Ivesa (firmonertinib)

Sunvozertinib, an oral, selective EGFR inhibitor, received U.S. Food and Drug Administration (FDA) accelerated approval in 2025, with an ORR of 46% and a median duration of response (DOR) of 11.1 months in platinum-pretreated patients. Emerging therapies, including zipalertinib and furmonertinib, have shown promising results in early-phase trials, with zipalertinib demonstrating activity in patients pretreated with amivantamab (ORR 31.5%) and furmonertinib achieving remarkable responses in treatment-naive patients (ORR 78.6% at 240 mg). This comprehensive review analyzes the molecular biology, structural mechanisms, current therapeutic options, and novel investigational agents for EGFR ex20ins-mutated NSCLC.

This comparative study demonstrated the improved and consistent activity of aumolertinib across diverse uncommon EGFR E19del subtypes compared to osimertinib, due to its enhanced binding affinity and structural adaptability. These findings support molecular subtype-guided TKI selection, aumolertinib as a first-line option for patients harboring uncommon EGFR E19del variants, particularly in settings lacking comprehensive molecular stratification.

P=N/A, N=4000, Completed, Fudan University | Trial completion date: Sep 2024 --> Feb 2026

The patient was switched to firmonertinib, with subsequent tumor regression. Five of the eleven cases harbored EGFR T790M, yielding a prevalence of 45%, which is similar to that seen in classical EGFR mutations. This case suggests that EGFR T790M mediates acquired resistance to first- and second-generation EGFR-TKIs in EGFR-KDD, mirroring the resistance pattern observed in classical EGFR mutations.

We compare established and emerging perioperative approaches, including aumolertinib, furmonertinib, befotertinib, and neoadjuvant or perioperative osimertinib-based strategies, while underscoring that encouraging early signals should not be equated with established survival benefit before mature event-free survival or overall survival data are available. We also address three unresolved questions: the role of adjuvant chemotherapy in the osimertinib era, the extent to which targeted therapy should move into the neoadjuvant setting, and whether minimal residual disease assessment may eventually support treatment personalization. Overall, current evidence supports adjuvant osimertinib as the reference standard for resected EGFR-mutant NSCLC, whereas other third-generation adjuvant TKIs and perioperative targeted strategies remain promising but should be interpreted according to the maturity of their supporting data and the presence or absence of overall survival benefit.

P2, N=25, Recruiting, Tianjin Medical University Cancer Institute and Hospital

P4, N=535, Recruiting, Peking Union Medical College Hospital; Peking Union Medical College Hospital

P=N/A, N=50, Shanghai General Hospital; Shanghai General Hospital

P2, N=36, Recruiting, West China Hospital, Sichuan University; West China Hospital, Sichuan University | Not yet recruiting --> Recruiting

However, both 3-year RFS and 5-year OS were significantly better in group A (P=0.045; P=0.046) and group B (P=0.004; P=0.006) compared with group C. For peripheral solid stage IA3 LUAD with pulmonary dysfunction, SR combined with EGFR-TKI did not increase the incidence rate of grade 1-2 AEs, and the 3y-RFS and 5y-OS were superior to those SR alone. Better study designs are required to compare long term survival between SR + EGFR-TKI and lobectomy.

P2, N=45, Not yet recruiting, Shanghai Pulmonary Hospital, Shanghai, China

P2, N=46, Completed, Sun Yat-sen University | Recruiting --> Completed | N=30 --> 46