Trodelvy® (sacituzumab govitecan-hziy)
Efficacy and Safety by Trop-2 Status in Patients with HR+/HER2- mBC
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)
Efficacy and Safety by Trop-2 Status in Patients With HR+/HER2- mBC
This document is in response to your request for information about Trodelvy® (sacituzumab govitecan-hziy [SG]) and trophoblast cell-surface antigen 2 (Trop-2) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC).
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 is indicated for the treatment of adult patients with unresectable locally advanced or metastatic HR+/HER2- (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and ≥2 additional systemic therapies in the metastatic setting.
SG is a Trop-2–directed antibody-drug conjugate. Sacituzumab is a humanized antibody that recognizes Trop‑2. The small molecule, SN‑38, is a topoisomerase I inhibitor, which is covalently attached to the antibody by a linker. Pharmacology data suggest that SG binds to Trop‑2–expressing cancer cells and is internalized with the subsequent release of SN-38 via hydrolysis of the linker. SN-38 interacts with topoisomerase I and prevents re-ligation of topoisomerase I-induced single strand breaks. The resulting DNA damage leads to apoptosis and cell death.
Efficacy and Safety by Trop-2 Status in Patients With HR+/HER2- mBC
TROPiCS-02, a phase 3 study, compared the safety and efficacy of SG 10 mg/kg IV on Days 1 and 8 of a 21-day cycle to chemotherapy TPC in 543 patients with HR+/HER2- mBC who were previously treated with ≥1 taxane, ≥1 endocrine therapy, and ≥1 CDK4/6i in any setting and who had received 2 to 4 prior chemotherapy regimens for metastatic disease.2
- An exploratory post hoc subgroup analysis (n=462) evaluated outcomes according to Trop-2 status. Across both H-score groups (<100 or ≥100), mPFS and mOS were numerically improved with SG vs TPC. The safety profile of SG was generally consistent regardless of Trop-2 expression.3
- A separate exploratory post hoc analysis (n=197) evaluated efficacy outcomes according to Trop-2 gene (TACSTD2) mRNA expression. Regardless of TACSTD2 expression, SG demonstrated a numerically higher mPFS and mOS compared to TPC; benefit was also seen with ORR, CBR, and DOR vs TPC.4
SACI-IO HR+, an ongoing, open-label, randomized, phase 2 study, is investigating SG + pembro vs SG monotherapy in patients (N=104) with HR+/HER2- mBC who have progressed on ≥1 line of endocrine therapy for metastatic disease who progressed on or within 12 mo of adjuvant endocrine therapy, and have received 0 to 1 prior chemotherapy regimen.5
- An exploratory analysis (n=82) evaluated outcomes according to Trop-2 expression by QIF. Trop-2 expression was not significantly associated with mPFS as a continuous variable (1 unit increase in log of amol/mm2), by quartiles, or dichotomized by LOL or median. mOS was significantly decreased in quartile 2 vs quartile 1 (mOS 12.5 [95% CI 10–NA], HR 3.46 [95% CI 1.19–10.1] P=0.02), however, no trend was observed across quartiles. No significant association between Trop-2 expression by QIF and Grade ≥3 TEAEs was observed.
Efficacy and Safety by Trop-2 Status in Patients With HR+/HER2- mBC
TROPiCS-02 Study in HR+/HER2- mBC
Study design and demographics
TROPiCS-02, a phase 3 study, compared the safety and efficacy of SG 10 mg/kg IV on Days 1 and 8 of a 21-day cycle to chemotherapy TPC in 543 patients who were previously treated with ≥1 taxane, ≥1 endocrine therapy, and ≥1 CDK4/6i in any setting and who had received 2 to 4 prior chemotherapy regimens for metastatic disease.2
In the primary analysis, SG demonstrated a significant risk reduction of PFS (HR, 0.66; P<0.001)2 and significantly improved OS vs TPC (median, 14.4 vs 11.2 mo; HR, 0.79; P=0.02).6
An exploratory post hoc subgroup analysis evaluated efficacy outcomes according to Trop‑2 expression. Membrane Trop-2 expression on archival tumor tissue was assessed by immunohistochemistry and expressed as a H‑score of 0 to 300. Outcomes were assessed in H-score groups of <100 and ≥100. Very low Trop-2 expression was further subdivided as H‑scores ≤10 and >10 to <100.3
A separate post hoc subgroup analysis evaluated efficacy outcomes according to TACSTD2 mRNA expression. RNA was isolated from archival tumor tissue samples. High and low TACSTD2 expression were defined as expression above 10.5 TPM and expression below the median (10.5 TPM), respectively.4
Patient disposition and demographics
Of the 543 randomized patients, 238 (88%) in the SG arm vs 224 (83%) in the TPC arm were evaluable for Trop-2. Approximately 95% of patients had tumors with a Trop-2 H‑score >0 (H-score <100, n=192 [42%] and H-score ≥100, n=270 [58%]).3 Of the 543 randomized patients, 100 (37%) in the SG arm and 97 (36%) in the TPC arm were evaluable for TACSTD2 expression.4 Baseline demographics and disease characteristics were generally consistent regardless of Trop-2 and TACSTD2 expression.3,4
Efficacy
Across both H-score groups (<100 and ≥100), PFS and OS were numerically improved with SG vs TPC (Table 1). Numerical benefits were also observed with SG vs TPC for PFS and OS in patients with very low Trop-2 expression (H-score ≤10); however, due to the small sample size, caution is recommended in the interpretation of this data.3
Table 1. TROPiCS-02: mPFS and mOS Outcomes According to Trop-2 Expression3
Trop-2 Expression, H‑Score | n/n (SG/TPC) | SG vs TPC | |||
mPFS, mo | HR (95% CI) | mOS, mo | HR (95% CI) | ||
≥100 | 142/128 | 6.4 vs 4.1 | 0.6 (0.44–0.81) | 14.4 vs 11.2 | 0.83 (0.62–1.11) |
<100 | 96/96 | 5.3 vs 4 | 0.77 (0.54–1.09) | 14.6 vs 11.3 | 0.75 (0.54–1.04) |
>10 to <100 | 62/51 | 5 vs 3.5 | 0.67 (0.42–1.07) | 13.7 vs 11 | 0.81 (0.54–1.23) |
≤10 | 34/45 | 5.5 vs 4.3 | 0.89 (0.51–1.57) | 17.6 vs 12.3 | 0.61 (0.34–1.08) |
In patients receiving SG, a disease response was observed in those with an H-score of ≤10 (n=34). A response was also observed in a Trop-2 negative subgroup (n=10), see Table 2.3
Table 2. TROPiCS-02: Response Rates According to Trop-2 Expression3
H-Score | ORR, n (%) | CBR,a n (%) | DOR, Median (95% CI), mo |
≤10 (n=34) | 8 (24) | 11 (32) | 7.5 (2.5–NR) |
>10 to <100 (n=62) | 11 (18) | 17 (27) | 7.4 (4.1–NR) |
≥100 (n=142) | 33 (23) | 55 (39) | 8.5 (5.9–16.9) |
Abbreviation: NR=not reached
aThe percentage of patients with a confirmed best overall response of complete response, partial response, and stable disease ≥6 mo.
Table 3 shows a numerical benefit for mPFS and mOS regardless of TACSTD2 expression.
Table 3. TROPiCS-02: mPFS and mOS Outcomes According to TACSTD2 Expression4
TACSTD2 | n/n (SG/TPC) | SG vs TPC | |||
mPFS, mo | HR (95% CI) | mOS, mo | HR (95% CI) | ||
<10.5 TPM | 47/51 | 5.6 vs 2.9 | 0.82 (0.5–1.35) | 14.2 vs 10.6 | 0.69 (0.44–1.1) |
≥10.5 TPM | 53/46 | 7.3 vs 5.6 | 0.62 (0.35–1.12) | 14.4 vs 11.8 | 1 (0.63–1.59) |
A numerical benefit was seen for SG vs TPC for ORR, CBR, and DOR by TACSTD2 expression (Table 4).
Table 4. TROPiCS-02: Responses According to TACSTD2 Expression4
| ITT | TACSTD2 <10.5 TPM | TACSTD2 ≥10.5 TPM | |||
SG (n=272) | TPC (n=271) | SG (n=47) | TPC (n=51) | SG (n=53) | TPC (n=46) | |
CR, n (%) | 2 (1) | 0 | 1 (2) | 0 | 0 | 0 |
PR, n (%) | 55 (20) | 38 (14) | 8 (17) | 8 (16) | 11 (21) | 4 (9) |
CBR,a n (%) | 92 (34) | 60 (22) | 16 (34) | 10 (20) | 20 (38) | 11 (24) |
OR (95% CI) | 1.8 (1.23–2.63) | 2.12 (0.85–5.3) | 1.93 (0.8–4.63) | |||
DOR, median (95% CI), mo | 8.1 (6.7–9.1) | 5.6 (3.8–7.9) | 7.4 (2.8–NR) | 6.8 (4.1–NR) | 18.6 (5.8–NR) | 4.3 (4.3–NR) |
Abbreviations: CR=complete response; OR=odds ratio; PR=partial response.
aThe percentage of patients with a confirmed best overall response of CR, PR, and stable disease ≥6 mo.
Safety2
Regardless of Trop-2 expression, the safety profile of SG was generally consistent.
Table 5. TROPiCS-02: Safety Summary According to Trop-2 Expression2
TEAEs, n (%) | SG (n=236) | TPC (n=219) | |||
H-Score <100 | H-Score ≥100 | H-Score <100 | H-Score ≥100 | ||
Grade ≥3 | 76 (79) | 103 (74) | 58 (62) | 78 (63) | |
Led to treatment discontinuation | 2 (2) | 11 (8) | 5 (5) | 5 (4) | |
Led to dose delay | 68 (71) | 93 (66) | 43 (46) | 52 (42) | |
Led to dose reduction | 32 (33) | 51 (36) | 37 (39) | 35 (28) | |
SAEs | 25 (26) | 42 (30) | 18 (19) | 27 (22) | |
Led to deatha | 1 (1) | 4 (3) | 0 | 0 | |
Treatment-related | 1 (1) | 0 | 0 | 0 | |
Select Grade ≥3 TEAEs | Neutropeniab | 56 (58) | 76 (54) | 43 (46) | 43 (35) |
Febrile neutropenia | 7 (7) | 9 (6) | 4 (4) | 6 (5) | |
Diarrhea | 10 (10) | 13 (9) | 1 (1) | 1 (1) | |
Abbreviations: SAE=serious adverse event; TEAE=treatment-emergent adverse event.
aFive of 6 patients who experienced a TEAE leading to death had a known H-score. One TEAE, septic shock due to neutropenic colitis, was considered to be treatment-related. The others were COVID-19 pneumonia, pulmonary embolism, pneumonia, nervous system disorder, and arrhythmia. No patterns were identified.
bIncluded combined terms of neutropenia, neutrophil count decreased, and febrile neutropenia.
SACI-IO HR+ Study in HR+/HER2- mBC5
SACI-IO HR+, an ongoing, open-label, randomized, phase 2 study, is investigating SG + pembro vs SG monotherapy in patients who have progressed on ≥1 line of endocrine therapy for metastatic disease who progressed on or within 12 mo of adjuvant endocrine therapy, and have received 0 to 1 prior chemotherapy regimen.
A prespecified exploratory analysis evaluated outcomes according to Trop-2 expression by QIF. Median follow-up was 11.2 mo. Of the 104 patients in the ITT population, 82 patients (SG + pembro, n=38 and SG, n=44) had baseline tissues available for Trop-2 QIF.
Efficacy
Trop-2 expression was not significantly associated with mPFS as a continuous variable, by quartiles, or dichotomized by LOL or median. mOS was significantly decreased in quartile 2 vs quartile 1, however, no trend was observed across quartiles (Table 6). Trop-2 expression was not significantly associated with PFS or OS by treatment arm or PD-L1 status.
Table 6. Association of Trop-2 with mPFS and mOS5
All (n=82) | Group | mPFS | HR (95% CI), | mOS | HR (95% CI), |
Continuous | 1-unit increase in log of amol/mm2 | - | 0.96 (0.83–1.1) 0.55 | - | 1.05 (0.85–1.3) 0.66 |
Limit of linearity | ≤ LOL (ref) | 6.7 (4–8.7) | 0.63 (0.3–1.34) 0.23 | 18 (16.9–NA) | 0.99 (0.29–3.38) 0.98 |
> LOL | 8.7 (5.6–NA) | NA (11.5–NA) | |||
Median | < Median (ref) | 5.9 (3–10) | 0.77 (0.46–1.28) 0.31 | 18 (16.9–NA) | 0.93 (0.43–2.01) 0.86 |
≥ Median | 6.7 (4.2–11.6) | 17.3 (15.8–NA) | |||
Quartile | ≤ 25% (ref) | 8.7 (2–NA) | - | 20 (18.5–NA) | - |
> 25-50% | 4.5 (2.5–NA) | 1.86 (0.91–3.8) 0.09 | 12.5 (10–NA) | 3.46 (1.19–10.1) 0.02 | |
> 50-75% | 6.7 (2.6–NA) | 1.14 (0.54–2.39) 0.74 | 16.6 (15.8–NA) | 1.73 (0.6–5.03) 0.31 | |
> 75% | 6.2 (4.2–NA) | 0.91 (0.44–1.9) 0.81 | 17.3 (12.4–NA) | 1.51 (0.4–5.66) 0.54 |
Safety
Table 7. ≥ Grade 3 TEAEs by Trop-2 QIF Expression (Overall Cohort)5
All (n=82) | Group | n/N | Odds Ratio | Wald Test P-value |
Continuous | 1-unit increase in log of amol/mm2 | - | 1 (0.74–1.31) | 0.99 |
Median | < Median (ref) | 30/41 | 0.89 (0.33–2.33) | 0.81 |
≥ Median | 29/41 | |||
Quartile | ≤ 25% (ref) | 14/21 | - | - |
> 25-50% | 16/20 | 2 (0.5–9.02) | 0.34 | |
> 50-75% | 13/20 | 0.93 (0.25–3.42) | 0.91 | |
> 75% | 16/21 | 1.6 (0.42–6.51) | 0.5 |
Abbreviation: n/N=number of events/number of patients analyzed.
References
Abbreviations
Page 1 of 7
CBR=clinical benefit rate
CDK4/6i=cyclin-dependent kinase 4/6 inhibitor
DOR=duration of response
H-score=histochemical-score
HER2-=human epidermal growth factor receptor 2‑negative
HR=hazard ratio
HR+=hormone receptor‑positive
LOL=limit of linearity
mBC=metastatic breast cancer
mOS=median overall survival
mPFS=median progression-free survival
ORR=objective response rate
OS=overall survival
Pembro=pembrolizumab
PFS=progression-free survival
QIF=quantitative immunofluorescence
SG-hziy=sacituzumab govitecan
TACSTD2=Trop-2 gene
TPC=treatment of physician’s choice
TPM=transcripts per million
Trop-2=trophoblast cell surface antigen-2
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:
☎ 1-888-983-4668 or www.askgileadmedical.com
Adverse Event Reporting
Please report all adverse events to:
Gilead Global Patient Safety ☎ 1-800-445-3235, option 3 or
https://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
Data Privacy
The Medical Information service at Gilead Sciences may collect, store, and use your personal information to provide a response to your medical request. We may share your information with other Gilead Sciences colleagues to ensure that your request is addressed appropriately. If you report an adverse event or concern about the quality of a Gilead or Kite product, we will need to use the information you have given us in order to meet our regulatory requirements in relation to the safety of our medicines.
It may be necessary for us to share your information with Gilead’s affiliates, business partners, service providers, and regulatory authorities located in countries other than your own. Gilead Sciences has implemented measures to protect the personal information you provide. Please see the Gilead Privacy Statement (www.gilead.com/privacy-statements) for more information about how Gilead handles your personal information and your rights. If you have any further questions about the use of your personal information, please contact privacy@gilead.com.
TRODELVY, GILEAD, and the GILEAD logo are registered trademarks of Gilead Sciences, Inc., or its related companies.
© 2024 Gilead Sciences, Inc.
Page 1 of 7