In the phase II DESTINY-Lung01 trial reported in The New England Journal of Medicine, Bob T. Li, MD, PhD, MPH, and colleagues found that fam-trastuzumab deruxtecan-nxki (T-DXd) showed durable activity in patients with metastatic HER2-mutant non–small cell lung cancer (NSCLC) refractory to standard treatment.
Study Details
In the study, 91 patients enrolled from sites in North America, Japan, and Europe between May 2018 and July 2020 were treated with T-DXd at 6.4 mg/kg every 3 weeks. Patients had received a median of two prior therapies; 95% had received platinum-based therapy and 66% had received PD-1 or PD-L1 inhibitor treatment. The primary outcome measure was objective response on independent central review.
Bob T. Li, MD, PhD, MPH
Responses
At data cutoff (May 2021), median duration of follow-up was 13.1 months (range = 0.7–29.1 months). Median duration of treatment was 6.9 months (range = 0.7–26.4 months).
Objective response was observed in 50 patients (55%; 95% confidence interval [CI] = 44%–65%), with complete response observed in 1 (1%). Median duration of response was 9.3 months (95% CI = 5.7–14.7 months). An additional 34 patients (37%) had stable disease; disease control was observed in 84 patients (92%, 95% CI = 85%–97%). Median time to response was 1.5 months (range = 1.2–9.3 months).
Objective responses were observed in patients with different HER2 mutation subtypes across three exon locations and in patients with no detectable HER2 expression or who tested negative for HER2 amplification. Among subgroups, objective response was observed in:
- 18 (55%) of 33 patients with and 32 (55%) of 58 without central nervous system (CNS) metastases at baseline
- 46 (53%) of 86 with prior platinum-based therapy and 37 (65%) of 57 with prior platinum-based therapy and PD-1 or PD-L1 inhibitor therapy
- 49 (58%) of 85 with a mutation in the HER2 kinase domain.
Median progression-free survival was 8.2 months (95% CI = 6.0–11.9 months). Median overall survival was 17.8 months (95% CI = 13.8–22.1 months). Among the 33 patients with CNS metastases at baseline, median progression-free survival was 7.1 months (95% CI = 5.5–9.8 months) and median overall survival was 13.8 months (95% CI = 9.8–20.9 months).
Adverse Events
The most common treatment-related adverse events of any grade were nausea (73%), fatigue (53%), alopecia (46%), and vomiting (40%). Grade ≥ 3 drug-related adverse events occurred in 46% of patients, most commonly neutropenia (19%), anemia (10%), and nausea (9%). Serious drug-related adverse events occurred in 20% of patients.
Drug-related adverse events led to treatment discontinuation in 23 patients (25%), including pneumonitis in 12 (13%) and interstitial lung disease in 5 (5%). Adjudicated drug-related interstitial lung disease occurred in 24 patients (26%) and was grade 3 in 4 patients and grade 5 in 2 patients. Adverse events led to death in 13 patients, with two deaths (those due to interstitial lung disease) considered related to treatment.
The investigators concluded, “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.”
Disclosure: The study was funded by Daiichi Sankyo and AstraZeneca. For full disclosures of the study authors, visit nejm.org.
