Antibody drug conjugate antineoplastic agent. ATC Code:
Not yet available.
Pharmacology: Pharmacodynamics: 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 inhibitory drug 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 internalisation and subsequent lysosomal degradation, resulting in release of DM1-containing cytotoxic catabolites (primarily lysine-MCC-DM1). Kadcyla 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, Kadcyla, 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 drug component of Kadcyla, binds to tubulin. By inhibiting tubulin polymerisation, both DM1 and Kadcyla 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.
Efficacy: Metastatic Breast Cancer: A Phase III, randomised, multicentre, international, open-label clinical trial (TDM4370g/BO21977) was conducted in patients with HER2-positive unresectable locally advanced breast cancer 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 within six months of completing adjuvant therapy. Prior to enrollment, breast tumour samples were required to be centrally confirmed for HER2-positive disease defined as a score of 3+ by IHC or gene amplification by ISH. Baseline patient and tumour characteristics were well balanced between treatment groups. For patients randomised to Kadcyla, the median age was 53 years, most patients were female (99.8%), the majority were Caucasian (72%), and 57% had estrogen-receptor and/or progesterone-receptor positive disease. The study compared the safety and efficacy of Kadcyla with that of lapatinib plus capecitabine. A total of 991 patients were randomised with Kadcyla or lapatinib plus capecitabine as follows: Kadcyla Arm: Kadcyla 3.6 mg/kg intravenously (IV) 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) and landmark (1-year and 2-year) survival rates.
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 trial. A change of 5 points in the TOI-B is considered clinically significant. (See Table 1.)
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A treatment benefit was seen in the subgroup of patients who 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 KADCYLA 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. (See Figure 1 and Figure 2.)
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Click on icon to see table/diagram/image
A randomised, multicentre, open-label Phase II study (TDM4450g/BO21976) evaluated the effects of Kadcyla versus trastuzumab plus docetaxel in patients with HER2-positive MBC who had not received prior chemotherapy for metastatic disease. Patients were randomised to receive Kadcyla 3.6 mg/kg IV every 3 weeks (n=67) or trastuzumab 8 mg/kg IV loading dose followed by 6 mg/kg IV every 3 weeks plus docetaxel 75-100 mg/m2
IV every 3 weeks (n=70).
The primary endpoint was PFS assessed by investigator. The median PFS was 9.2 months in the trastuzumab plus docetaxel arm and 14.2 months in the Kadcyla arm (hazard ratio, 0.59; p = 0.035), with a median follow-up of approximately 14 months in both arms. The ORR was 58.0% with trastuzumab plus docetaxel and 64.2% with Kadcyla. The median duration of response was not reached with Kadcyla vs. median duration 9.5 months in the control arm.
The worsening of the FACT-B TOI scores was delayed in the Kadcyla arm compared with the control arm (median time to symptom progression was 7.5 months in the Kadcyla arm vs. 3.5 months in the control arm; hazard ratio, 0.58; p = 0.022).
A Phase II, single-arm, open-label study (TDM4374g) evaluated the effects of Kadcyla in patients with HER2-positive incurable advance breast cancer, 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 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 Kadcyla 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).
As with all therapeutic proteins, there is the potential for an immune response to trastuzumab emtansine. Among 836 patients from six clinical studies tested at multiple time points for anti-therapeutic antibody (ATA) responses to Kadcyla. Forty four patients (5.3%) tested positive for anti-Kadcyla antibodies at one or more postdose time points; 28 of these patients had negative baseline samples. The clinical significance of anti-trastuzumab emtansine antibodies is not yet known.
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of antibodies to Kadcyla with the incidence of antibodies to other products may be misleading.
Kadcyla is administered IV. There have been no studies performed with other routes of administration.
Kadcyla when administered intravenously every 3 weeks exhibited linear pharmacokinetics 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.
Patients in TDM4370g/BO21977 who received 3.6 mg/kg of Kadcyla intravenously every 3 weeks had a mean maximum serum concentration (Cmax
) of trastuzumab emtansine of 83.4 (±16.5) μg/ml. Based on population pharmacokinetic analysis, following intravenous administration, the central volume of distribution of trastuzumab emtansine was (3.13 l) and approximated that of plasma volume.
Trastuzumab emtansine is expected to undergo deconjugation and catabolism by means of proteolysis in cellular lysosomes, with no significant involvement of cytochrome P450 isoenzymes. Catabolites including Lys-MCC-DM1, MCC-DM1 and DM1 are detected at low levels in human plasma.
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 CYP3A.
DM1 did not inhibit major CYP450 enzymes in vitro. In vitro
, DM1 was a substrate of P-glycoprotein (P-gp).
Based on population pharmacokinetic (PK) analysis, following IV administration of Kadcyla in patients with HER2-positive metastatic breast cancer, the clearance of Kadcyla was 0.68 l/day and the elimination half-life (t1/2
) was approximately 4 days. No accumulation of Kadcyla was observed after repeated dosing of IV infusion every 3 weeks.
Based on a population PK analysis (n=671), body weight, albumin, sum of longest diameter of target lesions by RECIST, HER2 ECD, baseline trastuzumab concentrations and AST were identified as statistically significant covariates for trastuzumab emtansine pharmacokinetic parameters. However, the magnitude of effect of these covariates on trastuzumab emtansine exposure suggests that, with the exception of body weight, these covariates are unlikely to have any clinically meaningful effect on KADCYLA exposure. Therefore, the body weight based dose of 3.6 mg/kg every 3 weeks without correction for other covariates is considered appropriate. In nonclinical studies, catabolites of trastuzumab emtansine including DM1, Lys-MCC-DM1, and MCC-DM1 are mainly excreted in the bile with minimal elimination in urine.
Pharmacokinetics in Special Populations:
The population pharmacokinetic analysis of Kadcyla showed that race did not appear to influence the pharmacokinetics of Kadcyla. Because most of the patients in Kadcyla clinical studies were females, effect of gender on the pharmacokinetics of Kadcyla was not formally evaluated.
Geriatric use: The population pharmacokinetic analysis of Kadcyla showed that age did not affect the pharmacokinetics of Kadcyla. No significant difference was observed in the pharmacokinetics of Kadcyla among patients <65 years (n=577), patients between 65 and 75 years (n=78) and patients >75 years (n=16).
Renal impairment: The population pharmacokinetic analysis of Kadcyla showed that creatinine clearance does not affect pharmacokinetics of Kadcyla. Pharmacokinetics of Kadcyla in patients with mild (creatinine clearance CLcr 60-89 ml/min, n=254) or moderate (CLcr 30-59 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 15-29 ml/min) is 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 Kadcyla to metastatic HER2- positive 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.
Kadcyla has not been studied in patients with severe hepatic impairment (Child-Pugh class C).
Toxicology: Preclinical Safety:
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.
Trastuzumab emtansine has not been tested for carcinogenicity.
No evidence of mutagenic activity was observed in an in vitro
bacterial reverse mutation assay of DM1. In an in vivo
micronucleus assay of trastuzumab emtansine in cynomolgus monkeys, no evidence of chromosomal damage to bone marrow cells was observed. However, in a rat bone marrow micronucleus assay, DM1 was positive for micronuclei formation after a single low dose in the DM1 concentration range measured in humans given trastuzumab emtansine, confirming that trastuzumab emtansine is an aneugen and/or clastogen.
Impairment of Fertility:
Dedicated fertility 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-fetal development studies have not been conducted in animals with trastuzumab emtansine. Development toxicity of trastuzumab has been identified in the clinical setting although it was not predicted in the non-clinical programme. In addition, developmental toxicity of maytansine has been identified in non-clinical studies which suggests that DM1, the microtubule-inhibiting cytotoxic maytansinoid drug component of trastuzumab emtansine, will be similarly teratogenic and potentially embryotoxic.