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TROP-2 in NSCLC

CME

Antibody‒Drug Conjugates Targeting TROP-2 in NSCLC: A Look to the Future

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: July 25, 2023

Expiration: July 24, 2024

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What Are Antibody‒Drug Conjugates?

Stephen Liu, MD: 
Today we are talking about antibody-drug conjugates  (ADCs). ADCs are an established class of agents in oncology, though they are new to lung cancer. Breast cancer paved the way for ADC development, with ADCs first approved in later lines of therapy but over time expanded to earlier treatment. Ado-trastuzumab emtansine received FDA approval in 2013 for patients with HER2-positive metastatic breast cancer who had previously received trastuzumab and a taxane, separately or in combination.1 In 2019, this approval was expanded to adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane- and trastuzumab-based treatment. Also in 2019, fam-trastuzumab deruxtecan-nxki was approved for the treatment of adult patients with unresectable or metastatic HER2-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.2 More recently, trastuzumab deruxtecan was granted accelerated approval for adult patients with unresectable or metastatic NSCLC whose tumors have an activating HER2 mutation and who have received a prior systemic therapy.

Multiple ADCs currently are in development for lung cancer, including those targeting HER3 (patritumab deruxtecan), B7-H3 (DS-7300), CEACAM5 (tusamitamab ravtansine), MET (telisotuzumab vedotin) and TROP-2 (sacituzumab govitecan-hziy and datopotamab deruxtecan), the last of which will be the focus of our discussion today.

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Antibody‒Drug Conjugates: Components

Stephen Liu, MD: 
Before we dive into the clinical data, Dr Heist, can you describe the general components of ADC structure that are important to the function of these agents?

Rebecca S. Heist, MD, MPH:
As the name implies, an ADC is an antibody that is connected to a drug to deliver chemotherapy more precisely to cancer cells, thereby avoiding broad toxicity to the normal tissue. The typical strategy is to use a humanized monoclonal antibody that specifically attaches to an antigen that is preferentially expressed on the cancer cell surface and not on normal tissue.3 A linker attaches the antibody to the “warhead” payload, which can be a very potent chemotherapy agent with cytotoxic activity in the subnanomolar range. 

The DAR is a measure of the amount of drug loaded onto each antibody molecule and is a key parameter of ADCs that can influence their efficacy and stability. As an example, the HER2-targeted ADC trastuzumab deruxtecan has the antibody trastuzumab conjugated to the camptothecin analogue deruxtecan (topoisomerase I inhibitor) and a higher DAR (~8) compared with other approved ADCs, such as ado-trastuzumab emtansine (DAR ~3.5). The higher DAR of trastuzumab deruxtecan was shown to deliver more drug into tumor cells compared with ado-trastuzumab emtansine, which was associated with greater activity in HER2-low tumors.4

However, a higher DAR sometimes can be associated with greater systemic clearance of the ADC, thus reducing its therapeutic efficacy.

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Antibody‒Drug Conjugates: Mechanism of Action

Stephen Liu, MD:
Dr Levy, can you outline how exactly ADCs work? 

Benjamin Levy, MD:
These drugs may work in various ways that can be independent of the payload antitumor activity.3 First, the antibody engages with the target molecule, which can directly stimulate antibody-dependent cellular toxicity, leading to tumor cell lysis. Alternatively, this engagement can disrupt target molecule structure and function, including downstream signaling. Then, internalization of the ADC eventually leads to processing and release of the cytotoxic payload, which causes cell death. 

Finally, membrane-permeable payloads from some ADCs can diffuse from cells, expressing the target molecule into nearby cells, thereby exerting a cytotoxic effect regardless of target molecule expression. This “bystander effect” is the key to enhanced activity against tumors with heterogeneous target molecule expression. However, such diffusion of cytotoxic payloads also can come with an increased risk for toxicity to the surrounding healthy tissue.

I think we have a basic understanding of the many ways these drugs can work, but much remains to be discovered about which types of tumors ADCs are best suited for, including the most appropriate biomarkers.

Stephen Liu, MD:
Everyone is passionate about immunotherapy, and we always are looking for different combination therapies that may enhance or evoke an immune response. Dr Borghaei, what immunologic effects are associated with ADCs?

Hossein Borghaei, MS, DO:
This is a good question and an area of active investigation. The idea is that anything that can cause tumor cell death could in fact be somewhat immunogenic because release of neoantigens or antigens that have not previously been exposed to the immune system (even if by an apoptotic process) could draw new antigen presenting cells to the environment. From an experimental point of view, although there is some evidence that ADCs can induce the immune system (because of their direct cancer cell‒killing ability), the extent to which it is clinically relevant is still under investigation. Studies are trying to examine the additive, hopefully synergistic activity with an immuno-oncology agent, but this is an area that needs more evaluation.

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The Appeal of ADCs

Stephen Liu, MD:
There is a lot of excitement about ADCs. Dr Johnson, why do you think this class of drugs is so exciting?

Melissa L. Johnson, MD:
The mechanism of action for ADCs is so distinct from current platinum-based chemotherapy and immunotherapy, and many patients with lung cancer may benefit from these drugs. In the drug development unit at the Sarah Cannon Research Institute, we talk about these drugs as being targeted like a smart bomb—if we know the target antigen is being expressed, then the chemotherapy can find its way to the tumor cells and leaves the normal cells alone. 

There is some debate about whether ADCs are actually targeted. Some HER2-specific ADCs, such as trastuzumab deruxtecan in breast cancer, are targeted. The appeal is the ability to identify patients who will have positive outcomes based on expression of the target antigen. I do not know if that is true for the TROP-2‒directed ADCs we will discuss today. However, the ability of some ADCs to have activity even when the target antigen is not expressed at high levels is important. For example, trastuzumab deruxtecan demonstrated substantial activity even in patients with HER2-low metastatic breast cancer.5 It may be that the bystander effect is more relevant in those patients. Thus, the universality of some ADCs may be the more appealing aspect, which will be discussed more later.

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