Sacituzumab Govitecan

Sacituzumab govitecan is a Trop-2-directed antibody-drug conjugate. The antibody, sacituzumab (a humanised hRS7 IgG1κ), recognises Trop-2, a surface protein highly expressed on many cancer cells. It carries SN-38, a small-molecule topoisomerase I inhibitor, attached by a hydrolysable linker; on average 7–8 SN-38 molecules are bound to each antibody molecule.

Mechanism of Action

• Binding and internalisation: the antibody binds Trop-2-expressing tumour cells and is rapidly taken into the cell.
• Release of the payload: SN-38 is released from the hydrolysable linker, most likely inside the cell.
• Topoisomerase I inhibition: SN-38 prevents the re-ligation of single-strand DNA breaks made by topoisomerase I. The resulting DNA damage leads to apoptosis and cell death.
• Antibody contribution: limited evidence suggests the antibody part may add antibody-directed cell toxicity of its own.

Pharmacokinetics

• Absorption: given intravenously. After the first 10 mg/kg dose the mean peak concentration was about 258 µg/mL for the conjugate and about 97 ng/mL for free SN-38. Pembrolizumab does not change the pharmacokinetics of either.
• Distribution: steady-state volume of distribution about 4.79 L. SN-38 stays mostly bound to the antibody in serum; free SN-38 was only about 2–5% of the total in an early study.
• Metabolism: no metabolism studies of the conjugate have been done. SN-38 is metabolised by UGT1A1, and its glucuronide is found in serum.
• Elimination: median half-life about 170 hours for the conjugate and 21.4 hours for free SN-38; clearance about 0.129 L/h. Renal elimination of SN-38 is minimal.
• Special populations: age, race and mild or moderate renal impairment had no effect on pharmacokinetics. Exposure is similar in mild hepatic impairment; data are limited in moderate or severe hepatic impairment, and absent in severe renal impairment.

• Triple-negative breast cancer (TNBC), with pembrolizumab: adults with unresectable locally advanced or metastatic TNBC who have not received prior systemic therapy for metastatic disease and whose tumours express PD-L1 with a combined positive score (CPS) of at least 10.
• TNBC, first-line monotherapy: adults with unresectable locally advanced or metastatic TNBC who have not received prior systemic therapy for metastatic disease and are not candidates for PD-1 or PD-L1 inhibitor therapy.
• TNBC, later-line monotherapy: adults with unresectable or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for advanced disease.
• Hormone receptor (HR)-positive, HER2-negative breast cancer, monotherapy: adults with unresectable or metastatic disease who have received endocrine-based therapy and at least two additional systemic therapies in the advanced setting.

• Hypersensitivity to sacituzumab govitecan or to any of the excipients (MES, polysorbate 80, trehalose dihydrate).

The lists below are for monotherapy (963 patients, pooled from four studies). The most common reactions were neutropenia (67.3%), nausea (62.1%), diarrhoea (59.9%), fatigue (57.4%), alopecia (48.3%), anaemia (40.1%), constipation (36.7%), vomiting (31.3%) and decreased appetite (23.3%). The most common grade 3 or higher reactions were neutropenia (48.6%), diarrhoea (10.0%), leukopenia (9.6%), anaemia (7.7%), fatigue (5.8%), febrile neutropenia (5.6%) and lymphopenia (3.1%). With pembrolizumab (221 patients) the profile was generally similar, with diarrhoea (70.1%) and nausea (67.9%) most frequent, and the combination did not increase pembrolizumab-related immune-mediated reactions. Frequencies are all-cause, so some events may have other causes.

Very common (≥1/10): urinary tract infection, upper respiratory tract infection, neutropenia, anaemia, leukopenia, lymphopenia, hypersensitivity, decreased appetite, hypokalaemia, hypomagnesaemia, headache, dizziness, dyspnoea, cough, diarrhoea, vomiting, constipation, stomatitis, nausea, abdominal pain, alopecia, rash, pruritus, back pain, arthralgia, fatigue (including asthenia), increased blood alkaline phosphatase.

Common (≥1/100 to <1/10): sepsis, pneumonia, influenza, bronchitis, nasopharyngitis, sinusitis, oral herpes, febrile neutropenia, thrombocytopenia, dehydration, hyperglycaemia, hypophosphataemia, hypocalcaemia, hyponatraemia, insomnia, anxiety, dysgeusia, hypotension, epistaxis, productive cough, rhinorrhoea, nasal congestion, upper airway cough syndrome, neutropenic colitis, colitis, upper abdominal pain, dyspepsia, gastro-oesophageal reflux disease, abdominal distension, maculopapular rash, skin hyperpigmentation, acneiform dermatitis, dry skin, musculoskeletal chest pain, muscle spasms, haematuria, proteinuria, dysuria, pain, chills, weight decreased, prolonged activated partial thromboplastin time, increased blood lactate dehydrogenase, infusion-related reaction.

Uncommon (≥1/1,000 to <1/100): enteritis.

Important serious reactions are severe or life-threatening neutropenia (neutropenia led to dose reduction in 14.2% of patients, and fatal infections secondary to neutropenia occurred in 0.6%), severe diarrhoea (median onset 13 days), and hypersensitivity (12.8% of patients up to the day after dosing; grade 3 or higher in 0.5%). Patients aged 65 or older had more febrile neutropenia, severe diarrhoea and fatal infections.

No interaction studies have been performed. SN-38 is cleared by UGT1A1, so medicines that affect this enzyme may change exposure.

• UGT1A1 inhibitors (for example propofol, ketoconazole, EGFR tyrosine kinase inhibitors): may raise SN-38 exposure and the rate of adverse reactions. Use with caution.
• UGT1A1 inducers (for example carbamazepine, phenytoin, rifampicin, ritonavir, tipranavir): may lower SN-38 exposure. Use with caution.
• In a small number of patients taking inhibitors (15) or inducers (7), free SN-38 exposure was comparable to that in patients taking neither.
• Pembrolizumab: no effect on the pharmacokinetics of sacituzumab govitecan or SN-38.

Sacituzumab govitecan must be prescribed and given by healthcare professionals experienced in anti-cancer therapy, in an environment with full resuscitation facilities. It is for intravenous use only and must be reconstituted and diluted by a healthcare professional experienced in handling anti-cancer medicines. It must not be given as an intravenous push or bolus.

Recommended Dose

• 10 mg/kg body weight as an intravenous infusion once weekly on day 1 and day 8 of 21-day cycles, alone or with pembrolizumab, until disease progression or unacceptable toxicity.
• With pembrolizumab: give sacituzumab govitecan first when both are given on the same day (see the pembrolizumab SmPC for its dose). PD-L1 status is tested with a CE-marked in vitro diagnostic device intended for use with pembrolizumab or, if none is available, another validated test.
• First infusion: over 3 hours. Later infusions: over 1 to 2 hours if the earlier ones were tolerated. Observe patients during each infusion and for at least 30 minutes afterwards for infusion-related reactions.

Preventive Treatment

• Before every dose: pre-infusion treatment against infusion reactions (antipyretics, H1 and H2 blockers or corticosteroids, for example 50 mg hydrocortisone or equivalent) and antiemetics (two or three medicines, for example dexamethasone with a 5-HT3 or an NK-1 receptor antagonist). Give patients take-home medicines for nausea and vomiting.
• Neutropenia: consider primary prophylaxis with G-CSF from the first cycle in patients at higher risk of febrile neutropenia.

Dose Adjustments

The dose can be reduced from 10 mg/kg to 7.5 mg/kg and then to 5 mg/kg; if a further reduction is needed, treatment is stopped. The dose is not re-escalated.

• Neutropenia: do not give on day 1 if the neutrophil count is below 1,500/mm³, on day 8 if it is below 1,000/mm³, or during neutropenic fever. After grade 3 or 4 neutropenia or febrile neutropenia, withhold until recovery, give G-CSF as indicated, and reduce one level for repeated febrile neutropenia or prolonged neutropenia.
• Nausea, vomiting, diarrhoea: for grade 3 or 4 events not controlled with supportive medicines, withhold until grade 1 or less, then reduce one level with each occurrence.
• Infusion reactions: slow or interrupt the infusion in grade 1 to 3 reactions; stop treatment in grade 4.
• Other grade 3 or 4 toxicities despite optimal management: withhold until grade 1 or less, then reduce one level.

Special Populations

• Elderly: no dose adjustment at 65 years or older; data from 75 years are limited.
• Hepatic impairment: no change in mild impairment (bilirubin up to 1.5 times the upper limit of normal and AST/ALT below 3 times). Safety in moderate or severe impairment is not established, and use should be avoided when bilirubin exceeds 1.5 times, or AST/ALT exceed 3 times (5 times with liver metastases), the upper limit.
• Renal impairment: no change in mild or moderate impairment. Not studied in severe impairment or end-stage renal disease (creatinine clearance below 15 mL/min).
• Children and adolescents: safety and efficacy from 0 to 18 years have not been established; no data.

Traceability

The name and batch number of each product given must be clearly recorded, to improve traceability of this biological medicine.

Neutropenia

Severe or life-threatening neutropenia can occur, and fatal infections with neutropenia were seen, mainly in the first two cycles. Neutrophil counts are monitored during treatment. Risk factors for febrile neutropenia include age 65 or older, earlier neutropenia, poor performance status, organ dysfunction and several comorbidities; G-CSF prophylaxis is considered in these patients.

Diarrhoea

Severe diarrhoea can occur, in some cases causing dehydration and acute kidney injury. Treatment is not given in grade 3 or 4 diarrhoea and resumes when it falls to grade 1 or less. At the onset of diarrhoea, if no infectious cause is found, loperamide is started, with fluid and electrolyte replacement as needed. Patients with an excessive cholinergic response (abdominal cramping, diarrhoea, salivation) can receive atropine before later doses.

Hypersensitivity and Infusion Reactions

Severe and life-threatening hypersensitivity, including anaphylaxis, can occur. Pre-infusion treatment is recommended, patients are observed during and for at least 30 minutes after each infusion, and the rate is slowed or the infusion interrupted if a reaction occurs. Treatment is stopped permanently for a life-threatening infusion-related reaction.

Nausea and Vomiting

The medicine is emetogenic, so preventive antiemetics are given. It is withheld for grade 3 nausea or grade 3 or 4 vomiting and resumed with extra supportive measures once these fall to grade 1 or less.

Reduced UGT1A1 Activity

People homozygous for the UGT1A1*28 allele have a higher risk of neutropenia, febrile neutropenia, anaemia and other adverse reactions: grade 3 or 4 neutropenia occurred in 59.6% of them, against 44.9% of patients with the wild-type gene, and rates were also higher in patients heterozygous for UGT1A1*6. Patients with known reduced UGT1A1 activity are monitored closely. Testing is not required, because management and dose modifications are the same for all patients.

Pregnancy, Breastfeeding and Fertility

• Contraception: women who could become pregnant must use effective contraception during treatment and for 6 months after the last dose; male patients with partners who could become pregnant, for 3 months after the last dose.
• Pregnancy: there are no data. The medicine can cause teratogenicity or embryo-foetal death, because it contains the genotoxic SN-38 and targets rapidly dividing cells. It should not be used in pregnancy unless the woman’s condition requires it, and pregnancy status is verified before treatment starts. A woman who becomes pregnant must contact her doctor at once.
• Breastfeeding: not known whether it passes into human milk; breastfeeding should stop during treatment and for 1 month after the last dose.
• Fertility: animal findings suggest it may impair fertility in women of reproductive potential; there are no human data.

Sodium

The medicine is prepared with a sodium chloride solution, which should be counted in the patient’s total daily sodium intake.

Effect on Driving

Sacituzumab govitecan has a minor influence on the ability to drive and use machines, for example through dizziness or fatigue.

Store the vials in a refrigerator at 2–8 °C. Do not freeze, and keep the vial in its outer carton to protect it from light. It is handled as a cytotoxic medicine and kept in an unbroken cold chain until the hospital pharmacy prepares the infusion. For storage after reconstitution and dilution, see Shelf Life.

• Unopened vial: 3 years. Do not use after the expiry date.
• After reconstitution: use the reconstituted solution immediately to prepare the diluted solution. The infusion bag with the diluted solution can be stored in a refrigerator at 2–8 °C for up to 24 hours, protected from light and not frozen, and then given at room temperature (up to 25 °C) within 8 hours, including the infusion time.

Prescription only (Rx), prescribed and given by healthcare professionals experienced in anti-cancer therapy. Sacituzumab govitecan is given as an intravenous infusion in hospital, so it is supplied to the hospital or clinic that administers it, in a refrigerated cold chain (2–8 °C). Each pack holds one 200 mg vial.