Kadcyla (Intravenous)

Kadcyla 100 mg powder for concentrate for solution for infusion.

Kadcyla 160 mg powder for concentrate for solution for infusion.

100 mg single-use vial containing powder for concentrate for infusion solution delivers 5 mL of 20 mg/mL of trastuzumab emtansine after reconstitution.

160 mg single-use vial containing powder for concentrate for infusion solution delivers 8 mL of 20 mg/mL of trastuzumab emtansine after reconstitution.

Trastuzumab emtansine is an antibody-drug conjugate that contains trastuzumab, a humanised IgG1 monoclonal antibody produced by mammalian (Chinese hamster ovary) cell suspension culture, covalently linked to DM1, a microtubule inhibitor, via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate).

Powder for concentrate for solution for infusion.

White to off-white lyophilised powder.

Kadcyla, as a single agent, is indicated for the treatment of adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:

- Received prior therapy for locally advanced or metastatic disease, or

- Developed disease recurrence during or within six months of completing adjuvant therapy.

Kadcyla should only be prescribed by a physician and administered under the supervision of a healthcare professional who is experienced in the treatment of cancer patients.

Patients treated with trastuzumab emtansine should have HER2 positive tumour status, defined as a score of 3 + by immunohistochemistry (IHC) or a ratio of > 2.0 by in situ hybridization (ISH) assessed by a CE-marked In Vitro Diagnostic (IVD) medical device. If a CE-marked IVD is not available, the HER2-status should be assessed by an alternate validated test.

In order to prevent medication errors it is important to check the vial labels to ensure that the medicinal product being prepared and administered is Kadcyla (trastuzumab emtansine) and not Herceptin (trastuzumab).

Posology

The recommended dose of trastuzumab emtansine is 3.6 mg/kg bodyweight administered as an intravenous infusion every 3 weeks (21-day cycle). Patients should be treated until disease progression or unacceptable toxicity.

The initial dose should be administered as a 90 minute intravenous infusion. Patients should be observed during the infusion and for at least 90 minutes following the initial infusion for fever, chills, or other infusion-related reactions. The infusion site should be closely monitored for possible subcutaneous infiltration during administration.

If the prior infusion was well tolerated, subsequent doses of trastuzumab emtansine may be administered as 30 minute infusions. Patients should be observed during the infusion and for at least 30 minutes after infusion.

The infusion rate of trastuzumab emtansine should be slowed or interrupted if the patient develops infusion-related symptoms. Trastuzumab emtansine should be discontinued in case of life-threatening infusion reactions.

Medicinal products to treat allergic/anaphylactic infusion reactions, as well as emergency equipment should be available for immediate use.

Delayed or missed dose

If a planned dose is missed, it should be administered as soon as possible; do not wait until the next planned cycle. The schedule of administration should be adjusted to maintain a 3-week interval between doses. The next dose should be administered in accordance with the dosing recommendations.

Dose modification

Management of symptomatic adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of Kadcyla as per guidelines provided in text and Tables 1 to 5.

Kadcyla dose should not be re-escalated after a dose reduction is made.

Table 1 Dose reduction schedule

Table 2 Dose modification guidelines for increased transaminases (AST/ALT)

ALT = alanine transaminase; AST = aspartate transaminase; ULN = upper limit of normal.

Table 3 Dose modification guidelines for hyperbilirubinemia

ULN = upper limit of normal.

Table 4 Dose modification guidelines for thrombocytopenia

Table 5 Dose modifications for left ventricular dysfunction

LVEF = Left ventricular ejection fraction

Peripheral neuropathy

Trastuzumab emtansine should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. At retreatment a dose reduction may be considered according to the dose reduction schedule (see Table 1).

Elderly patients

No dose adjustment is required in patients aged > 65 years. There are insufficient data to establish the safety and efficacy in patients > 75 years due to limited data in this subgroup. Population pharmacokinetic analysis indicates that age does not have a clinically meaningful effect on the pharmacokinetics of trastuzumab emtansine.

Renal impairment

No adjustment to the starting dose is needed in patients with mild or moderate renal impairment. The potential need for dose adjustment in patients with severe renal impairment cannot be determined due to insufficient data and therefore patients with severe renal impairment should be monitored carefully.

Hepatic impairment

No adjustment to the starting dose is required for patients with mild or moderate hepatic impairment. Trastuzumab emtansine was not studied in patients with severe hepatic impairment. Treatment of patients with hepatic impairment should be undertaken with caution due to known hepatotoxicity observed with trastuzumab emtansine.

Paediatric population

The safety and efficacy in children and adolescents below 18 years of age have not been established as there is no relevant use in the paediatric population for the indication of metastatic breast cancer (MBC).

Method of administration

Trastuzumab emtansine must be reconstituted and diluted by a healthcare professional and administered as an intravenous infusion. It must not be administered as an intravenous push or bolus.

In order to improve traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

In order to prevent medication errors it is important to check the vial labels to ensure that the medicinal product being prepared and administered is Kadcyla (trastuzumab emtansine) and not Herceptin (trastuzumab).

Pulmonary toxicity

Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or a fatal outcome, have been reported in clinical studies with trastuzumab emtansine. Signs and symptoms include dyspnoea, cough, fatigue, and pulmonary infiltrates.

It is recommended that treatment with trastuzumab emtansine be permanently discontinued in patients who are diagnosed with ILD or pneumonitis.

Patients with dyspnoea at rest due to complications of advanced malignancy and co-morbidities may be at increased risk of pulmonary events.

Hepatotoxicity

Hepatotoxicity, predominantly in the form of asymptomatic increases in the concentrations of serum transaminases (Grade 1-4 transaminitis), has been observed during treatment with trastuzumab emtansine in clinical studies. Transaminase elevations were generally transient with peak elevation at day 8 after administration of therapy and subsequent recovery to Grade 1 or less prior to the next cycle. A cumulative effect on transaminases has also been observed (the proportion of patients with Grade 1-2 ALT/AST abnormalities increases with successive cycles).

Patients with elevated transaminases improved to Grade 1 or normal within 30 days of the last dose of trastuzumab emtansine in the majority of the cases.

Serious hepatobiliary disorders, including nodular regenerative hyperplasia (NRH) of the liver and some with a fatal outcome due to drug-induced liver injury have been observed in patients treated with trastuzumab emtansine. Observed cases may have been confounded by comorbidities and/or concomitant medicinal products with known hepatotoxic potential.

Liver function should be monitored prior to initiation of treatment and each dose.

Cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies in patients treated with trastuzumab emtansine. NRH is a rare liver condition characterised by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. Diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on the computed tomography (CT) scan of the liver but with normal transaminases and no other manifestations of cirrhosis. Upon diagnosis of NRH, trastuzumab emtansine treatment must be permanently discontinued.

Trastuzumab emtansine has not been studied in patients with serum transaminases > 2.5 × ULN or total bilirubin > 1.5 × ULN prior to initiation of treatment. Treatment in patients with serum transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN should be permanently discontinued. Treatment of patients with hepatic impairment should be undertaken with caution.

Left ventricular dysfunction

Patients treated with trastuzumab emtansine are at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) < 40% has been observed in patients treated with trastuzumab emtansine, and therefore symptomatic congestive heart failure (CHF) is a potential risk. General risk factors for a cardiac event and those identified in adjuvant breast cancer studies with trastuzumab therapy include advancing age (> 50 years), low baseline LVEF values (< 55%), low LVEF levels prior to or following the use of paclitaxel in the adjuvant setting, prior or concomitant use of antihypertensive medicinal products, previous therapy with an anthracycline and high BMI (> 25 kg/m²).

Standard cardiac function testing (echocardiogram or multigated acquisition (MUGA) scanning) should be performed prior to initiation and at regular intervals (e.g. every three months) during treatment. In clinical studies, patients had a LVEF > 50% at baseline. Patients with a history of congestive heart failure (CHF), serious cardiac arrhythmia requiring treatment, history of myocardial infarction or unstable angina within 6 months of randomization, or current dyspnoea at rest due to advanced malignancy were excluded from clinical studies. The dose should be delayed or treatment discontinued as necessary in cases of left ventricular dysfunction.

Infusion-related reactions

Trastuzumab emtansine treatment has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR); treatment is not recommended for these patients. Patients should be observed closely for infusion-related reactions, especially during the first infusion.

Infusion-related reactions (due to cytokine release), characterized by one or more of the following symptoms have been reported: flushing, chills, pyrexia, dyspnoea, hypotension, wheezing, bronchospasm, and tachycardia. In general, these symptoms were not severe. In most patients, these reactions resolved over the course of several hours to a day after the infusion was terminated. Treatment should be interrupted in patients with a severe IRR until signs and symptoms resolve. Consideration for re-treatment should be based on clinical assessment of the severity of the reaction. Treatment must be permanently discontinued in the event of a life threatening infusion-related reaction.

Hypersensitivity reactions

Trastuzumab emtansine treatment has not been studied in patients who had trastuzumab permanently discontinued due to hypersensitivity; treatment with trastuzumab emtansine is not recommended for these patients.

Patients should be observed closely for hypersensitivity/allergic reactions, which may have the same clinical presentation as an IRR. Serious, anaphylactic reactions have been observed in clinical studies with trastuzumab emtansine. Medicinal products to treat such reactions, as well as emergency equipment, should be available for immediate use. In the event of a true hypersensitivity reaction (in which severity of reaction increases with subsequent infusions), trastuzumab emtansine treatment must be permanently discontinued.

Haemorrhage

Cases of haemorrhagic events, including central nervous system, respiratory and gastrointestinal haemorrhage, have been reported with trastuzumab emtansine treatment. Some of these bleeding events resulted in fatal outcomes. In some of the observed cases the patients had thrombocytopenia, or were also receiving anti-coagulant therapy or antiplatelet therapy; in others there were no known additional risk factors. Use caution with these agents and consider additional monitoring when concomitant use is medically necessary.

Thrombocytopenia

Thrombocytopenia, or decreased platelet counts, was commonly reported with trastuzumab emtansine and was the most common adverse reaction leading to treatment discontinuation. In clinical studies, the incidence and severity of thrombocytopenia were higher in Asian patients.

It is recommended that platelet counts are monitored prior to each trastuzumab emtansine dose. Patients with thrombocytopenia (≤ 100,000/mm³) and patients on anti-coagulant treatment (e.g. warfarin, heparin, low molecular weight heparins) should be monitored closely while on trastuzumab emtansine treatment. Trastuzumab emtansine has not been studied in patients with platelet counts ≤ 100,000/mm³ prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or greater (< 50,000/mm³), do not administer trastuzumab emtansine until platelet counts recover to Grade 1 (> 75,000/mm³).

Neurotoxicity

Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in clinical studies with trastuzumab emtansine. Patients with Grade > 3 peripheral neuropathy at baseline were excluded from clinical studies. Treatment with trastuzumab emtansine should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until symptoms resolve or improve to ≤ Grade 2. Patients should be clinically monitored on an ongoing basis for signs/symptoms of neurotoxicity.

Sodium content in excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium- free'.

No formal interaction studies have been performed.

In vitro metabolism studies in human liver microsomes suggest that DM1, a component of trastuzumab emtansine, is metabolised mainly by CYP3A4 and, to a lesser extent, by CYP3A5. Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) with trastuzumab emtansine should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medicinal product with no or minimal potential to inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying trastuzumab emtansine treatment until the strong CYP3A4 inhibitors have cleared from the circulation (approximately 3 elimination half-lives of the inhibitors) when possible. If a strong CYP3A4 inhibitor is coadministered and trastuzumab emtansine treatment cannot be delayed, patients should be closely monitored for adverse reactions.

Contraception in males and females

Women of childbearing potential should use effective contraception while receiving trastuzumab emtansine and for 7 months following the last dose of trastuzumab emtansine. Male patients or their female partners should also use effective contraception.

Pregnancy

There are no data from the use of trastuzumab emtansine in pregnant women. Trastuzumab, a component of trastuzumab emtansine, can cause foetal harm or death when administered to a pregnant woman. In the post-marketing setting, cases of oligohydramnios, some associated with fatal pulmonary hypoplasia, have been reported in pregnant women receiving trastuzumab. Animal studies of maytansine, a closely related chemical entity of the same maytansinoid class as DM1, suggest that DM1, the microtubule inhibiting cytotoxic component of trastuzumab emtansine, is expected to be teratogenic and potentially embryotoxic.

Administration of trastuzumab emtansine to pregnant women is not recommended and women should be informed of the possibility of harm to the foetus before they become pregnant. Women who become pregnant must immediately contact their doctor. If a pregnant woman is treated with trastuzumab emtansine, close monitoring by a multidisciplinary team is recommended.

Breast-feeding

It is not known whether trastuzumab emtansine is excreted in human milk. Since many medicinal products are excreted in human milk and because of the potential for serious adverse reactions in breast-feeding infants, women should discontinue breast-feeding prior to initiating treatment with trastuzumab emtansine. Women may begin breast-feeding 7 months after concluding treatment.

Fertility

No reproductive and developmental toxicology studies have been conducted with trastuzumab emtansine.

Trastuzumab emtansine has no or negligible influence on the ability to drive and use machines.

The significance of reported adverse reactions such as fatigue, headache, dizziness and blurred vision on the ability to drive or use machines is unknown. Patients experiencing infusion-related reactions should be advised not to drive and use machines until symptoms abate.

Summary of the safety profile

The safety of trastuzumab emtansine has been evaluated in1871 breast cancer patients in clinical studies. In this patient population:

- the most common serious ADRs (> 0.5% of patients) were haemorrhage, pyrexia, dyspnoea, musculoskeletal pain, thrombocytopenia, abdominal pain and vomiting.

- the most common adverse drug reactions (ADRs) (>25%) with trastuzumab emtansine were nausea, fatigue, and headache. The majority of ADRs reported were of Grade 1 or 2 severity.

- the most common National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade > 3 ADRs (> 2%) were thrombocytopenia, increased transaminases, anaemia, neutropenia, fatigue, hypokalaemia, musculoskeletal pain and haemorrhage.

Tabulated list of adverse reactions

The ADRs in1871 patients treated with trastuzumab emtansine are presented in Table 6. The ADRs are listed below by MedDRA system organ class (SOC) and categories of frequency. Frequency categories are defined as very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping and SOC, adverse reactions are presented in order of decreasing seriousness. ADRs were reported using NCI-CTCAE for assessment of toxicity.

Table 6 Tabulated list of ADRs in patients treated with trastuzumab emtansine

Description of selected adverse reactions

Transaminases increased (AST/ALT)

Increase in serum transaminases (Grade 1-4) has been observed during treatment with trastuzumab emtansine in clinical studies.4.

Left ventricular dysfunction

Left ventricular dysfunction was reported in 2.2% of patients in clinical studies with trastuzumab emtansine.).

Infusion-related reactions

Infusion-related reactions are characterised by one or more of the following symptoms: flushing, chills, pyrexia, dyspnoea, hypotension, wheezing, bronchospasm and tachycardia.4.

Hypersensitivity reactions

Hypersensitivity was reported in 2.6% of patients in clinical studies with trastuzumab emtansine, with one Grade 3 and one Grade 4 events reported.4.

Haemorrhage

The incidence of severe haemorrhagic events (Grade >3) occurred in 2.2% of the overall trastuzumab emtansine treated patients in clinical studies. In some of the observed cases the patients had thrombocytopenia, or were also receiving anti-coagulant therapy or antiplatelet therapy; in others there were no known additional risk factors. Cases of bleeding events with a fatal outcome have been observed.

Thrombocytopenia

Thrombocytopenia or decreased platelet counts were reported in 24.9% of patients in clinical studies with trastuzumab emtansine and was the most common adverse reaction leading to treatment discontinuation (2.6%).4.

Immunogenicity

As with all therapeutic proteins, there is the potential for an immune response to trastuzumab emtansine. A total of 836 patients from six clinical studies were tested at multiple time points for anti-therapeutic antibody (ATA) responses to trastuzumab emtansine. Following dosing, 5.3% (44/836) of patients tested positive for anti-trastuzumab emtansine antibodies at one or more post-dose time points. The clinical significance of anti-trastuzumab emtansine antibodies is not yet known.

Extravasation

Reactions secondary to extravasation have been observed in clinical studies with trastuzumab emtansine. These reactions were usually mild or moderate and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. These reactions have been observed more frequently within 24 hours of infusion. Specific treatment for trastuzumab emtansine extravasation is unknown at this time.

Laboratory abnormalities

Table 7 displays laboratory abnormalities observed in patients treated with trastuzumab emtansine in clinical study TDM4370g/BO21977.

Table 7 Laboratory abnormalities observed in patients treated with trastuzumab emtansine in study TDM4370g/BO21977

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 (see details below).

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

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 known antidote for trastuzumab emtansine overdose. In case of overdose, the patient should be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted. Cases of overdose have been reported with trastuzumab emtansine treatment, most associated with thrombocytopenia, and there was one death. In the fatal case, the patient incorrectly received trastuzumab emtansine 6 mg/kg and died approximately 3 weeks following the overdose; a causal relationship to trastuzumab emtansine was not established.

Pharmacotherapeutic group: Antineoplastic agent, other antineoplastic agents, monoclonal antibodies, ATC code: L01XC14

Mechanism of action

Kadcyla, trastuzumab emtansine, is a HER2-targeted antibody-drug conjugate which contains the humanised anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitor DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1 complex. An average of 3.5 DM1 molecules are conjugated to each molecule of trastuzumab.

Conjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for HER2-overexpressing tumour cells, thereby increasing intracellular delivery of DM1 directly to malignant cells. Upon binding to HER2, trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in release of DM1-containing cytotoxic catabolites (primarily lysine-MCC-DM1).

Trastuzumab emtansine has the mechanisms of action of both trastuzumab and DM1:

- Trastuzumab emtansine, like trastuzumab, binds to domain IV of the HER2 extracellular domain (ECD), as well as to Fcγ receptors and complement C1q. In addition, trastuzumab emtansine, like trastuzumab, inhibits shedding of the HER2 ECD, inhibits signalling through the phosphatidylinositol 3-kinase (PI3-K) pathway, and mediates antibody-dependent cell-mediated cytotoxicity (ADCC) in human breast cancer cells that overexpress HER2.

- DM1, the cytotoxic component of trastuzumab emtansine, binds to tubulin. By inhibiting tubulin polymerization, both DM1 and trastuzumab emtansine cause cells to arrest in the G2/M phase of the cell cycle, ultimately leading to apoptotic cell death. Results from in vitro cytotoxicity assays show that DM1 is 20-200 times more potent than taxanes and vinca alkaloids.

- The MCC linker is designed to limit systemic release and increase targeted delivery of DM1, as demonstrated by detection of very low levels of free DM1 in plasma.

Clinical efficacy

TDM4370g/BO21977

A Phase III, randomised, multicentre, international, open-label clinical study was conducted in patients with HER2-positive unresectable locally advanced breast cancer (LABC) or MBC who had received prior taxane and trastuzumab-based therapy, including patients who received prior therapy with trastuzumab and a taxane in the adjuvant setting and who relapsed during or within six months of completing adjuvant therapy. Only patients with Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 were eligible. Prior to enrolment, breast tumour samples were required to be centrally confirmed for HER2-positive status defined as a score of 3 + by IHC or gene amplification by ISH. Baseline patient and tumour characteristics were well balanced between treatment groups. Patients with treated brain metastases were eligible for enrollment if they did not require therapy to control symptoms. For patients randomised to trastuzumab emtansine, the median age was 53 years, most patients were female (99.8%), the majority were Caucasian (72%), and 57% had oestrogen-receptor and/or progesterone-receptor positive disease. The study compared the safety and efficacy of trastuzumab emtansine with that of lapatinib plus capecitabine. A total of 991 patients were randomised to trastuzumab emtansine or lapatinib plus capecitabine as follows:

- Trastuzumab emtansine arm: trastuzumab emtansine 3.6 mg/kg intravenously over 30-90 minutes on Day 1 of a 21-day cycle

- Control arm (lapatinib plus capecitabine): lapatinib 1250 mg/day orally once per day of a 21-day cycle plus capecitabine 1000 mg/m² orally twice daily on Days 1-14 of a 21-day cycle

The co-primary efficacy endpoints of the study were progression-free survival (PFS) as assessed by an independent review committee (IRC) and overall survival (OS) (see Table 8 and Figures 1 to 2).

Time to symptom progression, as defined by a 5-point decrease in the score derived from the Trials Outcome Index-Breast (TOI-B) subscale of the Functional Assessment of Cancer Therapy-Breast Quality of Life (FACT-B QoL) questionnaire was also assessed during the clinical study. A change of 5 points in the TOI-B is considered clinically significant. Kadcyla delayed patient-reported time to symptom progression for 7.1 months compared with 4.6 months for the control arm (Hazard Ratio 0.796 (0.667, 0.951); p-value 0.0121). The data are from an open-label study and no firm conclusions can be drawn.

Table 8 Summary of efficacy from study TDM4370g/BO21977 (EMILIA)

OS: overall survival; PFS: progression-free survival; ORR: objective response rate; OR: objective response; IRC: independent review committee; HR: hazard ratios; CI: confidence interval

* Stratified by: world region (United States, Western Europe, other), number of prior chemotherapeutic regimens for locally advanced or metastatic disease (0-1 vs. > 1), and visceral vs. non-visceral disease.

** The interim analysis for OS was conducted when 331 events were observed. Since the efficacy boundary was crossed at this analysis, this is considered the definitive analysis.

A treatment benefit was seen in the subgroup of patients who had relapsed within 6 months of completing adjuvant treatment and had not received any prior systemic anti-cancer therapy in the metastatic setting (n=118); hazard ratios for PFS and OS were 0.51 (95% CI: 0.30, 0.85) and 0.61 (95% CI: 0.32, 1.16), respectively. The median PFS and OS for the trastuzumab emtansine group were 10.8 months and not reached, respectively, compared with 5.7 months and 27.9 months, respectively, for the lapatinib plus capecitabine group.

Figure 1 Kaplan-meier curve of IRC-assessed progression-free survival

Figure 2 Kaplan-meier curve of overall survival

In study TDM4370g/BO21977, consistent treatment benefit of trastuzumab emtansine was seen in the majority of pre-specified subgroups evaluated, supporting the robustness of the overall result. In the subgroup of patients with hormone receptor-negative disease (n=426), the hazard ratios for PFS and OS were 0.56 (95% CI: 0.44, 0.72) and 0.75 (95% CI: 0.54, 1.03), respectively. In the subgroup of patients with hormone receptor-positive disease (n=545), the hazard ratios for PFS and OS were 0.72 (95% CI: 0.58, 0.91) and 0.62 (95% CI: 0.46, 0.85), respectively.

In the subgroup of patients with non-measurable disease (n=205), based on IRC assessments, the hazard ratios for PFS and OS were 0.91 (95% CI: 0.59, 1.42) and 0.96 (95% CI: 0.54, 1.68), respectively. In patients > 65 years old (n=138 across both treatment arms) the hazard ratios for progression-free survival (PFS) and Overall Survival (OS) were 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively. In patients 65 to 74 years old (n=113), based on IRC assessments, the hazard ratios for PFS and OS were 0.88 (95% CI: 0.53, 1.45) and 0.74 (95% CI: 0.37, 1.47), respectively. For patients 75 years or above, based on IRC assessments, the hazard ratios for PFS and OS were 3.51 (95% CI: 1.22, 10.13) and 3.45 (95% CI: 0.94, 12.65), respectively. The subgroup of patients 75 years or above did not demonstrate a benefit for PFS or OS, but was too small (n=25) to draw any definitive conclusions.

In the descriptive follow-up overall survival analysis, the hazard ratio was 0.75 (95% CI 0.64, 0.88). The median duration of overall survival was 29.9 months in the trastuzumab emtansine arm compared with 25.9 months in the lapatinib plus capecitabine arm. At the time of the descriptive follow-up overall survival analysis, a total of 27.4% of the patients had crossed over from the lapatinib plus capecitabine arm to the trastuzumab emtansine arm. In a sensitivity analysis censoring patients at the time of cross-over, the hazard ratio was 0.69 (95% CI 0.59, 0.82). The results of this descriptive follow-up analysis are consistent with the confirmatory OS analysis.

TDM4450g

A randomised, multicentre, open-label phase II study evaluated the effects of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with HER2-positive MBC who had not received prior chemotherapy for metastatic disease. Patients were randomised to receive trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks (n = 67) or trastuzumab 8 mg/kg intravenous loading dose followed by 6 mg/kg intravenously every 3 weeks plus docetaxel 75-100 mg/m² intravenously every 3 weeks (n = 70).

The primary endpoint was investigator assessed Progression-Free Survival (PFS). The median PFS was 9.2 months in the trastuzumab plus docetaxel arm and 14.2 months in the trastuzumab emtansine arm (hazard ratio, 0.59; p = 0.035), with a median follow-up of approximately 14 months in both arms. The objective response rate (ORR) was 58.0% with trastuzumab plus docetaxel and 64.2% with trastuzumab emtansine. The median duration of response was not reached with trastuzumab emtansine vs. 9.5 months in the control arm.

TDM4374g

A Phase II, single-arm, open-label study evaluated the effects of trastuzumab emtansine in patients with HER2-positive incurable, LABC or MBC. All patients were previously treated with HER2-directed therapies (trastuzumab and lapatinib), and chemotherapy (anthracycline, taxane, and capecitabine) in the neoadjuvant, adjuvant, locally advanced, or metastatic setting. The median number of anti-cancer agents that patients had received in any setting was 8.5 (range, 5-19) and in the metastatic setting was 7.0 (range, 3-17), including all agents intended for the treatment of breast cancer.

Patients (n = 110) received 3.6 mg/kg of trastuzumab emtansine intravenously every 3 weeks until disease progression or unacceptable toxicity.

The key efficacy analyses were ORR based on independent radiologic review and duration of objective response. The ORR was 32.7% (95% CI: 24.1, 42.1), n = 36 responders, by both IRC and investigator review. The median duration of response by IRC was not reached (95% CI, 4.6 months to not estimable).

Paediatric population

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Absorption

Trastuzumab emtansine is administered intravenously. There have been no studies performed with other routes of administration.

Distribution

Patients in TDM4370g/BO21977 who received 3.6 mg/kg of trastuzumab emtansine intravenously every 3 weeks had a mean maximum serum concentration (C_max) of trastuzumab emtansine of 83.4 (± 16.5) μg/mL. Based on population PK analysis, following intravenous administration, the central volume of distribution of trastuzumab emtansine was (3.13 L) and approximated that of plasma volume.

Biotransformation (trastuzumab emtansine and DM1)

Trastuzumab emtansine is expected to undergo deconjugation and catabolism by means of proteolysis in cellular lysosomes.

In vitro metabolism studies in human liver microsomes suggest that DM1, a small molecule component of trastuzumab emtansine, is metabolised mainly by CYP3A4 and to a lesser extent by CYP3A5. DM1 did not inhibit major CYP450 enzymes in vitro. In human plasma, trastuzumab emtansine catabolites MCC-DM1, Lys-MCC-DM1, and DM1 were detected at low levels. In vitro, DM1 was a substrate of P-glycoprotein (P-gp).

Elimination

Based on population pharmacokinetic (PK) analysis, following intravenous administration of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, the clearance of trastuzumab emtansine was 0.68 L/day and the elimination half-life (t_1/2) was approximately 4 days. No accumulation of trastuzumab emtansine was observed after repeated dosing of intravenous infusion every 3 weeks.

Based on population PK analysis, body weight, albumin, sum of longest diameter of target lesions by Response Evaluation Criteria In Solid Tumors (RECIST), HER2 shed extracellular domain (ECD), baseline trastuzumab concentrations, and aspartate aminotransferase (AST) were identified as statistically significant covariates for trastuzumab emtansine PK parameters. However, the magnitude of effect of these covariates on trastuzumab emtansine exposure, suggests that these covariates are unlikely to have any clinically meaningful effect on trastuzumab emtansine exposure. In addition, exploratory analysis showed that the impact of covariates (i.e., renal function, race and age) on the pharmacokinetics of total trastuzumab and DM1 was limited and was not clinically relevant. In nonclinical studies, trastuzumab emtansine catabolites including DM1, Lys-MCC-DM1, and MCC-DM1 are mainly excreted in the bile with minimal elimination in urine.

Linearity/non-linearity

Trastuzumab emtansine when administered intravenously every 3 weeks exhibited linear PK across doses ranging from 2.4 to 4.8 mg/kg; patients who received doses less than or equal to 1.2 mg/kg had faster clearance.

Elderly patients

The population PK analysis showed that age did not affect the PK of trastuzumab emtansine. No significant difference was observed in the PK of trastuzumab emtansine among patients < 65 years (n = 577), patients between 65-75 years (n = 78) and patients > 75 years (n = 16).

Renal impairment

No formal PK study has been conducted in patients with renal impairment. The population PK analysis showed that creatinine clearance does not affect the PK of trastuzumab emtansine. Pharmacokinetics of trastuzumab emtansine in patients with mild (creatinine clearance CLcr 60 to 89 mL/min, n = 254) or moderate (CLcr 30 to 59 mL/min, n = 53) renal impairment were similar to those in patients with normal renal function (CLcr > 90 mL/min, n = 361). Pharmacokinetic data in patients with severe renal impairment (CLcr 15 to 29 mL/min) are limited (n = 1), therefore no dosage recommendations can be made.

Hepatic impairment

The liver is a primary organ for eliminating DM1 and DM1-containing catabolites. The pharmacokinetics of trastuzumab emtansine and DM1-containing catabolites were evaluated after the administration of 3.6 mg/kg of trastuzumab emtansine to metastatic HER2+ breast cancer patients with normal hepatic function (n=10), mild (Child-Pugh A; n=10) and moderate (Child-Pugh B; n=8) hepatic impairment.

- Plasma concentrations of DM1 and DM1-containing catabolites (Lys-MCC-DM1 and MCC-DM1) were low and comparable between patients with and without hepatic impairment.

- Systemic exposures (AUC) of trastuzumab emtansine at Cycle 1 in patients with mild and moderate hepatic impairment were approximately 38% and 67% lower than that of patients with normal hepatic function, respectively. Trastuzumab emtansine exposure (AUC) at Cycle 3 after repeated dosing in patients with mild or moderate hepatic dysfunction was within the range observed in patients with normal hepatic function.

Trastuzumab emtansine has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Other special populations

The population PK analysis showed that race did not appear to influence the PK of trastuzumab emtansine. Because most of the patients in trastuzumab emtansine clinical studies were females, the effect of gender on the PK of trastuzumab emtansine was not formally evaluated.

Animal toxicology and/or pharmacology

Administration of trastuzumab emtansine was well tolerated in rats and monkeys at doses up to 20 and 10 mg/kg, respectively, corresponding to 2040 μg DM1/m² in both species, which is approximately equivalent to the clinical dose of trastuzumab emtansine in patients. In the GLP toxicity studies, with the exception of irreversible peripheral axonal toxicity (observed only in monkeys at > 10 mg/kg) and reproductive organ toxicity (observed only in rats at 60 mg/kg), partially or completely reversible dose dependent toxicities were identified in both animal models. Principal toxicities included liver (liver enzyme elevations) at > 20 mg/kg and > 10 mg/kg, bone marrow (reduced platelet and white blood cell count)/hematologic at > 20 mg/kg and > 10 mg/kg, and lymphoid organs at > 20 mg/kg and > 3 mg/kg, in rat and monkey, respectively.

Mutagenicity

DM1 was aneugenic or clastogenic in an in vivo single-dose rat bone marrow micronucleus assay at exposures that were comparable to mean maximum concentrations of DM1 measured in humans administered trastuzumab emtansine. DM1 was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.

Impairment of fertility and teratogenicity

Dedicated fertility studies have not been conducted with trastuzumab emtansine. However, based on results from general animal toxicity studies, adverse effects on fertility can be expected.

Dedicated embryo-foetal development studies have not been conducted in animals with trastuzumab emtansine. Developmental toxicity of trastuzumab has been identified in the clinical setting although it was not predicted in the non-clinical program. In addition, developmental toxicity of maytansine has been identified in non-clinical studies which suggests that DM1, the microtubule-inhibiting cytotoxic maytansinoid component of trastuzumab emtansine, will be similarly teratogenic and potentially embryotoxic.

Succinic acid

Sodium hydroxide

Sucrose

Polysorbate 20

Glucose (5%) solution should not be used for reconstitution or dilution since it causes aggregation of the protein.

3 years.

Shelf-life of the reconstituted solution

Chemical and physical in-use stability of the reconstituted solution has been demonstrated for up to 24 hours at 2°C to 8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, the reconstituted vials can be stored for up to 24 hours at 2°C to 8°C, provided it was reconstituted under controlled and validated aseptic conditions, and must be discarded thereafter.

Shelf-life of the diluted solution

The reconstituted Kadcyla solution diluted in infusion bags containing sodium chloride 9 mg/ml (0.9%) solution for infusion, or sodium chloride 4.5 mg/ml (0.45%) solution for infusion, is stable for up to 24 hours at 2°C to 8°C, provided it was prepared under controlled and validated aseptic conditions. Particulates may be observed on storage if diluted in 0.9% sodium chloride.

Store in a refrigerator (2°C - 8°C).

Kadcyla is provided in 15 ml (100 mg) or 20 ml (160 mg) Type 1 glass vial closed with a grey-butyl rubber stopper coated with fluoro-resin laminate, and sealed with an aluminium seal with a white or purple plastic flip-off cap.

Pack of 1 vial.

Appropriate aseptic technique should be used. Appropriate procedures for the preparation of chemotherapeutic medicinal products should be used.

The reconstituted Kadcyla solution should be diluted in polyvinyl chloride (PVC) or latex-free PVC-free polyolefin infusion bags.

The use of 0.20 or 0.22 micron in-line polyethersulfone (PES) filter is required for the infusion when the concentrate for infusion is diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion.

In order to prevent medication errors it is important to check the vial labels to ensure that the medicinal product being prepared is Kadcyla (trastuzumab emtansine) and not Herceptin (trastuzumab).

Instructions for reconstitution

- 100 mg trastuzumab emtansine vial: Using a sterile syringe, slowly inject 5 mL of sterile water for injection into the vial.

- 160 mg trastuzumab emtansine vial: Using a sterile syringe, slowly inject 8 mL of sterile water for injection into the vial.

- Swirl the vial gently until completely dissolved. Do not shake.

Reconstituted solution should be inspected visually for particulate matter and discolouration prior to administration. The reconstituted solution should be free of visible particulates, clear to slightly opalescent. The colour of the reconstituted solution should be colourless to pale brown. Do not use if the reconstituted solution contains visible particulates, or is cloudy or discoloured.

Instructions for dilution

Determine the volume of the reconstituted solution required based on a dose of 3.6 mg trastuzumab emtansine/kg body weight :

The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag containing 250 mL of sodium chloride 4.5 mg/ml (0.45%) solution for infusion or sodium chloride 9 mg/ml (0.9%) solution for infusion. Glucose (5%) solution should not be used. Sodium chloride 4.5 mg/ml (0.45%) solution for infusion may be used without a polyethersulfone (PES) 0.20 or 0.22-μm in-line filter. If sodium chloride 9 mg/ml (0.9%) solution for infusion is used for infusion, a 0.20 or 0.22 micron in-line polyethersulfone (PES) filter is required. Once the infusion is prepared it should be administered immediately. Do not freeze or shake the infusion during storage.

Disposal

The reconstituted product contains no preservative and is intended for single use only. Discard any unused portion.

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

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

EU/1/13/885/001

EU/1/13/885/002

Date of first authorisation: 15 November 2013

16 March 2018