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2013年11月21日，罗氏（Roche）抗体偶联药物Kadcyla（trastuzumab emtansine，T-DM1）获欧盟委员会（EC）批准，用于既往接受过赫赛汀（Herceptin，通用名：trastuzumab，曲妥珠单抗）及一种紫衫类药物（taxane）治疗的、不能手术切除的局部晚期或转移性HER2阳性乳腺癌患者的治疗。
Table 3 Dose modification guidelines for hyperbilirubinemia
Table 4 Dose modification guidelines for thrombocytopenia
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 (see sections 5.1 and 5.2). Patients with renal impairment No adjustment to the starting dose is needed in patients with mild or moderate renal impairment (see section 5.2). 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. Patients with hepatic impairment The safety and efficacy have not been studied in patients with hepatic impairment. No specific dose recommendations can be made (see section 4.4). 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 in 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. For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use In order to improve traceability of biological medicinal products, the tradename 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 (see section 4.8). 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 (see section 4.8). 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 (see section 4.8). 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. Patients with baseline elevation of ALT (e.g. due to liver metastases) may be predisposed to liver injury with a higher risk of a Grade 3-5 hepatic event or liver function test increase. Dose reductions or discontinuation for increased serum transaminases and total bilirubin are specified in section 4.2. 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. 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 (see section 4.8). 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 (see section 4.2). 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 (see section 4.8). 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 (see section 4.2). 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. Thrombocytopenia Thrombocytopenia, or decreased platelet counts, was commonly reported with trastuzumab emtansine and was the most common adverse reaction leading to treatment discontinuation (see section 4.8). In clinical studies, the incidence and severity of thrombocytopenia were higher in Asian patients (see section 4.8). Cases of bleeding events with a fatal outcome have been observed. Severe cases of haemorrhagic events, including central nervous system haemorrhage, have been reported in clinical studies; these events were independent of ethnicity. In some of the observed cases the patients were also receiving anti-coagulation therapy. 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) (see section 4.2). 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'. 4.5 Interaction with other medicinal products and other forms of interaction 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. 4.6 Fertility, pregnancy and lactation 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 (see section 5.3). 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. 4.7 Effects on ability to drive and use machines 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. 4.8 Undesirable effects Summary of the safety profile The safety of trastuzumab emtansine has been evaluated in 884 breast cancer patients in clinical studies. In this patient population: • the most common serious ADRs were pyrexia, thrombocytopenia, vomiting, abdominal pain, nausea, constipation, diarrhoea, dyspnoea and pneumonitis. • the most common adverse drug reactions (ADRs) (≥25%) with trastuzumab emtansine were haemorrhage (including epistaxis), increased transaminases, fatigue, musculoskeletal pain, 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 or 4 ADRs (> 2%) were thrombocytopenia, fatigue, increased transaminases, anaemia, hypokalaemia, musculoskeletal pain and neutropenia. Tabulated list of adverse reactions The ADRs in 884 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
Transaminases increased (AST/ALT) Increase in serum transaminases (Grade 1-4) has been observed during treatment with trastuzumab emtansine in clinical studies (see section 4.4). Transaminase elevations were generally transient. A cumulative effect of trastuzumab emtansine on transaminases has been observed, and generally recovered when treatment was discontinued. Increased transaminases were reported in 28% of patients in clinical studies. Grade 3 or 4 increased AST and ALT were reported in 4.1% and 2.8% of patients respectively and usually occurred in the early treatment cycles (1-6). In general, the Grade ≥ 3 hepatic events were not associated with poor clinical outcome; subsequent follow-up values tended to show improvement to ranges allowing the patient to remain on study and continue to receive study treatment at the same or reduced dose. No relationship was observed between trastuzumab emtansine exposure (AUC), trastuzumab emtansine maximum serum concentration (Cmax), total trastuzumab exposure (AUC), or Cmax of DM1 and increases in transaminase. For dose modifications in the event of increased transaminases, see sections 4.2 and 4.4. Left ventricular dysfunction Left ventricular dysfunction was reported in 2.0% of patients in clinical studies with trastuzumab emtansine. The majority of events were asymptomatic Grade 1 or 2 decrease in LVEF. Grade 3 or 4 events were reported in 0.3% of patients. These uncommon Grade 3 or 4 events usually occurred in the early treatment cycles (1-2). Additional LVEF monitoring is recommended for patients with LVEF ≤ 45% (See Table 5 in section 4.2 for specific dose modifications). 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. Infusion-related reactions were reported in 4.5% of patients in clinical studies with trastuzumab emtansine, with one Grade 3 and no Grade 4 events reported. Infusion-related reactions resolved over the course of several hours to a day after the infusion was terminated. No dose relationship was observed in clinical studies. For dose modifications in the event of infusion-related reactions, see sections 4.2 and 4.4. Hypersensitivity reactions Hypersensitivity was reported in 2.6% of patients in clinical studies with trastuzumab emtansine, with no Grade 3 or 4 events reported. Overall, the majority of hypersensitivity reactions were mild or moderate in severity and resolved upon treatment. For dose modifications in the event of hypersensitivity reactions, see sections 4.2 and 4.4. Thrombocytopenia Thrombocytopenia or decreased platelet counts were reported in 31.4% of patients in clinical studies with trastuzumab emtansine and was the most common adverse reaction leading to treatment discontinuation (1.4%). The majority of the patients had Grade 1 or 2 events (≥ 50,000/mm3), with the nadir occurring by day 8 and generally improving to Grade 0 or 1 (≥ 75,000/mm3) by the next scheduled dose. In clinical studies, the incidence and severity of thrombocytopenia were higher in Asian patients. Independent of race, the incidence of Grade 3 or 4 events (< 50,000/mm3) was 11.3% in patients treated with trastuzumab emtansine. The incidence of severe haemorrhagic events (Grade ≥3) occurred in 1.7% of the overall trastuzumab emtansine treated patients and 1% of Asian trastuzumab emtansine treated patients. In some of the observed cases the patients were also receiving anti-coagulation therapy. Cases of bleeding events with a fatal outcome have been observed. For dose modifications for thrombocytopenia, see sections 4.2 and 4.4. 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 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 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 Pharmacovigilance Section Health Products Regulatory Authority Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie e-mail: medsafety@hpra.ie Mata ADR Reporting The Medicines Authority Post-Licensing Directorate 203 Level 3, Rue D'Argens GŻR-1368 Gżira Website: www.medicinesauthority.gov.mt e-mail: postlicensing.medicinesauthority@gov.mt United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard 4.9 Overdose 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. 5. Pharmacological properties 5.1 Pharmacodynamic properties 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)
* 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
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