Trodelvy® (sacituzumab govitecan-hziy)

Use in Combination With Pembrolizumab in Patients With 1L PD-L1+ mTNBC

This document is in response to your request for information regarding Trodelvy® (sacituzumab govitecan-hziy [SG]) and its use in combination with pembrolizumab (pembro) as first-line (1L) treatment in patients with programmed death ligand-1 positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC).

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 1L PD-L1+ mTNBC. 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 Data on SG Use in Combination With Pembro in 1L PD-L1+ mTNBC

ASCENT-04, an ongoing, global, open-label, randomized, phase 3 study compared the efficacy and safety of SG + pembro vs chemotherapy TPC (eg, gem + carbo, paclitaxel, or nab-paclitaxel) + pembro, as 1L treatment in patients with PD-L1+ (CPS ≥10), inoperable, locally advanced or mTNBC. A total of 443 female patients were enrolled. Patients who experienced disease progression during treatment with TPC + pembro (as verified by BICR) could cross over to receive 2L SG monotherapy.1

• SG + pembro prolonged PFS by BICR per RECIST v1.1 (primary endpoint) vs TPC + pembro (11.2 vs 7.8 mo; HR, 0.65; 95% CI: 0.51–0.84; P<0.001).1
  • A higher proportion of patients treated with SG + pembro vs TPC + pembro were alive and progression-free at 6 mo, 72% (95% CI: 65–77) vs 63% (95% CI: 56–69), respectively, and at 12 mo, 48% (95% CI: 41–56) vs 33% (95% CI: 26–40), respectively.1
  • Median (range) follow-up at the time of the final PFS analysis was 14 (0.1–28.6) mo.1
• Results for OS were immature (26% maturity rate) at the time of the final PFS analysis; therefore, results are descriptive. A numerical trend in favor of SG + pembro vs TPC + pembro was observed (HR, 0.89; 95% CI: 0.62–1.29). Further follow-up for OS is ongoing.1

• An ORR of 60% was observed in patients receiving SG + pembro vs 53% for TPC + pembro (OR, 1.3; 95% CI: 0.9–1.9). DOR (95% CI) with SG + pembro vs TPC + pembro was 16.5 (12.7–19.5) mo vs 9.2 (7.6–11.3) mo, respectively. Formal statistical analyses of these results were not conducted at this time.1

• A total of 77 patients who progressed on TPC + pembro within the study crossed over to receive 2L SG monotherapy per protocol.1
• The safety profile of SG + pembro was consistent with the known safety profile of each agent. No new safety concerns emerged with the combination.1
  • The most common any-grade TEAEs were diarrhea (70 vs 29%), nausea (68 vs 38%), and neutropenia (63 vs 59%) with SG + pembro vs TPC + pembro, respectively.
  • In the SG + pembro vs TPC + pembro arms, respectively, treatment-emergent SAEs were 38 vs 31% of these, treatment-related SAEs were 28 vs 19%.
  • Incidence of TEAEs that led to treatment discontinuation was 12% with SG + pembro and 31% with TPC + pembro.
  • Rates of TEAEs that led to death were 3% in both treatment arms; 1% and <1% were deemed treatment-related with SG + pembro and TPC + pembro, respectively.
• In an exploratory safety analysis, the overall any-grade EAIRs (95% CI) were 69.09 (60.26–‍78.85) and 36.68 (31.98–41.87) for the SG + pembro and TPC + pembro arms, respectively.2
  • Immune-mediated AEs were reported less frequently with SG + pembro than with TPC + pembro.
  • The times to onset of any-grade and Grade ≥3 neutropenia and diarrhea were generally shorter with SG + pembro than with TPC + pembro.
  • In the SG + pembro and TPC + pembro arms, neutropenia led to treatment discontinuation in 1% and 2% of patients, respectively.
  • In the SG + pembro and TPC + pembro arms, diarrhea led to treatment discontinuation in <1% of patients in the TPC + pembro arm.
  • Primary prophylaxis of G-CSF was associated with less frequent and less severe neutropenia in the SG + pembro arm than in the TPC + pembro arm.

Clinical Data on SG Use in Combination With Pembro in 1L PD-L1+ mTNBC

ASCENT-04 Study

Study design and demographics1

ASCENT-04 is an ongoing, global, open-label, randomized, phase 3 study that is being conducted to investigate the efficacy and safety of SG + pembro vs TPC + pembro as 1L treatment in patients with PD-L1+ (CPS ≥10), inoperable, locally advanced or mTNBC (Figure 1).

A total of 443 female patients were enrolled. Patients who experienced disease progression during treatment with TPC + pembro (as verified by BICR) could crossover to receive 2L SG monotherapy.

Figure 1. ASCENT-04: Study Design1,3

Abbreviations: ADC=antibody-drug conjugation; AUC=area under the curve; IHC=immunohistochemistry; QoL=quality of life; TNBC=triple-negative breast cancer; ULN=upper limit of normal.

aHgb ≥9 g/dL, ANC ≥1500/mm3; platelets ≥100,000/mcL, bilirubin ≤1.5 × ULN, AST/ALT ≤2.5 × ULN or ≤5 × ULN with known liver metastases, serum albumin >3 g/dL, and CrCl ≥30 mL/min.

bUnresolved Grade ≤2 neuropathy, endocrine-related AEs, and any-grade alopecia were allowed.

cUp to 35% of patients with de novo mTNBC were eligible.

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

aAs reported by patients; “Other” includes American Indian or Alaska Native and not permitted.

bIncludes Argentina, Australia, Brazil, Chile, Czech Republic, Hong Kong, Hungary, Israel, Japan, Malaysia, Mexico, Poland, Singapore, South Africa, South Korea, Taiwan, and Turkey.

cOne patient in the TPC + pembro group had an ECOG PS ≥2.

dOther metastatic sites include pleura, pleural effusion, skin, soft tissue, chest wall, and muscle.

eActual chemotherapy received was consistent with what was selected prior to randomization; however, 2 patients underwent randomization but did not receive treatment.

fWhile 20 patients were included in the stratified subgroup of prior exposure to anti-PD-(L)1 therapy (yes) per the interactive response technology system, only 6 patients received prior treatment with anti-PD-(L)1 agents per the clinical database.

Efficacy1

Primary endpoint

SG + pembro significantly improved PFS vs TPC + pembro with a 35% reduction in the risk of disease progression or death and a numerically higher proportion of patients alive and progression-free at the 6- and 12-month timepoints (Table 2). The median (range) duration of follow‑up at the time of the final PFS analysis was 14 (0.1–28.6) mo. At the data cutoff date, 43% of patients (n=95) in the SG + pembro arm and 23% of patients (n=52) in the TPC + pembro arm remained on study treatment.

Table 2. ASCENT-04: PFS by BICR and Investigator Assessment1

aTwo-sided P-value from stratified log-rank test.

Secondary endpoints

At the data cutoff for the final PFS analysis, results for OS were immature (26% maturity rate); therefore, results for OS are descriptive. A numerical trend in favor of SG + pembro was observed (HR, 0.89; 95% CI: 0.62–1.29).

A total of 77 patients who progressed on TPC + pembro crossed over to receive 2L SG monotherapy per protocol.

Statistical testing was not conducted for subsequent endpoints in the statistical hierarchy, as the statistical boundary for OS was not crossed; therefore, results of these endpoints can only be presented descriptively. The ORR (95% CI) was 60% (52.9–66.3) with SG + pembro and 53% (46.4–59.9) with TPC + pembro (OR,1.3; 95% CI: 0.9–1.9). The median DOR (95% CI) was 16.5 (12.7–19.5) mo vs 9.2 (7.6–11.3) mo with SG + pembro vs TPC + pembro, respectively.  

Safety1

The median duration (range) of treatment was 8.9 (0–27.1) months for SG and 8.5 (0–‍26.8) months for pembro in the SG + pembro arm, and 6.2 (0–26.3) months for TPC and 6.4 (0–25.6) months for pembro in the TPC + pembro arm.

Overall, the safety profile of SG + pembro was consistent with the known safety profile of each agent, with no additive toxicity observed. The rate of SAEs was higher with SG + pembro vs TPC + pembro; however, the rate of TEAEs that led to treatment discontinuation was lower (Table 3).

TEAEs that led to death occurred in 7 patients in the SG + pembro arm (3 were deemed treatment related) and in 6 patients in the TPC + pembro arm (1 was deemed treatment related; Table 3). TEAEs that led to death with SG + pembro were pneumonia, sepsis, neutropenic sepsis, pulmonary embolism, and suicide (each, n=1); there were 2 deaths of unknown cause. TEAEs that led to death with TPC + pembro were cardiac arrest, large intestine perforation, pneumonia, sepsis, post-procedural complication, and death of unknown cause (each, n=1).

Table 3. ASCENT-04: Safety Summary1

aThe most common any-grade TEAEs that led to treatment discontinuation were pneumonitis (1%) for SG + pembro and peripheral neuropathy (5%), pneumonitis (3%), and thrombocytopenia (3%) for TPC + pembro.

bThere was no dose reduction for pembro per the protocol.

The most common any-grade and Grade ≥3 AEs are presented in Table 4.

Table 4. ASCENT-04: Most Common (≥20%) TEAEs1a

aTEAEs were defined as any adverse events that began or worsened on or after the first dose date of study drug up to 30 days (or 90 days for SAEs) after the last dose date of study drug or the initiation of subsequent anticancer therapy (including crossover treatment).

Note: Combined preferred terms of neutropenia include neutrophil count decreased; leukopenia includes WBC count decreased; anemia includes Hgb decreased and RBC count decreased; thrombocytopenia includes platelet count decreased; and fatigue includes asthenia.

AESIs are presented in Table 5; these events were consistent with the known safety profiles of each agent. No new safety concerns were observed.

Table 5. ASCENT-04: AESIs1

Abbreviations: SJS=Stevens-Johnson syndrome; TEN=toxic epidermal necrolysis.

aAESI observed in ≥1% of patients in either group. bGrouped term.

Exploratory safety analysis2

More than 99% of patients in each arm experienced any-grade TEAEs.

EAIRs (defined as the number of patients with ≥1 specified TEAE per PYE) were calculated as the number of patients with a specific TEAE divided by the total PYE in each group; PYE was defined as the sum of each patient's time at risk (exposure duration) within the study. Due to the exploratory nature of this post hoc analysis, all results presented in Table 6 should be considered nominal.

The overall EAIRs for any‑grade TEAEs (95% CI) were 69.09 (60.26–78.85) and 36.68 (31.98–41.87) for the SG + pembro and TPC + pembro arms, respectively.

Table 6. ASCENT-04 Exploratory Analysis: EAIRs2

aCombined preferred terms of TEAEs were as follows: neutropenia includes neutropenia and febrile neutropenia; fatigue includes fatigue and asthenia; anemia includes anemia, Hgb decreased, and RBC count decreased; colitis includes colitis, enterocolitis, and autoimmune colitis; thrombocytopenia includes thrombocytopenia and platelet count decreased; pneumonitis includes pneumonitis, interstitial lung disease, and immune-mediated lung disease.

Note: EAIR values <0 indicate a difference that favors SG + pembro, and values >0 indicate a difference that favors TPC + pembro.

Pembro-related TEAEs of special interest (≥5% in either arm) are shown in Table 7; 30% and 40% of patients in the SG + pembro and TPC + pembro arms, respectively, reported an immune-mediated AE.

Table 7. ASCENT-04: Pembro TEAEs of Special Interest2

Note: TEAEs were recorded if they occurred with or after the first dose of study drug through 30 d after the last study drug dose (up to 90 d after SAEs) or the day before the start of the subsequent chemotherapy agent (including crossover treatment if pursued); whichever date the first of either occurred was the end of the evaluation period.

Time to onset and duration of neutropenia and diarrhea

Neutropenia and diarrhea (any grade and Grade ≥3) generally occurred earlier in treatment vs later with SG + pembro. Median times to onset of any-grade and Grade ≥3 neutropenia and diarrhea were generally shorter with SG + pembro vs TPC + pembro (Table 8). Median duration of diarrhea and neutropenia was generally comparable between treatment arms. These results should be interpreted with caution due to small sample sizes in the TPC + pembro arm for the time to onset and the duration of any-grade and Grade ≥3 diarrhea, and due to the small sample size in the SG + pembro arm for the time to onset and the duration of Grade ≥3 diarrhea.

Table 8. ASCENT-04: Time to Onset and Duration of Neutropenia and Diarrhea2

aThe n for time to onset and duration may differ, as some events had no recorded end date or were ongoing.

bThe time to onset of the first event of neutropenia or diarrhea was calculated as follows: onset date or first event – first dose date of any study drug.

cNeutropenia includes preferred terms for neutrophil count decreased, neutropenia, and febrile neutropenia.

dThe duration of the first event (of multiple any-grade or Grade ≥3 events) of neutropenia or diarrhea was calculated as follows: end date of the event – onset date of the event + 1 day (per episode).

Management of neutropenia

In the SG + pembro and TPC + pembro arms, neutropenia led to dose reduction in 19% and 18% of patients, respectively, and to treatment discontinuation in 1% and 2% of patients.

The use of G-CSF as primary prophylaxis in the SG + pembro arm resulted in fewer cases of and less severe neutropenia than in the TPC + pembro arm (Table 9).

Table 9. ASCENT-04: Management of Neutropenia2

aExcluded patients who received G-CSF for primary prophylaxis and included patients eligible for G-CSF.

Management of diarrhea

Most instances of diarrhea were Grade 1 (SG + pembro, 37%; TPC + pembro, 17%) or Grade 2 (SG + pembro, 24%; TPC + pembro, 10%); the incidence rate of severe diarrhea in this study was similar that observed in earlier studies of SG. In the SG + pembro and TPC + pembro arms, diarrhea led to dose reduction in 5% and 1% of patients, respectively, and to treatment discontinuation in <1% of patients in the TPC + pembro arm. Nine of the 13 cases of colitis were non-severe; colitis led to the discontinuation of SG + pembro in 1 patient.

Of the patients who received treatment for diarrhea, 90% and 77% of patients in the SG + pembro and TPC + pembro arms, respectively, received loperamide; 12% and 3% received atropine. Cases of colitis were managed per the pembro product labeling.

References

1. Tolaney SM, De Azambuja E, Kalinsky K, et al. Sacituzumab govitecan plus pembrolizumab vs chemotherapy plus pembrolizumab in patients with previously untreated, PD-L1-positive, advanced or metastatic triple-negative breast cancer: primary results from the randomized, Phase 3 ASCENT-04/KEYNOTE-D19 study [Oral]. Presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; 30 May-03 June, 2025; Chicago, IL.
2. Kalinsky K, Schmid P, de Azambuja E, et al. Safety analysis of phase 3 ASCENT-04 study of sacituzumab govitecan + pembrolizumab vs chemotherapy + pembrolizumab for previously untreated PD-L1+ metastatic triple-negative breast cancer [Poster PS-02-28]. Presented at: San Antonio Breast Cancer Symposium (SABCS); December 9-12, 2025, 2025; San Antonio, TX.
3. Tolaney SM, De Azambuja E, Emens LA, et al. ASCENT-04/KEYNOTE-D19: phase 3 study of sacituzumab govitecan plus pembrolizumab vs treatment of physician’s choice plus pembro in first-line programmed death-ligand 1-positive metastatic triple-negative breast cancer [Poster 276TiP]. Presented at: European Society for Medical Oncology (ESMO) Congress; 9-13 September, 2022; Paris, France.

Abbreviations

1L=first line
2L=second line
AE=adverse event
AESI=adverse events of special interest
BICR=blinded independent
central review
carbo=carboplatin
CPS=combined positive score
EAIR=exposure-adjusted incidence rate
ECOG PS=Eastern Cooperative Oncology Group Performance Status
DOR=duration of response
G-CSF=granulocyte colony‑stimulating factor
gem=gemcitabine
HR=hazard ratio
mTNBC=metastatic triple‑negative breast cancer
OS=overall survival
OR=odds ratio
ORR=objective response rate
PD-(L)1=programmed death (ligand) 1
PD-L1=programmed death ligand-1
pembro=pembrolizumab
PFS=progression-free survival
PYE=patient-years of exposure
RECIST=Response Evaluation Criteria in Solid Tumors
SAE=serious adverse event
SG=sacituzumab govitecan‑hziy
TEAE=treatment-emergent adverse event
TPC=treatment of physicians’ choice

Product Label

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