Oral TKIs, CNS Activity, and Pipeline Data in EGFR Exon 20 NSCLC

In "Oral TKIs, CNS Activity, and Pipeline Data in EGFR Exon 20 NSCLC," Dr. Yu explores oral monotherapy data, central nervous system activity, and what lies ahead in drug development.

Dr. Yu notes that first-line sunvozertinib data were published in the New England Journal of Medicine and presented at ASCO in 2026. Amivantamab and zipalertinib were each combined with chemotherapy, mirroring the addition of osimertinib to chemotherapy for common sensitizing mutations. Sunvozertinib, by contrast, was tested as monotherapy against chemotherapy. It improved median progression-free survival to 10.3 months versus 7.5 months, with higher response rates. Diarrhea is a significant side effect. Still, she observes that many patients will choose an oral option even when it appears numerically less efficacious. The drug is not currently manufactured for the US market, though she expects access soon.

Dr. Yu stresses that CNS penetration is a key differentiator for sequencing. She urges sponsors to generate CNS data early in development. Zipalertinib shows significant evidence of CNS activity, and an ongoing REZILIENT cohort is evaluating patients with measurable brain metastases. She will present that analysis at ESMO this year. Amivantamab was once assumed too bulky to cross the blood-brain barrier, yet case reports now suggest CNS activity. She expects most of these TKIs to penetrate the CNS, though prospective sunvozertinib data are limited.

Looking ahead, Dr. Yu hopes to see oral targeted therapies approved for first-line use. She wants sequencing data showing whether patients can move from an oral TKI to amivantamab, and vice versa. A dedicated cohort has shown amivantamab can be effective after zipalertinib. Understanding resistance mechanisms will also guide next steps. She then reviews a negative phase 3 trial comparing two firmonertinib doses with platinum-based chemotherapy. Median progression-free survival was 11 months at 240 mg, 8.4 months at 160 mg, and 9.5 months with chemotherapy, without a statistically significant difference. Firmonertinib remains under first-line study for PACC and other uncommon EGFR mutations.

In "Adoption, Payer Priorities, and What's Next in EGFR Exon 20 NSCLC," Dr. Yu closes the series by examining real-world adoption, the priorities of payers, and how first-line care may change after upcoming regulatory decisions.