TRODELVY (SACITUZUMAB GOVITECAN) powder, for solution

Reconstitution

• TRODELVY is a hazardous drug. Follow applicable special handling and disposal procedures¹.
• Calculate the required dose (mg) of TRODELVY based on the patient's current body weight [see Dosage and Administration (2.2)].
• Using a sterile syringe, slowly inject 20 mL of 0.9% Sodium Chloride Injection, USP, into each 180 mg TRODELVY vial. Each vial contains overfill to compensate for liquid loss during preparation and after reconstitution, the total resulting volume delivers a concentration of 10 mg/mL.
• Gently swirl vials and allow to dissolve for up to 15 minutes. Do not shake. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be free of visible particulates, clear and yellow. Do not use the reconstituted solution if it is cloudy or discolored.
• Use reconstituted TRODELVY immediately to prepare a diluted TRODELVY infusion solution.

Dilution

• Calculate the required amount of the reconstituted TRODELVY solution needed to obtain the appropriate dose according to the patient's body weight.
• Determine the final volume of the infusion solution to deliver the appropriate dose at a TRODELVY concentration range of 1.1 mg/mL to 3.4 mg/mL.
• Use 0.9% Sodium Chloride Injection, USP only since the stability of the reconstituted TRODELVY solution has not been determined with other infusion-based solutions. Use a polyvinyl chloride, polypropylene/polyethylene, polyolefin, or ethylene vinyl acetate infusion bag.
• Withdraw and discard the volume of 0.9% Sodium Chloride Injection, USP from the final infusion bag that is necessary to achieve the indicated TRODELVY concentration following the addition of the calculated amount of reconstituted TRODELVY solution.
• Withdraw the calculated amount of the reconstituted TRODELVY solution from the vial(s) using a syringe. Discard any unused portion remaining in the vial(s).
• To minimize foaming, slowly inject the calculated amount of reconstituted TRODELVY solution into the infusion bag. Do not shake the contents.
• If not used immediately, the infusion bag containing TRODELVY solution can be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours protected from light. After refrigeration, administer diluted solution at room temperature up to 25°C (77°F) within 8 hours (including infusion time). Do Not Freeze or Shake.

Administration

• Administer TRODELVY as an intravenous infusion.
  • First infusion: Administer over 3 hours. Observe patients during the infusion and for at least 30 minutes following the initial dose, for signs or symptoms of infusion-related reactions [see Warning and Precautions (5.3)] .
  • Second and subsequent infusions: Administer over 1 to 2 hours if prior infusions were tolerated. Observe patients during the infusion and for at least 30 minutes after infusion.
• Protect infusion bag from light. The infusion bag should be covered during administration to the patient until dosing is complete. It is not necessary to cover the infusion tubing or to use light-protective tubing during the infusion.
• An infusion pump may be used.
• Do not mix TRODELVY, or administer in the same intravenous line, with other medicinal products.
• Upon completion of the infusion, flush the intravenous line with 20 mL 0.9% Sodium Chloride Injection, USP.

Locally Advanced or Metastatic Triple-Negative Breast Cancer  (TNBC)

Locally Advanced or Metastatic HR-Positive, HER2-Negative Breast Cancer

UGT1A1 Inhibitors

Avoid administering UGT1A1 inhibitors with TRODELVY.

SN-38 is a UGT1A1 substrate. Concomitant administration of TRODELVY with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38 [see Warnings and Precaution (5.5) and Clinical Pharmacology (12.3, 12.5)].

UGT1A1 Inducers

Avoid administering UGT1A1 inducers with TRODELVY.

SN-38 is a UGT1A1 substrate. Concomitant administration of TRODELVY with inducers of UGT1A1may reduce exposure to SN-38 [see Warnings and Precaution (5.5) and Clinical Pharmacology (12.3, 12.5)].

Risk Summary

Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. TRODELVY contains a genotoxic component, SN-38, and is toxic to rapidly dividing cells [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively.

Data

Risk Summary

There is no information regarding the presence of sacituzumab govitecan-hziy or SN-38 in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment and for 1 month after the last dose of TRODELVY.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to the initiation of TRODELVY.

Contraception

Infertility

Cardiac electrophysiology

At the recommended dose, the maximum mean change from baseline was 9.7 msec (the upper bound of the two-sided 90% confidence interval is 16.8 msec). The increase in QTc was concentration dependent based on SN-38 concentrations.

Distribution

Sacituzumab govitecan-hziy steady state volume of distribution is 4.6 L.

Elimination

The median elimination half-life (t_1/2) of sacituzumab govitecan-hziy is 6.5 days and free SN-38 is 22 hours. The terminal half-life (t_1/2) of sacituzumab govitecan-hziy is 6.7 days (23%) and the apparent half-life (t_1/2) of free SN-38 is 24 hours (50%). The clearance of sacituzumab govitecan-hziy is 0.13 L/h (20%).

Renal elimination is known to contribute minimally to the excretion of SN-38, the small molecule moiety of sacituzumab govitecan-hziy.

Metabolism

No metabolism studies with sacituzumab govitecan-hziy were conducted. SN-38 (the small molecule moiety of sacituzumab govitecan-hziy) is metabolized via UGT1A1. The glucuronide metabolite of SN-38 (SN-38G) was detectable in the serum of patients.

Specific Populations

No clinically significant differences in the pharmacokinetics of sacituzumab govitecan-hziy were observed based on: age (27 to 88 years), race (75% White, 8% Asian, or 5% Black), or CLcr 30 to 89 mL/min. There are no data on the pharmacokinetics of sacituzumab govitecan-hziy in patients with CLcr 15 to 29 mL/min, or end-stage renal disease (CLcr < 15 mL/min).

Patients with Hepatic Impairment

The exposure of sacituzumab govitecan-hziy for patients with mild hepatic impairment (total bilirubin ≤ ULN with AST > ULN, or bilirubin > 1 to ≤ 1.5 ULN with any AST) is within range of that of patients with normal hepatic function (total bilirubin and AST < ULN).

Sacituzumab govitecan-hziy 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.

Drug Interaction Studies

No drug-drug interaction studies were conducted with sacituzumab govitecan-hziy or its components. Inhibitors or inducers of UGT1A1 may increase or decrease SN-38 exposure, respectively.

Single Agent in Previously Untreated, Unresectable Locally Advanced or Metastatic TNBC

ASCENT-03

The efficacy of TRODELVY was evaluated in ASCENT-03 (NCT05382299), a multicenter, open-label, randomized study that enrolled 558 patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who had not received previous systemic therapy for advanced disease and who were not candidates for PD-1 or PD-L1 inhibitor therapy. Patients were enrolled if:

• Their tumors were PD-L1 negative (defined as having a tumor CPS < 10 using the IHC 22C3 assay), or
• Their tumors were PD-L1 positive (defined as having a CPS ≥ 10 using the IHC 22C3 assay) and they had received a PD-1 or PD-L1 inhibitor in the (neo)adjuvant setting or if they had a comorbidity precluding treatment with a PD-1 or PD-L1 inhibitor.

Patients were excluded if they had received anticancer treatment or surgery within the previous 6 months, had active central nervous system (CNS) metastases and ECOG performance status (PS) >1.

Randomization was stratified by de novo metastatic disease vs recurrent disease within 6 to 12 months from completion of treatment in the curative setting versus recurrent disease > 12 months from completion of treatment in the curative setting, and by geographic region (United States/Canada/Western Europe vs. Rest of World).

Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion:

• TRODELVY 10 mg/kg on Days 1 and 8 of a 21-day cycle (n=279)
• nab-paclitaxel 100mg/m³ on Days 1, 8, and 15 of a 28-day cycle (n=110), paclitaxel 90 mg/m² on days 1, 8, and 15 of a 28-day cycle (n=45), or gemcitabine 1000 mg/m² and carboplatin AUC2 on Days 1 and 8 of a 21-day cycle (n=124)

Assessment of tumor status was performed every 6 weeks for the first year followed by every 12 weeks thereafter. Crossover to TRODELVY monotherapy was allowed at the time of disease progression and study treatment discontinuation. The primary efficacy outcome was progression-free survival (PFS) as assessed by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Additional efficacy outcomes measures included overall survival (OS) and objective response rate (ORR).

The median age was 55 years (range: 23-86 years), 26% age 65 or older; 99.5% female; 64% White, 23% Asian, 4.5% American Indian or Alaskan Native, 3.0% Black; and 5.2% not specified , 72% non-Hispanic/non-Latino, 27% Hispanic/Latino, and 0.9% not reported; and 66% ECOG PS of 0 and 34% ECOG PS of 1. Of patients enrolled 31% had de novo disease, 21% had recurrent disease with a disease-free interval (DFI) of 6 to 12 months and 48% had recurrent disease with a DFI of > 12 months. Seventy-six percent of patients had visceral metastasis at baseline; and 5% had previously treated brain metastases. The majority of patients (99.5%) had tumor CPS < 10, and 0.4% had tumor CPS ≥ 10.

The trial demonstrated a statistically significant improvement in PFS. The OS data were immature and a total of 283 (51%) patients had died across both study arms.

Table 14 and Figure 1 summarize the efficacy results for ASCENT-03.

Figure 1: Kaplan Meier Plot of Progression Free Survival (PFS) by BICR in ASCENT-03

In Combination with Pembrolizumab in Previously Untreated, Unresectable Locally Advanced or Metastatic TNBC whose tumors express PD-L1

ASCENT-04

The efficacy of TRODELVY in combination with intravenous pembrolizumab was evaluated in ASCENT-04 (NCT5382286) a multicenter, open-label, randomized study that enrolled 443 patients with locally advanced or metastatic TNBC who had not received previous systemic therapy for advanced disease and whose tumors express PD-L1 (CPS ≥ 10)] according to the PD-L1 IHC 22C3 pharmDx assay. Patients may have received chemotherapy with or without a PD-1 or PD-L1 inhibitor and/or radiotherapy in early-stage TNBC: however, at least 6 months must have elapsed between the completion of systemic breast cancer therapy or surgery, and first local or distant recurrence. Patients with active autoimmune disease that required systemic therapy within 2 years or treatment or a medical condition that required immunosuppression were ineligible.

Randomization was stratified by de novo metastatic disease versus disease recurrence within 6 to 12 months from completion of treatment in the curative setting versus disease recurrence > 12 months from completion of treatment in the curative setting, by geographic region (United States/ Canada/ Western Europe versus rest of world), and prior exposure to PD-1 or PD-L1 inhibitor (yes versus no).

Patients were randomized (1:1) to receive one of the following treatment arms; all study medications were administered via intravenous infusion:

• TRODELVY 10 mg/kg on Day 1 and 8 of 21-day cycles in combination with pembrolizumab 200 mg on Day 1 of 21-day cycles (n=221)
• nab-paclitaxel 100 mg/m² on Days 1, 8 and 15 every 28 days (n=69), paclitaxel 90 mg/m² on Days 1, 8, and 15 every 28 days (n=45), or gemcitabine 1000 mg/m² and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days in combination with pembrolizumab 200 mg on Day 1 of 21-day cycles (n=108)

Assessment of tumor status was performed every 8 weeks for the first 18 months followed by every 12 weeks thereafter. Treatment beyond BICR-verified PD per RECIST was permitted if the patient was clinically stable and there was evidence of clinical benefit per the investigator. Crossover to TRODELVY monotherapy was allowed following disease progression and study treatment discontinuation. The primary efficacy outcome was progression-free survival (PFS) by BICR per RECIST v1.1. Additional efficacy outcomes measures included overall survival (OS) and objective response rate (ORR).

The median age was 55 years (range: 23-88 years); 26% age 65 years or older; 100% female; 58% White, 24% Asian, 6% American Indian or Alaska Native, 5% Black, and 6.5% not specified ; 29% Hispanic/Latino, 69% non-Hispanic/non-Latino and 2.0% not reported; and 70% ECOG PS of 0, 30% ECOG PS of 1, and 0.2% ECOG PS of 2. Of the patients enrolled 34% had de novo metastatic disease, 18% had recurrent disease with a DFI of 6 to 12 months and 48% had recurrent DFI of > 12 months. Sixty-five percent of patients had visceral metastasis at baseline; and 3% of patients had previously treated brain metastasis.

The trial demonstrated a statistically significant improvement in PFS. The OS data were immature and a total of 203 (46%) patients had died across both study arms.

Table 15 and Figure 2 summarize the efficacy results for ASCENT-04.

Figure 2: Kaplan Meier Plot of Progression Free Survival (PFS) by BICR in ASCENT-04

Previously Treated, Locally Advanced or Metastatic TNBC

ASCENT

The efficacy of TRODELVY was evaluated in ASCENT (NCT02574455), a multicenter, open-label, randomized study conducted in 529 patients with unresectable locally advanced or metastatic TNBC who were previously treated with at least two prior lines of chemotherapy, one of which could be in the neoadjuvant setting provided progression occurred within a 12-month period. Patients were required to have received treatment with a taxane (unless contraindicated or not tolerated) in the neoadjuvant, adjuvant, or advanced setting. Patients with brain metastases were eligible to enroll up to a pre-defined maximum of 15% of patients. Magnetic resonance imaging (MRI) to determine brain metastases was required prior to enrollment for patients with known or suspected brain metastases. Patients with known Gilbert’s disease or bone-only disease were excluded.

Randomization was stratified by the number of prior chemotherapies (2-3 vs > 3), geographic region (North America vs Europe), and presence of brain metastasis (yes vs no).

Patients were randomized (1:1) to one of the following treatment arms:

• TRODELVY 10 mg/kg via intravenous infusion on Days 1 and 8 of a 21-day cycle (n=267)
• eribulin 1.23 or 1.4 mg/m² via intravenous infusion on Days 1 and 8 of a 21-day cycle (n=139), capecitabine 1000-1250 mg/m² orally twice daily on days 1-14 of a 21-day cycle (n=33), gemcitabine 800-1200 mg/m² via intravenous infusion on Days 1, 8, and 15 of a 28 day cycle (n=38), or vinorelbine 25 mg/m² via intravenous infusion on Day 1 weekly (n=52).

Assessment of tumor status was performed every 6 weeks for 36 weeks, then every 9 weeks thereafter. The primary efficacy outcome was progression-free survival (PFS) in patients without brain metastases at baseline (BICR per RECIST v1.1). Additional efficacy outcome measures included PFS for the full population and overall survival (OS).

The median age was 54 years (range: 27 to 82 years); 19% age 65 or older; 99.6% female; 79% White, 12% Black, 4.2% Asian and 5% not specified; 43% ECOG PS 0 and 57% ECOG PS 1; and 8.1% with BRCA1/BRCA2 mutations. Forty-two percent of patients had hepatic metastases, and 12 had previously treated, stable brain metastases. Twenty-nine percent received prior PD-1/PD-L1 therapy and 13% in the TRODELVY arm received only 1 prior line of systemic therapy in the metastatic setting.

The study demonstrated a statistically significant PFS. Efficacy results for the subgroup of patients who had received only 1 prior line of systemic therapy in the metastatic setting (in addition to having disease recurrence or progression within 12 months of neoadjuvant/adjuvant systemic therapy) were consistent with those who had received at least two prior lines in the metastatic setting.

Table 16, Figure 3 and Figure 4 summarize the efficacy results for ASCENT.

Figure 3: Kaplan-Meier Plot of PFS by BICR (All Randomized Patients) in ASCENT

Figure 4: Kaplan-Meier Plot of OS (All Randomized Patients) in ASCENT

An exploratory analysis of PFS in patients with previously treated, stable brain metastases showed a stratified HR of 0.65 (95% CI: 0.35, 1.22). The median PFS in the TRODELVY arm was 2.8 months (95% CI: 1.5, 3.9) and the median PFS with single agent chemotherapy was 1.6 months (95% CI: 1.3, 2.9). Exploratory OS analysis in the same population showed a stratified HR of 0.87 (95% CI: 0.47, 1.63). The median OS in the TRODELVY arm was 6.8 months (95% CI: 4.7, 14.1) and the median OS with single agent chemotherapy was 7.4 months (95% CI: 4.7, 11.1).

IMMU-132-01

The efficacy of TRODELVY was evaluated in IMMU-132-01 (NCT01631552) a multicenter, single-arm, study that enrolled 108 patients with metastatic TNBC who had received at least two prior anticancer therapies for metastatic disease. Patients with bulky disease, defined as a mass > 7 cm and patients with known Gilbert’s disease were ineligible. Patients with treated brain metastases not receiving high dose steroids (> 20 mg prednisone or equivalent) for at least four weeks were eligible.

Patients received TRODELVY 10 mg/kg via intravenous infusion on Days 1 and 8 of a 21-day cycle.

Assessment of tumor status was performed every 8 weeks, with confirmatory scans obtained 4-6 weeks after an initial partial or complete response. The primary efficacy outcome measure was overall response rate (ORR) per RECIST v1.1. Duration of response (DoR) per RECIST v 1.1 was an additional efficacy outcome.

The median age was 55 years (range: 31 to 80 years); 13% age 65 years or older; 99% female; 76% White, 7% Black, 2.8% Asian, and 0.9% American Indian or Alaska Native; 7% Hispanic/Latino and 93% non-Hispanic/non-Latino; 29% EGOC PS 0 and 71% ECOG PS 1; and 11% had Stage IV disease at the time of initial diagnosis. Seventy-six percent had visceral disease, 42% had hepatic metastases, 56% had lung/pleura metastases, and 2% had brain metastases. The median number of prior systemic therapies received in the metastatic setting was 3 (range: 2 to 10). Prior chemotherapies in the metastatic setting included carboplatin or cisplatin (69%), gemcitabine (55%), paclitaxel or docetaxel (53%), capecitabine (51%), eribulin (45%), doxorubicin (24%), vinorelbine (16%), cyclophosphamide (19%), and ixabepilone (8%). Ninety-eight percent had received prior taxanes and 86% had received prior anthracyclines either in the (neo)adjuvant or metastatic setting.

Table 17 summarizes the efficacy results.

TROPiCS-02 Study

The efficacy of TRODELVY was evaluated in TROPiCS-02 (NCT 03901339), a multicenter, open label, randomized study conducted in 543 patients with unresectable locally advanced or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer whose disease has progressed after the following in any setting: a CDK 4/6 inhibitor, endocrine therapy, and a taxane. Patients must have received at least two prior chemotherapies in the metastatic setting (one of which could be in the neoadjuvant or adjuvant setting if recurrence occurred within 12 months).

Randomization was stratified by prior chemotherapy regimens for metastatic disease (2 vs. 3-4), visceral metastasis (Yes or No), and endocrine therapy in the metastatic setting for at least 6 months (Yes or No).

Patients were randomized (1:1) to receive one of the following treatment arms:

• TRODELVY 10 mg/kg via an intravenous infusion on Days 1 and 8 of a 21-day cycle (n=272)
• eribulin 1.23 or 1.4 mg/m² via intravenous infusion on Days 1 and 8 of a 21-day cycle (n=130), vinorelbine 25 mg/m² via intravenous infusion on day 1 of a weekly cycle (n=63), gemcitabine 800 to 1200 mg/m² via intravenous infusion on Days 1, 8, and 15 of a 28-day cycle (n=56), or capecitabine 1000 to 1250 mg/m² orally twice daily on days 1-14 of a 21-day cycle (n=22).

Assessment of tumor status was performed every 6 weeks for the first 54 weeks followed by every 12 weeks thereafter. Treatment beyond RECIST-defined disease progression was permitted if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. The primary efficacy outcome measure was PFS by BICR per RECIST v1.1. Additional efficacy measures included OS, ORR by BICR, and DOR by BICR.

The median age was 56 years (range: 27–86 years); 26% of patients were 65 years or older; 99% female; 67% White, 3.9% Black, 2.9% Asian, and 26% unknown race; and 45% ECOG PS 0 and 55% ECOG PS 1. Ninety-five percent of patients had visceral metastases. Patients received a median of 7 (range: 3 to 17) prior systemic regimens in any setting and 3 (range: 0 to 8) prior systemic chemotherapy regimens in the metastatic setting. Approximately 42% of patients had 2 prior chemotherapy regimens for treatment of metastatic disease compared to 58% of patients who had 3 to 4 prior chemotherapy regimens. Eighty-six percent of patients received endocrine therapy in the metastatic setting for ³ 6 months.

The trial demonstrated a statistically significant improvement in PFS and OS.

Table 18, Figure 5 and Figure 6 summarize the results of TROPiCS-02.

Figure 5: Kaplan-Meier Plot of PFS by BICR in TROPiCS-02

Figure 6: Kaplan-Meier Plot of OS in TROPiCS-02