Locally Advanced or Metastatic Breast Cancer

·         TRODELVY is indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.

·         TRODELVY is indicated for the treatment of adult patients with unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.

Important use information

Do NOT substitute TRODELVY for or use with other drugs containing irinotecan or its active metabolite SN-38.

 

 

 

Posology

The recommended dosage of TRODELVY is 10 mg/kg administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles. Continue treatment until disease progression or unacceptable toxicity. Do not administer TRODELVY at doses greater than 10 mg/kg.

 

Premedication

Prior to each dose of TRODELVY, premedication for prevention of infusion reactions and prevention of chemotherapy-induced nausea and vomiting (CINV) is recommended.

 

Dose modifications for infusion-related reactions

Slow or interrupt the infusion rate of TRODELVY if the patient develops an infusion-related reaction. Permanently discontinue TRODELVY for life-threatening infusion-related reactions (see section 4.4).

 

Dose modifications for adverse reactions

Withhold or discontinue TRODELVY to manage adverse reactions as described in Table 1. Do not re-escalate the TRODELVY dose after a dose reduction for adverse reactions has been made.

 

Table 1: Dose Modifications for Adverse Reactions

 

Adverse Reaction	Occurrence	Dose Modification
Severe Neutropenia [see section 4.4]
Grade 4 neutropenia ≥ 7 days, OR Grade 3-4 febrile neutropenia, OR At time of scheduled treatment, Grade 3-4 neutropenia which delays dosing by 2 or 3 weeks for recovery to ≤ Grade 1	First	25% dose reduction and administer granulocyte-colony stimulating factor (G-CSF).
	Second	50% dose reduction and administer G-CSF.
	Third	Discontinue treatment and administer G-CSF.
At time of scheduled treatment, Grade 3-4 neutropenia which delays dosing beyond 3 weeks for recovery to ≤ Grade 1	First	Discontinue treatment and administer G-CSF.
Severe Non-Neutropenic Toxicity
Grade 4 non-hematologic toxicity of any duration, OR Any Grade 3-4 nausea, vomiting or diarrhoea due to treatment that is not controlled with antiemetics and anti-diarrheal agents (see section 4.4) OR Other Grade 3-4 non-hematologic toxicity persisting > 48 hours despite optimal medical management, OR At time of scheduled treatment, Grade 3-4 non-neutropenic hematologic or non-hematologic toxicity, which delays dose by 2 or 3 weeks for recovery to ≤ Grade 1	First	25% dose reduction
	Second	50% dose reduction
	Third	Discontinue treatment
In the event of Grade 3-4 non-neutropenic hematologic or non-hematologic toxicity, which does not recover to ≤Grade 1 within 3 weeks	First	Discontinue treatment

 

 

 

Special populations

 

Elderly

No dose adjustment is required in patients ≥ 65 years old. Data from sacituzumab govitecan in patients ≥ 75 years are limited.

 

Hepatic impairment

No adjustment to the starting dose is required when administering TRODELVY to patients with mild hepatic impairment [see section 5].

 

The safety of TRODELVY in patients with moderate (total bilirubin > 1.5 to 3.0 × ULN) or severe (total bilirubin > 3.0 × upper limit of normal [ULN]) hepatic impairment has not been established. TRODELVY has not been tested in patients with AST or ALT > 3 ULN without liver metastases, or AST or ALT > 5 ULN with liver metastases. No recommendations can be made for the starting dose in these patients.

 

Renal impairment

No adjustment to the starting dose is required when administering TRODELVY to patients with mild or moderate renal impairment.

TRODELVY has not been studied in patients with severe renal impairment or end-stage renal disease (Creatinine Clearance [CrCl] < 15 mL/min).

 

Paediatric population

The safety and efficacy of TRODELVY in children aged 0 to 18 years have not been established. No data are available.

 

Method of administration

Administer TRODELVY as an intravenous infusion only. Do not administer as an intravenous push or bolus.

 

First infusion: Administer infusion 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 section 4.4).

 

Subsequent infusions: Administer infusion over 1 to 2 hours if prior infusions were tolerated. Observe patients during the infusion and for at least 30 minutes after infusion.

 

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

TRODELVY is contraindicated in patients who have experienced a severe hypersensitivity reaction to TRODELVY (see section 4.4).

Neutropenia

Severe, life-threatening, or fatal neutropenia can occur in patients treated with TRODELVY. Neutropenia occurred in 64% of patients treated with TRODELVY. Grade 3-4 neutropenia occurred in 49% of patients. Febrile neutropenia occurred in 6% of patients. The median time to first onset of neutropenia (including febrile neutropenia) was 16 days and has occurred earlier in some patient populations. Neutropenic colitis occurred in 1.4% of patients.

 

Withhold TRODELVY for absolute neutrophil count below 1500/mm³ on Day 1 of any cycle or neutrophil count below 1000/mm³ on Day 8 of any cycle. Withhold TRODELVY for neutropenic fever. Dose modifications may be required due to neutropenia. Administer G-CSF as clinically indicated or indicated in Table 1 (see sections 4.2 and 4.8).

 

Diarrhoea

TRODELVY can cause severe diarrhea. Diarrhea occurred in 64% of all patients treated with TRODELVY. Grade 3-4 diarrhea occurred in 11% of all patients treated with TRODELVY. One patient had intestinal perforation following diarrhea. Diarrhoea that led to dehydration and subsequent acute kidney injury occurred in 0.7% of all patients.

 

Withhold TRODELVY for Grade 3-4 diarrhea at the time of scheduled treatment administration and resume when resolved to ≤Grade 1 (see section 4.2).

 

At the onset of diarrhea, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated.

 

Patients who exhibit an excessive cholinergic response to treatment with TRODELVY (e.g., abdominal cramping, diarrhea, salivation, etc.) can receive appropriate premedication (e.g., atropine) for subsequent treatments.

 

Hypersensitivity and Infusion-Related Reactions

Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with TRODELVY treatment. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions (see section 4.3).

 

Hypersensitivity reactions within 24 hours of dosing occurred in 35% of patients treated with TRODELVY. Grade 3-4 hypersensitivity occurred in 2% of patients treated with TRODELVY. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.2%. The incidence of anaphylactic reactions was 0.2%.

 

Premedication for infusion reactions in patients receiving TRODELVY is recommended. Have medications and emergency equipment to treat infusion-related reactions, including anaphylaxis, available for immediate use when administering TRODELVY (see section 4.2).

 

Closely monitor patients for hypersensitivity and infusion-related reactions during each TRODELVY infusion and for at least 30 minutes after completion of each infusion (see section 4.2).

 

Permanently discontinue TRODELVY for Grade 4 infusion-related reactions (see section 4.2).

 

Nausea and vomiting

TRODELVY is emetogenic. Nausea occurred in 64% of all patients treated with TRODELVY. Grade 3-4 nausea occurred in 3% of patients.

 

Vomiting occurred in 35% of all patients treated with TRODELVY. Grade 3-4 vomiting occurred in 2% of these patients.

 

Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV) (see section 4.2).

 

Withhold TRODELVY doses for Grade 3 nausea or Grade 3-4 vomiting at the time of scheduled treatment administration and resume with additional supportive measures when resolved to ≤Grade 1 (see section 4.2).

 

Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

 

 

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity

Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia; and may be at increased risk for other adverse reactions when treated with TRODELVY.

 

The incidence of neutropenia and anemia was analyzed in 948 patients who received TRODELVY and had UGT1A1 genotype results. In patients homozygous for the UGT1A1 *28 allele (n=112), the incidence of Grade 3-4 neutropenia was 58%. In patients heterozygous for the UGT1A1*28 allele (n=420), the incidence of Grade 3-4 neutropenia was 49%. In patients homozygous for the wild-type allele (n=416), the incidence of Grade 3-4 neutropenia was 43% (see section 5.1). In patients homozygous for the UGT1A1 *28 allele, the incidence of Grade 3-4 anemia was 21%. In patients heterozygous for the UGT1A1*28 allele, the incidence of Grade 3-4 anemia was 10%. In patients homozygous for the wild-type allele, the incidence of Grade 3-4 anemia was 9%.

 

The median time to first neutropenia including febrile neutropenia was 9 days in patients homozygous for the UGT1A1*28 allele, 15 days in patients heterozygous for the UGT1A1*28 allele, and 20 days in patients homozygous for the wild-type allele. The median time to first anemia was 21 days in patients homozygous for the UGT1A1*28 allele, 25 days in patients heterozygous for the UGT1A1*28 allele, and 28 days in patients homozygous for the wild-type allele.

 

Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 enzyme activity (see section 4.2).

 

Embryo-Fetal Toxicity

Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. TRODELVY contains a genotoxic component, SN-38, and targets rapidly dividing cells (see sections 5.1 and 5.3). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose (see section 4.6).

UGT1A1 inhibitors

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 section 4.4 and sections 5.1 and 5.2). Avoid administering UGT1A1 inhibitors with TRODELVY.

UGT1A1 inducers

Exposure to SN-38 may be reduced in patients concomitantly receiving UGT1A1 enzyme inducers (see section 4.4 and sections 5.1 and 5.2). Avoid administering UGT1A1 inducers with TRODELVY.

Pregnancy

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 sections 5.1 and 5.3). 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.

Animal data

There were no reproductive and developmental toxicology studies conducted with sacituzumab govitecan.

 

Breast-feeding

There is no information regarding the presence of sacituzumab govitecan 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.

 

Women of childbearing potential

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

 

Contraception in males and females

Females

TRODELVY can cause fetal harm when administered to a pregnant woman (see section 4.6). Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose.

Males

Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose.

Fertility

Based on findings in animals, TRODELVY may impair fertility in females of reproductive potential.

TRODELVY has minor influence on the ability to drive and use machines.

4.8.1 Adverse reactions

 

Summary of the safety profile

The safety profile for TRODELVY as monotherapy is based on pooled data in 1063 patients across multiple tumor types, including patients with breast cancer who received TRODELVY 10 mg/kg. The median exposure to TRODELVY in this population was 4.1 months. Table 2 presents adverse reactions reported with TRODELVY. Frequency estimates include all reported adverse events for each listed adverse reaction.

 

Tabulated list of adverse reactions

Table 2 presents adverse reactions reported with TRODELVY. Frequency estimates include all reported adverse events for each listed adverse reaction. Adverse reactions are listed by System Organ Class and frequency category. Frequency categories are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) or not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in decreasing order of all severity grade frequencies.

 

Table 2: List of adverse reactions in patients treated with Trodelvy

 

System Organ Class	All Grade
Blood and lymphatic system disorders
Neutropenia1	Very Common
Anemia2	Very Common
Leukopenia3	Very Common
Lymphopenia4	Very Common
Thrombocytopenia5	Common
Febrile neutropenia	Common
Gastrointestinal disorders
Nausea	Very Common
Diarrhoea	Very Common
Constipation	Very Common
Vomiting	Very Common
Abdominal pain	Very Common
Stomatitis	Common
Abdominal pain upper	Common
Dyspepsia	Common
Abdominal distension	Common
Gastrooesophageal reflux disease	Common
Colitis	Common
Neutropenic colitis6	Common
Enteritis	Uncommon
General disorders and administration site conditions
Fatigue7	Very Common
Chills	Common
Pain	Common
Immune system disorders
Hypersensitivity8	Very Common
Anaphylactic reaction	Uncommon
Infections and infestations
Urinary tract infection	Very Common
Upper respiratory tract infection	Common
Pneumonia	Common
Sepsis	Common
Injury, poisoning and procedural complications
Infusion related reaction	Common
Investigations
Weight decreased	Very Common
Blood alkaline phosphatase increased	Common
Blood lactate dehydrogenase increased	Common
Activated partial thromboplastin time prolonged	Common
Metabolism and nutrition disorders
Decreased appetite	Very Common
Hypokalaemia	Very Common
Hypomagnesaemia	Very Common
Hypophosphatemia	Very Common
Dehydration	Very Common
Hyperglycaemia	Common
Hyponatraemia	Common
Hypocalcaemia	Common
Musculoskeletal and connective tissue disorders
Arthralgia	Very Common
Nervous system disorders
Headache	Very Common
Dizziness	Very Common
Dysgeusia	Common
Psychiatric disorders
Insomnia	Common
Renal and urinary disorders
Proteinuria	Common
Respiratory, thoracic and mediastinal disorders
Dyspnoea9	Very Common
Cough	Very Common
Epistaxis	Common
Rhinorrhoea	Common
Nasal congestion	Common
Skin and subcutaneous tissue
Alopecia	Very Common
Rash	Very Common
Pruritus	Very Common
Dry skin	Common
Rash maculo-papular	Common
Skin hyperpigmentation	Common
Dermatitis acneiform	Common
Vascular disorders
Hypotension	Common

1: Includes the following preferred terms: neutropenia; neutrophil count decreased.

2: Includes the following preferred terms: anemia; hemoglobin decreased; red blood cell count decreased.

3: Includes the following preferred terms: leukopenia; white blood cell count decreased.

4: Includes the following preferred terms: lymphopenia; lymphocyte count decreased.

5: Includes the following preferred terms: thrombocytopenia; platelet count decreased.

6: Includes the preferred term of neutropenic colitis and events reported as typhlitis.

7: Includes the following preferred terms: fatigue, asthenia.

8: Hypersensitivity events reported up to the end of the day after treatment was administered. Includes events coded to the following preferred terms: Cough; dyspnea; rash; pruritus; stomatitis; hypotension; rash maculopapular; flushing; erythema; chest discomfort; hypersensitivity; rhinitis allergic; wheezing; localized edema; dermatitis acneiform; conjunctivitis; rash pruritic; edema; rash macular; rash pustular; swelling; swelling face; urticaria; anaphylactic reaction; asthma; bronchospasm; conjunctivitis allergic; dermatitis; dermatitis contact; eye pruritus; mouth ulceration; periorbital edema; rash erythematous; scrotal edema; seasonal allergy; skin exfoliation; swollen tongue; tachypnoea; throat tightness; Type IV hypersensitivity reaction; choking.

9:  Includes the following preferred terms: dyspnea; dyspnea exertional.

 

Description of selected adverse reactions

 

Immunogenicity

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of TRODELVY.

During the median 4-month treatment period across clinical studies in patients treated with TRODELVY, 9 (1.1%) of 785 patients developed antibodies to sacituzumab govitecan; 6 of these patients (0.8% of all patients treated with TRODELVY) had neutralizing antibodies against sacituzumab govitecan. Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of sacituzumab govitecan is unknown.

 

To report any side effect(s):

· The National Pharmacovigilance Centre (NPC):   -          SFDA Call Center: 19999 -          E-mail: npc.drug@sfda.gov.sa -          Website: https://ade.sfda.gov.sa/

 

In a clinical trial, planned doses of up to 18 mg/kg (approximately 1.8 times the maximum recommended dose of 10 mg/kg) of TRODELVY were administered. In these patients, a higher incidence of severe neutropenia was observed.

In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, in particular severe neutropenia, and appropriate treatment instituted.

Pharmacotherapeutic group: antineoplastic agents, ATC code: L01FX17.

 

Mechanism of action

Sacituzumab govitecan 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 sacituzumab govitecan 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. Sacituzumab govitecan decreased tumor growth in mouse xenograft models of triple-negative breast cancer.

 

Pharmacodynamic effects

 

The TRODELVY exposure-response relationships and pharmacodynamic time course for efficacy have not been fully characterized.

 

Cardiac electrophysiology 

The maximum mean change from baseline was 9.7 msec (the upper bound of the two-sided 90% confidence interval is 16.8 msec) at the recommended dose. A positive exposure-response relationship was observed between QTc increases and SN-38 concentrations.

 

Clinical efficacy and safety

 

Locally Advanced or Metastatic Triple-Negative Breast Cancer

 

ASCENT

Efficacy was evaluated in a multicenter, open-label, randomized study (ASCENT; NCT02574455) conducted in 529 patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who had relapsed after at least two prior chemotherapies for breast cancer (one of which could be in the neoadjuvant or adjuvant setting provided progression occurred within a 12 month period). All patients received previous taxane treatment in either the adjuvant, neoadjuvant, or advanced stage unless there was a contraindication or intolerance to taxanes during or at the end of the first taxane cycle. Magnetic resonance imaging (MRI) to determine brain metastases was required prior to enrollment for patients with known or suspected brain metastases. Patients with brain metastases were allowed to enroll up to a pre-defined maximum of 15% of patients in the ASCENT study. Patients with known Gilbert’s disease or bone-only disease were excluded.

 

Patients were randomized (1:1) to receive TRODELVY 10 mg/kg as an intravenous infusion on Days 1 and 8 of a 21-day (n=267) or physician’s choice of single agent chemotherapy (n=262). Single agent chemotherapy was determined by the investigator before randomization from one of the following choices: eribulin (n=139), capecitabine (n=33), gemcitabine (n=38), or vinorelbine (n=52).

 

Patients were treated until disease progression or unacceptable toxicity. The major efficacy outcome was progression-free survival (PFS) in patients without brain metastases at baseline (i.e., BMNeg) as measured by a blinded, independent, centralized review assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Additional efficacy measures included PFS for the full population (all patients with and without brain metastases) and overall survival (OS).

 

The median age of patients in the full population (n = 529) was 54 years (range: 27 to 82 years); 99.6% were female; 79% were White, 12% were Black/African American; and 81% of patients were < 65 years of age. All patients had an ECOG performance status of 0 (43%) or 1 (57%). Forty-two percent of patients had hepatic metastases, 9% were BRCA1/BRCA2 mutational status positive, and 70% were TNBC at diagnosis. Twelve percent had baseline brain metastases previously treated and stable (n=61; 32 on TRODELVY arm and 29 on single agent chemotherapy arm).

Overall, 29% of patients had received prior PD-1/PD-L1 therapy. Thirteen percent of patients in the TRODELVY group in the full population received only 1 prior line of systemic therapy in the metastatic setting.

 

The efficacy results are summarized in Table 3 and are shown in Figure 1 and Figure 2. 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 3: Efficacy Results from ASCENT

	All Randomized Patients
	TRODELVY n=267		Single Agent Chemotherapy n=262
Progression-Free Survival1 per BICR
Disease Progression or Death (%)	190 (71%)	171 (65%)
Median PFS in months (95% CI)	4.8 (4.1, 5.8)	1.7 (1.5, 2.5)
Hazard ratio2 (95% CI)	0.43 (0.35, 0.54)
p-value	<0.0001
Overall Survival
Deaths (%)	179 (67%)	206 (79%)
Median OS in months (95% CI)	11.8 (10.5, 13.8)	6.9 (5.9, 7.6)
Hazard ratio2 (95% CI)	0.51 (0.41, 0.62)
p-value	<0.0001

¹ PFS is defined as the time from the date of randomization to the date of the first radiological disease progression or death due to any cause, whichever comes first.

² Stratified log-rank test adjusted for stratification factors: number of prior chemotherapies, presence of known brain metastases at study entry, and region.

CI = Confidence Interval

 

 

Figure 1: Kaplan-Meier Plot of PFS by BICR (All Randomized Patients) in ASCENT

 

 

 

 

 

Figure 2: 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 a multicenter, single-arm, study (NCT01631552) that enrolled 108 patients with metastatic triple-negative breast cancer (mTNBC) who had received at least two prior anticancer therapies for metastatic disease. Patients with bulky disease, defined as a mass >7 cm, were not eligible. Patients with treated brain metastases not receiving high dose steroids (>20 mg prednisone or equivalent) for at least four weeks were eligible. Patients with known Gilbert’s disease were excluded.

 

Patients received TRODELVY 10 mg/kg intravenously on Days 1 and 8 of a 21-day treatment cycle. Patients were treated with TRODELVY until disease progression or intolerance to the therapy. Tumor imaging was obtained every 8 weeks, with confirmatory CT/MRI scans obtained 4-6 weeks after an initial partial or complete response, until progression requiring treatment discontinuation. Major efficacy outcome measures were investigator assessed overall response rate (ORR) using RECIST 1.1 and duration of response.

 

The median age was 55 years (range: 31 to 80 years); 87% of patients were younger than 65 years. The majority of patients were female (99%) and White (76%). At study entry, all patients had an ECOG performance status of 0 (29%) or 1 (71%). Seventy-six percent had visceral disease, 42% had hepatic metastases, 56% had lung/pleura metastases, and 2% had brain metastases. Twelve patients (11%) had Stage IV disease at the time of initial diagnosis.

 

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%).

 

Overall, 98% of patients had received prior taxanes and 86% had received prior anthracyclines either in the (neo)adjuvant or metastatic setting.

 

Table 4 summarizes the efficacy results.

Table 4: Efficacy results for patients with mTNBC in IMMU-132-01

 

TRODELVY (N = 108) Overall Response Ratei   ORR (95% CI) 33.3% (24.6, 43.1) Complete response 2.8% Partial response 30.6% Duration of responsei   Number of responders 36 Median, Months (95% CI) 7.7 (4.9, 10.8) Range, Months 1.9+, 30.4+ % with duration ≥ 6 months 55.6% % with duration ≥ 12 months 16.7% CI: confidence interval iinvestigator assessment +: denotes ongoing

 

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

 

TROPiCS-02 Study

 

The efficacy of TRODELVY was evaluated in a multicenter, open label, randomized study (TROPiCS-02; NCT03901339) 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 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).

 

Patients were randomized (1:1) to receive TRODELVY 10 mg/kg as an intravenous infusion on Days 1 and 8 of a 21 day cycle (n=272) or single agent chemotherapy (n=271). Single agent chemotherapy was determined by the investigator before randomization from one of the following choices: eribulin (n=130), vinorelbine (n=63), gemcitabine (n=56), or capecitabine (n=22).  Randomization was stratified by the following factors: 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 treated until disease progression or unacceptable toxicity. Administration of TRODELVY was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. The primary efficacy outcome measure was PFS as determined by BICR per RECIST v1.1. Additional efficacy measures included OS, ORR by BICR, and DOR by BICR.

The median age of patients in the study population was 56 years (range: 27–86 years), 26% of patients were 65 years or over. The majority of patients were female (99%); 67% were White, 4% were Black and 3% were Asian, and 26% were of unknown race. 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 and all patients had an ECOG performance status of 0 (45%) or 1 (55%). Ninety-five percent of patients had visceral metastases. Most patients received endocrine therapy in the metastatic setting for ³ 6 months (86%).

TRODELVY demonstrated a statistically significant improvement in PFS and OS versus single agent chemotherapy.

The efficacy results are summarized in Table 5 and Figure 3 and Figure 4.

Table 5: Efficacy Results from TROPiCS-02

	All Randomized Patients
	TRODELVY n=272		Single Agent Chemotherapy n=271
Progression-Free Survival by BICR1
Median PFS in months (95% CI)	5.5 (4.2, 7.0)		4.0 (3.1, 4.4)
Hazard ratio (95% CI)	0.661 (0.529, 0.826)
p-value2	0.0003
Overall Survival3
Median OS in months (95% CI)		14.4 (13.0, 15.7)	11.2 (10.1, 12.7)
Hazard ratio (95% CI)		0.789 (0.646, 0.964)
p-value2		0.0200
Objective Response Rate3 by BICR
Response Rate, % (95% CI)	21.0 (16.3, 26.3)		14.0 (10.1, 18.7)
Odds ratio (95% CI)	1.625 (1.034, 2.555)
p-value	0.0348
Duration of Response3 (DOR) by BICR
Median DOR in months (95% CI)	8.1 (6.7, 9.1)		5.6 (3.8, 7.9)

¹ PFS is defined as the time from the date of randomization to the date of the first radiological disease progression or death due to any cause, whichever comes first.

² Stratified log-rank test adjusted for stratification factors: prior chemotherapy regimens for metastatic disease (2 vs. 3-4), visceral metastasis (Y/N), and endocrine therapy in the metastatic setting for at least 6 months (Yes or No).

BICR = Blinded Independent Central Review; CI = Confidence Interval

³ Second interim OS analysis (conducted when 390 OS events were observed)

Figure 3: Kaplan-Meier Plot of PFS by BICR in TROPiCS-02

 

Figure 4: Kaplan-Meier Plot of OS in TROPiCS-02

 

 

The serum pharmacokinetics of sacituzumab govitecan and SN-38 were evaluated in patients with mBC who received sacituzumab govitecan as a single agent at a dose of 10 mg/kg. The pharmacokinetic parameters of sacituzumab govitecan and free SN-38 are presented in Table 6.

 

 

Table 6: Summary of Mean PK Parameters (CV%) of sacituzumab govitecan and Free SN-38

 

	Sacituzumab govitecan (N=693)	Free SN-38 (N=681)
Cmax [ng/mL]	239000 (11%)	98.0 (45%)
AUC0-168 [ng*h/mL]	5640000 (22%)	3696 (56%)

^*Parameters estimated based on population PK analyses

C_max: maximum serum concentration from 0-168 hours after the first dose

AUC_0-168: area under serum concentration curve through 168 hours after the first dose

 

Distribution

Based on population pharmacokinetic analysis, steady state volume of distribution of sacituzumab govetican is 3.6 L.

 

Elimination

The median elimination half-life of sacituzumab govitecan half-life (t_1/2) and free SN-38 in patients with metastatic triple negative breast cancer was 23.4 and 17.6 hours, respectively. Based on population pharmacokinetic analysis, the estimated mean (%CV) clearance of the sacituzumab govitecan is 0.13 L/h (12%).

 

Metabolism

No metabolism studies with sacituzumab govitecan have been conducted. SN-38 (the small molecule moiety of sacituzumab govitecan) is metabolized via UGT1A1. The glucuronide metabolite of SN-38 (SN-38G) was detectable in the serum of patients. Genetic variants of the UGT1A1 gene such as the UGT1A1*28 allele lead to reduced UGT1A1 enzyme activity. Individuals who are homozygous or heterozygous for the UGT1A1*28 allele are potentially at increased risk for neutropenia, febrile neutropenia, and anaemia from TRODELVY compared to individuals who are wildtype (*1/*1). Approximately 20% of the Black or African American population, 10% of the White population, and 2% of the East Asian population are homozygous for the UGT1A1*28 allele (*28/*28). Approximately 40% of the Black or African American population, 50% of the White population, and 25% of the East Asian population are heterozygous for the UGT1A1*28 allele (*1/*28). Decreased function alleles other than UGT1A1*28 may be present in certain populations.

 

Special Populations

Pharmacokinetic analyses in patients treated with TRODELVY did not identify an effect of age (27 to 88 years), race (White, Black, or Asian), or mild renal impairment to moderate renal impairment (CLcr 30 to 89 mL/min) on the pharmacokinetics of sacituzumab govitecan. Renal elimination is known to contribute minimally to the excretion of SN-38, the small molecule moiety of sacituzumab govitecan. There are no data on the pharmacokinetics of sacituzumab govitecan in patients with severe renal impairment (CLcr 15 to 29 mL/min), or end-stage renal disease (CLcr < 15 mL/min).

 

Patients with Hepatic impairment

The exposure of sacituzumab govitecan is similar in patients with mild hepatic impairment (bilirubin ≤ULN and AST > ULN, or bilirubin >1.0 to ≤1.5 ULN and AST of any level; n=257) to patients with normal hepatic function (total bilirubin or AST ≤ ULN; n=526).

Sacituzumab govitecan and free SN-38 exposures are unknown in patients with moderate (total bilirubin > 1.5 to 3.0 × ULN) or severe (total bilirubin > 3.0 × ULN) hepatic impairment.

 

Drug Interaction Studies

No drug-drug interaction studies were conducted with sacituzumab govitecan or its components. Inhibitors or inducers of UGT1A1 may increase or decrease SN-38 exposure, respectively (see section 4.5).

Carcinogenicity studies have not been conducted with sacituzumab govitecan.

SN-38 was clastogenic in an in vitro mammalian cell micronucleus test in Chinese hamster ovary cells and was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.

Fertility studies with sacituzumab govitecan have not been conducted. In a repeat-dose toxicity study in cynomolgus monkeys, intravenous administration of sacituzumab govitecan on Day 1 and Day 4 resulted in endometrial atrophy, uterine hemorrhage, increased follicular atresia of the ovary, and atrophy of vaginal epithelial cells at doses ≥60 mg/kg (≥ 6 times the human recommended dose of 10 mg/kg based on body weight).

2-(N-morpholino)ethane sulfonic acid (MES)

Polysorbate 80

Trehalose dihydrate

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Unopened vial 3 years After reconstitution The reconstituted solution should be used immediately to prepare the diluted solution for infusion. If not used immediately, the infusion bag containing diluted solution can be stored in a refrigerator (2°C to 8°C) for up to 24 hours protected from light.

Store in a refrigerator (2°C-8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

 

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Type I colorless, clear glass 50 mL vial, with an elastomeric butyl stopper and sealed with an aluminum flip-off overseal.

Each pack contains one vial.

TRODELVY is a cytotoxic drug. Applicable special handling and disposal procedures have to be followed.

 

Reconstitution

·                Calculate the required dose (mg) of TRODELVY based on the patient’s body weight at the beginning of each treatment cycle (or more frequently if the patient’s body weight changed by more than 10% since the previous administration).

·                Allow the required number of vials to warm to room temperature.

·                Using a sterile syringe, slowly inject 20 mL of sodium chloride 0.9% solution for injection, into each 180 mg TRODELVY vial. The resulting concentration will be 10 mg/mL.

·                Gently swirl vials and allow to dissolve for up to 15 minutes. Do not shake. The product should be inspected visually for particulate matter and discoloration prior to administration. The solution should be free of visible particulates, clear and yellow. Do not use the reconstituted solution if it is cloudy or discoloured.

·                Use immediately to prepare a diluted TRODELVY solution for infusion.

 

Dilution

·                Calculate the required volume of the reconstituted TRODELVY solution needed to obtain the appropriate dose according to patient’s body weight. Withdraw this amount from the vial(s) using a syringe. Discard any unused portion remaining in the vial(s).

·                Adjust the volume in the infusion bag as needed with sodium chloride 0.9% solution for injection, to obtain a concentration of 1.1 mg/mL to 3.4 mg/mL (the total volume should not exceed 500 mL). For patients whose body weight exceeds 170 kg, divide the total dosage of TRODELVY equally between two 500 mL infusion bags and infuse sequentially via slow infusion.

·                Slowly inject the required volume of reconstituted TRODELVY solution into a polyvinyl chloride, polypropylene, or polypropylene copolymer infusion bag to minimise foaming. Do not shake the contents.

·                Only sodium chloride 0.9% solution for injection should be used since the stability of the reconstituted product has not been determined with other infusion-based solutions. Use the diluted solution in the infusion bag immediately. If not used immediately, the infusion bag containing TRODELVY solution can be stored refrigerated at 2°C to 8°C for up to 24 hours protected from light. After refrigeration, administer diluted solution at room temperature up to 25°C within 8 hours (including infusion time).

 

Do not freeze or shake. Protect from light.

 

Administration

·                Administer TRODELVY as an intravenous infusion. Protect infusion bag from light.

·                An infusion pump may be used.

·                Do not mix TRODELVY, or administer as an infusion, with other medicinal products.

·                Upon completion of the infusion, flush the intravenous line with 20 mL sodium chloride 0.9% solution for injection.

 

Any unused medicinal product or waste material should be disposed of in accordance with local requirements