EGFR exon 20 insertion

The management of human epidermal growth factor receptor 2 (HER2)-mutant non-small cell lung cancer (NSCLC) remains a significant clinical challenge, with limited effective and accessible treatment options beyond antibody-drug conjugates such as trastuzumab deruxtecan (T-DXd)...Following chemotherapy and sintilimab failure in August 2025 due to progressive disease, furmonertinib rechallenge at 160 mg/day again induced a response within 5 days, with no grade ≥3 adverse events...The structural homology between HER2 p.Y772_A775dup and EGFR exon 20 "near-loop" insertions may facilitate TKI binding. Furmonertinib emerges as a potential, cost-effective oral therapeutic alternative for this patient population, especially when standard therapies are not feasible, warranting further prospective investigation.

There are several challenges including the lack of randomized perioperative trials, heterogeneity in pathological response assessment, and uncertainty regarding the reliability of surrogate endpoints. With the increasing integration of next-generation sequencing into the standard diagnostic workup of early-stage NSCLC, biomarker-directed perioperative strategies supported by prospective clinical trials enriched for specific genotypes are critical to achieving sustained clinical outcomes in these patient subgroups with rare targetable alterations.

However, its therapeutic activity against central nervous system metastases remains uncertain. Here, we report a case of a patient with NSCLC who developed leptomeningeal seeding (LMS) after the failure of first-line therapy and showed a marked clinical and radiologic response to amivantamab monotherapy.

The results show the limited effectiveness of TKIs in patients with EGFR Ex20Ins and highlight the need for specific therapies. Platinum-based chemotherapy performed better in preventing disease relapse.

There were no significant differences in terms of safety between the two treatment groups. First-line chemotherapy combined with immunotherapy was associated with significantly longer PFS than chemotherapy alone in patients with EGFR ex20ins-mutant NSCLC, without increased toxicity.

The study also highlighted superior sensitivity of NGS over PCR in detecting E20ins. This underscores necessity for improved detection strategies and effective treatments tailored to this mutation subgroup.

P3, N=285, Active, not recruiting, Taiho Oncology, Inc. | Recruiting --> Active, not recruiting

P1/2, N=30, Active, not recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Dec 2026 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2026

While responses to first- and second-generation EGFR tyrosine kinase inhibitors have been reported in EGFR-mutant CUP, evidence for the third-generation EGFR-TKI osimertinib remains limited. These cases highlight that early molecular profiling can identify actionable targets and enable lung cancer-standard therapies even when the primary lesion remains undetected.

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.