Dr Goldberg on Potential Strategies to Overcome Osimertinib Resistance in EGFR+ NSCLC

Sarah Goldberg, MD, MPH, associate professor, medical oncology, associate director, Medical Oncology-Hematology Program, research director, Center for Thoracic Cancers, chief, Thoracic Oncology, Yale School of Medicine, thoracic oncologist, Yale Cancer Center, Smilow Cancer Hospital, discusses potential strategies to overcome osimertinib (Tagrisso) resistance in EGFR-positive metastatic non–small cell lung cancer (NSCLC).

In April, 2018, osimertinib gained FDA approval as a first-line treatment for patients with NSCLC who express EGFR exon 19 deletions or exon 21 L858R mutations and have therefore acquired resistance to first-generation EGFR-directed TKIs. This was followed by the agent’s approval in the adjuvant setting for this same patient population in December 2020. 

Although osimertinib has substantially improved the treatment of patients with EGFR-mutant NSCLC over the past 5 years, all tumors will eventually become resistant to this agent. EGFR mutations are the most frequently observed alterations associated with resistance to osimertinib, but there is a wide array of alternative genetic pathways that may show involvement, Goldberg begins. Many research efforts in this space are focused on identifying these mechanisms of resistance, and developing effective, targeted strategies to overcome them, Goldberg says.

Many cases of osimertinib resistance also involve off-target mechanisms such as MET amplification. MET amplification is more commonly associated with this agent in the first-line setting than with other first- and second-generation EGFR inhibitors, Goldberg states. Accordingly, preliminary clinical data have demonstrated that the addition of MET inhibitors to first-line osimertinib can be effective in combating resistance, Goldberg reports. However, this approach has not yet gained FDA approval and is still under investigation, she notes.

More rare genetic alterations such as RET and ALK fusions have also been occasionally implicated in the emergence of osimertinib resistance, Goldberg adds. These are both potential targets for the future development of novel strategies to address or prevent osimertinib resistance, Goldberg concludes.