TRODELVY 200mg powder for concentrate infusion solution medication leaflet

Trodelvy 200 mg powder for concentrate for solution for infusion.

One vial of powder contains 200 mg sacituzumab govitecan.

After reconstitution, one mL of solution contains 10 mg sacituzumab govitecan.

Sacituzumab govitecan is a Trop-2-directed antibody-drug conjugate (ADC). Sacituzumab is ahumanised monoclonal antibody (hRS7 IgG1κ) that recognises Trop-2. The small molecule, SN-38, isa topoisomerase I inhibitor, which is covalently attached to the antibody by a hydrolysable linker.

Approximately 7-8 molecules of SN-38 are attached to each antibody molecule.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion

Off-white to yellowish powder.

Trodelvy as monotherapy is indicated for the treatment of adult patients with unresectable ormetastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemictherapies, including at least one of them for advanced disease (see section 5.1).

Trodelvy as monotherapy is indicated for the treatment of adult patients with unresectable ormetastatic hormone receptor (HR)-positive, HER2-negative breast cancer who have receivedendocrine-based therapy, and at least two additional systemic therapies in the advanced setting (seesection 5.1).

Trodelvy must only be prescribed and administered to patients by healthcare professionals experiencedin the use of anti-cancer therapies and administered in an environment where full resuscitationfacilities are available.

The recommended dose of sacituzumab govitecan is 10 mg/kg body weight administered as anintravenous infusion once weekly on Day 1 and Day 8 of 21-day treatment cycles. Treatment shouldbe continued until disease progression or unacceptable toxicity.

Prevention treatment

Prior to each dose of sacituzumab govitecan, treatment for prevention of infusion-related reactions andprevention of chemotherapy-induced nausea and vomiting (CINV) is recommended (see section 4.4).

Dose modifications for infusion-related reactions

The infusion rate of sacituzumab govitecan should be slowed down or infusion interrupted if thepatient develops an infusion-related reaction. Sacituzumab govitecan should be permanentlydiscontinued if life-threatening infusion-related reactions occur (see section 4.4).

Dose modifications for adverse reactions

Dose modifications to manage adverse reactions of sacituzumab govitecan are described in Table 1.

The sacituzumab govitecan dose should not be re-escalated after a dose reduction for adverse reactionshas been made.

Table 1: Recommended dose modifications for adverse reactions

Adverse reaction Occurrence Dose modification

Severe neutropenia

Grade 4 neutropenia ≥ 7 days or less if clinically indicated, First Administer granulocyte-

OR colony stimulating factor

Grade 3-4 febrile neutropenia (GCSF) as soon as, clinically indicated

OR Second 25% dose reduction;

At time of scheduled treatment, Grade 3-4 neutropenia which administer G-CSF as soondelays dosing by 2 or 3 weeks for recovery to ≤ Grade 1 as clinically indicated

Third 50% dose reduction;administer G-CSF as soonas clinically indicated

Fourth Discontinue treatment;administer G-CSF as soonas clinically indicated

At time of scheduled treatment, Grade 3-4 neutropenia which First Discontinue treatment;delays dosing beyond 3 weeks for recovery to ≤ Grade 1 administer G-CSF as soonas clinically indicated

Severe non-neutropenic toxicity

Grade 4 non-hematologic toxicity of any duration, First 25% dose reduction

OR Second 50% dose reduction

Any Grade 3-4 nausea, vomiting or diarrhoea due to treatment Third Discontinue treatmentthat is not controlled with antiemetics and anti-diarrhoeal agents,

OR

Other Grade 3-4 non-hematologic toxicity persisting > 48 hoursdespite optimal medical management,

OR

At time of scheduled treatment, Grade 3-4 non-neutropenichematologic or non-hematologic toxicity, which delays dose by 2or 3 weeks for recovery to ≤ Grade 1

In the event of Grade 3-4 non-neutropenic hematologic or non- First Discontinue treatmenthematologic toxicity, Grade 3 nausea or Grade 3-4 vomiting,which does not recover to ≤ Grade 1 within 3 weeks

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

No adjustment to the starting dose is required when administering sacituzumab govitecan to patientswith mild hepatic impairment (bilirubin ≤ 1.5 upper limit of normal [ULN] and aspartateaminotransferase [AST]/alanine aminotransferase [ALT] < 3 ULN).

The safety of sacituzumab govitecan in patients with moderate or severe hepatic impairment has notbeen established. Sacituzumab govitecan has not been studied in patients with any of the following:serum bilirubin > 1.5 ULN, or AST or ALT > 3 ULN in patients without liver metastases, or AST or

ALT > 5 ULN in patients with liver metastases. The use of sacituzumab govitecan should be avoidedin these patients.

No adjustment to the starting dose is required when administering sacituzumab govitecan to patientswith mild or moderate renal impairment.

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

The safety and efficacy of sacituzumab govitecan in children aged 0 to 18 years have not beenestablished. No data are available.

Sacituzumab govitecan is for intravenous use only. It must be reconstituted and diluted by a healthcareprofessional experienced in the handling of anti-cancer therapies. It must be administered as anintravenous 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 priorinfusions were tolerated.

Patients have to be observed during each infusion and for at least 30 minutes after each infusion forsigns or symptoms of infusion-related reactions (see section 4.4).

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

Sacituzumab govitecan can cause severe or life-threatening neutropenia (see section 4.8). Fatalinfections in the setting of neutropenia have been observed in clinical studies with sacituzumabgovitecan. Sacituzumab govitecan should not be administered if the absolute neutrophil count is below1500/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 monitored as clinically indicated duringtreatment. Sacituzumab govitecan should not be administered in case of neutropenic fever. Treatmentwith granulocyte-colony stimulating factor and dose modifications may be required due to severeneutropenia (see sections 4.2 and 4.8).

Sacituzumab govitecan can cause severe diarrhoea (see section 4.8). Diarrhoea in some cases wasobserved to have led to dehydration and subsequent acute kidney injury. Sacituzumab govitecanshould not be administered in case of Grade 3-4 diarrhoea at the time of scheduled treatment andtreatment should only be continued when resolved to ≤ Grade 1 (see section 4.2 and 4.8). At the onsetof diarrhoea, and if no infectious cause can be identified, treatment with loperamide should beinitiated. Additional supportive measures (e.g. fluid and electrolyte substitution) may also beemployed as clinically indicated.

Patients who exhibit an excessive cholinergic response to treatment with sacituzumab govitecan (e.g.abdominal cramping, diarrhoea, salivation, etc.) can receive appropriate treatment (e.g. atropine) forsubsequent treatments with sacituzumab govitecan.

Sacituzumab govitecan can cause severe and life-threatening hypersensitivity (see section 4.8).

Anaphylactic reactions have been observed in clinical studies with sacituzumab govitecan and the useof sacituzumab govitecan is contraindicated in patients with a known hypersensitivity to sacituzumabgovitecan (see section 4.3).

Pre-infusion treatment, including antipyretics, H1 and H2 blockers, or corticosteroids (e.g. 50 mghydrocortisone or equivalent, orally or intravenously), for patients receiving sacituzumab govitecan isrecommended. Patients should be closely observed for infusion-related reactions during eachsacituzumab govitecan infusion and for at least 30 minutes after completion of each infusion. Theinfusion rate of sacituzumab govitecan should be slowed down or infusion interrupted if the patientdevelops an infusion-related reaction. Sacituzumab govitecan should be permanently discontinued iflife-threatening infusion-related reactions occur (see section 4.2).

Nausea and vomiting

Sacituzumab govitecan is emetogenic (see section 4.8). Antiemetic preventive treatment with two orthree medicinal products (e.g. dexamethasone with either a 5-hydroxytryptamine 3 [5-HT3] receptorantagonist or a Neurokinin-1 [NK-1] receptor antagonist as well as other medicinal products asindicated) is recommended for prevention of chemotherapy-induced nausea and vomiting (CINV).

Sacituzumab govitecan should not be administered in case of Grade 3 nausea or Grade 3-4 vomiting atthe time of scheduled treatment administration and treatment should only be continued with additionalsupportive measures when resolved to ≤ Grade 1 (see section 4.2). Additional antiemetics and othersupportive measures may also be employed as clinically indicated. All patients should be given take-home medicinal products with clear instructions for prevention and treatment of nausea and vomiting.

Use in patients with reduced UGT1A1 activity

SN-38 (the small molecule moiety of sacituzumab govitecan) is metabolised via uridinediphosphate-glucuronosyl transferase (UGT1A1). Genetic variants of the UGT1A1 gene such as the

UGT1A1*28 allele lead to reduced UGT1A1 enzyme activity. Individuals who are homozygous for

UGT1A1*28 allele are at increased risk for neutropenia, febrile neutropenia, and anaemia and are atincreased risk for other adverse reactions following initiation of sacituzumab govitecan treatment (seesection 4.8). Approximately 20% of the Black population, 10% of the White population, and 2% of the

East Asian population are homozygous for the UGT1A1*28 allele. Decreased function alleles otherthan UGT1A1*28 may be present in certain populations. Patients with known reduced UGT1A1activity should be closely monitored for adverse reactions. When unknown, no testing of UGT1A1status is required as the management of adverse reactions including the recommended dosemodifications will be the same for all patients.

Embryo-foetal toxicity

Based on its mechanism of action, sacituzumab govitecan can cause teratogenicity and/orembryo-foetal lethality when administered to a pregnant woman. Sacituzumab govitecan contains agenotoxic component, SN-38, and targets rapidly dividing cells. Pregnant women and women ofchildbearing potential should be informed of the potential risk to the foetus. The pregnancy status offemales of reproductive potential should be verified prior to the initiation of sacituzumab govitecan(see section 4.6).

This medicinal product will be further prepared for administration with sodium-containing solution(see section 6.6) and this should be considered in relation to the total sodium intake to the patient fromall sources per day.

No interaction studies have been performed.

UGT1A1 inhibitors

Concomitant administration of sacituzumab govitecan with inhibitors of UGT1A1 may increase theincidence of adverse reactions due to potential increase in systemic exposure to SN-38. Sacituzumabgovitecan should be used with caution in patients receiving UGT1A1 inhibitors (e.g. propofol,ketoconazole, EGFR tyrosine kinase inhibitors).

UGT1A1 inducers

Exposure to SN-38 may be reduced in patients concomitantly receiving UGT1A1 enzyme inducers.

Sacituzumab govitecan should be used with caution in patients receiving UGT1A1 inducers (e.g.carbamazepine, phenytoin, rifampicin, ritonavir, tipranavir).

Based on the limited data available from patients who received UGT1A1 inhibitors (n=16) or inducers(n=5) while being treated with sacituzumab govitecan, free SN-38 exposures in these patients werecomparable to those in patients who did not receive UGT1A1 inhibitor or inducer.

Women of childbearing potential have to use effective contraception during treatment and for6 months after the last dose.

Male patients with female partners of childbearing potential have to use effective contraception duringtreatment with sacituzumab govitecan and for 3 months after the last dose.

There are no available data on the use of sacituzumab govitecan in pregnant women. However, basedon its mechanism of action, sacituzumab govitecan can cause teratogenicity and/or embryo-foetallethality when administered during pregnancy. Sacituzumab govitecan contains a genotoxiccomponent, SN-38, and targets rapidly dividing cells.

Sacituzumab govitecan should not be used during pregnancy unless the clinical condition of thewoman requires treatment with sacituzumab govitecan.

The pregnancy status of women of childbearing potential should be verified prior to the initiation ofsacituzumab govitecan.

Women who become pregnant must immediately contact their doctor.

It is unknown whether sacituzumab govitecan or its metabolites are excreted in human milk. A risk tobreastfed newborns/infants cannot be excluded. Breast-feeding should be discontinued duringtreatment with sacituzumab govitecan and for 1 month after the last dose.

Based on findings in animals, sacituzumab govitecan may impair fertility in females of reproductivepotential (see section 5.3). No human data on the effect of sacituzumab govitecan on fertility areavailable.

Sacituzumab govitecan has minor influence on the ability to drive and use machines, e.g. dizziness,fatigue (see section 4.8).

The most common adverse reactions reported in patients treated with sacituzumab govitecan were:neutropenia (67.6%), nausea (62.6%), diarrhoea (62.5%), fatigue (61.5%), alopecia (45.6%),anaemia (40.7%), constipation (36.2%), vomiting (33.6%), decreased appetite (25.7%), dyspnoea(22.1%) and abdominal pain (20.2%).

The most common grade 3 or higher adverse reactions were neutropenia (50.7%), leukopenia (10.5%),diarrhoea (10.3%), anaemia (9.3%), fatigue (6.8%), febrile neutropenia (6.1%), hypophosphataemia(4.2%), dyspnoea (3.1%), lymphopenia (2.9%), abdominal pain (2.8%), nausea (2.8%), vomiting(2.5%), hypokalaemia (2.5%), pneumonia (2.3%) and aspartate aminotransferase increased (2.2%).

The most frequently reported serious adverse reactions in patients treated with sacituzumab govitecanwere febrile neutropenia (4.8%), diarrhoea (3.9%), neutropenia (2.6%) and pneumonia (2%).

The frequencies of adverse reactions are based on pooled data from three clinical studies involving688 patients who received sacituzumab govitecan 10 mg/kg body weight for the treatment ofmetastatic TNBC and HR+/HER2- breast cancer. The median exposure to sacituzumab govitecan inthis data set was 4.63 months.

The adverse reaction frequencies are based on all-cause adverse event frequencies, where a proportionof the events for an adverse reaction may have other causes than sacituzumab govitecan, such as thedisease, other medicinal products or unrelated causes. The severity of adverse drug reactions wasassessed based on the Common Terminology Criteria for Adverse Events (CTCAE), defininggrade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, and 5 = death.

Adverse reactions are listed by System Organ Class and frequency category. Frequency categories aredefined 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); and not known (cannot be estimated from theavailable data). Within each frequency grouping, adverse reactions are presented in the order ofdecreasing seriousness.

Table 2: List of adverse reactions

System organ class (SOC) Frequency Adverse reactions

Very common Urinary tract infection

Upper respiratory tract infection

Common Sepsis

Influenza

Bronchitis

Nasopharyngitis

Sinusitis

Oral herpes

Very common Neutropenia1

Anaemia2

Leukopenia3

Lymphopenia4

Common Febrile neutropenia

Thrombocytopenia5

Very common Hypersensitivity6

Very common Decreased appetite

Hypomagnesaemia

Common Dehydration

Hypophosphataemia

Hyponatraemia

Very common Insomnia

Common Anxiety

Very common Headache

Dizziness

Common Dysgeusia

Common Hypotension

Very common Dyspnoea7

Cough

Common Epistaxis

Productive cough

Rhinorrhoea

Nasal congestion

Upper airway cough syndrome

Very common Diarrhoea

Nausea

Abdominal Pain

Common Neutropenic colitis8

Stomatitis

Abdominal pain upper

Dyspepsia

Gastrooesophageal reflux disease

Abdominal distension

Uncommon Enteritis

Very common Alopecia

Pruritus

Common Rash maculopapular

Skin hyperpigmentation

Dry skin

Very common Back pain

Arthralgia

Common Musculoskeletal chest pain

Muscle spasms

Common Haematuria

Proteinuria

Dysuria

Very common Fatigue9

Common Pain

Chills

Common Weight decreased

Blood alkaline phosphatase increased

Activated partial thromboplastin time prolonged

Blood lactate dehydrogenase increased

Uncommon Infusion related reaction1: Includes the following preferred terms: neutropenia; neutrophil count decreased.2: Includes the following preferred terms: anaemia; haemoglobin 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: Hypersensitivity events reported up to the end of the day after treatment was administered. Includes events coded to thefollowing preferred terms: dyspnoea; hypotension; flushing; erythema; chest discomfort; rhinitis allergic; wheezing;oedema; urticaria; anaphylactic reaction; mouth ulceration; skin exfoliation; swollen tongue; throat tightness7: Includes the following preferred terms: dyspnoea; dyspnoea exertional8: Includes the preferred term of neutropenic colitis and events reported as typhlitis9: Includes the following preferred terms: fatigue, asthenia

The median time to onset of neutropenia (including febrile neutropenia) following the start of the firsttreatment cycle was 16 days. The median duration of neutropenia was 8 days.

Neutropenia occurred in 67.6% (465/688) of patients treated with sacituzumab govitecan, including

Grade 3-4 neutropenia in 50.7% of patients. Neutropenia was the reason for dose reduction in 12.4%of patients. Neutropenic colitis was observed in 1% (7/688) of patients.

Febrile neutropenia occurred in 6.1% (42/688) of patients treated with sacituzumab govitecan. Febrileneutropenia was the reason for dose reduction in 2.9% of patients.

Use in patients with reduced UGT1A1 activity

The incidence of Grade 3-4 neutropenia was 60.6% (43/71) in patients homozygous for the

UGT1A1*28 allele, 52.9% (144/272) in patients heterozygous for the UGT1A1*28 allele, and 49.1%(140/285) in patients homozygous for the wild-type allele. The incidence of Grade 3-4 febrileneutropenia was 14.1% (10/71) in patients homozygous for the UGT1A1*28 allele, 5.9% (16/272) inpatients heterozygous for the UGT1A1*28 allele, and 4.6% (13/285) in patients homozygous for thewild-type allele. The incidence of Grade 3-4 anaemia was 15.5% (11/71) in patients homozygous forthe UGT1A1*28 allele, 7.4% (20/272) in patients heterozygous for the UGT1A1*28 allele, and 8.1%(23/285) in patients homozygous for the wild-type allele.

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

The median time to onset of diarrhoea following the start of the first treatment cycle was 13 days. Themedian duration of diarrhoea was 8 days.

Diarrhoea occurred in 62.5% (430/688) of patients treated with sacituzumab govitecan. Grade 3 eventsoccurred in 10.3% (71/688) of patients. Three of 688 patients (< 1%) discontinued treatment becauseof diarrhoea.

Hypersensitivity reactions reported up to the end of the day following dosing occurred in33.0% (227/688) of patients treated with sacituzumab govitecan. Grade 3 and above hypersensitivityoccurred in 1.7% (12/688) of patients treated with sacituzumab govitecan. The incidence ofhypersensitivity reactions leading to permanent discontinuation of sacituzumab govitecan was0.1% (1/688).

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

There was no difference in discontinuation rate due to adverse events in patients aged 65 years or oldercompared with younger patients with mTNBC. There was a higher discontinuation rate due to adversereactions in patients aged 65 years or older (14%) compared with younger patients (3%) with

HR+/HER2- metastatic breast cancer. There was a higher incidence rate of serious adverse events inpatients aged 75 years or older (67%) compared to patients aged 65 years or older (43%) and patientsyounger than 65 years (24%) with HR+/HER2- metastatic breast cancer.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In clinical studies, doses of up to 18 mg/kg (approximately 1.8 times the maximum recommendeddose of 10 mg/kg body weight) 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 appropriate treatment instituted.

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies and antibody drugconjugates, other monoclonal antibodies, ATC code: L01FX17.

Sacituzumab govitecan binds to Trop-2-expressing cancer cells and is internalised with the subsequentrelease of SN-38 from a hydrolysable linker. SN-38 interacts with topoisomerase I and preventsre-ligation of topoisomerase I-induced single strand breaks. The resulting DNA damage leads toapoptosis and cell death.

Unresectable or metastatic Triple Negative Breast Cancer (ASCENT)

The efficacy and safety of sacituzumab govitecan was assessed in ASCENT (IMMU-132-05), aninternational Phase 3, multicentre, open-label, randomised study conducted in 529 patients withunresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who had relapsedafter at least two prior chemotherapies (no upper limit) for breast cancer. Earlier adjuvant orneoadjuvant therapy for more limited disease qualified as one of the required prior regimens if thedevelopment of unresectable, locally advanced or metastatic disease occurred within a 12-monthperiod of time after completion of chemotherapy. All patients received previous taxane treatment ineither the adjuvant, neoadjuvant, or advanced stage unless they had a contraindication or wereintolerant to taxanes. Poly-ADP ribose polymerase (PARP) inhibitors were allowed as one of the twoprior chemotherapies for patients with a documented germline BRCA1/BRCA2 mutation.

Patients were randomised (1:1) to receive sacituzumab govitecan 10 mg/kg as an intravenous infusionon Day 1 and Day 8 of a 21-day treatment cycle or Treatment of Physician’s Choice (TPC) which wasdosed based on body surface area and per the approved product information. TPC was determined bythe investigator before randomisation from one of the following single-agent regimens: eribulin(n = 139), capecitabine (n = 33), gemcitabine (n = 38), or vinorelbine (except if patient had ≥ Grade 2neuropathy, n = 52). Patients with stable brain metastases (pre-treated, non-progressive, without anti-seizure medicinal products and on stable corticosteroid dose for at least 2 weeks) were eligible.

Magnetic resonance imaging (MRI) to determine brain metastases was required only for patients withknown or suspected brain metastases. Patients with known Gilbert’s disease, bone-only disease,known history of unstable angina, myocardial infarction, or congestive heart failure, active chronicinflammatory bowel disease or gastrointestinal (GI) perforation, human immunodeficiency virus(HIV), active hepatitis B or C infection, live vaccine within 30 days, or who have previously receivedirinotecan were excluded.

Patients were treated until disease progression or unacceptable toxicity. The primary efficacy endpointwas progression-free survival (PFS) in patients without brain metastases at baseline (i.e. BMNeg) asmeasured by a blinded, independent, centralised review (BICR) group of radiology experts using

Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria. Secondary efficacy endpointsincluded PFS by BICR for the overall population, including all patients with and without brainmetastases, overall survival (OS), objective response rate (ORR) and duration of response (DOR).

The primary analysis included 235 BMNeg patients in the sacituzumab govitecan group and233 BMNeg patients in the TPC group. The analysis of the overall population included 267 patients inthe sacituzumab govitecan group and 262 patients in the TPC group.

The demographics and baseline characteristics of the overall population (n = 529) were: median age of54 years (range: 27-82 years) and 81% < 65 years; 99.6% female; 79% White; 12% Black; mediannumber of prior systemic therapies was 4; 69% had previously received 2 to 3 prior chemotherapies;31% had previously received > 3 prior chemotherapies; 42% had hepatic metastases; 12% had presentor a history of brain metastases. 8% were BRCA1/BRCA2 mutational status positive; BRCA statuswas available for 339 patients. At study entry, all patients had an ECOG performance status of 0(43%) or 1 (57%). The median time from diagnosis of Stage 4 to study entry was 16.2 months (range:

- 0.4 to 202.9 months). The most frequent prior chemotherapies were cyclophosphamide (83%),anthracycline (83%) including doxorubicin (53%), paclitaxel (78%), carboplatin (65%), capecitabine(67%), gemcitabine (36%), docetaxel (35%), and eribulin (33%). Overall, 29% of patients hadreceived prior PD-1/PD-L1 therapy. Thirteen percent of patients in the sacituzumab govitecan group inthe overall population received only 1 prior line of systemic therapy in the metastatic setting.

The efficacy results in the BMNeg population showed a statistical significant improvement ofsacituzumab govitecan over TPC in PFS and OS with hazard ratios (HR) of 0.41 (n=468; 95% CI:0.32, 0.52; p-value: <0.0001) and 0.48 (n=468; 95% CI: 0.38, 0.59; p-value: <0.0001), respectively.

The median PFS was 5.6 months vs 1.7 months; the median OS was 12.1 months vs 6.7 months, inpatients treated with sacituzumab govitecan and TPC, respectively.

The efficacy results in the overall population were consistent with the BMNeg population in the pre-specified final analysis (11 March 2020 cut-off date) and are summarised in Table 3.

Table 3: Efficacy endpoints (overall population) - Pre-specified Final Analysis

Pre-specified Final Analysis(11 March 2020 cut-off date)

Sacituzumab govitecan Treatment of physician’sn=267 choice (TPC)n=262

Progression-free survival1

Number of events (%) 190 (71.2) 171 (65.3)

Median PFS in months (95% CI) 4.8 1.7(4.1,5.8) (1.5, 2.5)

Hazard ratio (95% CI) 0.43 (0.35, 0.54)p-value2 <0.0001

Overall Survival

Number of deaths (%) 179 (67.0) 206 (78.6)

Median OS in months (95% CI) 11.8 6.9(10.5, 13.8) (5.9, 7.7)

Hazard ratio (95% CI) 0.51 (0.41, 0.62)p-value2 <0.0001

Overall response rate (ORR)

Number of responders (%) 83 (31) 11 (4)

Odds ratio (95% CI) 10.99 (5.66, 21.36)p-value3 <0.0001

Complete response, n (%) 10 (4) 2 (1)

Partial response, n (%) 73 (27) 9 (3)

Duration of response (DOR)

Median DOR in months 6.3 3.6(95% CI) (5.5, 9.0) (2.8, NE)1 PFS is defined as the time from the date of randomization to the date of the first radiological disease progressionor death due to any cause, whichever comes first.2 Stratified log-rank test adjusted for stratification factors: number of prior chemotherapies, presence of knownbrain metastases at study entry, and region.3 Based on Cochran-Mantel-Haenszel test.

CI = Confidence Interval

In an updated efficacy analysis (final database lock 25 February 2021), results were consistent with thepre-specified final analysis. The median PFS by BICR was 4.8 months vs 1.7 months, in patientstreated with sacituzumab govitecan and TPC, respectively (HR of 0.41; 95% CI: 0.33, 0.52). Themedian OS was 11.8 months vs 6.9 months, respectively (HR of 0.51; 95% CI: 0.42, 0.63). Kaplan-

Meier curves for updated PFS by BICR and OS are presented in Figures 1 and 2.

Figure 1: Progression free survival (overall population; final database lock 25 February 2021)by BICR

Trodelvy

TPC

Censored

Time (months)

Number of Patients at Risk

Trodelvy 267 184 135 82 55 34 23 17 11 8 5 1 0

TPC 262 86 36 12 6 3 1 1 0 0 0 0 0

Figure 2: Overall survival (overall population; final database lock 25 February 2021)

Trodelvy

TPC

Censored

Time (months)

Number of Patients at Risk

Trodelvy 267 250 232 209 178 152 125 108 79 62 49 37 25 14 7 2 0

TPC 262 222 174 132 101 66 54 45 34 31 26 12 7 3 2 0 0

Sub-group analysis

In subgroup analyses, improvements in PFS and OS in patients treated with sacituzumab govitecancompared to TPC were consistent across patient subgroups irrespective of age, race, BRCA status,prior number of systemic therapies overall (2 and >2, 2-3 and >3) and in the metastatic setting (1 and>1), prior therapy with anthracycline or PDL1, and liver metastases.

Probability of OS (%) Probability of PFS (%)

Brain metastases

An exploratory analysis of PFS and OS in patients with previously treated, stable brain metastasesshowed a stratified HR of 0.65 (n=61; 95% CI: 0.35, 1.22) and 0.87 (n=61; 95% CI: 0.47, 1.63),respectively. The median PFS was 2.8 months vs 1.6 months; the median OS was 6.8 months vs 7.5months, in patients treated with sacituzumab govitecan and TPC, respectively.

Trop-2 expression

Additional subgroup analyses were conducted to evaluate the efficacy by tumour Trop-2 expressionlevels and the results were consistent across the different scoring methods used. In patients with low

Trop-2 levels using membrane H-score by quartiles, benefit of sacituzumab govitecan over TPC wasshown for both PFS (HR 0.64; 95% CI: 0.37, 1.11) and OS (HR of 0.71; 95% CI: 0.42, 1.21).

Unresectable or metastatic hormone receptor (HR)-positive/human epidermal growth factorreceptor 2 (HER2)-negative breast cancer (TROPiCS-02)

The efficacy of sacituzumab govitecan was evaluated in a multicentre, open-label, randomised study

TROPiCS-02 (IMMU-132-09) conducted in 543 patients with unresectable locally advanced ormetastatic HR-positive, HER2-negative (IHC 0, IHC 1+, or IHC 2+/ISH-) breast cancer whose diseasehas progressed after the following in any setting: a CDK 4/6 inhibitor, endocrine therapy, and ataxane; patients received at least two prior chemotherapies in the metastatic setting (one of whichcould be in the neoadjuvant or adjuvant setting if progression or recurrence occurred within 12 monthsof completion of the chemotherapy). Patients with bone-only disease, active chronic inflammatorybowel disease and known history of bowel obstruction, known history of unstable angina ormyocardial infarction or congestive heart failure or active hepatitis B or C infection were excludedfrom the study.

Patients were randomised (1:1) to receive sacituzumab govitecan 10 mg/kg as an intravenous infusionon Days 1 and 8 of a 21-day cycle (n=272) or TPC (n=271). TPC was determined by the investigatorbefore randomisation from one of the following single-agent regimens: eribulin (n=130), vinorelbine(n=63), gemcitabine (n=56), or capecitabine (n=22). Randomisation was stratified based on priorchemotherapy regimens for metastatic disease (2 vs. 3-4), visceral metastasis (yes vs. no), andendocrine therapy in the metastatic setting for at least 6 months (yes vs. no).

Patients were treated until disease progression or unacceptable toxicity. The primary efficacy outcomemeasure was PFS as determined by BICR per RECIST v1.1. Additional efficacy outcome measureswere OS, ORR by BICR, and DOR by BICR.

The median age of the study population was 56 years (range: 27-86 years), and 26% of patients were65 years or over. Almost all patients were female (99%). The majority of patients were White (67%);4% were Black, 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 systemicchemotherapy regimens in the metastatic setting. Approximately 42% of patients had 2 priorchemotherapy regimens for metastatic disease compared to 58% of patients who had 3 to 4 priorchemotherapy regimens. Most patients received endocrine therapy in the metastatic setting for ≥ 6months (86%). Patients had an ECOG performance status of 0 (44%) or 1 (56%). Ninety-five percentof patients had visceral metastases; 4.6% of patients had stable, pre-treated brain metastases.

Sacituzumab govitecan demonstrated a statistically significant improvement in PFS by BICR and OSversus TPC. The improvement in PFS by BICR and OS was generally consistent across pre-specifiedsubgroups. Efficacy results are summarized in Table 4.

Table 4. Efficacy endpoints - Pre-specified Final Analysis

Sacituzumab govitecan TPCn=272 n=271

Progression-Free Survival by BICR1

Number of events (%) 170 (62.5%) 159 (58.7%)

Median PFS in months (95% CI) 5.5 (4.2, 7.0) 4.0 (3.1, pct. 4.4)

Hazard ratio (95% CI) 0.661 (0.529, 0.826)p-value2 0.0003

PFS rate at 12 months, % (95% 21.3 (15.2, 28.1) 7.1 (2.8, 13.9)

CI)

Overall Survival3

Number of events (%) 191 (70.2%) 199 (73.4%)

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 Rate by BICR3

Number of responders (%) 57 (21.0%) 38 (14.0%)

Odds ratio (95% CI) 1.625 (1.034, 2.555)p-value 0.03481 PFS is defined as the time from the date of randomisation to the date of the first radiological disease progression or deathdue to any cause, whichever comes first (data cut-off 3 January 2022).2 Stratified log-rank test adjusted for stratification factors: prior chemotherapy regimens for metastatic disease (2 vs. 3-4),visceral metastasis (yes vs. no), and endocrine therapy in the metastatic setting for at least 6 months (yes vs. no).3 Based on second interim OS analysis (data cut-off 1 July 2022).

BICR = Blinded Independent Central Review; CI = Confidence Interval

In an updated efficacy analysis with a median duration of follow-up of 12.8 months (data cut-off 1

December 2022), results were consistent with the pre-specified final analysis. The median PFS by

BICR was 5.5 months vs 4.0 months, in patients treated with sacituzumab govitecan and TPC,respectively (HR of 0.65; 95% CI: 0.53, 0.81). The median OS was 14.5 months vs 11.2 months,respectively (HR of 0.79; 95% CI: 0.65, 0.95). Kaplan-Meier curves for updated PFS by BICR and OSare presented in Figures 3 and 4.

Figure 3: Progression free survival by BICR (data cut-off 1 December 2022)

Figure 4: Overall Survival (data cut-off 1 December 2022)

The European Medicines Agency has waived the obligation to submit the results of studies withsacituzumab govitecan in all subsets of the paediatric population for the treatment of breast cancer (seesection 4.2 for information on paediatric use).

The serum pharmacokinetics of sacituzumab govitecan and SN-38 were evaluated in the ASCENTstudy in a population of mTNBC patients who received sacituzumab govitecan as a single agent at adose of 10 mg/kg body weight. 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

Sacituzumab govitecan Free SN-38

Cmax [ng/mL] 242 000 (22%) 91 (65%)

AUC0-168 [ng*h/mL] 5 560 000 (24%) 2 730 (41%)

Cmax: maximum serum concentration

AUC0-168: area under serum concentration curve through 168 hours

Based on population pharmacokinetic analyses, the steady state volume of distribution of sacituzumabgovitecan was 3.58 L.

The median elimination half-life (t1/2) of sacituzumab govitecan and free SN-38 in patients withmetastatic triple negative breast cancer was 23.4 and 17.6 hours, respectively. Based on populationpharmacokinetic analyses, the clearance of sacituzumab govitecan is 0.128 L/h.

No metabolism studies with sacituzumab govitecan have been conducted.

SN-38 (the small molecule moiety of sacituzumab govitecan) is metabolised via UGT1A1.

Pharmacokinetic analyses in patients treated with sacituzumab govitecan (n = 789) did not identify aneffect of age, race, and mild or moderate renal impairment on the pharmacokinetics of sacituzumabgovitecan.

Renal elimination is known to contribute minimally to the excretion of SN-38, the small moleculemoiety of sacituzumab govitecan. There are no data on the pharmacokinetics of sacituzumab govitecanin patients with severe renal impairment or end-stage renal disease (CrCl < 15 mL/min).

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 patientswith normal hepatic function (bilirubin and AST ≤ ULN; n = 526).

Sacituzumab govitecan and free SN-38 exposures are unknown in patients with moderate or severehepatic impairment.

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

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

Non-clinical data for the novel excipient MES reveal no special hazard for humans based onconventional repeated dose toxicity and genotoxicity studies.

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

Polysorbate 80 (E433)

Trehalose dihydrate

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

Unopened vial3 years.

The reconstituted solution should be used immediately to prepare the diluted solution for infusion. Ifnot used immediately, the infusion bag containing diluted solution can be stored in a refrigerator (2°Cto 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 and dilution of the medicinal product, see section 6.3.

Type I colourless, clear glass 50 mL vial, with an elastomeric butyl stopper and sealed with analuminum flip-off overseal containing 200 mg of sacituzumab govitecan.

Each pack contains one vial.

Trodelvy is a cytotoxic medicinal product. Applicable special handling and disposal procedures haveto be followed.

* Calculate the required dose (mg) of Trodelvy based on the patient’s body weight at thebeginning of each treatment cycle (or more frequently if the patient’s body weight changed bymore than 10% since the previous administration).

* Allow the required number of vials to warm to room temperature (20°C to 25°C).

* Using a sterile syringe, slowly inject 20 mL of sodium chloride 9 mg/mL (0.9%) solution forinjection into each 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 shouldbe inspected visually for particulate matter and discoloration prior to administration. Thesolution should be free of visible particulates, clear and yellow. Do not use the reconstitutedsolution if it is cloudy or discoloured.

* Use immediately to prepare a diluted solution for infusion.

* Calculate the required volume of the reconstituted solution needed to obtain the appropriatedose according to the patient’s body weight.

* Determine the final volume of the infusion solution to deliver the appropriate dose at asacituzumab govitecan concentration range of 1.1 mg/mL to 3.4 mg/mL.

* Withdraw and discard a volume of sodium chloride 9 mg/mL (0.9%) solution for injection fromthe final infusion bag that is equivalent to the required volume of the reconstituted solution.

* Withdraw the calculated amount of the reconstituted solution from the vial(s) using a syringe.

Discard any unused portion remaining in the vial(s).

* To minimize foaming, slowly inject the required volume of reconstituted solution into apolyvinyl chloride, polyolefin (polypropylene and/or polyethylene) or ethylene vinyl acetateinfusion bag. Do not shake the contents.

* If necessary, adjust the volume in the infusion bag as needed with sodium chloride 9 mg/mL(0.9%) solution for injection, to obtain a concentration of 1.1 mg/mL to 3.4 mg/mL. Onlysodium chloride 9 mg/mL (0.9%) solution for injection should be used since the stability of thereconstituted product has not been determined with other infusion-based solutions.

* If not used immediately, the infusion bag containing diluted solution can be stored refrigerated2°C to 8°C for up to 24 hours protected from light. Do not freeze. After refrigeration, administerthe diluted solution at room temperature up to 25°C within 8 hours (including infusion time).

* Administer Trodelvy as an intravenous infusion. Protect the infusion bag from light. Theinfusion bag should be covered during administration to the subject until dosing is complete. Itis 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 as an infusion, with other medicinal products.

* Upon completion of the infusion, flush the intravenous line with 20 mL sodium chloride9 mg/mL (0.9%) solution for injection.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/21/1592/001

Date of first authorisation: 22 November 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.