Updates in the Diagnosis and Management of HER2-Mutant NSCLC

Scientific Interchange & Workshop | <b>Updates in the Diagnosis and Management of HER2- Mutant NSCLC</b>

On January 30, 2025, a group of thoracic oncologists gathered for an in-person workshop to discuss advances in diagnosing and treating non–small cell lung cancer (NSCLC) related to an HER2 mutation. The session was moderated by Joshua Sabari, MD; and Benjamin Levy, MD. As they focused on HER2 biomarker testing, treatment sequencing, and emerging therapies (including antibody-drug conjugates [ADCs] and TKIs), the faculty reviewed clinical trial data, shared real-world experiences, and debated evolving treatment strategies.

Session Overview & Highlights

Diagnosing HER2-Mutant NSCLC

Faculty emphasized the importance of comprehensive molecular testing using both tissue and liquid biopsy to ensure that HER2 mutations are not missed. Adoption of next-generation sequencing (NGS) varies across institutions with some using in-house panels and others relying on commercial assays like Caris, Foundation, or Tempus. HER2 immunohistochemistry (IHC) testing remains inconsistent due to limited tissue availability and financial barriers. Many patients seeking a second opinion lack full NGS results upon referral, which delays optimal treatment selection.

ADCs in HER2-Mutant NSCLC

Trastuzumab deruxtecan (T-DXd) is the preferred second-line treatment per NCCN and FDA guidelines; its frontline potential is being evaluated in HERTHENA-Lung04. Faculty reviewed data from the DESTINY-Lung01, DESTINY-Lung02, and DESTINY-PanTumor02 trials that continue to shape the role of T-DXd in treatment sequencing. Interstitial lung disease (ILD) remains a concern that requires early monitoring and steroid intervention for patients on T-DXd. Central nervous system (CNS) efficacy is uncertain, with some faculty reporting intracranial responses and others observing progression of brain disease. Toxicities including fatigue and ILD are common; cardiotoxicity, however, appears to be minimal, leading to questions about the necessity of routine echocardiography. A key debate emerged over whether T-DXd functions more as targeted therapy or chemotherapy given its mechanism of action and toxicity profile.

HER2-Targeted TKIs: Emerging Options

The use of HER2-targeted TKIs, particularly zongertinib, is gaining traction. When compared with previous TKIs (eg, poziotinib), zongertinib demonstrates high selectivity and tolerability. Faculty reviewed Beamion LUNG-1 data and discussed the ongoing Beamion LUNG-2 trial, evaluating zongertinib’s efficacy compared to chemotherapy. Poziotinib therapy failed due to toxicity despite promising early response rates. Zongertinib avoids wild-type EGFR inhibition, reducing the toxicity seen with previous TKIs. CNS efficacy remains a key concern, as patients with HER2-mutant disease frequently develop brain metastases. Other HER2-targeted TKIs (eg, VAL-330, Enliven-002, Iambic-001) are in development with a focus on CNS activity and durability. Faculty debated the place of zongertinib in treatment sequencing; some favored first-line use due to oral administration and tolerability, whereas others preferred to use it after T-DXd.

Discussion Themes and Expert Insights

HER2-mutant NSCLC appears less responsive to chemotherapy, which raises concerns about the use of chemotherapy-immunotherapy regimens in this setting. Financial barriers continue to impact treatment choices, particularly for HER2 IHC 2+ patients, who currently do not qualify for T-DXd under existing guidelines.

The future of HER2-mutant NSCLC treatment will likely involve combination approaches that incorporate ADCs, TKIs, and bispecific antibodies and focus on sequencing strategies to improve durability of response. Faculty emphasized the need to study resistance mechanisms, as a better understanding of HER2-driven pathways could guide more effective treatment strategies.

Unmet Needs and Recommendations

Standardized HER2 testing is critical for reducing missed diagnoses and ensuring timely treatment selection. Given the high rate of CNS metastases, HER2-targeted therapies must demonstrate strong intracranial activity to prevent disease progression.

Faculty debated whether TKIs like zongertinib should replace ADCs in the frontline setting, emphasizing the need for further clinical validation. Future research should focus on combination strategies (eg, ADCs plus TKIs, chemotherapy combinations, or novel targeted agents) to improve treatment durability.

Finally, payer coverage and reimbursement policies must evolve along with treatment advances to ensure broad patient access to new HER2-targeted therapies.

Conclusion

The treatment landscape for NSCLC related to HER2 mutation is evolving rapidly, and ongoing clinical trials are poised to reshape frontline therapy. While T-DXd remains the preferred second-line option, HER2-targeted TKIs like zongertinib are gaining attention due to oral convenience and lower toxicity.

Faculty agreed that treatment sequencing, CNS activity, and combination approaches must be carefully considered moving forward. With multiple novel therapies in development, the coming years are expected to redefine HER2-mutant NSCLC treatment paradigms and provide new hope for patients with this rare but challenging disease.

References

  • NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 3.2025. Accessed January 30, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  • Yu Y, Zhang X, Li W, Fan Y. Targeting HER2 alterations in non-small cell lung cancer: Therapeutic breakthrough and challenges. Cancer Treat Rev. 2023;114:102520. doi:10.1016/j.ctrv.2023.102520
  • Reuss JE. Trastuzumab deruxtecan in non-small cell lung cancer. Clin Lung Cancer. 2021;22(5):e655-e664. doi:10.1016/j.cllc.2021.05.006
  • Jänne 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. Abstract presented at: the 2024 Annual Meeting of the American Society of Clinical Oncology; May 31 to June 4, 2024; Chicago, IL. Abstract 8543.
  • Li BR, 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. Abstract presented at: the European Society for Medical Oncology Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract 1321MO. OncologyPro. Accessed February 19, 2025. https://oncologypro.esmo.org/meeting-resources/esmo-congress-2023/trastuzumab-deruxtecan-t-dxd-in-patients-pts-with-her2-erbb2-mutant-her2m-metastatic-non-small-cell-lung-cancer-nsclc-with-and-without-br
  • Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2024;42(1):47-58. doi:10.1200/JCO.23.02005
  • Daiichi Sankyo. Trastuzumab deruxtecan [package insert]. Revised April 2024.
  • Yamamoto N, Opdam F, Barve M, et al. Beamion Lung 1, a phase Ia/Ib trial of the HER2 TKI, BI 1810631 in patients with advanced solid tumors with HER2 aberrations. Abstract presented at: theInternational Association for the Study of Lung Cancer World Conference on Lung Cancer 2023; September 9-12, 2023; Singapore. Abstract MA13.08. Accessed February 19, 2025. https://cattendee.abstractsonline.com/meeting/10925/presentation/1006
  • Ruiter H, De Langen AJ, et al. Phase Ib analysis of Beamion LUNG-1: zongertinib (BI 1810631) in patients with HER2-mutant NSCLC. Abstract presented at: theInternational Association for the Study of Lung Cancer World Conference on Lung Cancer 2024; September 7-10, 2024; San Diego, CA. Abstract PL04.04. Boehringer Ingelheim. Accessed February 19, 2025. https://content.boehringer-ingelheim.com/DAM/71718ecf-c236-4a8c-9f3e-b1f0010dcb8e/congress%20hub%20wclc%202024%20poster%20presentation%20slides%20-%20ruiter.pdf
  • Wu YL, Opdam F, Yamamoto N, Yoshida T, Heymach J. P3.12D.06 Beamion LUNG-1 And LUNG-2: the zongertinib clinical program in patients with non-small cell lung cancer and HER2 mutations. Abstract presented at: the International Association for the Study of Lung Cancer World Conference on Lung Cancer 2024; September 7-10, 2024; San Diego, CA. Abstract P3.12D.06. Accessed February 19, 2025.
  • Girard N, Kim TM, Kim YR, et al. Safety and anti-tumor activity of BAY 2927088 in patients with HER2-mutant NSCLC: results from an expansion cohort of the SOHO-01 phase I/II study. J Clin Oncol. 2024;42(suppl 17):LB8598
  • Le X, Girard N, Janne PA, et al. PL04.03 Safety and efficacy of BAY 2927088 In patients with HER2-mutant NSCLC: expansion cohort from the phase I/II SOHO-01 study. J Thorac Oncol. 2024;19(10; suppl):S4. doi:10.1016/j.jtho.2024.09.017
  • Sun Y, Andrews KL, Tangpeerachaikul A, et al. Abstract 1979: Preclinical characterization of NVL-330, a selective and brain penetrant HER2 tyrosine kinase inhibitor with broad activity on HER2 oncogenic alterations. Cancer Res. 2024;84(suppl 6):1979. doi:10.1158/1538-7445.AM2024-1979