Levy Delves Into the Evolution of ADCs in NSCLC

Before investigators can answer whether antibody-drug conjugates (ADCs) should become a frontline standard of care in advanced non–small cell lung cancer (NSCLC), researchers must first look to establish robust biomarkers of response and the exact mechanisms of action at play, according to Benjamin Levy, MD.

“We have a lot of work to do to try to figure out how to leverage these drugs. We are in chapter 1 of what’s going to be a very long novel about ADCs in NSCLC,” Levy stated in an interview with OncLive^®.

In the interview, Levy discussed remaining questions regarding the utility of ADCs, expanded on the patient and disease characteristics that may render a patient eligible for treatment with an ADC, and highlighted ongoing and planned research within the treatment arena.Levy is the clinical director of Medical Oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, and an associate professor of oncology at Johns Hopkins University School of Medicine, in Baltimore, Maryland.

OncLive: How has research evolved with ADCs since the approval of fam-trastuzumab deruxtecan (Enhertu) in HER2-mutant NSCLC?

Levy: We’ve come a long way in the field of ADCs, specifically for NSCLC. Of course, we have trastuzumab deruxtecan that’s now approved for patients with HER2 exon 20 insertion mutations. However, that’s just the beginning of the story. We’re just beginning to scratch the surface.

Other ADCs are in development such as patritumab deruxtecan [HER3-DXd], a HER3 ADC that’s being leveraged and looked at in EGFR-mutant lung cancer. There are others, such as MET-directed ADCs that look promising.

Of course, there are also the TROP2-directed ADCs. [Overall], there is a lot of movement in this field, and over the next 6 to 12 months we’re going see more and more data come out with how to use these drugs.

Apart from its primary mechanism, how can an ADC induce antitumor activity?

We only have a nascent understanding of how these ADCs work. On paper, the monoclonal antibody component of the ADC should target the cell surface protein on the cancer cell and then be internalized and release the payload. The story is a little bit more complicated than that.

Target engagement of a cell surface protein is one mechanism of action. However, we also have the bystander effect where payload moiety can move to adjacent cells once released, and kill those cells, even if they don’t have the target. [There is also] antibody-dependent cellular cytotoxicity. These drugs may work not only by targeting cell surface antigens and releasing the payload, but also by engaging effector immune cells and bringing them into the tumor. [In that sense] we can view them as immunotherapy [agents]. That’s yet another way we think these drugs may work.

What patient and disease characteristics help you determine which patients should receive an ADC?

It’s important [to note] that as of February 2024, the only approved ADC in NSCLC [was] trastuzumab deruxtecan, and it’s approved for patients with HER2 mutations. I want to take a step back because HER2 alterations come in many sizes, shapes, and forms. There’s HER2 overexpression, which is looked at routinely in breast cancer. There’s HER2 amplification, and then there’s the HER2 mutation.

Keep in mind when you’re looking at your next-generation sequencing report or your molecular report that the patient must have that [mutation] to receive trastuzumab deruxtecan. Notably, the drug is approved after chemotherapy and not in the first-line setting. We have more data coming out, [but trastuzumab deruxtecan] is certainly a great drug to use after you’ve exhausted first-line options.

What can be done to improve the identification and selection of biomarkers of response for ADC selection?

We have a lot of work to do with biomarker selection and we have a lot of questions that are unanswered. The first is, are the IHC platforms that we currently have able to best predict the efficacy of these ADCs? Do we need other ways to look at IHC? I haven’t given up on IHC, but I think we need to look at it in a different way.

The second thing is that driver mutations may be the best predictor of ADC [efficacy], whether it be a HER2 exon 20 insertion, an ALK rearrangement, or an EGFR mutation. [Driver mutations] as we see it may be the best predictor of response to these drugs. A lot of work needs to happen here. We are just at the ground floor of understanding which patients are going to respond or who will develop toxicity. In addition, we need a tissue or a blood-based biomarker. It'll be very exciting to see over the next two years how things unfold.

One of the ADCs that is currently in development is ifinatamab deruxtecan (I-DXd; DS-7300). What distinguishes I-DXd from other ADCs in the space and what has been seen with this agent so far?

I-DXd is an ADC with a monoclonal antibody and IgG1, a linker, and a deruxtecan derivative payload. The monoclonal antibody targets B7, which is a protein that is expressed on multiple malignancies, including NSCLC. There are very preliminary data coming out [with this agent].

A lot of the data for I-DXd came out of small cell lung cancer [SCLC], though we’re learning in small data sets that this drug is active in NSCLC, and some squamous cell populations. We’re still learning about the ability to target B7H3, that’s the name of the protein, very early on. However, this drug looks promising both in SCLC and in NSCLC, demonstrating meaningful activity in a highly pretreated group of patients.

What does the future look like for ADC development in NSCLC?

There are a lot of questions about ADCs and how they’re going to unfold in NSCLC. The first question [has to do with] biomarker selection. We have a lot of work to do there. We now have a bona fide biomarker for trastuzumab deruxtecan with the HER2 exon 20 insertion. However, there a lot of questions about where these drugs are going to land in the treatment continuum. Are they going to be first-line [agents]? Are they going to be second-line [standards]? Are we going to be able to safely combine these drugs with immunotherapy and platinum?

Looking at [these agents] in the advanced stage setting [is vital], but [we must also consider] how these drugs perform in earlier-stage disease. Can we look at these agents in the neoadjuvant setting? Is there potential synergy with neoadjuvant immunotherapy? Some of these things are going to be played out in trials.