Dr. Camidge on Mechanisms of Resistance to TKIs in NSCLC

D. Ross Camidge, MD, PhD, director of thoracic oncology, University of Colorado, discusses mechanisms of resistance to targeted therapies in oncogene-driven non—small cell lung cancer (NSCLC).

Even though osimertinib (Tagrisso) is a better central nervous system (CNS) penetrant than the earlier-generation EGFR tyrosine kinase inhibitors (TKIs), it is not a perfect CNS drug, Camidge says. It is marketed as a CNS penetrant, but patients are still experiencing disease progression in the brain sooner than they are experiencing progression in the rest of the body. The future of research will focus on determining if the problem lies in the current dose of osimertinib or if there are better TKIs that can be developed to more effectively control CNS metastases.

Researchers understand most of the mechanisms of disease progression in the body, Camidge notes. For instance, there is an additional EGFR mutation called C797S that can cause disease progression, and there was some excitement in the field over the possibility of adding earlier-generation inhibitors to overcome this challenge. Although this approach was effective in preclinical studies, it has not proven successful in actual patients.

Clinical trials adding in antibodies such asnecitumumab (Portrazza) or cetuximab (Erbitux) are being conducted in the hope that this approach will effectively control the disease—at least for a short period of time—but this will also add toxicity, Camidge says. An actionable mechanism of resistance is the MET pathway, he adds, particularly in patients treated with osimertinib because C797S is being suppressed.