HER2-Mutated NSCLC: A Therapeutic Breakthrough

On August 7, 2025, a select group of hematologist-oncologists and medical oncologists from academic and cancer specialty institutions participated in a virtual workshop moderated by Joshua Sabari, MD. The group discussed insights and considerations for identifying and managing HER2-mutated non–small cell lung cancer (NSCLC), and provided perspectives on recently presented data from trials evaluating antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs) for the treatment of HER2-mutated NSCLC.

Key Takeaways

• Next-generation sequencing (NGS) and immunohistochemistry (IHC) testing are routine for diagnosing HER2-mutated NSCLC.
• Experience using trastuzumab deruxtecan (T-DXd) is extensive, however much of that experience comes from breast and/or gastric cancers and it is unclear why T-DXd appears to be less efficacious in HER2-mutated lung cancer compared to breast and other cancers.
• Zongertinib efficacy data were viewed to be impressive and toxicities manageable; there is a high level of enthusiasm about its pending approval.
• With the approval of newer agents, it is anticipated that targeted therapy will become preferred frontline over chemotherapy.

Session Overview and Presentation Highlights

Testing Recommendations for Diagnosing HER2-Mutated NSCLC

Dr Sabari described the incidence, distribution, and types of HER2 alterations in NSCLC (gene amplification, overexpression, and gene mutation). How HER2 alterations differ from those occurring in breast cancer, the clinical significance of HER2 in NSCLC, and NCCN testing recommendations were reviewed.1 Advisers were asked to share their current practices for identifying patients with HER2 mutations.

ADC Class Review for the Treatment of HER2-Mutated NSCLC

Study design, efficacy, and safety results for DESTINY-Lung01 (NCT03505710) and HORIZON-Lung (NCT04818333) trials were presented, which evaluated T-DXd and trastuzumab rezetecan, respectively. Advisers were asked to share their experience using T-DXd, managing its adverse effects, and their approach to treating brain metastases in patients with HER2-mutated NSCLC.2-5 Dr Sabari detailed the phase 1b trial of izalontamab brengitecan (BL-B01D1), highlighting response, HER2 subanalysis, and EGFR x HER3 bispecific ADC safety.6 Perspectives on the izalontamab brengitecan data were solicited, along with insights as to what treatments are considered for patients who progress on T-DXd and opinions on the role ADCs will play in the treatment of HER2-mutated NSCLC in the future.

TKIs in Development for HER2 NSCLC

Efficacy and safety results and patient-reported outcomes from the zongertinib Beamion LUNG-1 trial (NCT04886804) and sevabertinib (BAY 2927088) efficacy and safety results from select cohorts of the phase 1/2 SOHO-01 trial (NCT05099172) were presented.7-9 Advisers were asked to share their insights and perspectives on how efficacy results, safety profiles, and oral administration of zongertinib and sevabertinib might influence their role in treating those who have received prior systemic therapy. Additional clinical trials evaluating selective HER2 TKIs were briefly reviewed by Dr Sabari.

Discussion Themes/Summary

Faculty reported conducting NGS and IHC testing universally, with both tissue and plasma tested by most; they identified plasma testing as preferred if a diagnosis is needed quickly. Insufficient tissue availability was identified as one of the few barriers to testing and justification for concurrent plasma testing.

Familiarity with T-DXd is widespread, and while the panel expressed comfort with managing toxicities when using T-DXd in other cancers, some are more cautious about using it in the HER2-mutated NSCLC population due to the risk of interstitial lung disease (ILD) in patients who already have lung-related symptoms, especially those with preexisting ILD. Based on experience in breast cancer, many advisers said they would consider using T-DXd in NSCLC patients with brain metastases; however, a TKI is preferred by some because the smaller molecule is more likely to have better central nervous system penetration than a larger ADC. Compared to its efficacy in HER2-mutated breast and other cancers, several advisers noted T-DXd’s lower efficacy in NSCLC and questioned why that might be.

The data presented for zongertinib were met with a very high level of enthusiasm, especially given that the study included a pretreated population in a difficult-to-treat disease. The adverse-effect profile was also noted to be more favorable than T-DXd, and many predicted that zongertinib will eventually become a frontline treatment. While the convenience of oral therapy is typically an advantage, it was pointed out that due to delays related to prior authorization and obtaining zongertinib from a specialty pharmacy, it may be easier to start a patient on an IV therapy the same or next day, especially if they have a port in place. It was suggested that access barriers could be overcome by making zongertinib starter packs or samples available to bridge approval and procurement delays.

Approval of zongertinib is highly anticipated, with broad adoption for second-line treatment expected; movement into first-line treatment is also predicted. There is general appreciation for the development of new treatments and optimism for patients who will soon have more and safer options for the treatment of HER2-mutated NSCLC.

Unmet Needs and Recommendations

• Consider having a liberal sampling program or starter pack for zongertinib so that patients can be started while the prior authorization and drug procurement from specialty pharmacy processes are taking place.
• Studies evaluating zongertinib in combination with T-DXd were suggested.
• There is an unmet need for effective treatments in brain metastases and after progression on T-DXd.

References

1. NCCN. Clinical practice guidelines in oncology: non-small cell lung cancer, version 8.2025. Accessed August 19, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
2. Azar I, Alkassis S, Fukui J, et al. Spotlight on trastuzumab deruxtecan (DS-8201, T-DXd) for HER2 mutation positive non–small cell lung cancer. Lung Cancer (Auckl). 2021;12:103-114. doi:10.2147/LCTT.S307324
3. Janne PA, Goto Y, Kubo T, et al. Trastuzumab deruxtecan (T-DXd) in patients with HER2-mutant metastatic non–small cell lung cancer (mNSCLC): final analysis results of DESTINY-Lung02. J Clin Oncol. 2024;42 (suppl 16; abstr 8543). doi:10.1200/JCO.2024.42.16_suppl.8543
4. Li BT, Planchard D, Goto K, et al. 1321MO Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2 (ERBB2)-mutant (HER2m) metastatic non–small cell lung cancer (NSCLC) with and without brain metastases (BMs): pooled analyses from DESTINY-Lung01 and DESTINY-Lung02. Ann Oncol. 2023;34(S2):S762-S763. doi:10.1016/j.annonc.2023.09.2354
5. Lu S, Li Z, Wang Y, et al. SHR-A1811, a HER2-directed antibody-drug conjugate (ADC), in advanced HER2-mutant non-small cell lung cancer (NSCLC): updated phase 2 results from HORIZON-Lung. Cancer Res. 2005;85(8)(suppl 2):CT009. doi:10.1158/1538-7445.AM2025-CT009
6. Yang Y, Li Z, Ma Y, et al. Phase I study of iza-bren (BL-B01D1), an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with driver genomic alterations (GA) outside of classic EGFR mutations. J Clin Oncol. 2025; 43(suppl 16; abstr 3001). doi:10.1200/JCO.2025.43.16_suppl.3001
7. Heymach JV, Ruiter G, Ahn MJ, et al. Zongertinib in previously treated HER2-mutant non-small-cell lung cancer. NEJM. 2025;392(23):2321-2333. doi:10.1056/NEJMoa2503704
8. Sabari J, Nadal E, Hendriks L, et al. Patient-reported outcomes (PRO) evaluating physical functioning and symptoms in patients with pretreated HER2-mutant advanced non-small cell lung cancer (NSCLC): results from the Beamion LUNG-1 trial. J Clin Oncol. 2025; 43(suppl 16; abstr 8620). doi:10.1200/JCO.2025.43.16_suppl.8620
9. Loong HHF, Li L, Wu L, et al. SOHO-01: safety and efficacy of BAY 2927088 in patients with advanced HER2-mutant non-small cell lung cancer (NSCLC) who were pretreated but naïve to HER2-targeted therapy or had no received any treatment for advanced disease. J Clin Oncol. 2025; 43(suppl 16; abstr 8504). doi:10.1200/JCO.2025.43.16_suppl.8504