Alberto Montero, MD, MBA
University Hospitals Seidman Cancer Center, Cleveland, Ohio

Key Takeaways

  • Antibody-drug conjugate (ADC) therapy permits precise and potent delivery of cytotoxic drugs to tumors at relatively low blood concentration levels, offering improved tumor response for heavily pretreated patients who have progressed on standard first-line biologic-plus-taxane regimens.
  • The ADCs ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan-nxki (T-DXd), which are approved by the US Food and Drug Administration (FDA), have demonstrated efficacy as second-line therapies for advanced HER2-positive breast cancer. T-DXd is being evaluated in clinical trials for possible use as first-line therapy.
  • In the phase 3 DESTINY-Breast03 trial, T-DXd demonstrated superiority over T-DM1 as the ADC of choice in second-line therapy. In the phase 2 TUXEDO-1 trial, T-DXd also showed a high intracranial response rate in patients with breast cancer and brain metastasis.
  • Future advances in ADCs will likely enhance their immunogenic capabilities and allow targeting of gene expression and intracellular pathways through novel selection of antibody and payload components.

Roughly 20% to 30% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2). Among breast cancers, HER2-positive tumors are considered the second most aggressive type, as classified by receptor expression.1
Currently, standard first-line therapy is often a combination of trastuzumab, pertuzumab, and a taxane such as docetaxel or paclitaxel.2 Despite this regimen, and the additional availability of tyrosine kinase inhibitors (TKI), drug treatment fails due to resistance in up to 8.6% of cases.1 Furthermore, metastasis to the brain has become more common in HER2-positive breast cancer, perhaps in parallel with improvements in systemic therapy.3  In patients already treated with these first-line regimens, ADC therapy may offer survival advantages by combining a biologic and a chemotherapeutic drug into 1 molecule, compared to either therapy separately.
An ADC for the treatment of HER2-positive breast cancer is composed of a humanized (typically immunoglobulin G [IgG]) HER2 antibody, linked to either a tubulin inhibitor or topoisomerase inhibitor drug. The linking molecule is chosen for its stability properties while in systemic circulation and for its behavior under extracellular or intracellular proteolysis. Accordingly, the conjugate exhibits its therapeutic action as the link is degraded selectively in or near the tumor cell.
Currently, 2 ADCs are approved for metastatic HER2-positive breast cancer. T-DM1 was the first ADC to demonstrate positive outcomes in HER2-positive breast cancer, improving progression-free survival and overall survival in the phase 3 TH3RESA study ( identifier: NCT01419197).4 It was approved as second-line therapy initially for advanced, treatment-resistant HER2-positive breast cancer and more recently for early-stage, high-risk breast cancer with residual invasive mass at surgery after neoadjuvant therapy, given the results of the phase 3 KATHERINE trial ( identifier: NCT01772472).5,6 A second ADC — T-DXd — received accelerated FDA approval as third-line anti-HER2 therapy in the metastatic setting based on the results of the phase 2 DESTINY-Breast01 trial ( identifier: NCT03248492) in heavily pretreated patients.7 The FDA approved T-DXd as second-line therapy in May 2022 based on results of the comparative DESTINY-Breast03 trial ( identifier: NCT03529110) vs T-DM1.8 In that trial, T-DXd demonstrated superiority over T-DM1 for multiple outcomes, including disease-free progression, overall survival, and clinical tumor response. At the same time, T-DXd was also associated more frequently with adverse events. In August 2022, T-DXd was also approved for unresectable or metastatic HER2-low breast cancer.9  
Multiple other ADCs to treat HER2-positive metastatic breast cancer are in the pipeline. Some, such as trastuzumab duocarmazine (SYD985),10 employ the same trastuzumab antibody as the currently approved anti-HER2 ADCs. Others have been developed for specificity to both trastuzumab and pertuzumab binding sites or are engineered with modified HER2 binding affinity in order to improve efficacy and safety of the cytotoxic drug payload.
Alberto Montero, MD, MBA, CPHQ, is the clinical director of the Breast Cancer Medical Oncology Program at University Hospitals Seidman Cancer Center in Cleveland, Ohio, and is an associate professor of medicine at Case Western Reserve University School of Medicine in Cleveland. Dr Montero provides an update of research and clinical perspectives on currently approved ADCs, ADCs in the pipeline, and those that might be developed to realize the still-untapped capabilities of ADC therapy.

Can you give an overview of the current positioning of ADCs in the treatment of advanced, previously treated breast cancer and of the current limitations of ADCs as a therapeutic class?

Based on studies in patients who had already progressed on dual-antibody therapy plus chemotherapy, we have seen proof of principle that we are obtaining higher levels of cytotoxicity using ADCs (we are able to deliver chemotherapy in a very specific way and reach higher drug concentrations) than we would with standard chemotherapy. In particular, T-DXd has shown significant activity in a very refractory group of patients who had received multiple prior lines of therapy.7 T-DXd is also currently being compared to the standard first-line therapy: trastuzumab, pertuzumab, and a taxane11; however, we cannot make that comparison yet.
New developments and iterations will be important. T-DXd is a great drug and has shown an effectiveness that is unparalleled, but we know that there is a small but real risk of pneumonitis with this ADC.12 The question is, can you improve on that by changing the antibody or the payload? For example, there is an ADC in development that uses zanidatamab as the antibody, and there are early indications this ADC would not cause pneumonitis in the way that T-DXd can because it is using a different payload.13,14
Whereas ADCs may be efficient for delivering chemotherapy, they probably have less of an effect in interfering with the cell signaling in the HER2 pathway. By contrast, the “traditional” antibodies work not only by blocking HER2 signaling, but also because they have an immune effect through antibody-dependent cellular cytotoxicity (ADCC).15 So a question for the future is, can we engineer an ADC that, by binding in multiple ways, has all of the advantages of the traditional HER2 antibodies in blocking HER2 signaling and maintaining immunogenicity as well as delivering chemotherapy?

What has changed in the selection and sequencing of treatment that incorporates ADCs in the metastatic context?

The biggest change is that the phase 3 DESTINY-Breast03 trial showed superiority of T-DXd over T-DM1 in patients previously treated with trastuzumab and a taxane.12 We are using it earlier, and it has become the standard of care for second-line therapy. As mentioned earlier, the ongoing DESTINY-Breast09 trial ( identifier: NCT04784715) is evaluating T-DXd as first-line therapy.11 T-DXd could become first-line therapy, and our current and longstanding first-line therapy — trastuzumab, pertuzumab, and a taxane — may become later-line therapy.
Although the question is about HER2-positive tumors, the therapeutic paradigm is changing in other respects: previously, we would not have considered using anti-HER2 therapies to treat patients with HER2-negative tumors. But now, with newer ADCs like T-DXd and other drugs in the pipeline, we can consider treatment in the HER2-low category using therapies primarily developed to target HER2.16

The biggest change is that the phase 3 DESTINY-Breast03 trial showed superiority of T-DXd over T-DM1 in patients previously treated with trastuzumab and a taxane. We are using it earlier, and it has become the standard of care for second-line therapy.

What are other important considerations and best practices for patient selection for ADC therapy in the setting of metastasis?

As mentioned previously, T-DXd is the ADC of preference in metastatic breast cancer, but there are pulmonary side effects with that conjugate arising from its payload. In patients who have pulmonary issues, a prior history of pneumonitis, or other history that would raise concern about pneumonitis, one might not want to prescribe T-DXd. Additionally, there is more often gastrointestinal toxicity with T-DXd, so a patient with a history of inflammatory bowel disease or severe diarrhea may not want to use T-DXd.17
By contrast, in T-DM1, the payload is mertansine, which is a potent taxane that can cause neuropathy,1 as can most other drugs that we use in breast cancer. This can limit the therapeutic utility of T-DM1; many of our pretreated patients have received a lot of taxanes and have developed neuropathy. In this regard, an advantage of T-DXd is its irinotecan-based payload (DXd, a topoisomerase I inhibitor) because topoisomerase inhibitors only rarely cause neuropathy.18 This ADC, with its non-taxane payload, has opened up a lot of therapeutic possibilities and is important to consider in patient selection.
Brain metastasis is another consideration. The dogma used to be that because ADCs are big molecules, they are not going to cross the blood-brain barrier. However, now we have rather convincing data from the phase 2 TUXEDO-1 trial ( identifier: NCT04752059) showing that, in breast cancer patients with brain metastases, T-DXd shows benefits in the brain and activity against brain metastases.19 This is changing how we decide whether to use an ADC vs a TKI such as tucatinib for patients with brain metastases; we do not necessarily need to avoid using T-DXd in those patients. We have not seen data showing such activity with T-DM1; that is another difference between T-DXd and T-DM1.

True or False? ADCs cannot deliver drugs across the blood-brain barrier.
False. T-DXd demonstrated efficacy against brain metastases from HER2-positive breast cancer in the phase 2 TUXEDO-1 trial.

What is the next step for ADCs in dealing with brain metastasis?

The efficacy of T-DXd against brain metastases is still poorly understood because normally an antibody is too big to get across the blood-brain barrier. However, given the results of the clinical trials, there is a delivery of drug payload to the brain. With T-DXd, this could be related to the “bystander effect,”20 where the chemotherapeutic agent is released adjacent to where the antibody binds.

Still, because of very robust data in the HER2CLIMB trial ( identifier: NCT02614794) of tucatinib, trastuzumab, and capecitabine, which included patients with brain metastases,21 I think there is still a preference for tucatinib. But as we get more experience with T-DXd and more data in patients specifically with brain metastasis, we may gain a better idea of the relative efficacy of T-DXd compared with tucatinib. Perhaps we will start to combine these 2 therapies in patients with brain metastasis; there are already ongoing studies combining T-DXd and tucatinib.22 We do not have supportive data on that yet, but I think over the next couple of years, we will have more information on patients with breast cancer and brain metastasis and how our current paradigm can be changed to improve disease control.

What is on the horizon for ADC development?

A persistent issue is that there are laboratory-by-laboratory inconsistencies in identifying whether a patient’s tumor truly is expressing HER2,23,24 which we need to know in order to determine which patients are likely to benefit from these treatments.
So far, for HER2-positive breast cancer, both FDA-approved ADCs use the same antibody: trastuzumab. Newer ADCs in development use different antibodies to target HER2 differently. Similarly, we can talk about different payloads, as well as the advantages and disadvantages of each. These first iterations of ADC technology focused on how to deliver chemotherapeutic drugs in a directed manner because that has been the traditional treatment in oncology, but if you look ahead I think we are going to see an evolution away from delivering chemotherapy in the HER2-positive space. Maybe we will use the antibody to deliver biologics instead of cytotoxic drugs through this technology.
Newer iterations are addressing how we can develop an ADC with an immune agonist capability, such that it leverages the antibody’s cellular cytotoxicity. Likewise, can we use ADCs to deliver drugs that might block or moderate transcription of certain genes or intracellular pathways or that target a specific mutation?
For example, typically a drug such as a phosphatidylinositol 3-kinase (PIK3) blocker or a protein kinase B (AKT) inhibiting drug is delivered in an undirected manner,25 which requires dosing to higher blood concentration levels in order to ensure enough of the drug reaches the tumor. What if, instead, we put a PIK3 blocker or AKT inhibitor on the HER2 antibody and delivered that conjugate to the tumor? I think ADC therapy will move in that direction.

This Q&A was edited for clarity and length.


Alberto Montero, MD, MBA, CPHQ, reported affiliations with AstraZeneca Pharmaceuticals, LP; Carevive Systems, Inc; Celcuity, Inc; Genmab; New Century Health; Paragon Healthcare; Roche; Scorpion Therapeutics; Welwaze Medical, Inc; and Zymeworks, Inc.


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Reviewed January 2023