EGFR exon 20 mutation

iza-bren demonstrated encouraging antitumor activity and a manageable safety profile in pretreated NSCLC patients with diverse GAs outside of classical EGFR mutations, especially in EGFR exon20ins/nonclassical and HER2 mutations.

P3, N=308, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Sep 2026 --> Aug 2027

Since 1997, EGFR tyrosine kinase inhibitors (EGFR-TKIs) have evolved from first-generation agents, such as gefitinib, erlotinib, and icotinib, to second-generation agents like afatinib and dacomitinib, now to third-generation agents, including osimertinib, aumolertinib, furmonertinib, befotertinib, rezivertinib, rilertinib, limertinib, lazertinib, mifanertinib for EGFR L858R, sunvozertinib for EGFR exon 20 insertion (20ins), and zorifertinib for EGFR-sensitive mutation with brain metastases. Over the past 30 years, substantial advancements have been made in the comprehensive management of EGFR-mutant NSCLC. This systemic review provides the history of the development of EGFR-TKI therapy for NSCLC from 1997 to 2026, highlighting clinical milestones, emerging therapies, and future directions in this rapidly evolving field.

Recently developed agents such as amivantamab and mobocertinib have improved response rates, yet challenges related to tolerability, CNS penetration, and durability of benefit persist. Early-phase clinical trials, including the WU-KONG series, have reported promising clinical efficacy, including objective response rates ranging from 44-60% in previously treated patients and meaningful activity in treatment-naïve cohorts. The tolerability profile of the drug seems manageable, with diarrhea, rash, and stomatitis among the most commonly observed adverse events; these, however, tend to be milder compared with other agents targeting EGFR Ex20ins.

P2, N=93, Terminated, M.D. Anderson Cancer Center | Trial completion date: Dec 2027 --> Feb 2026 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2027 --> Feb 2026; <75% participation

Following the Chinese Society of Clinical Oncology and National Comprehensive Cancer Network guidelines for lung cancer, the patient was treated with furmonertinib, a third-generation targeted antitumor therapy. The present case provides notable insights for the diagnosis and treatment of NSCLC with coexisting EGFR exon 19 deletion and exon 20 T790M missense mutation, and a rare clinical example of breast metastasis from lung cancer.

P1/2, N=35, Not yet recruiting, Fondazione Ricerca Traslazionale

P2/3, N=131, Recruiting, Taiho Oncology Inc.

Amivantamab plus chemotherapy significantly delays symptomatic progression without compromising health-related quality of life, reinforcing its role as a first-line treatment for Ex20ins-mutated NSCLC.

Amivantamab-chemotherapy demonstrated superior PFS vs chemotherapy and represents a new standard of care for first-line treatment of Asian participants with Ex20ins-mutated NSCLC.

P2, N=520, Recruiting, Janssen Research & Development, LLC | Trial completion date: Aug 2027 --> Aug 2028