In the DESTINY LUNG-02 trial for HER2-mutant NSCLC, the lower 5.4 mg/kg dose of Trastuzumab-Deruxtecan (TDXD) yielded a 51% response rate, compared to 28% for the higher 6.4 mg/kg dose. This paradoxical outcome was driven by significantly higher toxicity, particularly interstitial lung disease (ILD), at the higher dose, which limited patients' ability to stay on treatment.
Unlike many targeted therapies, resistance to the antibody-drug conjugate Trastuzumab-Deruxtecan (TDXD) in HER2-mutant lung cancer is not caused by new HER2 mutations. Instead, resistance mechanisms are linked to the chemotherapy payload, such as the development of efflux pumps, which is a fundamentally different challenge for subsequent treatment strategies.
A practice gap exists in managing side effects of Trastuzumab-Deruxtecan (TDXD) between specialties. Breast oncologists, with more experience, are far more aggressive with prophylactic anti-emetics and frequent imaging to detect asymptomatic ILD. This proactive approach is a key lesson for lung cancer specialists and others now adopting the drug.
An expert oncologist indicated a willingness to use the TKI zongertinib off-label for stage III HER2-mutant NSCLC patients after chemoradiation, instead of the standard-of-care immunotherapy (durvalumab). This reflects a strong conviction that for driver mutation-positive cancers, targeted therapy is superior, even ahead of definitive clinical trial data in this specific setting.
While valuable in research, using circulating tumor DNA (ctDNA) to monitor HER2+ lung cancer patients in clinic can be counterproductive. It often induces patient anxiety due to fluctuations and high false-negative rates, and the results are not yet actionable for guiding treatment decisions like initiating a therapy holiday. For now, it's a tool that can add more stress than clarity.
Contrary to the expectation that large molecules like antibody-drug conjugates (ADCs) cannot penetrate the blood-brain barrier, Trastuzumab-Deruxtecan demonstrates significant CNS activity, with response rates over 40% in lung cancer patients with brain metastases. This finding is changing treatment paradigms and challenging long-held assumptions about drug delivery to the brain.