CE
Pharmacists: 1.00 contact hour (0.1 CEUs)
Released: July 09, 2025
Expiration: January 08, 2026
ADC Components: Antibody
Allison Butts, PharmD, BCOP:
ADCs are comprised of several components, each of which is important to the function of the agent.1,2 The backbone of an ADC is generally a humanized monoclonal IgG antibody that targets an antigen expressed on the tumor cell surface. A number of tumor targets are being explored or already have approved therapies. This module will focus on targeting HER2, TROP-2, and HER3.
ADC Components: Linker
Allison Butts, PharmD, BCOP:
The second component is the linker.1,2 The linker not only tethers the payload to the antibody but is an important feature of drug function and the toxicity profile. There are 2 main classes of linkers—cleavable and noncleavable. Cleavable linkers may function in a variety of ways including a disulfide bond that can be broken or an entity that is hydrolyzed within the acidic environment of the tumor cell. ADCs with noncleavable linkers are entirely internalized to a lysosome, broken down, and then the toxic agent is released.
ADC Components: Payload
Allison Butts, PharmD, BCOP:
The final component of an ADC is the payload, typically a toxic chemotherapeutic agent.1,2 There are a number of factors to consider regarding the payload including the drug-to-antibody ratio (DAR), which is how many of these toxin molecules are tethered to an individual antibody; the lipophilicity, which impacts the ability of the drug to permeate into neighboring cells; and the half-life, which could affect toxicity and efficacy of the agent. There are multiple different payloads currently in use.
ADC Mechanism of Action
Allison Butts, PharmD, BCOP:
Regarding the mechanism of action of ADCs, this figure illustrates a step-by-step process.2 The initial step is binding of the ADC to the target receptor on the cell surface, forming the ADC-antigen complex.
After binding, the ADC-antigen complex is internalized and targeted for destruction within the tumor cell. The ADC is broken down within endosomes or lysosomes, that releases the cytotoxic payload.
Many ADCs are designed to have a bystander effect via a cleavable linker. Once the toxin is released from the antibody, if it is membrane-permeable it can migrate to neighboring cells. That could be another tumor cell that may or may not be highly expressing the target surface receptor, or it could be a normal, healthy cell. Thus, the bystander effect has both benefits and potential risks.
Another mechanism of action is antibody-dependent cellular cytotoxicity in which the antibody component of the ADC can engage with immune effector cells that then kill the tumor cell.
ADC Mechanisms of Toxicity
Allison Butts, PharmD, BCOP:
No agent is without toxicity and ADCs are no exception.3,4 The mechanism of ADCs relies on a specific target expressed on the tumor cell, but some of these targets are also expressed on healthy cells. For example, HER2 is expressed on the endothelium throughout the body, so HER2-targeted ADCs are not only binding to tumor cells, but they also potentially target the cells of the epithelium that express HER2.
The location and mechanism of linker cleavage also affects toxicity. Although designed for linker cleavage within the tumor cell, if cleavage occurs outside the tumor cell, the toxin is released and may damage nearby cells. If the toxin is membrane permeable or lipophilic it can migrate out of the cell after cleavage within the tumor cell. If there is leakage of the toxin into the bloodstream or into neighboring cell areas, damage to healthy cells can occur in addition to the desired tumor cell targeting.
Timeline of FDA Decisions for ADCs Targeting HER2, HER3, and TROP-2
Allison Butts, PharmD, BCOP:
The first ADC to be approved was trastuzumab emtansine (T-DM1) that targets HER2 in 2013.5 Six years later, T-DM1 was approved for an additional indication and trastuzumab deruxtecan (T-DXd) was approved.6 After 2019 the pace of ADC approvals accelerated as these drugs demonstrated significant benefit in multiple tumor types.7,8
HER2: A Key Targetable Biomarker in Cancer
Allison Butts, PharmD, BCOP:
HER2 is a transmembrane receptor that functions by dimerizing with another member of the HER/ErbB family [EGFR (HER1), HER2, 3, or 4].9 After dimerization, downstream signaling occurs through the PI3K and RAS pathways ultimately leading to survival, proliferation, and angiogenesis of the tumor cell.10,11
Drugs targeting HER2 have the potential for use in a number of different cancers due to the high level of HER2 expression on many solid tumor types, including breast cancers, gastric cancers, and a number of others.10,12
HER2 is expressed almost ubiquitously on epithelium throughout the body.13 Some of the toxicities associated with anti-HER2 therapies are due to their binding to normal tissues that express HER2 including the lining of the gastrointestinal tract, the skin, and cardiac myocytes.
Trastuzumab Emtansine: HER2-Targeted ADC
Allison Butts, PharmD, BCOP:
The first ADC approved was the HER2-targeted ADC, T-DM1.5 The antibody backbone is trastuzumab.14 Linked to trastuzumab via a noncleavable linker is a very potent maytansine derivative that is a microtubule inhibitor. The DAR is on the lower end, with approximately 3.5 toxin molecules per antibody. T-DM1 is broken down in the lysosomes of the target cell to release the cytotoxic agent.
T-DM1: 2 FDA-Approved Indications
Allison Butts, PharmD, BCOP:
The FDA-approved indications for T-DM1 currently are twofold, both in breast cancer.5 T-DM1 is indicated for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. The basis for this approval was improved progression-free survival (PFS) and overall survival (OS) with T-DM1 vs lapatinib plus capecitabine in the phase III EMILIA trial.15
Six years later, T-DM1 was approved for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment, on the basis of impressive disease-free survival and OS benefit with T-DM1 vs trastuzumab in the phase III KATHERINE trial.16,17
Trastuzumab Deruxtecan: HER2-Targeted ADC
Allison Butts, PharmD, BCOP:
T-DXd has the same trastuzumab antibody backbone as T-DM1 but both the cytotoxic payload and the linker differ.18 In T-DXd, the payload is a topoisomerase-1 inhibitor, deruxtecan, that is membrane-permeable. T-DXd has a much higher DAR of approximately 8 molecules of toxin to 1 antibody. The linker tethering the toxins to the antibody is cleavable thus allowing for bystander effects. The combination of higher DAR, membrane permeability, and cleavable linker mean that T-DXd is a very potent drug, and as such, it has been approved for a number of different indications.6
T-DXd: 3 FDA-Approved Indications in Breast Cancer
Allison Butts, PharmD, BCOP:
T-DXd received its first approval in the HER2-positive metastatic breast cancer setting.6 Based on evidence from the phase III DESTINY-Breast03 trial, the first indication for T-DXd is for adult patients with unresectable or metastatic HER2-positive (IHC 3+ or IHC 2+/in situ hybridization [ISH] positive) breast cancer who have received a prior anti-HER2–based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. The DESTINY-Breast03 trial demonstrated that T-DXd significantly improved PFS and OS vs T-DM1 in the second-line setting for HER2-positive advanced breast cancer.19-21
The second indication for T-DXd is for unresectable or metastatic HER2-low breast cancer after previous chemotherapy in the metastatic setting or disease recurrence during or within 6 months of completing adjuvant chemotherapy. HER2-low is defined as tumors that are IHC1+, or IHC2+ and ISH negative. In the phase III DESTINY-Breast04 trial, T-DXd significantly improved PFS and OS vs chemotherapy in this patient population.22
The most recent indication for T-DXd in breast cancer is based on data from the phase III DESTINY‑Breast06 trial that examined efficacy in patients with hormone receptor (HR)–positive, HER2-low or HER2-ultralow tumors after 1 or more endocrine therapies in the metastatic setting. HER2-ultralow is defined as IHC 0 with membrane staining.23 PFS was significantly improved with T-DXd in this patient population vs chemotherapy in the DESTINY-Breast06 trial.
T-DXd: FDA-Approved Indication in HER2+ Advanced Gastric/GEJ Adenocarcinoma
Allison Butts, PharmD, BCOP:
T-DXd is also approved for HER2-positive locally advanced or metastatic gastric or gastroesophageal junction carcinoma after a previous trastuzumab-based regimen.6 This approval is based on the open-label, phase II DESTINY-Gastric01 trial that showed T-DXd improved PFS and OS vs physician's choice of chemotherapy.24,25
HER2-Positive NSCLC
Allison Butts, PharmD, BCOP:
The definition of HER2-positive in non-small-cell lung cancer (NSCLC) differs from that in breast cancer. In NSCLC, HER2-positive refers to tumors that contain a HER2-activating mutation.9,26 Approximately 2%-4% of patients with advanced NSCLC have a HER2 gene mutation as detected by next-generation sequencing. Mutations in exon 20 are common activating mutations.
T-DXd: FDA-Approved Indication in HER2-Mutated mNSCLC
Allison Butts, PharmD, BCOP:
The accelerated approval for T-DXd in NSCLC is for adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations, as detected by an FDA approved test, and who have received a prior systemic therapy.6
This approval was based on the phase II DESTINY-Lung02 study that showed an impressive median PFS of 10 months and a median OS of 19 months.27,28
T-DXd: FDA-Approved Indication in Unresectable/Metastatic HER2+ Solid Tumors
Allison Butts, PharmD, BCOP:
T-DXd now has a pan tumor indication for adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors after previous systemic therapy who have no satisfactory alternative treatment options.6
Data from several studies supported this accelerated approval including the phase II DESTINY-PanTumor02 trial that included patients with a number of different tumor types.29 Additional evidence from the DESTINY-Lung01 and DESTINY-CRC02 trials in NSCLC and colorectal cancer respectively supported this approval.30,31
TROP-2 as a Therapeutic Target
Allison Butts, PharmD, BCOP:
TROP-2 is another therapeutic target with approved ADCs. TROP-2 is an epithelial adhesion molecule and a transmembrane glycoprotein.32 It regulates many different components of the cell cycle, including regeneration, growth, and transformation.
TROP-2 Overexpression Across Tumor Types
Allison Butts, PharmD, BCOP:
TROP-2 is overexpressed on many different tumor types.33,34 We will focus on breast cancer, but there are opportunities in multiple different tumor types.
Sacituzumab Govitecan: TROP-2‒Targeted ADC
Allison Butts, PharmD, BCOP:
Sacituzumab govitecan is an ADC with a humanized anti-TROP–2 antibody as the backbone.35 The DAR is approximately 8:1, similar to T-DXd. There is a pH-sensitive, cleavable linker that aids in the release of the toxic payload within the tumor cell. The payload is SN-38, the active metabolite of irinotecan.
Sacituzumab Govitecan: 2 FDA-Approved Indications
Allison Butts, PharmD, BCOP:
Sacituzumab govitecan received its first approval for TNBC based on evidence from the phase III ASCENT trial.36-38 In this trial, sacituzumab govitecan significantly improved PFS and OS vs physician’s choice of treatment. Sacituzumab govitecan is indicated for patients with advanced or metastatic TNBC after 2 or more lines of therapy with at least 1 of those therapies being in the metastatic setting.7
Sacituzumab govitecan was later approved for HR-positive breast cancer based on data from the phase III TROPiCS-02 trial, which compared sacituzumab govitecan with chemotherapy in patients with HR-positive, HER2-negative advanced breast cancer after at least 1 prior endocrine therapy, 1 line of CDK4/6 inhibition, and 2-4 lines of chemotherapy including a taxane for metastatic disease. Sacituzumab govitecan significantly improved PFS and OS vs chemotherapy.39,40 The indication is for patients with advanced or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.7
Datopotamab Deruxtecan: Novel TROP-2‒Targeted ADC
Allison Butts, PharmD, BCOP:
Datopotamab deruxtecan (Dato-DXd), is a newer anti–TROP-2 ADC.41 The backbone is a humanized IgG1 anti–TROP-2 antibody. The linker is a tetrapeptide-based, tumor-selective cleavable linker. The payload is the topoisomerase-1 inhibitor, deruxtecan with a DAR of 4:1. The linker and payload are the same as T-DXd and as such, Dato-DXd also has a bystander effect.
Title: Dato-DXd: 2 FDA-Approved Indications
Allison Butts, PharmD, BCOP:
Dato-DXd is approved in breast cancer based on the phase III TROPION-Breast01 trial, which compared Dato-DXd to physician’s choice of therapy in patients with HR-positive metastatic breast cancer after progression on endocrine therapy.42 There was a significant improvement in PFS with Dato-DXd. More recently, Dato-DXd has been approved for adults with locally advanced or metastatic EGFR-mutated NSCLC after previous EGFR-targeted therapy and platinum-based chemotherapy.43-45
HER3: Biology
Allison Butts, PharmD, BCOP:
Agents targeting HER3 are still in development. Similar to HER2, HER3 is a receptor that dimerizes with other members of the ErbB/HER family.
HER3 is not an oncoprotein itself, but it heterodimerizes with other members of the family, which then leads to the downstream signaling cascade.46 HER3 expression can mediate resistance to targeted therapies, specifically EGFR-targeted therapies used in lung cancer, so that is the primary area of study at this time.
Patritumab Deruxtecan (HER3-DXd): Novel HER3-Targeted ADC
Allison Butts, PharmD, BCOP:
Patritumab deruxtecan (HER3-DXd) is comprised of an anti-HER3 IgG1 antibody and a tumor-selective, tetrapeptide-based linker that links deruxtecan to the antibody. The DAR is approximately 8:1.
Phase II HERTHENA-Lung01: Patritumab Deruxtecan in EGFRm NSCLC After Prior EGFR TKI and Platinum CT
Allison Butts, PharmD, BCOP:
The HERTHENA-Lung01 trial, produced an overall response rate of 30% in patients with EGFR-mutated advanced NSCLC after an EGFR TKI and platinum-based chemotherapy.47 The phase III HERTHENA-Lung02 trial demonstrated improved PFS with HER3-DXd vs platinum-based chemotherapy but failed to improve improved OS in patients with previously treated EGFR-mutated NSCLC.48 These data led to a voluntary withdrawal of this agent from FDA review.
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