Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Daiichi Sankyo Europe GmbH, Zielstattstrasse 48, 81379 Munich, Germany
Pharmacotherapeutic group: Antineoplastic agents, HER2 (Human Epidermal Growth Factor Receptor 2) inhibitors
ATC code: L01FD04
Enhertu, trastuzumab deruxtecan, is a HER2-targeted antibody-drug conjugate. The antibody is a humanised anti-HER2 IgG1 attached to deruxtecan, a topoisomerase I inhibitor (DXd) bound by a tetrapeptide-based cleavable linker. The antibody-drug conjugate is stable in plasma. The function of the antibody portion is to bind to HER2 expressed on the surface of certain tumour cells. After binding, the trastuzumab deruxtecan complex then undergoes internalisation and intracellular linker cleavage by lysosomal enzymes that are upregulated in cancer cells. Upon release, the membrane-permeable DXd causes DNA damage and apoptotic cell death. DXd, an exatecan derivative, is approximately 10 times more potent than SN-38, the active metabolite of irinotecan.
In vitro studies indicate that the antibody portion of trastuzumab deruxtecan, which has the same amino acid sequence as trastuzumab, also binds to FcγRIIIa and complement C1q. The antibody mediates antibody-dependent cellular cytotoxicity (ADCC) in human breast cancer cells that overexpress HER2. In addition, the antibody inhibits signalling through the phosphatidylinositol 3-kinase (PI3-K) pathway in human breast cancer cells that overexpress HER2.
The efficacy and safety of Enhertu were studied in DESTINY-Breast01, a multicentre, open-label, single-arm Phase 2 study that enrolled patients with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2-based regimens, including trastuzumab emtansine (100%), trastuzumab (100%), and pertuzumab (65.8%). Archival breast tumour samples were required to show HER2 positivity defined as HER2 IHC 3+ or ISH-positive. The study excluded patients with a history of treated ILD or ILD at screening, patients with untreated or symptomatic brain metastases, and patients with a history of clinically significant cardiac disease. Patients enrolled had at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Enhertu was administered by intravenous infusion at 5.4 mg/kg once every three weeks until disease progression, death, withdrawal of consent, or unacceptable toxicity. The primary efficacy outcome measure was confirmed objective response rate (ORR) according to RECIST v1.1 in the intent-to-treat (ITT) population as evaluated by independent central review. The secondary efficacy outcome measure was duration of response (DOR).
Of the 184 patients enrolled in DESTINY-Breast01, baseline demographic and disease characteristics were: median age 55 years (range: 28 to 96); 65 years or older (23.9%); female (100%); White (54.9%), Asian (38.0%), Black or African-American (2.2%); Eastern Cooperative Oncology Group (ECOG) performance status 0 (55.4%) or 1 (44.0%); hormone receptor status (positive: 52.7%); presence of visceral disease (91.8%); previously treated and stable brain metastases (13.0%); median number of prior therapies in the metastatic setting: 5 (range: 2 to 17); sum of diameters of target lesions (<5 cm: 42.4%, ≥5 cm: 50.0%).
An earlier analysis (median duration of follow-up 11.1 months [range: 0.7 to 19.9 months]) showed a confirmed objective response rate of 60.9% (95% CI: 53.4, 68.0) with 6.0% being complete responders and 54.9% being partial responders; 36.4% had stable disease, 1.6% had progressive disease and 1.1% were not evaluable. Median duration of response at that time was 14.8 months (95% CI: 13.8, 16.9) with 81.3% of responders having a response of ≥6 months (95% CI: 71.9, 87.8). Efficacy results from an updated data cutoff with median duration of follow-up of 20.5 months (range: 0.7 to 31.4 months) are shown in Table 4.
Table 4. Efficacy results in DESTINY-Breast01 (intent-to-treat analysis set):
| DESTINY-Breast01 N=184 | |
|---|---|
| Confirmed objective response rate (95% CI)*† | 61.4% (54.0, 68.5) |
| Complete response (CR) | 6.5% |
| Partial response (PR) | 54.9% |
| Duration of response‡ | |
| Median, months (95% CI) | 20.8 (15.0, NR) |
| % with duration of response ≥6 months (95% CI)§ | 81.5% (72.2, 88.0) |
ORR 95% CI calculated using Clopper-Pearson method
CI = confidence interval
95% CIs calculated using Brookmeyer-Crowley method
* Confirmed responses (by blinded independent central review) were defined as a recorded response of either CR/PR, confirmed by repeat imaging not less than 4 weeks after the visit when the response was first observed.
† Of the 184 patients, 35.9% had stable disease, 1.6% had progressive disease and 1.1% were not evaluable.
‡ Includes 73 patients with censored data.
§ Based on Kaplan-Meier estimation.
NR = not reached
Consistent anti-tumour activity was observed across pre-specified subgroups based on prior pertuzumab therapy and hormone receptor status.
The European Medicines Agency has waived the obligation to submit the results of studies in all subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
Trastuzumab deruxtecan is administered intravenously. There have been no studies performed with other routes of administration.
Based on population pharmacokinetic analysis, the volume of distribution of the central compartment (Vc) of trastuzumab deruxtecan and topoisomerase I inhibitor, DXd, were estimated to be 2.77 L and 27.4 L, respectively.
In vitro, the mean human plasma protein binding of DXd was approximately 97%.
In vitro, the blood to plasma concentration ratio of DXd was approximately 0.6.
Trastuzumab deruxtecan undergoes intracellular cleavage by lysosomal enzymes to release the DXd.
The humanised HER2 IgG1 monoclonal antibody is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
In vitro metabolism studies in human liver microsomes indicate that DXd is metabolised mainly by CYP3A4 via oxidative pathways.
Based on population pharmacokinetic analysis, following intravenous administration of trastuzumab deruxtecan in patients with metastatic HER2-positive breast cancer, the clearance of trastuzumab deruxtecan was estimated to be 0.42 L/day and the clearance of DXd was 19.2 L/h. In cycle 3, the apparent elimination half-life (t1/2) of trastuzumab deruxtecan and released DXd was approximately 7 days. Moderate accumulation (approximately 35% in cycle 3 compared to cycle 1) of trastuzumab deruxtecan was observed.
Following intravenous administration of DXd to rats, the major excretion pathway was faeces via the biliary route. DXd was the most abundant component in urine, faeces, and bile. Following single intravenous administration of trastuzumab deruxtecan (6.4 mg/kg) to monkeys, unchanged released DXd was the most abundant component in urine and faeces. DXd excretion was not studied in humans.
In vitro studies indicate DXd does not inhibit major CYP450 enzymes including CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A. In vitro studies indicate that DXd does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP transporters.
In vitro, DXd was a substrate of P-gp, OATP1B1, OATP1B3, MATE2-K, MRP1, and BCRP. No clinically meaningful interaction is expected with medicinal products that are inhibitors of MATE2-K, MRP1, P-gp, OATP1B1, or BCRP transporters (see section 4.5).
The exposure of trastuzumab deruxtecan and released DXd when administered intravenously increased in proportion to dose in the 3.2 mg/kg to 8.0 mg/kg dose range (approximately 0.6 to 1.5 times the recommended dose) with low to moderate inter-subject variability. Based on population pharmacokinetic analysis, inter-subject variability in trastuzumab deruxtecan and DXd elimination clearances was approximately 25% and for central volume of distribution was approximately 16% and 42%, respectively. The intra-subject variability in trastuzumab deruxtecan and DXd AUC values (area under the serum concentration versus time curve) was approximately 8% and 14%, respectively.
Based on population pharmacokinetic analysis, age (23-96 years), race, ethnicity, sex and body weight did not have a clinically meaningful effect on exposure of trastuzumab deruxtecan or released DXd.
No dedicated renal impairment study was conducted. Based on population pharmacokinetic analysis including patients with mild (creatinine clearance [CLcr] ≥60 and <90 mL/min) or moderate (CLcr ≥30 and <60 mL/min) renal impairment (estimated by Cockcroft-Gault), the pharmacokinetics of the released DXd was not affected by mild or moderate renal impairment as compared to normal renal function (CLcr ≥90 mL/min).
No dedicated hepatic impairment study was conducted. Based on population pharmacokinetic analysis, the impact of changes on pharmacokinetics of trastuzumab deruxtecan in patients with total bilirubin ≤1.5 times ULN, irrespective of AST level, is not clinically meaningful. There are insufficient data for patients with total bilirubin >1.5 to 3 times ULN, irrespective of AST level, to draw conclusions, and no data is available for patients with total bilirubin >3 times ULN, irrespective of AST level (see sections 4.2 and 4.4).
No studies have been conducted to investigate the pharmacokinetics of trastuzumab deruxtecan in children or adolescents.
In animals, toxicities were observed in lymphatic and haematopoietic organs, intestines, kidneys, lungs, testes and skin following the administration of trastuzumab deruxtecan at exposure levels of the topoisomerase I inhibitor (DXd) below clinical plasma exposure. In these animals, antibody-drug conjugate (ADC) exposure levels were similar or above clinical plasma exposure.
DXd was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay.
Carcinogenicity studies have not been conducted with trastuzumab deruxtecan.
Dedicated fertility studies have not been conducted with trastuzumab deruxtecan. Based on results from general animal toxicity studies, trastuzumab deruxtecan may impair male reproductive function and fertility.
There were no animal reproductive or developmental toxicity studies conducted with trastuzumab deruxtecan. Based on results from general animal toxicity studies, trastuzumab deruxtecan and DXd were toxic to rapidly dividing cells (lymphatic/haematopoietic organs, intestine, or testes), and DXd was genotoxic, suggesting the potential for embryotoxicity and teratogenicity.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
