Dr Liu on the Significance of T-DXd For Patients With HER2-Mutant NSCLC and Brain Metastases

Stephen V. Liu, MD, associate professor, medicine, Georgetown University, director, Thoracic Oncology, head, Developmental Therapeutics, Georgetown Lombardi Comprehensive Cancer Center, discusses the significance of using fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) inpatients with HER2-mutant non–small cell lung cancer (NSCLC) and brain metastases according to pooled findings from exploratory analyses of the phase 2 DESTINY-Lung01 (NCT03505710) and DESTINY-Lung02 (NCT04644237) trials.

Treating patients with HER2-mutated non-small cell lung cancer (NSCLC) who have brain metastases often poses a unique challenge, and effective therapeutic options are limited for patients in this population. Historically, large molecules, such as monoclonal antibodies and antibody-drug conjugates, were thought to be ineffective against brain metastases because of their potential difficulties crossing the blood-brain barrier, Liu explains. This belief led to the exploration of various combinations with small molecules and raised concerns about the need for radiation therapy in central nervous system disease management, he continues. However, insights from breast cancer research have challenged these assumptions, Liu states.

As the first HER2-directed therapy for patients with HER2-mutated NSCLC, T-DXd holds significant promise for this subgroup of patients with brain metastases, he says. Accordingly, a post hoc pooled analysis of the intracranial responses with the agent in the DESTINY-Lung01 and DESTINY-Lung02 trials was conducted, Liu details. Patients from DESTINY-Lung01 with or without baseline brain metastases who received T-DXd at 6.4 mg/kg were included in the analysis, as were patients from DESTINY-Lung02 who either did or did not have baseline brain metastases and received T-DXd at 5.4 mg/kg.

Data from the pooled analysis showed that T-DXd produced encouraging and consistent intracranial responses in patients with HER2-mutated NSCLC who had treated or untreated brain metastases at baseline across different doses, Liu reports. The confirmed intracranial overall response rate (IC-cORR) from DESTINY-Lung02, as assessed by independent central review, was 50.0% (95% CI, 23.0%-77.0%) with the 5.4 mg/kg dose of T-DXd. The confirmed intracranial disease control rate (IC-DCR) was 92.9% (95% CI, 66.1%-99.8%), with a median intracranial duration of response (IC-DOR) of 9.5 months (95%, 3.6–not evaluable).

Moreover, the confirmed IC-cORR was 30.0% (95% CI, 14.7%-49.4%) in patients with baseline brain metastases from DESTINY-Lung01 or DESTINY-Lung02 treated with 6.4 mg/kg of T-DXd. Similarly, the IC-DCR was 73.3% (95% CI, 54.1%-87.7%), and the median IC-DOR was 4.4 months (95%, 2.9-10.2).

Overall, these findings add to the building evidence that large molecules, such as T-DXd, demonstrate clear activity in the brain, Liu emphasizes. Further research is needed to validate these findings and explore their broader implications.