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HER2 Directed ADCs in NSCLC
Evolving Role of HER2-Directed Antibody–Drug Conjugates in the Management of Patients With Advanced NSCLC

Released: November 05, 2025

Matthew Gubens
Matthew Gubens, MD, MS, FASCO
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Key Takeaways
  • HER2 can be mutated, overexpressed, or amplified in non-small-cell lung cancer (NSCLC), and these changes are not always seen together; some tumors harbor HER2 mutations without HER2 overexpression, and vice versa.
  • Screening for HER2 overexpression by immunohistochemistry and HER2 mutations by next-generation sequencing at initial diagnosis or after disease progression is essential to guide treatment decisions for advanced NSCLC in the second-line setting and beyond.
  • Trastuzumab deruxtecan is indicated for patients with advanced NSCLC harboring activating HER2 mutations and HER2-positive (IHC 3+) advanced solid tumors in the second-line setting and beyond.

HER2 Alterations and Essential Testing in Advanced NSCLC
HER2 is a receptor tyrosine kinase that belongs to the ErbB family of proteins which includes EGFR (also known as HER1), HER3, and HER4. The key mechanisms of HER2 oncogenic activation are HER2 mutations, HER2 protein overexpression and HER2 amplifications. In breast cancer, the role of HER2 is well characterized. In lung cancer, it is increasingly becoming more evident that HER2 plays a critical role in a subset of patients with the disease.

HER2 mutations occur in approximately 1% to 5%, HER2 protein overexpression in approximately 2% to 30%, and HER2 amplifications in approximately 2% to 6% of all non-small-cell lung cancer (NSCLC) cases. Of note, coalterations of HER2 also exist in tumors, and this adds to the complexity of this phenomenon.

HER2 mutation status is determined using standard DNA and RNA-based next-generation sequencing (NGS), which is now standard practice in NSCLC. HER2 protein overexpression is determined by immunohistochemistry (IHC). Testing for HER2 status in tumor tissue collected from a patient with NSCLC can be performed at initial diagnosis or after first-line therapy, especially if there is concern about the amount of available tissue sample. For patients with newly diagnosed NSCLC in need of a decision about first-line therapy, available tumor tissue should be prioritized for NGS and PD-L1 testing. It is often more convenient to test for HER2 and MET protein overexpression at the same time given that the FDA approval for agents targeting these biomarkers (HER2 and MET protein overexpression) are in the second-line or later disease settings.

T-DXd for Patients With Advanced NSCLC and HER2 Mutations
In August 2022, the FDA granted accelerated approval to trastuzumab deruxtecan (T-DXd), a HER2-directed antibody–drug conjugate (ADC), for adults with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received a prior line of systemic therapy. T-DXd is the first drug approved for patients with HER2-mutant NSCLC. The approval was based on the results of the randomized, dose-blinded, phase II DESTINY-Lung02 trial which investigated the safety and efficacy of intravenously administered T-DXd at 5.4 mg/kg vs 6.4 mg/kg every 3 weeks for patients with HER2-mutant advanced NSCLC (NCT04644237). After a median follow-up of 15.8 months (5.4 mg/kg) and 16.5 months (5.4 mg/kg), DESTINY-Lung02 demonstrated a confirmed objective response rate (primary endpoint) of 50% at the 5.4 mg/kg dose vs 56% at the 6.4 mg/kg dose. The median progression-free survival was 10.0 months and 12.9 months, respectively, and the median overall survival was 19.0 months and 17.3 months, respectively. However, more drug-related grade ≥3 treatment-emergent adverse events occurred at the 6.4 mg/kg dose. The results obtained at the 5.4 mg/kg dose compared favorably with historical results from second-line treatments like docetaxel and this made this dose the favored choice in this setting. On this basis, the recommended dose for T-DXd for lung cancer is 5.4 mg/kg administered intravenously every 3 weeks until disease progression or unacceptable toxicity.

T-DXd for Patients With Advanced NSCLC and HER2 Overexpression
Several trials have also examined the efficacy and safety of T-DXd in HER2 overexpressing solid tumors. In April 2024, the FDA granted accelerated tumor agnostic approval to T-DXd for adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. This indication is based on results from 3 trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831). These 3 trials excluded patients with a history of interstitial lung disease (ILD)/pneumonitis in need of treatment with steroids or with ILD/pneumonitis at screening and those with clinically significant cardiac disease. Patients were also excluded from these trials if they had active brain metastases or an Eastern Cooperative Oncology Group performance status greater than 1.

Key Adverse Event Challenges Associated with T-DXd
As with many ADCs, ILD/pneumonitis is an important toxicity to remember with T-DXd and requires careful monitoring while receiving treatment. Patients should be educated to report signs and symptoms of ILD/pneumonitis including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Regular imaging and proactive follow-up of relevant symptoms between visits are necessary. It is also recommended that consultation with a pulmonologist should be considered. In the DESTINY-Lung02 trial, treatment-emergent ILD and pneumonitis associated with study drug discontinuation were reported in 6/101 (5.9%) and 5/101 (5.0%) of patients, respectively, at the 5.4 mg/kg dose. Adjudicated drug-related ILD was reported in 15/101 (14.9%) of patients who received the 5.4 mg/kg dose, largely grade 1 or 2 with 1 grade 5 event in each of the treatment arms. The rate of ILD was lower on the 5.4 mg/kg arm vs the 6.4 mg/kg arm (32.0%). Like standard practice with trastuzumab, regular echocardiogram follow-up is required to evaluate changes in ejection fraction, especially because HER2 is important for heart development and it is expressed in cardiac muscle. Left ventricular ejection fraction should be assessed prior to T-DXd initiation and at regular intervals during treatment as clinically indicated. Of note, grade 1 or 2 cytopenias, especially neutropenia, and gastrointestinal toxicity, in particular, nausea and decreased appetite, are commonly observed with T-DXd.

Future Directions and a More Complex Therapeutic Landscape for HER2 in Advanced NSCLC
There are several ongoing trials investigating various HER2-directed therapies in patients with HER2-altered NSCLC in earlier lines of therapy. For example, the randomized, phase III DESTINY-Lung06 is investigating the efficacy of T-DXd in combination with pembrolizumab vs platinum-based chemotherapy plus pembrolizumab as first-line therapy for patients with locally advanced unresectable or metastatic HER2 overexpressing and PD-L1 tumor proportion score <50% nonsquamous NSCLC (NCT06899126). DESTINY-Lung04 is an ongoing phase III trial investigating the efficacy and safety of T-DXd vs standard of care as first-line therapy for patients with unresectable, locally advanced, or metastatic NSCLC harboring HER2 exon 19 or 20 mutations (NCT05048797).

Disitamab vedotin is a novel HER2-directed ADC that is currently under investigation in combination with tislelizumab, an anti–PD-1 immune checkpoint inhibitor, and bevacizumab in a multicohort, phase II trial for patients with locally advanced or metastatic NSCLC harboring HER2 mutation, HER2 amplification or HER2 expression (IHC 1+/2+/3+) (NCT06749860). Other HER2-directed treatment modalities, including bispecific antibodies and tyrosine kinase inhibitors are also in clinical development for patients with HER2-altered NSCLC.

In August 2025, zongertinib, a tyrosine kinase inhibitor, was granted accelerated approval for patients with unresectable or metastatic nonsquamous NSCLC whose tumors have HER2 tyrosine kinase domain activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy.

All these ongoing studies indicate that the field of HER2-altered NSCLC is rapidly evolving. With the availability of an increasing number of HER2-directed agents and potential new indications, more opportunities will arise for the selection and sequencing of these agents to benefit our patients with advanced NSCLC whose tumors harbor these alterations. Of course, these opportunities will bring with them more challenges for our multidisciplinary healthcare teams as we strive to provide the best care possible for our patients.

Your thoughts?
How are you testing for HER2 alterations in your patients with advanced NSCLC? What questions or challenges do you have related to the care of patients with advanced NSCLC and HER2 alterations? Let us know in the comments.

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In your practice, how often do you confirm that IHC testing for HER2 overexpression is completed for your patients with advanced NSCLC at first disease progression?

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