ADCs have moved from bench to bedside as standard later-line treatment options for select patients with advanced and metastatic non–small cell lung cancer (NSCLC). Our expert panelists consider the current ADC landscape with an eye to the future.

Currently, we have 3 US Food and Drug Administration (FDA)–approved ADCs in the later-line NSCLC treatment space, and this comes at a time when we are also incorporating additional biomarker testing. We have the c-Met–directed ADC telisotuzumab vedotin (Teliso-V); we have the TROP2-directed ADC datopotamab deruxtecan (Dato-DXd), which has an indication in the EGFR-mutant setting; and we have the HER2 (ERBB2)-directed ADC trastuzumab deruxtecan (T-DXd), which has an NSCLC HER2-mutant and a tumor-agnostic immunohistochemistry (IHC) 3+ indication.

These ADCs are useful because they add to our later-line treatment options across different molecular subsets of patients with advanced or metastatic disease. This includes patients with driver-negative disease who received prior chemoimmunotherapy (eg, Teliso-V for patients with c-Met protein overexpression) and some patients with driver-positive disease (eg, Dato-DXd after EGFR-targeted therapy and platinum-based chemotherapy).

In many ways, the FDA-approved ADCs can be viewed as chemotherapy, although they are being delivered in a very targeted fashion. I tell my patients that myelosuppression and some chemotherapy-related toxicity are still possible and are to be expected. Additionally, we should be aware that interstitial lung disease or pneumonitis can occur with ADC therapy; even if this is rare, we want to be vigilant in monitoring so that we can treat it immediately.

Refined biomarkers may help guide the optimal use of ADCs in the future. We currently have IHC biomarkers, which can be quite crude, but we are exploring novel tools such as computational artificial intelligence–based biomarkers (eg, TROP2 normalized membrane ratio by quantitative continuous scoring). These approaches are actually being integrated into clinical trials, which is important for prospective validation.

ADCs represent an area with a large pipeline, many trials, and rapid expansion, so there is a big wave of excitement surrounding them. I think that they are definitely additive. Two of the 3 ADCs may involve IHC testing. As Dr Aggarwal noted, for Teliso-V, we have an FDA approval for patients with nonsquamous NSCLC and c-Met protein overexpression, and, for T-DXd, we have an approval for patients with pan-solid tumors based on high HER2 IHC expression. This adds another layer to our testing. Not only do we want to obtain next-generation sequencing on all our patients but we also need to find time and tissue for c-Met and HER2 IHC testing. There is interest in making such testing more reflexive, which would allow us to have the data at the time of progression on first-line treatment.

The other recently available ADC is Dato-DXd, which is TROP2 directed. It received accelerated approval from the FDA in the post–TKI/platinum-based chemotherapy, EGFR-mutant NSCLC setting. The relevant biomarker, at least for now, is the EGFR mutation, not TROP2-high by IHC. The approval was based on a pooled analysis across 2 trials (ie, TROPION-Lung05 and TROPION-Lung01) showing benefit in the EGFR-mutant group. We know that some actionable alterations lead to cancers that have greater sensitivity to chemotherapy and that seem to have greater sensitivity to ADCs as well. Dato-DXd gives us another later-line option after osimertinib and platinum-based chemotherapy, in the same setting in which we might also consider amivantamab.

The available ADCs are additive, and I agree that they are essentially very similar to chemotherapy. Their efficacy, while significantly better than some of the other options, is not at the level of immunotherapy or targeted therapy for our patients. However, there is enthusiasm for different payloads. In the future, there are going to be clinical trials of different payload-based ADCs that I think will generate a lot of excitement.

Having followed the negative CARMEN-LC03 trial, which studied tusamitamab ravtansine vs docetaxel, I know the familiar sequence of early excitement, negative results, and disappointment. Over time, that can make one more guarded about getting excited. However, what I have seen over the years—something that is applicable not only to the 3 FDA-approved ADCs but also to many novel candidates in development—is that the design of ADCs is becoming more refined.

Investigators first considered ADCs that were already successful in other tumors (eg, TROP2-directed sacituzumab govitecan for triple-negative breast cancer) for testing in NSCLC; that approach met with only limited success. Newer agents such as sacituzumab tirumotecan represent the next generation. Better payloads and linkers are arriving, yet ADCs are still additive.

I do like T-DXd for HER2-driven resistance after EGFR TKIs, and I have been very successful with this approach, but I recommend rebiopsy at anatomic progression. Sometimes rebiopsy may not be possible, but you do need a good sample of tissue for HER2 IHC testing.

To summarize, the ADCs are here to stay, including in combination regimens, but they should not be framed as being chemotherapy free. They might be better described as an antibody plus a cytotoxic payload, and this structure means that toxicities can linger longer than with immunotherapy and can be different from targeted therapy (ie, the chemotherapy-like side effects of myelosuppression and mucositis). I think that it will be important to keep an eye on the next-generation ADCs in development, such as izalontamab brengitecan (iza-bren), a novel bispecific ADC simultaneously targeting both EGFR and HER3.