The Landscape of EGFR Exon 20-Positive Lung Cancer Treatment

Helena Yu, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, discusses the treatment landscape of EGFR exon 20 insertion (ex20ins)-mutated non–small cell lung cancer (NSCLC) and how the novel agent zipalertinib fills unmet needs.

According to data from the phase 2b REZILIENT1 study (NCT04036682) presented at the IASLC 2025 World Conference on Lung Cancer earlier this month, zipalertinib continues to show clinically meaningful efficacy with a manageable safety profile in this patient population.

The current therapeutic landscape for EGFR exon20ins mutation-positive lung cancer highlights a distinct need for more convenient and patient-friendly treatment options. Amivantamab (Rybrevant), a commonly used drug in this population, functions as an EGFR-MET bispecific antibody and is administered intravenously or subcutaneously. The delivery method contrasts with many other successful targeted therapies in lung cancer, which are often administered orally. Oral therapies frequently offer advantages in terms of patient preference, convenience, and potentially better overall tolerability, creating a significant unmet need for an effective oral targeted therapy in this particular patient population.

In response to this gap, the novel agent zipalertinib was developed. Zipalertinib is an oral EGFR tyrosine kinase inhibitor (TKI) designed to specifically target this challenging mutation. The potential of zipalertinib was initially explored in a phase 1/2a study. This initial research proved crucial, successfully demonstrating the drug's promising clinical activity and an acceptable safety profile. Furthermore, the study was instrumental in identifying the optimal dose of zipalertinib to carry forward into larger, more definitive phase 2 and phase 3 clinical trials. The positive outcomes from this foundational study were essential in paving the way for the subsequent REZILIENT1 phase 2b study, which aimed to further evaluate zipalertinib's efficacy and safety.

To fully appreciate the significance of this research, one must understand the prevalence of EGFR mutations in lung cancer. EGFR-mutant lung cancer accounts for approximately 15% to 20% of all lung cancer cases diagnosed in the United States. However, this prevalence is notably higher on a global scale, where the figure rises to an estimated 30% to 35% of all lung cancers.