Fam-trastuzumab deruxtecan-nxki (Enhertu^®): A narrative drug review

Abstract

Human epidermal growth factor receptor 2 (HER2) is a subset of the epidermal growth factor receptor family that expresses tyrosine kinase activity. Dimerization of the receptor initiates various cellular signaling pathways, ultimately leading to the proliferation and division of cancer cells. The HER2 receptors are expressed in a multitude of cancers, such as metastatic breast cancer, gastric cancer, gastroesophageal adenocarcinoma, and non-small-cell lung cancer. Owing to its expression in several cancers, precision medicine products such as antibodies can be conjugated with conventional drugs to form antibody-drug conjugates (ADCs). These ADCs, like fam-trastuzumab deruxtecan-nxki, could be employed against these cancers, especially when previous lines of therapy have failed. This drug review aims to explore the pharmacodynamics, pharmacokinetics, clinical indications, contraindications, dosing regimen, dose modifications, adverse drug events, and the storage and administration of fam-trastuzumab deruxtecan-nxki. We screened all previous trials and tabulated the results to provide a bird’s eye view of the clinical outcomes. This review was prepared after an exhaustive literature search in PubMed, ScienceDirect, Google Scholar, Dimensions, and EBSCO Host, as well as by searching the websites of the United States Food and Drug Administration (US FDA), drug manuals, and conference presentations, using terms such as “fam-trastuzumab deruxtecan-nxki”, “Enhertu” and “HER2”. Of a total of 755 publications, 29 were found pertinent, and after rigorous scrutiny, 13 were included for curating this drug review. Supporting data were obtained from various abstracts and conference proceedings.

INTRODUCTION

Breast cancer is one of the most common forms of cancer in women. The Global Cancer Observatory (GLOBOCAN) 2020 report suggested that there are approximately 2,261,419 cases of breast cancer in women, across all ages. Additionally, with an over 6.9% mortality rate, it ranks as one of the leading causes of death in women. A key receptor involved in cancer growth and development is the human epidermal growth factor receptor 2 (HER2), which is responsible for the proliferation and division of breast cells.^[1] HER2-positive breast cancer is characterized by overexpression of the HER2 receptor, which precipitates an uncontrolled proliferation of breast cells and subsequent metastasis, ultimately leading to breast cancer.^[2]

The frequency of HER2 overexpression in gastric and gastroesophageal cancer ranges from 4.4% to 53.4%, with a mean of 17.9%.^[3] The results derived from multiple clinical studies clearly identify HER2 as a negative prognostic factor, suggesting a strong correlation between its overexpression and amplification with the development and progression of gastric cancer.^[3] The current armamentarium of drugs specifically targeting the HER2 receptor includes trastuzumab and pertuzumab. Fam-trastuzumab deruxtecan-nxki is a novel anti-HER2 drug containing a HER2 monoclonal antibody bound to a deoxyribonucleic acid (DNA) topoisomerase inhibitor via a tetrapeptide-based cleavable linker.^[2] The key features of fam-trastuzumab deruxtecan-nxki are summarized in Table 1.

Table 1: Key features of fam-trastuzumab deruxtecan-nxki (Enhertu®)

METHODS

Data searches were conducted in ScienceDirect, PubMed, Google Scholar, Dimensions, and EBSCO Host.”Fam-trastuzumab deruxtecan-nxki”, “Enhertu”, “HER2”, and “cancer.” Additionally, to counter the paucity of available data, government websites, such as the United States Food and Drug Administration (US FDA), UpToDate, and approved drug manuals, like Micromedex and CareNotes, were searched. Furthermore, to curate the data presented in the clinical trials and add to the veracity of the data presented, we included abstracts and proceedings from various international conferences. We shortlisted articles that were published in English since the inception of fam-trastuzumab deruxtecan-nxki. Out of the 755 documents that mentioned fam-trastuzumab deruxtecan-nxki, only 29 were shortlisted as they included a mention of fam-trastuzumab deruxtecan-nxki in their abstracts and/or titles. Subsequently, 13 articles were included in this drug review. The other articles were excluded as they were reviews of research data, or reiterated data presented in the official labels or drug manuals. We tabulated the data from the recent ongoing clinical trials by searching ClinicalTrials.gov, by using keywords such as “Enhertu”, “trastuzumab”, “deruxtecan”, and “cancers”, until September 01, 2022. Only the trials that were completed or nearing completion with published data were included. Furthermore, upcoming, registered, and recruiting trials were also added to the drug review watchlist, for future reference. A flow chart of the methodological search strategy is presented in Figure 1.

Figure 1: Flow diagram illustrating the methodology followed to include articles for the fam-trastuzumab deruxtecan-nxki (Enhertu^®) drug review

HISTORY

In 2019, the FDA approved fam-trastuzumab deruxtecan-nxki for human use, and it was awarded an orphan drug status. Later, in 2021, it was approved in the United States of America (USA) for patients previously treated for HER2-positive advanced breast cancer. Subsequently, in 2022, the drug was further approved for use in patients with HER2-positive metastatic breast cancer, who had been previously treated with an anti-HER2-based regimen. Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody-drug conjugate (ADC) designed by AstraZeneca’s ADC scientific platform by employing Daiichi Sankyo’s deruxtecan (DXd) ADC technology in Japan.^[4] Following the results of the DESTINY-Breast04 trial, fam-trastuzumab deruxtecan-nxki was granted breakthrough therapy designation in the USA for the treatment of metastatic HER2-positive breast cancer in adults who had previously received therapy. Currently, a global development program is underway to evaluate and validate the efficacy and safety of fam-trastuzumab deruxtecan-nxki for HER2-expressing cancers such as gastric, breast, lung, and colorectal cancers.^[5]

MECHANISM OF ACTION

Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody-drug conjugate, comprising a humanized anti-HER2 immunoglobin G1 antibody and a small molecule topoisomerase 1 inhibitor, DXd, attached via a cleavable linker. Subsequent to its binding to the HER2 receptor on tumor cells, fam-trastuzumab deruxtecan-nxki undergoes internalization, where the intracellular linker gets cleaved by lysosomal enzymes. Ultimately, the membrane-permeable DXd binds to the cancer cells and facilitates the damage of DNA, thereby leading to apoptotic cell death. The trastuzumab portion of fam-trastuzumab deruxtecan-nxki attaches to the HER2 receptor on the cancer cells, thereby preventing the multiplication and proliferation of the cancer cells.^[6,7]

CLINICAL INDICATIONS

1. FDA approved indications
1. Treatment of adult patients with metastatic HER2-positive breast cancer who have previously received an anti-HER2-based regimen. It is also indicated in patients whose disease has recurred within 6 months of treatment completion.^[8]
2. Locally advanced or metastatic HER2-positive gastric cancer.^[8]
3. Patients with HER2-positive gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.^[9]
2. Non-FDA-approved off-label uses
Non-small-cell lung cancer (NSCLC) with a HER2 mutation that has been treated previously. Though fam-trastuzumab deruxtecan-nxki showed durable responses in patients affected with this disease, two cases of fatal interstitial lung disease (ILD) were reported in a multicenter trial.^[10]

CONTRAINDICATIONS

There are no specific contraindications.^[7]

DOSAGE AND ADMINISTRATION

For Injection (intravenous): Commercially available as a 100 mg lyophilized powder in a single-dose vial.^[7] Currently, multi-dose vials are not available. It should be administered as an intravenous infusion, where the dose is determined by calculation based on the patient’s body weight. The drug dose needs to be reconstituted in an infusion bag containing 100 mL 5% dextrose injection, United States Pharmacopoeia (USP). Fam-trastuzumab deruxtecan-nxki is compatible with an infusion bag synthesized from polyolefin or polyvinyl chloride. Any unused portion left in the vial has to be discarded.^[11]

• 1.Metastatic HER2-positive breast cancer in patients who have been previously treated with an anti-HER2 regimen but have relapsed within 6 months of completing the therapy
• Premedication: Administration of prophylactic antiemetic medications as per the local institutional directives, as the medication is moderately emetogenic and may cause delayed nausea and/or vomiting.^[8]
• Usual Dosage: 5.4 mg/kg intravenous infusion, once every 21 days. The first infusion should be administered over 90 minutes, while subsequent infusions can be over 30 minutes if previous infusions were well tolerated.^[8]
• Duration of Therapy: Continue until disease progression or the occurrence of unacceptable toxicity.^[8]
• 2.Locally advanced HER2-positive gastric cancer, previously treated with trastuzumab
• Premedication: Administration of prophylactic antiemetic medications as per the local institutional directives, as the medication is moderately emetogenic and may cause delayed nausea and/or vomiting.^[8]
• Usual Dosage: 6.4 mg/kg intravenous infusion, once every 3 weeks. The first infusion should be administered over 90 minutes, while subsequent infusions can be over 30 minutes if previous infusions were well tolerated.^[8]
• Duration of Therapy: Continue until disease progression or the occurrence of unacceptable toxicity.^[8]
• 3.Metastatic gastroesophageal adenocarcinoma, previously treated with a trastuzumab-based regimen
• Usual Dosage: 6.4 mg/kg intravenous infusion, once every 3 weeks. The first infusion should be administered over 90 minutes, while subsequent infusions can be over 30 minutes if previous infusions were well tolerated.^[10]
• Duration of Therapy: Continue until disease progression or the occurrence of unacceptable toxicity.^[10]
• 4.Advanced stage previously treated HER2-positive non-small-cell lung cancer
• Usual off-label dosage: 6.4 mg/kg intravenous infusion, once every 3 weeks.^[9]
• Duration of Therapy: Continue until disease progression or the development of unacceptable toxicity.^[9]

Dose Modifications

• a.Mild or moderate renal impairment, with creatinine clearance (CrCl) between 30 and 90 mL/min: No adjustment needed.^[7]
• b.Severe renal impairment: No specific recommendations available.^[7]
• c.Mild or moderate hepatic impairment: No dose adjustment is needed. However, due to potentially increased exposure, patients with moderate hepatic impairment need to be closely monitored for increased toxicities related to deruxtecan (DXd).^[7]
• d.Severe hepatic impairment: No specific recommendations available.^[7]
• e.Geriatric: No specific recommendations available. No overall differences in safety or efficacy were observed in patients aged 65 years or more compared to younger patients diagnosed with gastric cancer or gastroesophageal junction adenocarcinoma. However, there was a higher incidence of grade 3 or 4 adverse reactions observed in patients with breast cancer aged 65 years or more.^[10]Table 2 summarizes the recommended dose reductions for intolerance, or hypersensitivity.

Table 2: Recommended dose reduction regimen of fam-trastuzumab deruxtecan-nxki

Administration

• 1.Fam-trastuzumab deruxtecan-nxki is not to be substituted for or administered with trastuzumab or ado-trastuzumab emtansine.^[7]
• 2.Fam-trastuzumab deruxtecan-nxki should only be administered as an intravenous infusion.^[7]
• 3.Fam-trastuzumab deruxtecan-nxki should not be administered as an intravenous push or bolus. It should not be administered with sodium chloride injection, USP.^[7]
• 4.The patient should be pre-medicated with prophylactic antiemetics as per the local institutional directives for preventing chemotherapy-induced nausea and vomiting.^[7]

PHARMACOKINETICS

1. For fam-trastuzumab deruxtecan-nxki, single dose, intravenous route (131 µg/mL)[⁸]
1. Drug concentration levels
The peak plasma concentration (C_max) increases proportionately over a dose range of 3.2 to 8 mg/kg and is reported to be approximately 131 µg/mL (coefficient of variation was reported to be 20%) for patients with breast cancer. There are no significant variations in the pharmacokinetics of fam-trastuzumab deruxtecan-nxki based on age (20 to 96 years), race or body weight.^[8]

2. Area Under the Curve (AUC)
The AUC increases proportionately over the dose range of 3.2 to 8 mg/kg (approximately 0.6 to 1.5 times the usual dosage) and was found to be 769 µg•day/mL (coefficient of variation reported to be 28%) in patients with HER2-positive breast cancer.^[8,10]

3. Steady-state
Plasma accumulation of fam-trastuzumab deruxtecan-nxki is 39% (cycle 3) at the steady state in patients with HER2-positive breast cancer.^[10]

4. The Absorption, Distribution, Metabolism, and Elimination (ADME) Profile
1. Distribution
Plasma protein binding of DXd is approximately 97%^[7]
Blood-to-plasma ratio is 0.6^[7]
The volume of distribution (V_d) of the central compartment of fam-trastuzumab deruxtecan-nxki is nearly 2.71L^[7]

2. Metabolism
The humanized HER2 IgG1 monoclonal antibody is mainly metabolized by CYP3A4 and is degraded into peptides and amino acids via catabolic pathways similar to those of endogenous IgG. DXd is primarily metabolized by CYP3A4. However, DXd is also a substrate of the organic anion-transporting polypeptides (OATP) OATP1B1, and OATP1B3, multidrug and toxin extrusion (MATE2-K), p-glycoprotein (P-GP), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP).^[7]

3. Excretion
In patients with metastatic HER2-positive breast and gastric cancers, the estimated clearance of fam-trastuzumab deruxtecan-nxki is 0.42 L/day.^[8]

4. Elimination half-life (t_1/2)
The median t_1/2 in patients with metastatic HER2-positive breast and gastric cancers is 5.7 to 5.8 days.^[10]

2. For fam-trastuzumab deruxtecan-nxki, multiple doses, intravenous route (126µg/mL),^[10]
1. Drug concentration levels
The C_max is approximately 126 µg/mL (the coefficient of variation was found to be 18%). There are no significant differences in the pharmacokinetics of fam-trastuzumab deruxtecan-nxki based on age (20 to 96 years), race, body weight, or mild and moderate renal impairment.^[10]

2. AUC
In patients diagnosed with HER2-positive gastric cancer, the geometric mean of AUC was reported to be 743 µg•day/mL (coefficient of variation was reported to be 26%), following the usual recommended dose.^[10]

3. Steady-state
Plasma accumulation was approximately 35% at steady state (cycle 3) in patients with HER2-positive gastric cancer.^[10]

4. ADME Profile
Same as discussed earlier in the ADME profile of fam-trastuzumab deruxtecan-nxki, single dose, intravenous route.

WARNINGS AND PRECAUTIONS

1. Interstitial Lung Disease (ILD)/Pneumonitis
ILD or pulmonary fibrosis is a group of conditions that are characterized by lung inflammation. Symptoms include cough, dyspnea, fever, and other common respiratory complaints. In patients with symptomatic ILD, fam-trastuzumab deruxtecan-nxki must be permanently discontinued.^[7]

2. Neutropenia
Severe neutropenia, including febrile neutropenia, has been reported following fam-trastuzumab deruxtecan-nxki therapy. Thus, it is advised to monitor complete blood counts (CBC) before administering fam-trastuzumab deruxtecan-nxki and prior to the commencement of a subsequent dose of therapy.^[12]
For Grade 3 neutropenia, with an absolute neutrophil count (ANC) between 0.5 to 1.0 x 10⁹/L, therapy should be stopped until the condition resolves to Grade 2 or less, following which the dose needs to be maintained.^[12]
For Grade 4 neutropenia, with an ANC less than 0.5 x 10⁹/L, the therapy needs to be stopped until the condition resolves to Grade 2 or less, following which the dose needs to be reduced by one level.^[12]
In cases of febrile neutropenia, with an ANC between 0.5 to 1.0 x 10⁹/L and temperature >38.3°C or ≥38°C for more than an hour, the therapy needs to be stopped until symptoms recede, following which the dose needs to be reduced by one level.^[12]

3. Left Ventricular Ejection Fraction (LVEF) decrease
Patients receiving fam-trastuzumab deruxtecan-nxki therapy are at a higher risk of developing left ventricular dysfunction. Additionally, LVEF decrease has been reported following fam-trastuzumab deruxtecan-nxki therapy. Thus, it is advised to assess the LVEF before initiating fam-trastuzumab deruxtecan-nxki therapy, and at regular intervals during the course of treatment.^[12]
If the LVEF is >45% and the absolute decrease from baseline is 10% to 20%, cessation of fam-trastuzumab deruxtecan-nxki therapy is not required.^[12]
However, if LVEF is between 40% to 45% and the absolute decrease from baseline is less than 10%, continue with fam-trastuzumab deruxtecan-nxki therapy, but LVEF must be monitored every 3 weeks.^[12]
Alternatively, if LVEF is between 40% to 45% and the absolute decrease from baseline is between 10% to 20%, interrupt fam-trastuzumab deruxtecan-nxki therapy, and assess LVEF within 3 weeks. If LVEF has not recovered to within 10% from baseline, it is advisable to permanently discontinue fam-trastuzumab deruxtecan-nxki therapy. However, if LVEF recovers to within 10% of baseline, resume fam-trastuzumab deruxtecan-nxki therapy without dose reduction.^[12]
In cases where LVEF is <40% or the absolute decrease from baseline is >20%, interrupt the fam-trastuzumab deruxtecan-nxki therapy, and reassess LVEF within 3 weeks. If the LVEF as <40% or the absolute decrease from baseline is >20%, permanently discontinue fam-trastuzumab deruxtecan-nxki therapy. Additionally, permanently discontinue fam-trastuzumab deruxtecan-nxki therapy following symptomatic congestive heart failure.^[12]

4. Embryo-fetal toxicity
The post-marketing surveillance^[7] reported cases of oligohydramnios that manifested as fatal pulmonary hypoplasia, and ultimately neonatal death. This effect of fam-trastuzumab deruxtecan-nxki has been attributed to the topoisomerase 1 inhibitor, DXd that can cause fetal harm in pregnant women, owing to its genotoxic effect, which targets the actively dividing cells.^[7]

ADVERSE DRUG EFFECTS

The most common side effects of fam-trastuzumab deruxtecan-nxki, when administered for the management of breast and gastric cancer include:

1. Serious adverse drug effects
Cardiovascular: Left ventricular systolic dysfunction (in 2.6% patients)
Gastrointestinal: Perforation of the intestine (0.8%)
Hematologic:

• Decreased neutrophil count, grades 3 or 4 (breast cancer [18%], and gastric or gastroesophageal junction adenocarcinoma [51%])
• Disseminated intravascular coagulation (0.8%)
• Febrile neutropenia (1.1% when administered as 5.4 mg/kg to 4.8% at 6.4 mg/kg)
Respiratory: Interstitial lung disease (10% to 13%)

2. Common Adverse Drug Effects
Dermatologic: Alopecia (gastric or gastroesophageal junction adenocarcinoma [22%] and breast cancer [37% to 46%])
Endocrine/metabolic: Hypokalemia (12%)
Gastrointestinal:

• Abdominal pain (14% to 19%)
• Constipation (24% to 35%)
• Decrease in appetite (breast cancer [29% to 32%], and gastric or gastroesophageal junction adenocarcinoma [60%])
• Diarrhea (29% to 32%)
• Nausea (63% to 79%)
• Stomatitis (11% to 20%)
• Vomiting (26% to 49%).
Hematologic:

• Anemia, all grades (breast cancer [31% to 33%], and gastric or gastroesophageal junction adenocarcinoma [58%])
• Decreased neutrophil count, in all grades (68% to 72%)
• Leukopenia, all grades (22%)
• Thrombocytopenia, all grades (20%).

Musculoskeletal: Musculoskeletal pain (31%)

Neurological: Headache (19% to 22%)

Respiratory: Cough (11% to 20%), respiratory tract infection (22%)

Miscellaneous: Fatigue (49% to 59%)

DRUG INTERACTIONS

There no conclusive data on the interaction of fam-trastuzumab deruxtecan-nxki with other drugs, food, tobacco or ethanol.

IMPORTANT CLINICAL STUDIES

The relevant clinical trials with published data have been provided in Table 3.

Table 3: Comparison of significant clinical trials with published data

In addition, several clinical trials are underway and/or registered, to evaluate the efficacy of fam-trastuzumab deruxtecan-nxki in various other cancers and to compare its efficacy to that of other treatment regimens. Some of these trials are BEGONIA, DEBBRAH, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Breast05, DESTINY-Breast06, DESTINY-Breast07, DESTINY-Breast08, DESTINY-Gastric02, DESTINY-Gastric03, DESTINY-Lung02, DESTINY-Lung03, DESTINY-PanTumor01, DESTINY-PanTumor02, HERB, HER2CLIMB-04, and HUDSON. The results from these trials will guide the development of optimal treatment regimens in various patient cohorts.

INDIAN DATA

Currently, fam-trastuzumab deruxtecan-nxki is not available for purchase in India and needs to be imported. We were unable to find any trials registered in the Clinical Trials Registry of India (CTRI) for fam-trastuzumab deruxtecan-nxki in India.

STORAGE

The powder of solution must be stored in the original carton and refrigerated at 2-8°C (36-46°F). However, it should not be frozen and must be duly protected from light. The reconstituted solution can be used up to a maximum of 24 hours post the time of reconstitution.^[7]

CONCLUSION

Globally, with the increasing prevalence of cancers, the need for novel therapeutic regimens has never been higher. The current clinical armamentarium has certain lacunae. With recent innovations and the advent of precision medicine, the landscape of cancer therapy has evolved. The HER2 receptor is one of the key targets in the development of precision therapeutics. HER2 overexpression has been reported in a number of cancers including gastric and gastro-esophageal junction cancer, breast cancer, and NSCLC. Thus, fam-trastuzumab deruxtecan-nxki could potentially act as a novel drug for a large number of cancers harboring the HER2 mutation. The efficacy of fam-trastuzumab deruxtecan-nxki has been established in numerous clinical trials. Moreover, its projected efficacy in the management of HER2-positive cancers in patients with comorbidities is promising. Future areas of research include the extrapolation of the clinical armamentarium to various other antibody-drug conjugates, against different cancers.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.