In a phase II trial (DESTINY-Lung01) reported in The New England Journal of Medicine, Bob T. Li, MD, PhD, MPH, of the Thoracic Oncology and Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York, 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.1
Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC.— Bob T. Li, MD, PhD, MPH, and colleagues
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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 until disease progression or unacceptable toxicity. Patients who had received a HER2 antibody or an antibody-drug conjugate were ineligible for participation; those who had received a HER2 tyrosine kinase inhibitor were eligible. Patients with a history of noninfectious interstitial lung disease treated with glucocorticoids or current or suspected interstitial lung disease that could not be ruled out by imaging at screening were ineligible. The primary outcome measure was an objective response using Response Evaluation Criteria in Solid Tumors version 1.1 on independent central review.
In the trial population, the median patient age was 60 (range = 29–88 years), 66% were female, 44% were White, 34% were Asian, 1% were Black, and 21% were other. Eastern Cooperative Oncology Group performance status was 0 (25%) or 1 in all patients. HER2 mutation location was kinase domain in 93% and extracellular domain in 7%. Overall, 90 patients (99%) had received prior anticancer therapy, and patients had received a median of two prior lines of therapy (range = 0–7). Prior therapy included platinum-based therapy in 95%, a PD-1 or PD-L1 inhibitor in 66%, docetaxel in 20%, and HER2 tyrosine kinase inhibitor in 14%. At baseline, 36% had central nervous system metastases, 57% were never-smokers, and 22% had prior lung resection.
At data cutoff (May 2021), the median duration of follow-up was 13.1 months (range = 0.7–29.1 months), with 15 patients (16%) remaining on treatment. The median duration of treatment was 6.9 months (range = 0.7–26.4 months).
An objective response was observed in 50 patients (55%; 95% confidence interval [CI] = 44%–65%), with a complete response in 1 (1%). The 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).
Among subgroups, an objective response was observed in 18 of 33 patients (64.5%) with and 32 of 58 (55.2%) without central nervous system metastases at baseline; 46 of 86 (53.5%) with prior platinum-based therapy and 37 of 57 (64.9%) with prior platinum-based therapy and PD-1 or PD-L1 inhibitor therapy; and in 49 of 85 (57.6%) with 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 central nervous system 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).
All patients had locally reported HER2 mutations. Overall, 86% were exon 20 insertions; other mutations were single-nucleotide variants in exon 19 or 20 of the kinase domain or in exon 8 of the extracellular domain. Among patients who could be evaluated, any HER2 protein expression (1+ to 3+ on immunohistochemistry) was detected in 44 of 53 patients, and HER2 amplification was detected in 2 of 45 patients. Objective responses were observed in patients with different HER2 mutation subtypes across 3 exon locations and in patients with no detectable HER2 expression or no HER2 amplification.
The most common treatment-related adverse events of any grade were nausea (73%), fatigue (53%), alopecia (46%), vomiting (40%), neutropenia (35%), anemia (33%), diarrhea (32%), and decreased appetite (30%). Grade ≥ 3 treatment-related adverse events occurred in 46% of patients, most commonly neutropenia (19%), anemia (10%), nausea (9%), and fatigue (7%). Serious treatment-related adverse events occurred in 20% of patients. Treatment-related adverse events led to treatment discontinuation in 23 patients (25%), including pneumonitis in 12 (13%) and interstitial lung disease in 5 (5%). Treatment-related and non–treatment-related adverse events led to death in 13 patients; 2 deaths, both due to interstitial lung disease, were considered related to treatment.
Adjudicated drug-related interstitial lung disease occurred in 24 patients (26%) and was of grade 3 in 4 patients and grade 5 in 2 patients. At data cutoff, among the 22 surviving patients, 13 had fully recovered, 1 had recovered with sequelae, 2 were in recovery, and 6 had not recovered over a period of 22 to 40 days.
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. Dr. Li has received institutional research funding from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Eli Lilly, Genentech, Grail, Guardant Health, Hengrui USA, and the National Institutes of Health; has been reimbursed for travel from Jiangsu Hengrui Medicine and MORE Health; and holds patents or other intellectual property with Memorial Sloan Kettering Cancer Center, Karger Publishers, and Shanghai Jiao Tong Unviersity.
1. Li BT, Smit EF, Goto Y, et al: Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer. N Engl J Med 386:241-251, 2022.
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