Dr Liu on the Activity of Trastuzumab Deruxtecan in HER2-Mutated NSCLC

Stephen V. Liu, MD, associate professor of medicine, Georgetown University, director of Thoracic Oncology, head of Developmental Therapeutics, Georgetown Lombardi Comprehensive Cancer Center, discusses the activity of fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with HER2-mutated non–small cell lung cancer (NSCLC).

In August 2022, the FDA granted an accelerated approval to trastuzumab deruxtecan for patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations. The antibody-drug conjugate (ADC) has displayed efficacy and garnered approvals across other histologies, such as breast cancer and gastric cancer; however, in these malignancies, HER2 is referred to in the context of expression, or amplification, compared with HER2 mutations in NSCLC, Liu says. In lung cancer, the presence of a HER2 mutation is more relevant and predictive of response vs overexpression, Liu expands.

Trastuzumab deruxtecan was evaluated in previously treated patients with HER2-mutant NSCLC in the phase 2 DESTINY-Lung01 study (NCT03505710), where the ADC administered at 6.4 mg/kg every 3 weeks elicited an overall response rate of 54.9%. The study showed activity in a subset of patients where a targeted agent was not previously approved, and it represented a potential way to address an unmet need in patients with NSCLC, Liu adds

However, due to concerns over rates of interstitial lung disease (ILD)/pneumonitis observed in the phase 2 study, the phase 2 DESTINY-Lung02 study (NCT04644237) evaluated trastuzumab deruxtecan at a dose of either 6.4 mg/kg once every 3 weeks or 5.4 mg/kg once every 3 weeks. Responses were consistent across both doses, and after lower rates of ILD/pneumonitis were observed with the 5.4 mg/kg dose, it became the recommended dose.

Findings from DESTINY-Lung02 revealed that the ORR was 58% (95% CI, 43%-71%) with a median duration of response of 8.7 months (95% CI, 7.1–not estimable). Findings from this study supported the accelerated approval of trastuzumab deruxtecan for the treatment of patients with unresectable or metastatic NSCLC with activating HER2mutations. This is now the clear standard of care in the second-line setting for this subset of patients, and this ADC has a large therapeutic window and high index of activity, Liu concludes.