Long term survival with trastuzumab deruxtecan for heavily pretreated, HER2 mutated advanced non-small cell lung cancer

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) mutations occur in approximately 4% of non-small cell lung cancer (NSCLC) patients and represent targetable gene alteration. Trastuzumab deruxtecan (T-DXd), an anti-HER2 antibody-drug conjugate, was approved in China, the USA and EU based on the results of DESTINY-Lung02 and DESTINY-Lung05 for the treatment of pretreated unresectable or metastatic HER2-mutated NSCLC patients. Herein, we present five cases of HER2-mutated advanced NSCLC who received T-DXd in second or later line settings. CASE PRESENTATION: The median age of patients was 67 years (range 48-76 years). Four patients were males, and one was female. All five patients had HER2 exon 20 insertional mutations. They received T-DXd in the 2nd or later line settings. One patient had complete response, two had partial response and two had stable disease. T-DXd led to a progression-free survival of up to 41 months from the start of T-DXd therapy. The median overall survival of the five patients was 15 months post T-DXd treatment (range 9-41 months). Adverse events during T-DXd treatment were expected and manageable. Challenge with T-DXd was successful in a patient with a history of interstitial lung disease. CONCLUSION: In this small case series, T-DXd demonstrated encouraging antitumor activity and manageable safety in heavily pretreated patients with HER2 mutated, metastatic NSCLC. Although selected patients had durable benefits, the findings are anecdotal and should be interpreted with caution. Larger real‑world cohorts and prospective studies are needed to validate the consistency, durability, and safety of T‑DXd in routine clinical practice.