Trodelvy® (sacituzumab govitecan-hziy)

Use in Localized Breast Cancer

This document is in response to your request for information regarding Trodelvy® (sacituzumab govitecan-hziy [SG]) and its use in localized breast cancer (BC).

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 localized BC. 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 is indicated for the treatment of adult patients with unresectable locally advanced or metastatic TNBC who have received ≥2 prior systemic therapies, ≥1 of them for metastatic disease.

SG is indicated for the treatment of adult patients with unresectable locally advanced or metastatic HR+/HER2- (IHC 0, IHC 1+ or IHC 2+/ISH-) BC who have received endocrine‑based therapy and ≥2 additional systemic therapies in the metastatic setting.

SG is not indicated for the treatment of localized BC.

Clinical Studies: SG Use in Localized BC

SASCIA, an ongoing phase 3 study, is evaluating patients with primary HER2- BC and residual disease after NACT.2,3 A prespecified SIA, conducted after 50 patients had completed 4 treatment cycles (SG or TPC, including cape), demonstrated higher rates of any-grade AEs, any-grade hematological AEs, and Grade 3 to 4 hematological AEs with SG vs TPC. Rates of ≥1 dose delay and delays for hematological toxicity were higher with SG than with cape; rates of ≥1 dose reduction were numerically similar.2

NeoSTAR, an ongoing, multicohort, phase 2 study, is evaluating neoadjuvant SG ± pembro in patients with localized BC. In the completed Cohort A1, 50 treatment-naive patients with localized TNBC received SG. After 4 cycles of SG, 29 patients went directly to surgery, and 21 patients received additional NACT prior to surgery. Fifteen patients (30%) had pCR, and 32 patients (64%) had ORR after SG monotherapy. Grade 3/4 TRAEs included neutropenia, diarrhea, leukopenia, fatigue, and nausea. Six percent of patients required reductions in their SG dose. No patients discontinued SG due to an AE or PD.4,5

Clinical Studies: SG Use in Localized BC

SASCIA Study in Primary HER2- BC

Study design and prespecified SIA population and demographics

SASCIA is an ongoing, phase 3, prospective, multicenter, randomized, open‑label, parallel‑group study (NCT04595565) in patients with primary HER2- BC with residual disease after NACT (Figure 1). iDFS is defined as the time from randomization until the first iDFS event (primary endpoint). OS and iDFS are also being assessed according to stratified and predefined exploratory subgroups.2,3,6

At the time of the SIA, 88 patients were included in the dataset: SG, n=45; TPC, n=43 (cape, n=32; observation, n=11; Table 1). At the time of presentation, the following proportions of patients were still receiving treatment: SG, 75% (n=33); cape, 65.6% (n=21). Five patients (11.4%) in the SG arm and 8 (25%) in the cape arm had completed treatment.2

Figure 1. SASCIA Study Design2,3,6

Abbreviations: ASCO/CAP=American Society of Clinical Oncology/College of American Pathologists; FISH=fluorescence in situ hybridization; PLT=platinum; ypT1mi=very small tumor after neoadjuvant therapy.

aNumber of patients included in the prespecified SIA.

bIncluded local invasive recurrence following mastectomy, local invasive recurrence in the ipsilateral breast after lumpectomy, regional or distant recurrence, contralateral invasive BC, second non‑breast primary cancer (excluding squamous or basal cell carcinoma of the skin), or death from any cause.

Table 1. SASCIA SIA: Select Baseline Demographics and Disease Characteristics2

Abbreviations: EC/AC=epirubicin + cyclophosphamide/doxorubicin + cyclophosphamide; iddETC=intense dose‑dense epirubicin, paclitaxel, and cyclophosphamide; TAC=docetaxel + doxorubicin + cyclophosphamide.

aCutoff: ≥1% positive stained cells from residual cancer, lymph nodes, or core biopsy.

SIA results2

A higher rate of any-grade AEs was observed with SG vs TPC (Table 2). Six SAEs occurred with SG (blood and lymphatic system disorders, n=2; infections and infestations, cardiac disorders, gastrointestinal disorders, and investigations, n=1 each), and 1 SAE occurred with TPC (infection and infestation).

Table 2. SASCIA SIA: Incidence of Any-Grade (≥30%) and High-Grade AEs in Overall Treatment Arms and Among Those Treated With Cape2

aP<0.05, for SG vs TPC arms for any-grade AEs.

bP<0.05, for SG vs TPC for high-grade AEs.

cFebrile neutropenia was observed in 3 patients in the SG arm and in no patients in the TPC arm.

The dose modification rate was generally similar between arms (Table 3), and no unanticipated AEs/toxicities were observed with SG; as a result, the independent data monitoring committee recommended continuation of the study with no modifications.

Table 3. SASCIA SIA: Dose Delays, Reductions, and Treatment Discontinuation2

aPatient decision (SG, n=3; cape, n=1); investigator decision (SG, n=2; cape, n=1); relapse (SG, n=1; cape, n=1).

Efficacy data for the SASCIA study have not yet been presented.

NeoSTAR Study in Localized BC

Study design and demographics

NeoSTAR is an ongoing, multicohort, single-arm, phase 2 study (NCT04230109) evaluating the safety and efficacy of neoadjuvant SG 10 mg/kg IV on Days 1 and 8 of a 21-day cycle ± pembro on Day 1 of each cycle in treatment-naive patients with localized BC across different subtypes. The primary objective is to assess the pCR rate with SG.4

Several cohorts are enrolling patients: Cohort A2, SG + pembro in TNBC (defined as a primary tumor >2 cm or node+); Cohort B1/2, SG ± pembro in HR+/HER2- BC (defined as Stage II–‍III BC with a primary tumor >1.5 cm and high genomic risk); and Cohort C, SG + pembro in HER2- inflammatory BC (defined as T4d and any N).4,7

In Cohort A1, the median (range) age of patients at diagnosis was 48.5 (31–77) years, 39 patients (78%) had node-negative disease, and 9 (18%) were BRCA+ (unknown status, n=1). Most patients (52%; n=26) had Stage II disease; 13 (26%) had Stage I and 11 (22%) had Stage III disease. Most patients (98%) received 4 cycles of SG as monotherapy.4

Figure 2. NeoSTAR: Cohort A1 Response-Guided Study Design4,5

Abbreviations: RECIST=Response Evaluation Criteria in Solid Tumors; T=tumor status (size and extent).

aIf progression occurred during SG treatment, patients could discontinue SG and undergo surgery or receive NACT (taxane/carbo or dose-dense doxorubicin + cyclophosphamide) per investigator discretion.

bIf biopsy-confirmed residual disease was found on Week 12 imaging (after 4 cycles of SG), additional neoadjuvant therapy could be administered per investigator discretion.

Efficacy results: Cohort A14

After 4 cycles of neoadjuvant SG, 29 patients went directly to surgery; 21 patients received additional NACT prior to surgery. Fifteen patients (30%) had a pCR (Figure 3), and 32 patients (64%) had an ORR with SG (Table 4).

Figure 3. NeoSTAR Cohort A1: Disposition After 4 Cycles of SG Overall and by RCB4

Abbreviation: RCB=residual cancer burden.

aOne patient with RCB-3 at surgery had a metastatic recurrence during radiation therapy.

bNone received adjuvant chemotherapy.

Table 4. NeoSTAR: pCR and ORR Overall, by Disease Stage, and by BRCA Status4

aEvaluated for pCR, n=12.

bFive patients achieved a CR or partial response, and 4 patients had stable disease.

cTwenty-seven patients achieved a CR or partial response, 12 had stable disease, and 1 had PD.

After a median follow-up duration of 18.9 months (95% CI: 16.3–21.9), the Year 2 EFS was 95% (95% CI: 88–100%). Of the 15 patients who had a pCR after 4 cycles of SG, the Year 2 EFS was 100% (95% CI: inestimable), and the Year 2 EFS was 92% (95% CI: 82–‍100%; P=0.29) among the 35 patients who had residual disease after SG. The 2 events (death due to BC) occurred in patients with residual disease who had Stage III disease, high Trop-2 expression, and low TILs.

Safety results: Cohort A14,5

The most common (>50%) all-grade TRAEs included nausea (84%), fatigue (80%), hair loss (76%), neutropenia (58%), and diarrhea (56%). Grade 3 TRAEs included neutropenia (10%), diarrhea (10%), leukopenia (4%), fatigue (4%), and nausea (2%); Grade 4 TRAEs included neutropenia (4%) and leukopenia (2%). Six percent of patients required a reduction in their SG dose. No patients discontinued SG due to an AE or PD. One patient discontinued SG at the discretion of the investigator due to minimal response to therapy.

Biomarker results: Cohort A14

Ninety percent of patients had baseline samples for Ki-67, Trop-2, and %TILs available for analysis. The median (range) Ki-67 and %TIL values were 67 (17.3–90.8) and 40 (1–90), respectively. Twenty-eight patients had H-scores >100; 14 patients had H‑scores ≥100, and 3 had H‑scores <100.

Ki-67 values at baseline were significantly higher among patients with pCR after SG monotherapy than among those who had residual disease (71.5 vs 55.3; P=0.007). Similarly, TIL values at baseline were significantly higher among those with pCR than among those with residual disease (55% vs 31%; P=0.002). Trop-2 expression (P=0.44) and H‑score (P=0.626) were not significantly associated with achievement of pCR.

ASCENT-05: SG in Localized BC8

The ongoing phase 3 ASCENT-05 study (NCT05633654) will compare the efficacy and safety of SG 10 mg/kg IV on Days 1 and 8 of a 21-day cycle + pembro 200 mg IV on Day 1 of a 21-day cycle for 8 cycles with that of TPC (pembro [dosed as above] ± cape 1000 mg/m2 orally twice daily on Days 1 to 14 of a 21-day cycle for 8 cycles) in patients with TNBC and residual disease after surgery and neoadjuvant therapy.

References

1. TRODELVY® Gilead Sciences Inc. Trodelvy (sacituzumab govitecan-hziy) for injection, for intravenous use. U.S. Prescribing Information. Foster City, CA.
2. Marmé F, Hanusch C, Furlanetto J, et al. Safety interim analysis of the phase III postneoadjuvant SASCIA study evaluating sacituzumab govitecan in patients with primary HER2-negative breast cancer at high relapse risk after neoadjuvant treatment [Oral Presentation]. Presented at: ESMO Breast Cancer Congress.; May 03-05, 2022; Berlin, Germany.
3. Marme F, Stickeler E, Furlanetto J, et al. Phase III postneoadjuvant study evaluating sacituzumab govitecan, an antibody drug conjugate in primary HER2-negative breast cancer patients with high relapse risk after standard neoadjuvant treatment - SASCIA [Poster TPS-5602]. Presented at: American Society of Clinical Oncology; June 4-8, 2021; Virtual Meeting.
4. Spring LM, Tolaney SM, Fell G, et al. Response-guided neoadjuvant sacituzumab govitecan for localized triple-negative breast cancer: results from the NeoSTAR trial. Ann Oncol. 2024;35(3):293-301.
5. Spring LM, Tolaney SM, Fell G, et al. Response-guided neoadjuvant sacituzumab govitecan for localized triple-negative breast cancer: results from the NeoSTAR trial [Supplement]. Ann Oncol. 2024;35(3).
6. ClinicalTrials.gov. Sacituzumab govitecan in primary HER2-negative breast cancer (SASCIA). Available at: https://clinicaltrials.gov/ct2/show/NCT04595565. .
7. Spring LM, Garrido-Castro, Lynce F, et al. Phase 2 study of response-guided neoadjuvant sacituzumab govitecan (IMMU-132) in patients with localized breast cancer (NeoSTAR) [Poster PO2-19-03]. Presented at: San Antonio Breast Cancer Symposium (SABCS); December 5-9, 2023; San Antonio, TX, USA.
8. Tolaney SM, DeMichele A, Takano T, et al. ASCENT-05/OptimICE-RD (AFT-65): phase 3, randomized, open-label study of adjuvant sacituzumab govitecan + pembrolizumab vs pembrolizumab ± capecitabine in patients with triple-negative breast cancer and residual disease after neoadjuvant therapy and surgery [Poster TPS619]. Presented at: American Society of Clinical Oncology (ASCO); June, 2-6, 2023; Chicago, IL & Online.

Abbreviations

AE=adverse event
BC=breast cancer
BRCA=breast cancer gene
cape=capecitabine
carbo=carboplatin
CPS+EG=clinical stage and post-treatment pathologic score and estrogen receptor status and tumor grade
CTCAE=Common Terminology Criteria for Adverse Events
ECOG PS=Eastern Cooperative Oncology Group Performance Status
EFS=event-free survival
ER=estrogen receptor
ET=endocrine therapy
H‑score=histochemical score
HER2=human epidermal growth factor receptor 2
HR=hormone receptor
IBC=inflammatory breast cancer
iDFS=invasive disease-free survival
IHC=immunohistochemistry
ISH=in situ hybridization
Ki-67=antigen Kiel 67
N=node status
Nab-paclitaxel=nanoparticle albumin-bound paclitaxel
NACT=neoadjuvant chemotherapy
ORR=overall response rate
OS=overall survival
pCR=pathological complete response
PD=progressive disease
pembro=pembrolizumab
QoL=quality of life
SAE=serious adverse event
SG=sacituzumab govitecan-hziy
SIA=safety interim analysis
TIL=tumor infiltrating lymphocyte
TNBC=triple-negative breast cancer
TPC=treatment of physician’s choice
TRAE=treatment-related adverse event
Trop-2=trophoblast cell surface antigen 2
ypN=lymph node status after neoadjuvant therapy

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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