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Trastuzumab Deruxtecan Promising for HER2-Mutant Non-Small Cell Lung Cancer

A majority of non-squamous non-small cell lung cancers (NSCLCs) are oncogene driven, which means that the oncogene can potentially be a target for a targeted therapy. Indeed, the development of precision medicine based on molecular characterization of the tumor has led to a significant improvement in the prognosis for patients with specific molecular alterations for which targeted therapy is available. About 3% of patients with non-squamous NSCLC harbor mutations in the gene encoding human epidermal growth factor receptor 2 (HER2). These patients, who are more likely to be younger, female, and never-smokers, generally face a poor prognosis. Therapies that target HER2 have not been approved for patients with NSCLC, despite transformational success in HER2-related breast and gastric cancers. Patients with HER2-mutant NSCLC typically receive standard chemotherapy or immunotherapy, despite limited activity. Different experimental strategies have been evaluated in clinical trials, including the use of HER2 tyrosine kinase inhibitors, HER2 antibodies, and the antibody-drug conjugate (ADC) trastuzumab emtansine. However, reported efficacy results were rather disappointing and inconsistent across the trials, with trastuzumab emtansine being the most effective but with a duration of response of only about 4 months. Another ADC, trastuzumab deruxtecan, has shown meaningful survival benefits in previously treated patients with metastatic HER2-positive breast and gastric cancers and has been approved in countries worldwide for these indications. Furthermore, encouraging activity with this agent has been shown in a phase I trial in a cohort of patients with HER2-mutant NSCLC.

In the multicenter, two-cohort, phase II DESTINY-Lung01 trial, investigators further assessed the efficacy and safety of trastuzumab deruxtecan (6.4 mg per kilogram of body weight intravenously every 3 weeks) in patients with HER2-overexpressing or HER2-mutant NSCLC who were refractory to standard treatment. The results of the HER-2 mutant cohort were published recently in the New England Journal of Medicine. Among 91 patients, 50 patients (55%) had a confirmed objective response as assessed by independent central review, including one complete response. The median duration of response was 9.3 months, median progression-free survival (PFS) was 8.2 months, and median overall survival (OS) was 17.8 months. Efficacy was observed across different subgroups including those previously treated with immunotherapy or HER2 tyrosine kinase inhibitors and those with central nervous system (CNS) metastases. At baseline, 33 patients had CNS metastases; the median PFS in this subgroup was 7.1 months, while the median OS was 13.8 months. The overall safety profile was consistent with that seen in previous studies. Nearly every patient (97%) had at least one treatment-related adverse event (AE). Almost half of the patients (46%) had grade 3 or higher treatment-related AEs, with neutropenia and anemia being the most common. About 1 in 4 patients (26%) had drug-related interstitial lung disease (ILD); of these, 75% were grade 1 or 2, but 4 patients had grade 3 disease, which resulted in 2 deaths, leading the investigators to note, “the development of this toxic effect was not predictable; as a consequence, patients must be carefully monitored.”

In assessing the robustness of the DESTINY-Lung01 trial results for HER2-mutant NSCLC, the authors of an accompanying editorial noted that “responses were observed regardless of HER2-specific mutation sites, including the extracellular or kinase domains, and regardless of the presence of concomitant HER2 expression or amplification. These results establish the new standard of care for patients with NSCLC harboring HER2 mutations.” Regarding the potential for severe ILD, the editorialists called for improvements in clinical management, including early detection, tailored intervention guidelines, and the investigation of the clinical efficacy of a reduced dose of trastuzumab deruxtecan, which is underway in the DESTINY-Lung02 trial.

References:
Li BT, et al. N Engl J Med. 2022;386:241-251.
Passaro A & Peters S. N Engl J Med. 2022;386:286-289.