGT1A1 allele) due to severe sepsis with concurrent Grade 4 febrile neutropenia (onset was 4 days after the last dose of Cycle 3, Day 1) that was initially treated with G-CSF and broad‑spectrum antibiotics (the patient also had Grade 3 thrombocytopenia).3,5

IMMU-132-01 Study in Metastatic Epithelial Cancer

Study design and demographics

The safety and efficacy of SG were evaluated in a multicenter, single-arm, phase 1/2 basket study that enrolled 495 adult patients with metastatic epithelial cancers, including mUC (n=49), who had relapsed after or were refractory to ≥1 prior standard therapeutic regimen. Patients received SG IV on Days 1 and 8 of 21-day cycles and were treated with SG until disease progression or unacceptable toxicity, death, or withdrawal of consent. Overall, the median (range) follow‑up duration for the OSP (defined as all patients who received ≥1 dose of SG at 8, 10, 12, or 18 mg/kg) at data cutoff was 8.97 (0.26–55.72) months.5-7

Of the patients with mUC, 45 patients received SG 10 mg/kg, 3 received SG 8 mg/kg, and 1 received SG 12 mg/kg.12 Baseline demographics for patients with mUC who received SG 10 mg/kg are listed in Table 10.

Table 10. IMMU-132-01: Baseline Demographics and Disease Characteristics in the mUC Cohort Who Received SG 10 mg/kg8

Efficacy among patients with mUC who received SG 10 mg/kg

Among patients in the mUC cohort who received SG 10 mg/kg, the ORR was 28.9%. See Table 11 for details of further response rates in this cohort.5

Table 11. IMMU-132-01: Efficacy Data in the mUC Cohort Who Received SG 10 mg/kg5

Preliminary efficacy results showed that, among the 33 patients who had visceral involvement, the ORR was 27% (n=9); among CPI‑treated patients, the ORR was 23% (4/17).8

Safety

Results from the mUC cohort8

The most common (≥5% of patients) Grade ≥3 AEs included the following: neutropenia/decreased neutrophil count (38%), anemia (11%), hypophosphatemia (11%), diarrhea (9%), fatigue (9%), and febrile neutropenia (7%).

Results from the OSP5

Nearly all patients (n/N=494/495) experienced ≥1 AE during the study; of these patients, 97.6% experienced TRAEs (Table 12). Nausea, neutropenia, diarrhea, fatigue, alopecia, vomiting, and anemia were the most commonly reported (≥20%) TRAEs.

Table 12. IMMU-132-01: Key TRAEs of Interest Observed in ≥20% of Patients in the OSP5

aNo Grade 5 febrile neutropenia events were reported. For 1 patient, febrile neutropenia was entered as Grade 2 per investigator assessment; however, febrile neutropenia is Grade ≥3 by definition.

Overall, 38.8% of study patients in the OSP experienced SAEs, and 15.2% of the SAEs were considered to be related to SG. The most common treatment-related SAEs were febrile neutropenia (4%), diarrhea (2.8%), vomiting (1.4%), neutropenia (1.4%), and nausea (1.2%). Dose reductions were required in 32.3% of patients, and 8.3% of patients permanently discontinued SG due to AEs.

Post hoc analyses showed that treatment-related neutropenia of any grade had a median onset of 19 days and a median duration of 8.5 days; treatment-related diarrhea of any grade had a median onset of 14 days and a median duration of 8 days.

References

1. Powles T, Tagawa S, Vulsteke C, et al. Sacituzumab govitecan in advanced urothelial carcinoma: TROPiCS-04, a phase III randomized trial. Annals of Oncology. 2025 Feb 7: S0923-7534(25)00015-8. doi: 10.1016/j.annonc.2025.01.011. Epub ahead of print.
2. ClinicalTrials.gov. Phase II Open Label Study of IMMU-132 in Metastatic Urothelial Cancer. ClinicalTrials.gov Identifier: NCT03547973. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03547973.
3. Loriot Y, Petrylak DP, Kalebasty AR, 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: updated safety and efficacy outcomes. Ann Oncol. 2024;35(4):392-401.
4. Loriot Y, Petrylak DP, Kalebasty AR, 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: updated safety and efficacy outcomes [Supplementary manuscript]. Ann Oncol. 2024. https://www.ncbi.nlm.nih.gov/pubmed/38244927
5. 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. 2021;32(6):746-756.
6. Ocean AJ, Starodub AN, Bardia A, et al. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics. Cancer. 2017;123(19):3843-3854.
7. Starodub AN, Ocean AJ, Shah MA, et al. First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors. Clin Cancer Res. 2015;21(17):3870-3878.
8. Tagawa ST, Faltas BM, Lam ET, et al. Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): Results from a phase I/II study [Abstract]. American Society of Clinical Oncology. 2019;37(7):354-354.
9. Powles T, Tagawa S, Vulsteke C, et al. Sacituzumab govitecan in advanced urothelial carcinoma: TROPiCS-04, a phase III randomized trial [Supplementary Appendix]. Annals of Oncology. 2025 Feb 7: S0923-7534(25)00015-8. doi: 10.1016/j.annonc.2025.01.011. Epub ahead of print.
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. J Clin Oncol. 2021;39(22):2474-2485.
11. Tagawa ST, Balar AV, Petrylak DP, et al. Updated outcomes in TROPHY-U-01 cohort 1, a phase 2 study of sacituzumab govitecan in patients with metastatic urothelial cancer who progressed after platinum-based chemotherapy and a checkpoint inhibitor [Poster 526]. Presented at: American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium; 16-18 February, 2023; San Francisco, CA.
12. 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.

Abbreviations

2L=second line
AE=adverse event
AESI=adverse event of special interest
ASCO=American Society of Clinical Oncology
BICR=blinded independent central review
BOR=best overall response
CBR=clinical benefit rate
CPI=checkpoint inhibitor
CR=complete response
DOR=duration of response
ECOG PS=Eastern Cooperative Oncology Group Performance Status
EV=enfortumab vedotin
G-CSF=granulocyte colony‑stimulating factor
H-score=histochemical score
HR=hazard ratio
mUC=metastatic urothelial cancer
ORR=objective response rate
OS=overall survival
OSP=overall safety population
PD=progressive disease
PD-(L)1=programmed death (ligand)-1
PFS=progression-free survival
PLT=platinum
PR=partial response
RECIST=Response Evaluation Criteria in Solid Tumors
SAE=serious adverse event
SD=stable disease
SG=sacituzumab govitecan‑hziy
TEAE=treatment-emergent adverse event
TPC=treatment of physician’s choice
TRAE=treatment-related adverse event
UGT1A1=uridine diphosphate glucuronosyl transferase family 1 member A1

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.

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