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 lines of systemic therapies, at least one of them given for unresectable locally advanced or metastatic disease (see section 5.1).

TRODELVY must only be prescribed and administered to patients by healthcare professionals experienced in the use of anti-cancer therapies and should be administered in an environment where resuscitation facilities are available (see section 4.3 and 4.4).

Posology

The recommended dose 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.

Premedication

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

• Premedicate with antipyretics, and H1 and H2 blockers prior to infusion, and corticosteroids may be used for patients who had prior infusion reactions.

• 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).

Dose modifications for infusion-related reactions

The infusion rate of TRODELVY should be slowed down or infusion interrupted if the patient develops an infusion-related reaction. TRODELVY should be permanently discontinued if life-threatening infusion-related reactions occur, see section 4.4 Special warnings and precautions for use.

Dose modifications for adverse reactions

Dose modifications to manage adverse reactions of TRODELVY are described in Table 1. The TRODELVY dose should not be re-escalated after a dose reduction for adverse reactions has been made.

Table 1: Recommended dose modifications for adverse reactions

Grading according to NCI-CTCAE v.4.03

NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events

Special populations

Elderly

No overall differences in safety and effectiveness were observed between patients ≥ 65 years old and younger patients.

Hepatic impairment

No adjustment to the starting dose is required when administering TRODELVY to patients with mild hepatic impairment (see section 5.2)

The safety of TRODELVY in patients with moderate or severe hepatic impairment has not been established. TRODELVY has not been studied in patients with any of the following: serum bilirubin > 1.5 ULN, AST or ALT > 3 ULN in patients without liver metastases, or AST or ALT > 5 ULN in patients with liver metastases. The use of TRODELVY is not recommended in these patients.

Renal impairment

No adjustment to the starting dose is required when administering TRODELVY to patients with mild renal impairment. TRODELVY has not been studied in patients with moderate renal impairment, severe renal impairment, or end-stage renal disease.

Paediatric population

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

Method of administration

TRODELVY should only be administered as an intravenous infusion, not as an intravenous push or bolus.

First infusion: the infusion should be administered over a period of 3 hours.

Subsequent infusions: the infusion should be administered over a period of 1 to 2 hours if prior infusions were tolerated.

Patients have to be observed during the infusion and for at least 30 minutes after each infusion, for signs or symptoms of infusion-related reactions.

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

Hypersensitivity to the active substance, to any of the excipients listed in section 6.1, or to previous irinotecan therapy

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Neutropenia

TRODELVY can cause severe or life-threatening neutropenia. TRODELVY should not be administered if the absolute neutrophil count is below 1500/mm³ on Day 1 of any cycle or if the neutrophil count is below 1000/mm³ on Day 8 of any cycle. Therefore, it is recommended that patients' blood counts are routinely tested prior to each dose of TRODELVY and as clinically indicated. TRODELVY should not be administered in case of neutropenic fever. Administration of G-CSF and dose reduction are required due to severe neutropenia or febrile neutropenia (see section 4.2). Consider G-CSF for secondary prophylaxis.

Diarrhoea

TRODELVY can cause severe diarrhoea. Diarrhoea in some cases was observed to have led to dehydration and subsequent acute kidney injury. TRODELVY should not be administered in case of Grade 3-4 diarrhoea at the time of scheduled treatment and treatment should only be continued when resolved to ≤ Grade 1 (see section 4.2).

Patients should be advised of the risk of diarrhoea and be closely monitored. Instruct patients to immediately contact their healthcare provider if they experience diarrhoea for the first-time during treatment.

At the onset of diarrhoea, and if no infectious cause can be identified, promptly initiate loperamide 4 mg initially followed by 2 mg with every episode of diarrhoea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhoea resolves. In patients with infectious diarrhoea, initiate anti-infective treatment as clinically indicated. Additional supportive measures (e.g. fluid and electrolyte substitution) may also be employed as clinically indicated.

Instruct patients to immediately contact their healthcare provider if they experience melena, haematochezia, dehydration, an inability to tolerate oral fluids or an inability to manage diarrhoea within 24 hours.

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

Hypersensitivity

TRODELVY can cause severe and life-threatening hypersensitivity. Anaphylactic reactions have been observed in clinical trials with TRODELVY and the use of TRODELVY is contraindicated in patients with a known hypersensitivity to sacituzumab govitecan (see section 4.3). Other hypersensitivity events observed during and within 24 hours following the infusion included dyspnoea; rash; pruritus; hypotension; wheezing; oedema including facial and tongue; urticaria; and bronchospasm. Inform patients of the risk of serious infusion reactions and anaphylaxis. Instruct patients to immediately contact their healthcare provider if they experience these signs and symptoms. Medication to treat life-threatening hypersensitivity, as well as emergency equipment, should be available for immediate use.

Infusion-related reactions

Pre-infusion medication for patients receiving TRODELVY is recommended (see section 4.2). Patients should be closely observed for infusion-related reactions during each TRODELVY infusion and for at least 30 minutes after completion of each infusion. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use. The infusion rate of TRODELVY should be slowed down or infusion interrupted if the patient develops an infusion-related reaction. TRODELVY should be permanently discontinued if life-threatening infusion-related reactions occur (see section 4.2).

Nausea and vomiting

TRODELVY is emetogenic. Premedication with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK-1 receptor antagonist as well as other drugs as indicated) is recommended for prevention of chemotherapy-induced nausea and vomiting (CINV).

TRODELVY should not be administered in case of Grade 3 nausea or Grade 3-4 vomiting at the time of scheduled treatment administration and treatment should only be continued 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

Individuals who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk of severe neutropenia, severe diarrhoea, febrile neutropenia, and anaemia and may be at increased risk for other adverse reactions following initiation of TRODELVY treatment (see section 4.8). Patients with known reduced UGT1A1 activity should be closely monitored 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 activity (see section 4.2).

No interaction studies have been performed. SN-38 (the small molecule moiety of sacituzumab govitecan) is primarily metabolised via UGT1A1. Inhibitors or inducers of UGT1A1 are expected to increase or decrease SN-38 exposure, respectively.

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. TRODELVY should be used with caution with UGT1A1 inhibitors (e.g. propofol, ketoconazole, EGFR tyrosine kinase inhibitors), and patients should be closely monitored.

UGT1A1 inducers

Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. TRODELVY should be used with caution with UGT1A1 inducers (e.g. carbamazepine, phenytoin, rifampicin, protease inhibitors), and patients should be closely monitored.

CYP3A

SN-38 (the small molecule moiety of sacituzumab govitecan) is primarily metabolised via UGT1A1. Inhibitors or inducers of CYP3A are not anticipated to impact SN-38 exposure.

Pregnancy

Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-foetal lethality when administered during pregnancy. TRODELVY contains a genotoxic component, SN-38, and targets rapidly dividing cells. TRODELVY is not recommended during pregnancy. Advise female patients to contact their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to the foetus and potential loss of the pregnancy.

Women of Childbearing Potential / Contraception in Males and Females

Women of childbearing potential have to use effective contraception during treatment and for 6 months after the last dose. Male patients with female partners of childbearing potential have to use effective contraception during treatment with TRODELVY and for 3 months after the last dose. The pregnancy status of women of childbearing potential should be verified prior to the initiation of TRODELVY.

Breast-feeding

It is unknown whether TRODELVY or metabolites are excreted in human milk. Breast-feeding should be discontinued during treatment with TRODELVY and for 1 month 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. Dizziness has been reported. Advise patients to use caution when driving or using machines.

Summary of the safety profile

The safety profile for TRODELVY is derived from pooled data from two clinical studies (IMMU-132-01 and IMMU-132-05 [N=258; ASCENT]) involving 366 patients who received TRODELVY 10 mg/kg for the treatment of TNBC (the Overall TNBC population). The median exposure to TRODELVY in this data set was 4.9 months.

The most common adverse drug reactions (ADRs) (reported at a frequency of ≥ 20%) in the overall TNBC population were diarrhoea (64.5%), nausea (64.2%), neutropenia (64.2%), fatigue (52.5%), alopecia (44.3%), anaemia (43.4%), vomiting (38.5%), constipation (36.3%), decreased appetite (28.1%), cough (22.7%) and abdominal pain (20.5%).

The most common serious adverse reactions (reported at a frequency of ≥ 2%) were neutropenia (2.5%), febrile neutropenia (5.5%), diarrhoea (3.6%), and pneumonia (2.7%). Fatal adverse reactions occurred in 0.5% of patients who received TRODELVY, including respiratory failure (0.3%).

The most common Grade 3 or higher ADRs (reported at a frequency of ≥ 2%) were neutropenia (49.7%), leukopenia (12.0%), diarrhoea (10.9%), anaemia (10.1%), febrile neutropenia (6.6%), fatigue (5.2%), hypophosphataemia (5.2%), nausea (4.1%), dyspnoea (3.6%), pneumonia (3.3%), vomiting (3.3%), hypokalaemia (2.5%), lymphopenia (2.5%), abdominal pain (2.2%), and aspartate aminotransferase increased (2.2%). A higher proportion of patients with body weight > 95 kg experienced Grade 3 or higher ADRs on TRODELVY 10 mg/kg.

The most common ADRs leading to treatment interruption (reported at a frequency of ≥ 2%) were neutropenia (42.3%), leukopenia (6.3%), diarrhoea (4.4%), anaemia (4.1%), pyrexia (2.7%), and febrile neutropenia (2.2%).

The most common ADRs leading to dose reduction reported (at a frequency of ≥ 2%) were neutropenia (6.3%) and diarrhoea (3.6%).

The most common ADRs leading to treatment discontinuation (reported in >1 patient) were fatigue (0.8%) and pneumonia (0.5%).

Adverse reactions in patients with reduced UGT1A1 activity

In 91.0% (333/366) of patients the Overall TNBC population had retrospective UGT1A1 genotype results available, the incidence of Grade 3 or higher neutropenia in the Overall TNBC population and anaemia were 56.1% (23/41) and 19.5% (8/41), respectively, in patients homozygous for the UGT1A1*28 allele, 46.7% (63/135) and 6.7% (9/135), respectively, in patients heterozygous for the UGT1A1*28 allele, and 52.9% (83/157) and 8.3% (13/157), respectively, in patients homozygous for the wild-type allele. (See sections 4.2 and 4.4)

Compared to patients homozygous for the wild-type allele, earlier median onset of neutropenia and anaemia was observed in patients homozygous for the UGT1A1*28 allele and in patients heterozygous for the UGT1A1*28 allele.

Tabulated list of adverse reactions

Table 2 lists adverse reactions from the Overall TNBC population. The adverse reactions are classified by System Organ Class and sorted by frequencies calculated from all reported events, using the following convention: 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).

Table 2: Adverse reactions observed in the Overall TNBC Population, comprising of patients treated with TRODELVY in studies IMMU-132-01 and IMMU-132-05

1: No frequency is provided for those events for which a Grade ≥ 3 event was not observed among the pooled safety data.

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

3: Includes the following preferred terms: anaemia; haemoglobin decreased; red blood cell count decreased.

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

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

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

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

8: Includes the following preferred terms: dyspnoea; dyspnoea exertional.

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

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

Description of selected adverse reactions

Neutropenia

In IMMU-132-05, neutropenia occurred in 64.0% (165/258) of patients in the TRODELVY arm compared to 43.8% (98/224) of patients in the Treatment of Physician's Choice (TPC; chosen from one of the following single-agent chemotherapies: eribulin, vinorelbine, gemcitabine or capecitabine) arm. Grade 3-4 neutropenia occurred in 52.3% (135/258) of patients in the TRODELVY arm compared to 33.9% (76/224) of patients in the TPC arm. The incidence of neutropenia in the Overall TNBC population was similar (64.2%). In the Overall TNBC population, no patients in the TRODELVY arm had neutropenia leading to permanent discontinuation and neutropenic colitis was observed in 0.8% (3/366) of patients.

Granulocyte-colony stimulating factor (G-CSF) was used beyond treatment cycle 1 in 45.4% (166/366) of patients who received TRODELVY. G-CSF was used at any time during the study for prophylaxis for neutropenia by 25.4% of patients (93/366) and/or treatment of neutropenia by 34.4% of patients (126/366).

The median time to onset of neutropenia (including febrile neutropenia) following the start of the first treatment cycle was 15 days [1-302 days] and has occurred earlier in some patient populations (see Adverse reaction in patients with reduced UGT1A1 activity section). Neutropenia was reversible with a median duration of 8 days [1-200 days].

In IMMU-132-05, febrile neutropenia (all were Grade 3-4) occurred in 5.8% (15/258) of patients treated with TRODELVY compared to 2.7% (6/224) of patients in the TPC arm. Of the patients homozygous for the UGT1A1*28 allele, the incidence of febrile neutropenia was 17.6% (6/34). No patients had febrile neutropenia leading to permanent discontinuation.

Diarrhoea

In IMMU-132-05, diarrhoea occurred in 65.1% (168/258) of patients in the TRODELVY arm compared to 17.0% (38/224) of patients in the TPC arm. Grade 3 diarrhoea occurred in 11.6% (30/258) of patients in the TRODELVY arm compared to 0.9% (2/224) of patients in the TPC arm. No Grade 4 events were reported.

The incidence of diarrhoea in the Overall TNBC population was similar (64.5%). In the Overall TNBC population, 1 patient (< 1%) discontinued treatment because of diarrhoea.

The median time to onset of diarrhoea following the start of the first treatment cycle was 13 days [1-364 days]. The median duration of diarrhoea was 8 days [1-154 days].

Hypersensitivity

In IMMU-132-05, hypersensitivity reactions within 24 hours of dosing occurred in 34.1% (88/258) of patients in the TRODELVY arm compared to 20.5% (46/224) of patients in the TPC arm. Grade 3-4 hypersensitivity occurred in 1.2% (3/258) of patients in the TRODELVY arm compared to 1.3% (3/224) of patients in the TPC arm. In the Overall TNBC population, the incidence of hypersensitivity was similar, and 1 patient discontinued treatment because of a hypersensitivity reaction.

Nausea and vomiting

In IMMU-132-05, nausea occurred in 62.4% (161/258) of patients in the TRODELVY arm compared to 30.4% (68/224) of patients in the TPC arm. Grade 3-4 nausea occurred in 3.1% (8/258) of patients compared to 0.4% (1/224) of patients in the TPC arm.

Vomiting occurred in 33.7% (87/258) of patients in the TRODELVY arm compared to 16.1% (36/224) of patients in the TPC arm. Grade 3-4 vomiting occurred in 1.9% (5/258) of patients in the TRODELVY arm compared to 1.3% (3/224) of patients in the TPC arm.

In the Overall TNBC population, the incidences of nausea and vomiting were similar.

Alopecia

In IMMU-132-05, alopecia occurred in 46.9% (121/258) of patients in the TRODELVY arm compared to 16.1% (36/224) of patients in the TPC arm.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies may be misleading.

Across clinical studies in patients treated with TRODELVY, 9 (1.1%) of 785 patients developed antibodies to TRODELVY; 6 of these patients (0.8% of all patients treated TRODELVY) had neutralizing antibodies against TRODELVY.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no information on overdose with TRODELVY. In clinical trials, doses of up to 18 mg/kg (approximately 1.8 times the maximum recommended dose of 10 mg/kg) led to a higher incidence of severe neutropenia.

In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, in particular severe neutropenia and severe diarrhoea, 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 humanised antibody that recognises Trop-2. The small molecule, SN-38, is a topoisomerase I inhibitor, which is covalently attached to the antibody by a linker. Sacituzumab govitecan binds to Trop-2-expressing cancer cells and is internalised 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 tumour growth in mouse xenograft models of triple-negative breast cancer.

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

The efficacy of TRODELVY in the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received at least two prior lines of chemotherapies was evaluated in two studies: ASCENT (IMMU-132-05) and IMMU-132-01.

ASCENT (IMMU-132-05)

ASCENT was a multicentre, open-label, randomised Phase 3 study conducted in 529 patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who had relapsed after at least two prior lines of chemotherapies (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. Poly-ADP ribose polymerase (PARP) inhibitors were allowed as one of the two prior chemotherapies for patients with a documented germline BRCA1/BRCA2 mutation.

Patients with brain metastases had to have stable disease for at least 4 weeks, and were allowed to enrol up to a pre-defined maximum of 15% of the trial population. Of the 529 patients randomised, 61 patients had brain metastases, 468 patients did not have brain metastases. Patients with Gilbert's disease, chronic inflammatory bowel disease/bowel obstruction, ECOG performance status 2 or higher, bone-only disease, or who had received live attenuated vaccine within 30 days before the start of TRODELVY, or who were pregnant, or breastfeeding were excluded.

Patients were randomised 1:1 to receive TRODELVY 10 mg/kg as a slow intravenous infusion on Days 1 and 8 of a 21-day treatment cycle (n = 267) or physician's choice of single-agent chemotherapy as per approved labelling (TPC, n = 262). Single-agent chemotherapy was determined by the investigator before randomisation from one of the following regimens: eribulin (n = 139), capecitabine (n = 33), gemcitabine (n = 38), or vinorelbine (n = 52).

Prior to the administration of TRODELVY, all patients were given pre-medication for prevention of chemotherapy-induced nausea and vomiting (e.g. dexamethasone with either a 5-HT3 receptor antagonist or a NK1 receptor antagonist and other drugs as indicated). Premedication, with antipyretics, H1 and H2 blockers, or corticosteroids (50 mg hydrocortisone or equivalent orally or IV), was strongly recommended to prevent infusion reactions with TRODELVY. All patients were given additional medications for prevention and treatment of nausea, vomiting, and diarrhoea for use at home.

Patients were treated until disease progression or unacceptable toxicity. The primary efficacy endpoint was progression-free survival (PFS) in patients without brain metastases at baseline (i.e. BMNeg) as measured by a blinded, independent, review committee (BIRC) using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria. Key secondary efficacy endpoints included overall survival (OS), objective response rate (ORR) and duration of response (DOR) in BMNeg patients, and PFS and OS for the full population (including all patients with and without brain metastases).

The primary analysis included 235 BMNeg patients in the TRODELVY group and 233 BMNeg patients in the TPC group. The demographics of the BMNeg population were: median age of 54 years (range: 27– 82 years) with 81% < 65 years; ECOG performance status of 0 (44%) or 1 (57%); 99.6% female; 78.8% White; 12% Black/African American. The baseline disease characteristics were: 42.5% had hepatic metastases; 7.3% were BRCA1/BRCA2 mutational status positive; 70.5% had previously received 2 to 3 prior systemic therapies. Overall, 27.1% of patients had received prior PD-1/PD-L1 therapy. The median number of prior systemic therapies was 4.0 (range: 2 – 17). 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 in the BMNeg population are summarised in Table 3, Figure 1, and Figure 2.

Table 3: Efficacy Endpoints (Brain Metastases-Negative Population) from ASCENT

Figure 1: Kaplan-Meier Plot of Progression Free Survival by BICR (Brain Metastases-Negative Population) in ASCENT

Figure 2: Kaplan-Meier Plot of Overall Survival (Brain Metastases Negative Population) from in ASCENT

The analysis of the overall population included 267 patients in the TRODELVY group (235 BMNeg patients and 32 patients with brain metastases) and 262 patients in the TPC group (233 BMNeg patients and 29 patients with brain metastases. The demographics and baseline characteristics of the BMNeg patients and overall population were similar.

The efficacy results in the overall population were consistent with the BMNeg population. Analyses of PFS (HR=0.43; 95% CI: 0.35, 0.54) and OS (HR=0.51; 95% CI: 0.41, 0.62) for the overall population were in favour of the TRODELVY arm.

In study IMMU-132-05, a generally consistent treatment effect of TRODELVY compared to TPC was seen in all pre-specified subgroups evaluated in favour of the TRODELVY arm. 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.

An exploratory analysis of PFS in 61 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 7.5 months (95% CI: 4.7, 11.1).

IMMU-132-01

IMMU-132-01 (NCT01631552) was a multicentre, single-arm, clinical study that enrolled 108 patients with metastatic triple-negative breast cancer (mTNBC) who had received at least two prior treatments 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. Tumour 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: 31-80 years); 82% 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. Fourteen patients (13%) 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: 2-10). 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 summarises the efficacy results.

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

ⁱ investigator assessment

CI: confidence interval

+: denotes ongoing

Paediatric population

The Medicines and Healthcare Regulatory Agency has waived the obligation to submit the results of studies with TRODELVY in all subsets of the paediatric population for the treatment of breast cancer (see section 4.2 for information on paediatric use).

The serum pharmacokinetics of sacituzumab govitecan and SN-38 were evaluated in study IMMU-132-05 in a population of mTNBC patients 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 5.

Table 5: Summary of Mean PK Parameters (CV%) of Sacituzumab Govitecan and Free SN-38

C_max: maximum serum concentration

AUC_0-168: area under serum concentration curve through 168 hours

Distribution

Based on population pharmacokinetic analyses, the central volume distribution of sacituzumab govitecan is 2.96 L.

Elimination

The mean half-life of sacituzumab govitecan and free SN-38 was 15.3 and 19.7 hours, respectively. Based on population pharmacokinetic analyses, the clearance of the sacituzumab govitecan is 0.14 L/h.

Metabolism

No metabolism studies with sacituzumab govitecan have been conducted. The glucuronide metabolite of SN-38 (SN-38G) was detectable in the serum of patients.

SN-38 (the small molecule moiety of sacituzumab govitecan) is metabolised via UGT1A1. Genetic variants of the UGT1A1 gene such as the UGT1A1*28 allele lead to reduced UGT1A1 enzyme activity. Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia, febrile neutropenia, and anaemia from TRODELVY (see sections 4.4 & 4.5). 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. Decreased function alleles other than UGT1A1*28 may be present in certain populations.

Special Populations

Pharmacokinetic analyses in patients treated with TRODELVY (n = 527) did not identify an effect of age, race, or mild renal impairment 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 moderate or severe renal impairment or end-stage renal disease.

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 = 59) to patients with normal hepatic function (bilirubin and AST ≤ ULN; n = 191).

Sacituzumab govitecan exposure is unknown in patients with moderate or severe hepatic impairment. SN-38 exposure may be elevated in such patients due to decreased hepatic UGT1A1 activity.

Non-clinical data reveal no special hazard for humans based on conventional nonclinical safety studies. Effects in non-clinical studies were observed at levels considered sufficiently in excess of the maximum human exposure, those with possible relevance to clinical use were as follows.

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.

In a repeat-dose toxicity study in cynomolgus monkeys, intravenous administration of sacituzumab govitecan resulted in endometrial atrophy, uterine haemorrhage, increased follicular atresia of the ovary, and atrophy of vaginal epithelial cells at doses ≥ 60 mg/kg (1.9 times the human recommended dose of 10 mg/kg based on body weight allometric scaling).

No toxicity was attributed to the novel excipient, MES, upon evaluation in two in vitro cellular cytotoxicity assays either alone or in combination with sacituzumab govitecan at dose levels which exceed clinical exposure. In addition, the toxicity of MES was assessed in a mouse toxicity study and two repeat dose toxicity studies in monkeys. No adverse or toxicologically significant findings were observed for MES in repeat-dose toxicity studies at concentrations that exceeded clinical exposure.

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

24 months

After reconstitution

The infusion bag containing TRODELVY solution can be stored in a refrigerator at 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 1 clear glass single-dose 50 mL vials, with a dark grey butyl rubber stopper and crimp-sealed with an aluminum flip-off cap.

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.

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.