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THERAPEUTIC APPROACHES WITH ANTIBODY-DRUG CONJUGATES FOR THE TREATMENT OF ONCOLOGY DISEASE STATES

Structure of Antibody-Drug Conjugates

The idea of targeting a drug to a specific site of action has been a vision since at least the early 1900s with Dr. Paul Ehrlich’s “magic bullet” concept.¹ That vision particularly resonates in the field of oncology where toxicity to nonmalignant cells has plagued cancer chemotherapy for decades due to the nature of the mechanisms of action of cancer drugs and the inability to selectively target malignant cells. To a large extent, antibody-drug conjugates (ADCs) are modern approximations of such “magic bullets.”² An ADC consists of 3 distinct components: 1) monoclonal antibody (mAb); 2) linker; and 3) payload (FIGURE 1).³ The mAb acts as the targeting moiety to guide the ADC to the cells that selectively express particular cell-surface proteins. Linkers connect the payload (ie, the chemotherapeutic agent) to the mAb via a variety of chemistries. With the ability to selectively target cancer cells, ADCs are most commonly used in oncology. Excluding the ADC with an immunotoxin payload (moxetumomab pasudotox), there are 11 FDA-approved ADC oncology products with chemotherapeutic payloads.⁴

Monoclonal Antibody

The ability of a mAb to selectively bind to a protein provides an ADC with its cell-specific targeting capability. The mAbs for ADCs are designed to target cell-surface proteins that cancer cells differentially express compared to nonmalignant cells. The cluster of differentiation (CD) family of cell surface antigens provides a variety of targets for ADCs, including CD19, CD22, CD30, CD33, and CD79b. Other cell surface proteins used as ADC targets include nectin-4, tissue factor, B-cell maturation antigen (BCMA), human epidermal growth factor receptor 2 (HER2), and tumor-associated calcium signal transducer 2 (TROP2).^4,5 The ADCs and their corresponding targets are listed in TABLE 1. The mAbs of the immunoglobulin G (IgG) class are typically used in ADCs with IgG1 and IgG4 being the most commonly used IgG subtypes. Of the available ADCs, gemtuzumab ozogamicin and inotuzumab ozogamicin use IgG4, while the remaining ADCs use IgG1 for their mAb components. As biological products, the mAbs of ADCs are produced in cell culture. The mAbs may be fully human, humanized, or chimeric, which can affect immunogenicity and hypersensitivity reactions.⁴

Linker

The linker is the chemical moiety that attaches the payload to the mAb of the ADC. The choices of the mAb and the linker are the critical components for limiting toxicity and adverse events by reducing off-target release of the payload. Linkers are classified into 2 broad types: cleavable or non-cleavable. Cleavable linkers are designed to degrade either by pH-dependent, glutathione-mediated, or enzymatic mechanisms.^3,6 Regardless of the type of linker employed, the payload is typically released in the target cancer cells after endocytosis and degradation in the cytosol or lysosome.^6,7

A common pH-dependent linker is the hydrazone group, which is stable at pH 7.5 and hydrolyzes in the acidic environments of the endosome and lysosome.^3,6,7 For glutathione-dependent cleavage, disulfide linkers are used to capitalize on higher concentrations of glutathione in tumor cells.^3,6,7 Intracellular proteases, such as cathepsin B, in the lysosome cleave enzymatically labile linkers, the most common of which are the dipeptides valine-citrulline or valine-alanine.^3,6,7

Non-cleavable linkers remain relatively stable in the physiological milieu until degradation in the lysosome. For ADCs with non-cleavable linkers, the payload is designed to be released after proteolytic degradation of the mAb.⁷ Belantamab mafodotin and ado-trastuzumab emtansine use the non-cleavable linkers, maleimidocaproyl and 4-(N-maleimidomethyl)cyclohexane-1-carboxylate, respectively.^8,9 Since the non-cleavable linker remains attached to the payload, studies indicate that the payload-linker moieties in belantamab mafodotin and ado-trastuzumab emtansine retain the intended chemotherapeutic activity.⁶

Payload

The payload is the active pharmacological agent of an ADC. In early studies of ADCs, payloads were common anticancer chemotherapy drugs such as methotrexate, doxorubicin, or vinca alkaloids.^10-13 Even with mAb targeting, only a small percentage (~0.1%) of the ADC dose reaches the intended target tissue and more potent payloads (eg, IC50 in the picomolar to nanomolar range) were required for efficacy.^3,4 The trade off with the increased potency is that off-target release of the payload can lead to increased toxicity. Current payloads of marketed ADCs are ozogamicin, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), maytansine, deruxtecan, govitecan, and tesirine (TABLE 1).

Mechanism(s) of Action

The mechanism of action of an ADC not only encompasses the specific payload mechanism of action but also the overall process by which the ADC interacts with target cells.¹⁴ Tong et al summarize that overall process in 8 steps (FIGURE 2)⁴:

1. Circulation of ADC in plasma
2. Binding of ADC to target cell-surface antigen
3. Receptor-mediated endocytosis
4. Transcytosis to extracellular space OR
   Endosomal release of payload via cleavable linker
5. Endosome-lysosome fusion
6. Lysosomal degradation leading to release of payload from cleavable or non-cleavable linker
7. Payload exerting its intracellular mechanism of action
8. Payload export/efflux out of target cell to act on neighboring tumor cells (bystander effect).⁴

Treatment Indications

For the purposes of this activity, treatment indications will be discussed from a broad perspective. The cell-surface protein target is the major factor determining the indication for an ADC, which can be classified into 2 categories: 1) solid tumors and 2) hematology. Solid tumor indications include urothelial cancer, cervical cancer, breast cancer, and gastric cancer. Many of the solid tumor indications focus on locally advanced or metastatic cancers. Hematology indications include acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), classical Hodgkin lymphoma, anaplastic large cell lymphoma (ALCL), peripheral T-cell lymphomas (PTCLs), mycosis fungoides, and diffuse large B-cell lymphoma (DLBCL). Specific indications, places in therapy, and related dosing regimens can be found in the prescribing information for the ADCs and in guidelines such as those from the National Comprehensive Cancer Network (NCCN).^8,9,16-25

Dosing

The ADCs all require intravenous (IV) infusion for administration with recommended infusion times ranging from 30 to 120 minutes. ADCs are dosed on a per kilogram body weight or per square meter basis and are dependent on multiple factors including the payload, the indication, and the chemotherapy regimen cycle, among others.^8,9,16,18-25 Dose modifications based on adverse reactions are also common. As with the mechanisms of action and treatment indications, clinicians should consult the package inserts for specifics on dosing and administration.

Mono- and/or Combination Therapy

While many oncology protocols call for the use of multiple agents, only 3 of the currently available ADCs have combination therapy indications. With no monotherapy indication, polatuzumab vedotin has a combination indication for relapsed or refractory DLBCL when administered with bandmaster and a rituximab product.²¹ Brentuximab vedotin can be used in combination with doxorubicin, vinblastine, and dacarbazine for stage III or IV classical Hodgkin lymphoma (previously untreated). Brentuximab vedotin can also be used in combination with cyclophosphamide, doxorubicin, and prednisone for previously untreated PTCLs that express CD30 or previously untreated systemic ALCL. Brentuximab vedotin also has monotherapy indications for classical Hodgkin lymphoma, systemic ALCL, primary cutaneous ALCL, and CD30-expressing mycosis fungoides.²⁰ The combination therapy indication for gemtuzumab ozogamicin (combined with daunorubicin and cytarabine) is in newly diagnosed patients with de novo AML (CD33 positive).¹⁸ The remaining ADCs (inotuzumab ozogamicin, enfortumab vedotin, tisotumab vedotin, belantamab mafodotin, ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, sacituzumab govitecan, and loncastuximab tesirine) have monotherapy indications. TABLE 2 summarizes the indications of the ADCs.^8,9,16,18-25

Compounding/Preparation

As complex drug products, the ADCs require careful and specific preparation procedures. Since recommended procedures can change and in lieu of listing those procedures for 11 products, clinicians should consult the package inserts.^8,9,16,18-25 There are several shared compounding/preparation highlights between the ADCs. All of the ADCs are supplied as lyophilized powders that require reconstitution. With the cytotoxic nature of the payloads, special handling and disposal procedures are required for all ADCs.²⁶ Being biological products, ADCs are sensitive to handling and temperature and 3 warnings are included in all of the ADC package inserts: 1) do not shake the product vial to reconstitute the solution, 2) do not freeze the prepared product, and 3) avoid mixing with other drugs in the IV bag and/or in the IV infusion line. After reconstitution, dilution instructions often specify a concentration range for the final IV bag, and many ADCs require an in-line or add-on filter for IV administration. Avoiding exposure to direct sunlight is a common recommendation. As with many reconstituted IV products, ADCs may require a specific diluent and IV solution, which are indicated in the package inserts.

MANAGEMENT OF ADVERSE EVENTS ASSOCIATED WITH ADC AGENTS

Review of Adverse Events

Adverse events associated with ADCs are typically due to the biological nature of the mAb component and the payload. Infusion of mAbs can cause 2 common adverse events—hypersensitivity/allergic reactions and infusion reactions, which are distinct phenomena that can have overlapping symptoms (eg, dyspnea, urticaria).²⁷ Infusion reactions typically occur 30 to 120 minutes after the initiation of ADC infusion and can range from mild/moderate symptoms (eg, headache, chills, dyspnea, fever, rash) to severe (eg, anaphylactic or cardiac reactions).^28,29

Non-infusion-related adverse events vary based on the payload. Some of these adverse events can be severe, even deadly, and the majority of ADCs carry black box warnings (BBWs), the exceptions being polatuzumab vedotin and loncastuximab tesirine.^16,21 For sacituzumab govitecan, the BBW cautions for neutropenia and diarrhea.²⁵ Belantamab mafodotin and tisotumab vedotin carry BBWs for ophthalmic toxicities—corneal epithelium damage that can result in change in vision, severe vision loss, and/or corneal ulcer.^8,23 For belantamab mafodotin, the risk is sufficiently severe that the FDA requires a Risk Evaluation and Mitigation Strategy (REMS) program.^8,30 The black box for enfortumab vedotin focuses on severe and potentially fatal dermatological toxicities—toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS).²² Brentuximab vedotin carries a BBW for progressive multifocal leukoencephalopathy and death caused by John Cunningham virus (JCV) infection.²⁰

The black boxes for gemtuzumab ozogamicin and inotuzumab ozogamicin warn for hepatoxicity that can lead to veno-occlusive disease or sinusoidal obstruction syndrome, while the inotuzumab ozogamicin BBW also includes an increased risk of nonrelapse mortality in patients who are post-hematopoietic stem cell transplant.^18,19 Hepatoxicity, cardiac toxicity, and embryo-fetal toxicity are highlighted in the BBW for ado-trastuzumab emtansine.⁹ In addition, the black box for fam-trastuzumab deruxtecan warns for interstitial lung disease and embryo-fetal toxicity.²⁴ Clinicians should consult the full prescribing information for details on BBWs and potential adverse events. ^{8,9,16,18-25,30}

Recognition and Monitoring

For those ADCs with the potential for serious toxicities, clinicians should be prepared to recognize, monitor, and prevent the adverse reactions.³¹ With belantamab mafodotin, which has a REMS program, patients will need to have eye exams before they begin therapy and before each dose of the drug. In addition, patients should use preservative-free lubricating eye drops 4 or more times per day during treatment and should avoid wearing contact lenses.³⁰ Treatment for ophthalmic toxicities may include dose adjustments or discontinuation of the drug.⁸ Precautions with tisotumab vedotin are similar in that a baseline eye exam is required prior to therapy with follow-up exams before each dose. Treatment with tisotumab vedotin, however, also requires use of corticosteroid eye drops before and 72 hours after an infusion, the use of vasoconstrictor drops prior to infusion, and application of lubricating eye drops throughout therapy and for 30 days after the last dose of ADC.²³

The potential to develop veno-occlusive disease with gemtuzumab ozogamicin or inotuzumab ozogamicin can be difficult to manage as effective remedies are limited. Patients should be screened with hepatic function tests prior to each dose of gemtuzumab ozogamicin or inotuzumab ozogamicin. If elevations in hepatic function tests or other symptoms (eg, hepatomegaly, ascites, rapid weight gain) are observed, the ADC therapy may need to be withheld, dose reduced, or therapy discontinued.^18,19 Management of pulmonary toxicity with trastuzumab deruxtecan is based on severity and generally consists of pausing therapy until symptoms resolve with the administration of corticosteroids, if needed, or discontinuation of therapy if symptoms are sufficiently severe.²⁴ There is an increased risk of fluid retention with loncastuximab tesirine therapy and premedication with dexamethasone is recommended.^16,32 The severe diarrhea that may occur with sacituzumab govitecan can be managed with fluids and electrolytes. For early onset diarrhea (onset during infusion or within several hours of infusion), an anticholinergic such as atropine may be administered. For late onset diarrhea not caused by an infectious agent, high-dose loperamide is recommended.²⁵

Management Strategies: Infusion Reactions

Step-by-Step Process to Practice Incorporation of Available Guidelines Into Decision-Making for Preventing and Managing Toxicities

Many of the ADCs require premedication in their prescribing information with the goal to prevent infusion-related reactions. Even if premedication is not required per the package insert, institutions may set premedication protocols for ADCs. The most common drugs used in premedication regimens are acetaminophen, an antihistamine, and a corticosteroid. Dexamethasone (4 mg PO or IV daily for 3 days prior to therapy) is recommended for loncastuximab tesirine to help prevent edema.^16,32 Premedication for preventing infusion-related reactions is specified in the prescribing information for polatuzumab vedotin (nonspecific antihistamine and antipyretic at least 30 minutes before infusion); brentuximab vedotin (suggest acetaminophen, antihistamine, and corticosteroid if the patient had a prior infusion-related reaction); gemtuzumab ozogamicin (acetaminophen, diphenhydramine, and methylprednisolone); inotuzumab ozogamicin (nonspecific corticosteroid, antihistamine, and antipyretic prior to infusion); belantamab mafodotin (nonspecific premedication if patient had a prior infusion-related reaction); and sacituzumab govitecan (nonspecific antipyretics and histamine [H1 and H2] blockers prior to infusion; corticosteroid also if prior infusion-related reaction).^8,18-21,25

CONSIDERATIONS FOR ONCOLOGY PHARMACISTS

Patient-Centered Therapy Selection

Patient-centered oncology care (PCOC) models are based on the patient-centered medical home (PCMH), a framework of coordinating health care with a solid patient-physician relationship at its core.³³ Key oncology-specific components of a PCOC model include a triage process to address symptom management, employing evidence- and standard-based protocols for symptom management, providing patient navigators, incorporating patient preferences in treatment decisions, and coordinating care between the myriad clinicians on the health care team.^33,34 Implementing a PCOC model may improve coordination of care, patient satisfaction, and health outcomes.^33,34

Patient Education

Education may be considered a foundational building block for PCOC.^33,34 The oncology pharmacist is well positioned to provide that education, which would not be limited to oncology treatments. Pharmacist-led patient education can cover a wide range of topics including overall drug management (eg, oncology treatments, prescription drugs, over-the-counter [OTC] drugs, herbal medications), drug interactions, potential adverse effects, and medication errors. Providing such education will help empower patients to take ownership of their care.³⁵ Pharmacists should ideally be present to assist patients with treatment decisions and therapy selection based on their oncologic history, comorbidities, preferences, and goals. They can educate the patient, nurse, physician, and other team members on how to monitor adverse events associated with ADCs during the course of treatment. Additionally, as toxicities occur or patients have questions about their therapy, pharmacists should be available to answer these types of questions throughout the course of the patient's treatment.

Drug-Drug Interactions

Overall, the payload drives the drug-drug interactions (DDIs) that may be observed with a particular ADC. Clinicians may consider that the overall dose of payload may be a limiting factor in the potential for DDIs. Several ADCs have apparent risk of DDIs such that changes in pharmacotherapy may be warranted. Interactions with CYP3A4 inhibitors or inducers and p-glycoprotein inhibitors are possible with the vedotin payload ADCs (tisotumab vedotin, polatuzumab vedotin, enfortumab vedotin, and brentuximab vedotin).^20-23 CYP3A4 interactions are also possible with ado-trastuzumab emtansine.⁹ Drugs that are known to prolong QT interval should be avoided in patients receiving inotuzumab ozogamicin since concomitant use “may increase the risk of a clinically significant QTc interval prolongation.”¹⁹ For sacituzumab govitecan, potential interactions may occur with inhibitors or inducers of UGT1A1.²⁵

Provider Consultations

With the complexities of oncology treatments and protocols, pharmacists can be valuable resources on the oncology team.³⁵ Pharmacists will often provide knowledge of potential adverse events and how to mitigate them; potential DDIs; and proper preparation, handling, and administration.^35,36 Whereby permitted by state law, pharmacists may enter in collaborative practice agreements under a physician’s oversight to provide enhanced care to oncology patients.³⁵

Managing Financial Toxicities

As with most other antibody-based therapeutics, ADCs come with hefty price tags. For example, with the cost of inotuzumab ozogamicin estimated to be approximately $67,000 to $90,000 per cycle of treatment and 2 to 6 treatment cycles possible for patients, cost of treatment can reach close to $450,000.³⁷ Estimates (from 2013) of other ADCs include brentuximab vedotin with average annual treatment costs of >$100,000 and ado-trastuzumab emtansine with an average monthly cost of $9,800.³⁸ Even with insurance coverage, the out-of-pocket cost of an ADC can be beyond the reach of many patients. The inability to pay for pharmacological treatments leads to a condition termed financial toxicity.³⁹ Financial toxicity related to cancer treatment can negatively impact a range of patient outcomes from health-related quality of life to overall survival.⁴⁰ Pharmacists may help patients navigate the complexities of health insurance coverage as well as patient-assistance programs that may be available from manufacturers of ADCs.

SUMMARY

ADCs are complex and potent biological/drug products that use the specific protein-binding ability of mAbs to selectively target cancer cells. Coupled with highly potent payloads, modern ADCs represent significant advances in medical oncology. While researcher have made substantial progress in ADC technologies (ie, mAbs, linkers, payloads), toxicity and adverse events, due in part to off-target release of payload, can still limit application of ADCs. Clinicians should be aware of the structure-function of ADCs and their components. As the list of available ADCs grows, clinicians should stay up-to-date on new approvals and indications. Staying knowledgeable in the advances of ADCs allows clinicians the best opportunity to provide patients with quality information so that patients can make informed decisions on therapy. Finally, with the exorbitant costs of drugs such as ADCs, pharmacists may want to be prepared to assist patients in avoiding financial toxicities.

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