Trastuzumab Emtansine

Trastuzumab emtansine is a HER2-targeted antibody-drug conjugate. The antibody is trastuzumab, a humanised IgG1 made in Chinese hamster ovary cells. It is joined by a stable thioether linker (MCC) to DM1, a maytansine derivative that inhibits microtubules; the linker and DM1 together are called emtansine, and each antibody carries on average 3.5 DM1 molecules. Conjugation gives DM1 selectivity for HER2-overexpressing tumour cells and delivers it directly into them.

Mechanism of Action

• Targeting: the trastuzumab part binds domain IV of the extracellular region of HER2, as unconjugated trastuzumab does. It also binds Fcγ receptors and complement C1q.
• Internalisation and release: after binding, the conjugate is taken into the cell and degraded in lysosomes, releasing DM1-containing cytotoxic catabolites, mainly lysine-MCC-DM1.
• Microtubule inhibition: DM1 binds tubulin and inhibits its polymerisation. Cells arrest in the G2/M phase and die by apoptosis. In vitro, DM1 was 20–200 times more potent than taxanes and vinca alkaloids.
• Trastuzumab actions retained: the conjugate inhibits shedding of the HER2 extracellular domain and signalling through the PI3-K pathway, and mediates antibody-dependent cell-mediated cytotoxicity (ADCC) in HER2-overexpressing human breast cancer cells.

Pharmacokinetics

• Absorption and distribution: given intravenously, the only route studied. At 3.6 mg/kg every 3 weeks the mean peak serum concentration in cycle 1 was about 73–83 µg/mL, and exposure is linear from 2.4 to 4.8 mg/kg. The central volume of distribution is about 3.13 L, close to plasma volume; the DM1 component is about 93% bound to plasma proteins.
• Metabolism: the conjugate is expected to be broken down by proteolysis in lysosomes, and low levels of the catabolites MCC-DM1, Lys-MCC-DM1 and DM1 appear in plasma. In vitro, DM1 is metabolised mainly by CYP3A4 and less by CYP3A5, did not inhibit the major CYP450 enzymes and is a P-glycoprotein substrate.
• Elimination: clearance about 0.68 L/day and half-life about 4 days, with no accumulation on 3-weekly dosing. In animal studies the catabolites were excreted mainly in bile.
• Special populations: exposure did not differ between the adjuvant and metastatic settings, and age, race and mild or moderate renal impairment had no clinically relevant effect. In mild or moderate hepatic impairment, cycle 1 exposure was lower (by about 38% and 67%) but was within the normal range by cycle 3.

Trastuzumab emtansine is used as a single agent in adults with HER2-positive breast cancer.

• Early breast cancer (adjuvant treatment): HER2-positive early breast cancer with residual invasive disease, in the breast and/or lymph nodes, after neoadjuvant taxane-based and HER2-targeted therapy.
• Metastatic breast cancer: HER2-positive, unresectable locally advanced or metastatic breast cancer in patients who previously received trastuzumab and a taxane, separately or in combination. They should either have received prior therapy for locally advanced or metastatic disease, or have developed recurrence during or within six months of completing adjuvant therapy.

• Hypersensitivity to trastuzumab emtansine or to any of the excipients (succinic acid, sodium hydroxide, sucrose, polysorbate 20).

Safety was assessed in 2,611 patients with breast cancer. The most common reactions (≥25% of patients) were nausea, fatigue, musculoskeletal pain, haemorrhage, headache, increased transaminases, thrombocytopenia and peripheral neuropathy; most were grade 1 or 2. The most common grade 3 or higher reactions (more than 2%) were thrombocytopenia, increased transaminases, anaemia, neutropenia, fatigue and hypokalaemia.

Very common (≥1/10): urinary tract infection, thrombocytopenia, anaemia, insomnia, peripheral neuropathy, headache, haemorrhage, epistaxis, cough, dyspnoea, stomatitis, diarrhoea, vomiting, nausea, constipation, dry mouth, abdominal pain, increased transaminases, musculoskeletal pain, arthralgia, myalgia, fatigue, pyrexia, asthenia.

Common (≥1/100 to <1/10): neutropenia, leukopenia, drug hypersensitivity, hypokalaemia, dizziness, dysgeusia, memory impairment, dry eye, conjunctivitis, blurred vision, increased lacrimation, left ventricular dysfunction, hypertension, dyspepsia, gingival bleeding, increased blood alkaline phosphatase, increased blood bilirubin, rash, pruritus, alopecia, nail disorder, palmar-plantar erythrodysaesthesia syndrome, urticaria, peripheral oedema, chills, infusion-related reactions.

Uncommon (≥1/1,000 to <1/100): pneumonitis (interstitial lung disease), hepatotoxicity, nodular regenerative hyperplasia of the liver, portal hypertension, injection site extravasation, radiation pneumonitis.

Rare (≥1/10,000 to <1/1,000): hepatic failure.

Serious reactions include haemorrhage (sometimes fatal), severe thrombocytopenia, liver injury, left ventricular dysfunction, interstitial lung disease and hypersensitivity.

No formal interaction studies have been performed. DM1 is metabolised mainly by CYP3A4 and, to a lesser extent, CYP3A5.

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole): avoid, as DM1 exposure and toxicity may rise; consider an alternative with no or minimal CYP3A4 inhibition. If the combination is unavoidable, consider delaying trastuzumab emtansine until the inhibitor has cleared (about 3 of its elimination half-lives), or otherwise monitor closely for adverse reactions.
• Anticoagulant and antiplatelet medicines (for example warfarin, heparin, low molecular weight heparins): haemorrhagic events, some fatal, have occurred, in some cases in patients also taking these medicines. Use with caution and consider additional monitoring.
• Grapefruit: grapefruit products inhibit CYP3A4 and may increase exposure, so avoid them.

Trastuzumab emtansine must be prescribed by a physician and given as an intravenous infusion under the supervision of a healthcare professional experienced in treating cancer, in a setting that can manage allergic or anaphylactic infusion reactions with full resuscitation facilities immediately available. A healthcare professional reconstitutes and dilutes the powder (see the SmPC). It must never be given as an intravenous push or bolus.

Before Treatment

• HER2 status: tumours must be HER2-positive (immunohistochemistry 3+, or an in situ hybridisation ratio of at least 2.0), assessed with a CE-marked in vitro diagnostic device or, if none is available, another validated test.
• Product identity: check the vial label to be sure the medicine is Kadcyla (trastuzumab emtansine) and not trastuzumab or trastuzumab deruxtecan.

Recommended Dose

• 3.6 mg/kg body weight as an intravenous infusion every 3 weeks (21-day cycle).
• First infusion: over 90 minutes, with observation during the infusion and for at least 90 minutes afterwards. Later infusions: over 30 minutes if the previous one was well tolerated, with observation for at least 30 minutes afterwards. Slow or interrupt the infusion if reactions appear, and stop treatment in life-threatening reactions. Watch the infusion site for subcutaneous infiltration.
• Duration: early breast cancer, 14 cycles in total unless the disease recurs or toxicity cannot be managed; metastatic breast cancer, until progression or unmanageable toxicity.

Dose Adjustments

The dose can be reduced from 3.6 mg/kg to 3 mg/kg and then to 2.4 mg/kg; if a further reduction is needed, treatment is stopped. The dose is not re-escalated. The SmPC tables give the thresholds, which differ between early and metastatic disease; in outline:

• Thrombocytopenia: withhold until platelets recover to at least 75,000/mm³; reduce one level after grade 4 (below 25,000/mm³).
• Liver tests: withhold until recovery, then continue at the same or a lower dose according to grade; stop for the most severe rises, permanently for drug-induced liver injury or nodular regenerative hyperplasia, and (unless another cause is likely) if transaminases exceed 3 times the upper limit of normal with bilirubin above 2 times.
• Left ventricular dysfunction: withhold and repeat the ejection fraction within 3 weeks if it falls below the set thresholds; stop if it does not recover, or in symptomatic heart failure.
• Interstitial lung disease or pneumonitis: stop permanently (for radiation pneumonitis in early breast cancer, at grade 3 or 4, or grade 2 not responding to treatment).
• Peripheral neuropathy: withhold in grade 3 or 4 until it improves to grade 2 or less.
• Missed dose: give it as soon as possible rather than waiting for the next cycle, then keep a 3-week interval to the following dose.

Special Populations

• Elderly: no dose adjustment at 65 years or older; data are insufficient to establish safety and efficacy from 75 years.
• Renal impairment: no change to the starting dose in mild or moderate impairment; in severe impairment the need for adjustment cannot be determined for lack of data, so monitor carefully.
• Hepatic impairment: no change to the starting dose in mild or moderate impairment. Not studied in severe impairment; use with caution because of known liver toxicity.
• Children and adolescents: safety and efficacy below 18 years have not been established, as breast cancer has no relevant use in this age group.

Traceability

The name and batch number of each product given must be clearly recorded, to improve traceability of this biological medicine. It is not interchangeable with trastuzumab or trastuzumab deruxtecan.

Thrombocytopenia and Haemorrhage

Thrombocytopenia was the most common reaction leading to discontinuation, dose reduction or interruption, and was more frequent and severe in Asian patients. Platelet counts are checked before each dose; patients with counts at or below 100,000/mm³, or taking anticoagulants, need close monitoring, and the medicine has not been studied below that level before treatment. Bleeding events, including central nervous system, respiratory and gastrointestinal haemorrhage, were fatal in some cases, with or without thrombocytopenia or anticoagulant or antiplatelet use.

Hepatotoxicity

Transaminase rises (grade 1 to 4) were usually symptomless and transient, peaking about 8 days after a dose, but built up over successive cycles. Serious liver disorders have occurred, including some fatal drug-induced liver injury and nodular regenerative hyperplasia, which is confirmed only by histology and should be considered if portal hypertension is suspected but transaminases are normal. Liver function is checked before treatment and before each dose; raised ALT at baseline, for example from liver metastases, carries a higher risk. The medicine has not been studied with transaminases above 2.5 or bilirubin above 1.5 times the upper limit of normal before treatment.

Cardiac Function

Left ventricular dysfunction is a risk (an ejection fraction below 40% has been seen), so symptomatic heart failure is possible. Risk factors include age over 50, low baseline ejection fraction, earlier anthracycline therapy, antihypertensive use and a body mass index above 25. Cardiac function is tested before treatment and at regular intervals, for example every three months. In metastatic disease with a baseline ejection fraction of 40–49%, use only after a careful benefit-risk assessment and with close monitoring.

Lung and Nerve Toxicity

Interstitial lung disease, including pneumonitis (some cases with acute respiratory distress syndrome or a fatal outcome), has been reported; patients with dyspnoea at rest or receiving lung radiotherapy may be at higher risk. Peripheral neuropathy was mainly grade 1 and sensory, and patients are monitored for signs of neurotoxicity.

Infusion Reactions, Hypersensitivity and Extravasation

Infusion-related reactions (flushing, chills, pyrexia, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia) were generally not severe. Interrupt the infusion in a severe reaction and stop permanently in a life-threatening one. Anaphylactic reactions have been seen, so treatment and emergency equipment must be at hand; a true hypersensitivity reaction means permanent discontinuation. The medicine is not recommended if trastuzumab was permanently stopped for infusion reactions or hypersensitivity. Extravasation may cause local pain and, exceptionally, severe tissue lesions and epidermal necrosis within days to weeks; stop the infusion immediately and examine the patient regularly.

Pregnancy, Breastfeeding and Fertility

• Contraception: women who could become pregnant should use effective contraception during treatment and for at least 7 months after the last dose; male patients with partners who could become pregnant, for at least 4 months after the last dose.
• Pregnancy: no data in pregnant women. Trastuzumab can cause foetal harm or death, and oligohydramnios, some linked to fatal pulmonary hypoplasia, has been reported with it; animal studies of maytansine suggest DM1 is expected to be teratogenic and possibly embryotoxic. Use is not recommended. A woman who becomes pregnant must contact her doctor at once, and close monitoring by a multidisciplinary team is recommended if she is treated.
• Breastfeeding: it is not known whether the medicine passes into human milk. Women should stop breastfeeding before treatment and may restart 7 months after it ends.
• Fertility: no reproductive and developmental toxicology studies have been conducted.

Excipients with Known Effect

Polysorbate 20 (1.1 mg per 100 mg vial, 1.7 mg per 160 mg vial) may cause allergic reactions. Each dose contains less than 1 mmol (23 mg) of sodium (1.38 mg per 100 mg vial, 2.24 mg per 160 mg vial), so it is essentially sodium-free.

Effect on Driving

Trastuzumab emtansine has a minor influence on the ability to drive and use machines. Whether fatigue, headache, dizziness and blurred vision affect driving is unknown. Patients with infusion-related reactions should not drive or use machines until the symptoms have gone.

Store the vials in a refrigerator at 2–8 °C. As a refrigerated biological medicine it is kept in an unbroken cold chain from manufacture to the pharmacy or ward that prepares the infusion. For storage after reconstitution and dilution, see Shelf Life.

• Unopened vial: 4 years. Do not use after the expiry date.
• Reconstituted solution: stable for up to 120 hours (5 days) at 2–8 °C after reconstitution with sterile water for injection or sodium chloride 0.45%. Microbiologically it should be used immediately; otherwise in-use times are the user’s responsibility and would normally not exceed 24 hours at 2–8 °C, unless reconstitution was done under controlled and validated aseptic conditions.
• Diluted solution: in sodium chloride 0.9% or 0.45% infusion bags, stable for up to 24 hours at 2–8 °C if prepared under controlled and validated aseptic conditions. The product has no preservative and is for single use.

Prescription only (Rx), on the prescription of a physician, with treatment supervised by a healthcare professional experienced in treating cancer. Trastuzumab emtansine is given as an intravenous infusion by healthcare professionals, so it is supplied to the hospital or clinic that administers it, in a refrigerated cold chain (2–8 °C). Each pack holds one 100 mg or 160 mg vial.