Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer

Abstract

Background: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively.

Methods: We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed.

Results: A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification.

Conclusions: Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.).

Copyright © 2021 Massachusetts Medical Society.

Figures

Figure 1.. Antitumor Activity.

Panel A shows the best percentage change from baseline in the sum of the largest diameters of measurable tumors in 85 of 91 patients for whom data from both baseline and postbaseline assessments of target lesions by independent central review were available. The upper horizontal line indicates a 20% increase in tumor size in the patients who had disease progression, and the lower horizontal line indicates a 30% decrease in tumor size (partial response). Below the graph, blank cells indicate patients whose tumor samples could not be evaluated or were not assessed. In the HER2 mutation row, numbers indicate the exon in which the mutation is located (8, 19, or 20). In the HER2 expression row, numbers indicate the immunohistochemical scores (0 [no detectable expression], 1+ [faint or barely detectable expression], 2+ [weak to moderate expression], or 3+ [strong expression]). HER2 denotes human epidermal growth factor receptor 2, I insertion, N no, S substitution, TKI tyrosine kinase inhibitor, and Y yes. Panel B shows the percentage change from baseline in the sum of the largest diameters of measurable tumors from baseline over time. The asterisk indicates a patient outlier with an increase of 236% in tumor diameter from baseline at week 18.

Figure 2.. Kaplan–Meier Analysis of Progression-free Survival and Overall Survival.

Panel A shows progression-free survival in the overall population. Of the 91 patients, 41 had progressive disease and 15 had died by the data cutoff date; data for 35 patients were censored, as indicated by tick marks. Panel B shows overall survival in the overall population. Of the 91 patients, 47 had died by the cutoff date; data for 44 patients were censored, as indicated by tick marks. In each panel, the dashed lines indicate the 95% confidence interval.