HER-2 exon 20 insertion

P1/2, N=251, Recruiting, Pierre Fabre Medicament | N=185 --> 251 | Trial completion date: Jun 2028 --> Dec 2029 | Trial primary completion date: Jun 2027 --> Dec 2029

She received eight additional cycles (nine in total), resulting in tumor regression without ILD recurrence. Given that T-DXd is currently the only approved HER2-targeted therapy for NSCLC in our country, this case underscores the importance of early detection and appropriate management of ILD to maximize the therapeutic benefits.

We furthermore demonstrate the activity of sevabertinib in a cancer cell line dependent on a fusion of NRG1, a ligand for the HER2 family member and heterodimerization partner, HER3. Finally, we report patient responses to sevabertinib from a Phase 1/2 clinical trial, indicating potential benefit for patients with HER2-mutant lung cancer.

P1, N=160, Active, not recruiting, ArriVent BioPharma, Inc. | Trial completion date: Sep 2025 --> Dec 2025 | Trial primary completion date: Sep 2025 --> Jun 2025

P1/2, N=350, Recruiting, ORIC Pharmaceuticals | Trial completion date: Mar 2026 --> Sep 2027 | Trial primary completion date: Mar 2025 --> Sep 2026

The BM incidence in HER2-mutated NSCLC is high and similar across genetic subtypes. ADC treatments may potentially contribute to prolonged OS for patients with HER2-mutated NSCLC and BM. Besides, brain radiotherapy could confer significant OS benefits.

To the best of our knowledge, this study represents the first reported case demonstrating the promising efficacy of pyrotinib in HER2-altered NSCLC harboring the ra-re exon 12 R456C mutation. Heterogeneous alterations in the HER2 extracellular segment, such as R456C, may be targetable and could confer survival benefits with HER2-targeted inhibitors.

P1, N=91, Terminated, Black Diamond Therapeutics, Inc. | Phase classification: P1/2 --> P1

After several subsequent lines of treatment including erlotinib and carboplatin+pemetrexed+osimertinib, repeat genetic sequencing identified a HER2 exon 20 insertion (A775_G776insYVMA) in both blood and tissue. This report represents the first published case detailing the safety and efficacy of a combination fam-trastuzumab-deruxtecan and osimertinib in a patient with NSCLC and HER2-mutated resistance after EGFR-targeted therapy. The findings from this report suggest that fam-trastuzumab-deruxtecan can be safely given in combination with osimertinib and should be considered as subsequent-line therapy for patients who progress on osimertinib and develop a HER2 resistance mutation.

P1/2, N=334, Active, not recruiting, Takeda | Trial completion date: Mar 2025 --> Oct 2026 | Trial primary completion date: Mar 2025 --> Oct 2026

This study highlights the clinical features and outcomes of advanced HER2-mutant NSCLC in Taiwan. PC + ICI may be more effective than other regimens as first-line therapy. The prognostic role of HER2 exon 20 insertion mutations warrants further investigation.

STX-721 (53) is a potent, irreversible inhibitor of the majority of EGFR/HER2 ex20ins mutants and demonstrates excellent mutant vs wild-type selectivity both in vitro and in vivo. STX-721 is currently in phase 1/2 clinical trials for EGFR/HER2 ex20ins-driven NSCLC.