Dr Ashraf on the Utility of T-DXd in HER2-Mutated NSCLC

Noman Ashraf, MD, hematologist-oncologist, Tampa General Hospital; associate professor, medicine, Division of Hematology/Oncology, the University of South Florida Health Morsani College of Medicine, discusses notable data seen with the HER2-directed antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in patients with previously treated HER2-mutated and -overexpressing non–small cell lung cancer (NSCLC).

The phase 2 DESTINY-Lung01 study (NCT03505710) evaluated 2 patient cohorts: one with HER2 overexpression and another with HER2 mutations, Ashraf begins. Both cohorts benefited from T-DXd, but patients with HER2 mutations who received the agent at 6.4 mg/kg appeared to derive greater benefit, with a confirmed objective response rate (ORR) of 55% (95% CI, 44%-65%), a median progression-free survival of 8.2 months (95% CI, 6.0-11.9), and a median overall survival of 17.8 months (95% CI, 13.8-22.1), he reports. The phase 2 DESTINY-Lung02 trial (NCT04644237) further examined T-DXd dosing, revealing that a lower dose of 5.4 mg/kg resulted in efficacy outcomes comparable with those achieved with a higher dose, as well as reduced toxicity; subsequently, in 2022, the FDA approved T-DXd at a recommended dose of 5.4 mg/kg for the treatment of patients with HER2-mutant NSCLC, Ashraf explains.

In DESTINY-Lung01, patients with HER2 overexpression (classified as HER2 expression of 2+ or 3+ per immunohistochemistry) who received T-DXd at 6.4 mg/kg had a lower ORR of 26.5% (95% CI, 15.0%-41.1%) compared with those in the HER2-mutated cohort, he continues. Both DESTINY-Lung01 and DESTINY-Lung02 administered T-DXd in the second line and beyond. There is a growing interest in using ADCs like T-DXd as frontline therapy for patients with HER2 overexpression or mutations, Ashraf states.

In the HER2 overexpression cohorts of DESTINY-Lung01, 49 patients received T-DXd at 6.4 mg/kg and 41 patients received the agent at 5.4 mg/kg. Efficacy outcomes were similar across doses, but the 5.4-mg/kg dose was associated with a lower incidence of toxicity. ADC-related toxicities generally mimic those seen with chemotherapy, including cytopenias and alopecia, according to Ashraf. However, a unique risk associated with ADCs is interstitial lung disease (ILD), which can be fatal in some cases, he says. Thus, managing and minimizing ILD risk remains crucial to optimize patient outcomes when balancing therapeutic efficacy and safety, Ashraf concludes.