Author: D. Ross Camidge, MD, PhD
Until recently, the focus for the treatment of lung cancer has been on immunotherapy and targeted therapy, but I think that antibody–drug conjugates (ADCs) are going to have a massive role in the management of this disease in the future.
What Is an ADC?
ADCs are a therapeutic modality that enables the targeted delivery of highly potent cytotoxic payloads to tumors. An ADC has 3 main components: the antibody, the linker, and the cytotoxic agent. The antibody binds to antigens selectively expressed on cancer cells. The linkage between the antibody and the cytotoxic payload is a critical component of an ADC. The linker attaches that antibody to a relevant payload, determining when and where that payload gets released, with the best linkers selectively releasing the cytotoxic payload inside the target cells while minimizing the release of the toxic agent in the circulation. Finally, there is the cytotoxic payload that classically included topoisomerase I inhibitors or microtubule inhibitors, with DNA binding agents now being explored. In addition, noncytotoxic agents, such as BCL2 inhibitors, are also being explored in some ADCs. The basic idea is that ADCs are just a means of changing where you deliver the drug. The hope is that, by delivering a higher therapeutic dose to only some cells in the body, you will have increased efficacy and reduced toxicity.
Targeted Epitopes vs Oncogenic Driver Mutations/Fusions
An interesting issue in this field is the confusion regarding where the epitopes have been used. People are confused because they think this is an epitope that we are using as a signal transduction inhibitor, for example, MET. MET can certainly function as a driver oncogene in some subtypes of non-small-cell lung cancer (NSCLC) and antibodies against MET have been used to interrupt the signaling and have not been particularly successful in the past. However here, with ADCs, we are, for example, using MET simply as an address label, so it affects our way of thinking. We must think about, disregarding where MET antibodies did not work as that no longer matters because we are using MET just as an address label to deliver a cytotoxic agent.
This brings other interesting aspects. The expression level of antigens on the surface of the cell is clearly a continuous variable. This raises the question of whether there is an antigen level below which you are not going to deliver the drug or you are not going to deliver it differentially compared with normal tissues and, therefore, whether those patients should be prescreened and excluded from treatment. Even at the level where you are getting activity, do higher levels result in greater activity? Consequently, do you have different cutoff points that might be associated with different lines of therapy where you could use these ADCs? There are obvious analogies with PD-L1 expression levels in that regard.
Variables Affecting Response to ADC Therapy
We have started to see occasional reports of patients experiencing dramatic responses to ADCs that are long lived, perhaps because we really are just destroying the cancer cells with very large amounts of toxin. We have also started to see that, in addition to the epitope and the linker and the payload, there is an additional variable—the actual cell that you are targeting.
It turns out that some driver oncogene subtypes that may express certain epitopes more than other ones might be particularly sensitive to the cytotoxic therapy when you deliver it. For example, in the phase II DESTINY-Lung01 study, trastuzumab deruxtecan, when given to patients with HER2-mutant NSCLC, has a quite phenomenal 62% response rate. It is not just that the toxin is remarkable, but it is also when you deliver that toxin to those particular cells. We have known for a long time that certain driver oncogene subtypes are more sensitive to some chemotherapies than others.
In general, we are tending to see many of these different ADCs appearing to compete with one another. We are seeing NaPi2b antibodies, MET antibodies, HER3-directed antibodies, HER2-directed antibodies, TROP2-directed antibodies, or PTK7-directed antibodies.
Future Considerations for Using ADCs in the Clinic
As a clinician, it is difficult to make sense of all these investigational ADCs. It is likely that in the future, we will do some form of multiplex screening for all of the different tumor cell epitopes targeted by ADCs. As part of this type of expression testing, I suspect that it is likely that not just a simple positive vs negative expression result will help guide treatment decisions with ADCs, but that the level of epitope expression (higher vs lower) may allow us to choose among the different ADCs available.
What will happen when you use an ADC that initially is effective but then the patient progresses with acquired resistance? We are just starting to figure this out, but it can be put into 2 very broad categories. First, is the toxin still being delivered to the target tumor cells? For instance, tumor cells may be selected for survival during ADC therapy if they stop making the targeted cellular epitope, and therefore, the delivery system is impaired. Second, you are delivering the toxin to the tumor cells, but now they have become resistant in the same way they might become resistant to other chemotherapies. Although mechanisms of resistance not yet being explored, I think there is a lot of potential here in the future. As this class of agents is adopted into practice, it is worth considering a rebiopsy to show that the tumor cell epitope is still there. If it is, do you need to give something directed against the same epitope but change the toxin? If the epitope is no longer expressed, the tumor cells may still be sensitive to the toxin. In this case, do you change the target epitope but keep the toxin the same?
Finally, with the ADC class of therapy, it is not just about single-agent activity, although they will likely be approved at least initially as monotherapy; the efficacy and safety of ADCs in combination with platinum agents and with immunotherapy will definitely be an area of future investigation in the setting of lung cancer. Overall, I think that ADCs are going to be tremendously important in the future, along with the targeted therapies. For example, if a patient is receiving a targeted therapy and progresses and has a biomarker that is targeted by an ADC expressed on the surface of their tumor cells, maybe combining an appropriate ADC with the current tyrosine kinase inhibitor will get that disease back under control, rather than just going on to single-agent cytotoxic therapy as we have classically done.
ADCs in NSCLC are coming and I believe they are going to have a significant impact on our treatment paradigms.
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