Dr Levy on Unanswered Questions Regarding the Mechanism of Action of ADCs in NSCLC

Benjamin Levy, MD, clinical director, Medical Oncology, Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital; associate professor, oncology, Johns Hopkins University School of Medicine, discusses unanswered questions regarding the mechanism of action of antibody-drug conjugates (ADCs) and unmet needs regarding the use of biomarkers to select patients with non–small cell lung cancer (NSCLC) who are most likely to respond to treatment with these agents.

ADCs include a monoclonal antibody component that targets a cancer cell surface protein and is then internalized by the cell, into which it releases a payload, Levy says. However, beyond this, several questions remain regarding the mechanism of action of ADCs, he notes. For instance, ADCs also have a bystander effect, by which payload moieties, once released, can move to and kill adjacent cells—even those that don’t have the ADC target, Levy explains.

Antibody-dependent cellular toxicities should also be considered, according to Levy. Future research with ADCs may focus on the ability of these agents to engage effector immune cells, he notes.

A lot of work is needed to increase the accuracy of biomarker selection for ADCs, Levy says. Firstly, the immunohistochemistry (IHC) platforms currently in use may not be ideal for accurately predicting the efficacy of these agents in different patient subgroups, Levy explains. Other methods of analyzing IHC results may prove more effective, he adds. Secondly, driver mutations, such as HER2 exon 20 insertion mutations, ALK rearrangements, or EGFR mutations, may be the most accurate predictors of ADC response in patients with NSCLC, according to Levy.

Furthermore, a blood-based biomarker may be more effective at predicting ADC response than tissue-based biomarkers, Levy adds. The NSCLC research field is only beginning to understand which patients will respond to ADCs and which will develop toxicities, and further developments will unfold over the next couple years, Levy concludes.