As reported in The Lancet Oncology by Egbert F. Smit, MD, and colleagues, primary analysis in the HER2-overexpressing unresectable or metastatic non–small cell cancer (NSCLC) cohorts of the phase II DESTINY-Lung01 trial show activity of fam-trastuzumab deruxtecan-nxki (T-DXd) in this setting.

Prior reporting from the trial showed activity of the agent in a cohort with activating HER2 mutations. The agent was granted accelerated approval in this latter setting in November 2022, based on findings from the DESTINY-Lung02 trial.     

Given the low antitumor activity of existing treatment options in this patient population, [T-DXd] might have the potential to fill a large unmet need in HER2-overexpressing NSCLC.

— Egbert F. Smit, MD, and colleagues

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Study Details

In the recent study, 90 patients from sites in France, Japan, the Netherlands, Spain, and the United States were enrolled between August 2018 and January 2020 into two consecutive cohorts: 49 patients received T-DXd at 6.4 mg/kg every 3 weeks in one cohort, and 41 received 5.4 mg/kg every 3 weeks in the second cohort. The primary endpoint was confirmed objective response rate on independent central review.

Responses

As of data cutoff in December 2021, the median treatment duration was 4.1 months in the 6.4-mg/kg cohort and 5.5 months in the 5.4-mg/kg cohort; the median follow up was 12.0 months and 10.6 months, respectively.

Among 49 patients receiving 6.4 mg/kg of T-DXd, confirmed objective responses (all partial) were observed in 13 (26.5%, 95% confidence interval [CI] = 15.0%–41.1%). An additional 21 patients (43%) had stable disease, yielding a disease control rate of 69.4%. The median response duration was 5.8 months (95% CI = 4.3 months to not evaluable).

Among 41 patients receiving 5.4 mg/kg of T-DXd, confirmed objective responses were observed in 14 (34.1%, 95% CI = 20.1%–50.6%), including complete response in 2 (5%). An additional 18 patients (44%) had stable disease, yielding a disease control rate of 78%. The median response duration was 6.2 months (95% CI = 4.2–9.8 months).

Adverse Events

Drug-related grade ≥ 3 adverse events occurred in 53% of patients in the 6.4-mg/kg group vs 22% of the 5.4-mg/kg group, most commonly neutropenia (24% vs 0%), pneumonia (12% vs 5%), and fatigue (12% vs 7%), Drug-related serious adverse events occurred in 20% vs 7%, most commonly pneumonitis (8% vs 2%). Drug-related adverse events led to treatment discontinuation in 16% vs 7% of patients, most commonly because of pneumonitis (14% vs 5%). Drug-related interstitial lung disease/pneumonitis of any grade was reported in 20% vs 5% of patients. Adverse events leading to death included bronchospasm, hydrocephalus, respiratory failure, and pneumonitis (1 patient each) in the 6.4-mg/kg group, and dyspnea, malignant neoplasm, and sepsis (1 patient each) in the 5.4-mg/kg group; one death in the 6.4-mg/kg group, from pneumonitis, was considered treatment-related. A death occurring in the 5.4-mg/kg group after data cutoff was also considered to be from treatment-related pneumonitis.

The investigators concluded: “Given the low antitumor activity of existing treatment options in this patient population, [T-DXd] might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of [T-DXd] in patients with HER2-overexpressing NSCLC.”

Dr. Smit, of the Department of Pulmonary Diseases, Leiden University Medical Center, Netherlands, is the corresponding author of The Lancet Oncology article.

Disclosure: The study was funded by Daiichi Sankyo and AstraZeneca. For full disclosures of the study authors, visit thelancet.com.