Dr Girard on Mechanisms of Action for TKIs vs ADCs in HER2-Mutated NSCLC

“With TKIs, we are inhibiting the intracellular domain of HER2—the kinase domain—which is associated with the activation of the pathways involved in cell proliferation and resistance to apoptosis. [Conversely,] with antibody-drug conjugates, it’s a completely different strategy, where you have drugs that [comprise] an antibody targeting the extracellular part of HER2 [and] a cytotoxic payload.”

Nicolas Girard, MD, professor, respiratory medicine, Versailles Saint Quentin University; head, Curie-Montsouris Thorax Institute; chair, Medical Oncology Department, Institut Curie, discusses differences in the mechanisms of action for HER2-directed TKIs vs antibody-drug conjugates (ADCs) in the treatment of patients with HER2-mutant non–small cell lung cancer (NSCLC).

TKIs and ADCs employ distinct mechanisms of targeting HER2 mutations; accordingly, each drug class confers unique benefits and treatment considerations, Girard begins. TKIs inhibit the intracellular kinase domain of HER2, which drives pathways associated with cell proliferation and resistance to apoptosis, he details. These agents bind to the ATP binding pocket of HER2, disrupting downstream signaling, Girard adds. However, the presence of HER2 mutations within the ATP binding domain can affect the efficacy of TKIs, Girard notes. In such cases, TKIs with alternative binding conformations may be required, he explains. The advantages of TKIs include their oral administration and well-characterized safety profiles, though their sensitivity can vary depending on the specific HER2 mutation present, according to Girard.

In contrast, ADCs consist of an antibody targeting the extracellular domain of HER2,which is linked to a cytotoxic payload, Girard continues. The antibody component inhibits HER2-mediated signaling at the cell surface and delivers the cytotoxic payload directly into HER2-expressing cancer cells, he says. This targeted delivery enhances specificity for cancer cells compared with systemic chemotherapy, Girard adds. ADCs also demonstrate efficacy across HER2 alterations, including mutations, amplifications, and overexpression, he reports. This broadens their therapeutic potential regardless of the specific HER2 alteration expressed, Girard concludes.