*January 2025*
Treatments are rapidly evolving in the second-line setting and beyond for patients with HER2-mutated non–small cell lung cancer (NSCLC), with several promising TKIs under development looking to join fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in this setting.
Following standard of care (SOC) systemic frontline therapy, T-DXd is the NCCN guideline preferred option alongside the other recommended regimen ado-trastuzumab emtansine (Kadcyla).1 Data from the final analysis of the phase 2 DESTINY-Lung02 trial (NCT04644237) that were presented at the 2024 ASCO Annual Meeting showed that patients with metastatic HER2-mutated NSCLC who received at least 1 prior anticancer therapy achieved a confirmed objective response rate (ORR) of 50.0% (95% CI, 39.9%-60.1%) when treated with 5.4 mg/kg of the antibody-drug conjugate (ADC; n = 102).2 Patients who received 6.4 mg/kg of T-DXd (n = 50) achieved an ORR of 56.0% (95% CI, 41.3%-70.0%). The median overall survival (OS) was 19.0 months (95% CI, 14.7-not estimable [NE]) in the 5.4 mg/kg arm and 17.3 months (95% CI, 13.8-NE) in the 6.4 mg/kg arm.
HER2 alterations are not as common in NSCLC as in other tumor types—occurring in approximately 1% to 4% of patients—but challenges remain regarding treatments for patients with HER2-mutant NSCLC such as the optimal sequencing of therapies.3 Balancing toxicities with efficacy for patients with HER2-mutated NSCLC is also a key consideration. The safety of T-DXd reported in the final analysis of DESTINY-Lung02 showed that the 5.4 mg/kg dose was associated with a more favorable benefit/risk profile than the 6.4 mg/kg dose.2
There were also no significant changes in toxicity seen according to the longer follow-up data. Drug-related treatment-emergent adverse effects (TEAEs) in the 5.4 mg/kg and 6.4 mg/kg arms were grade 3 or higher (39.6%; 60.0%, respectively), serious (13.9%; 28.0%), and associated with treatment discontinuation (14.9%; 26.0%), treatment interruption (30.7%; 54.0%), dose reduction (16.8%; 34.0%), and death (1.0%; 2.0%). Further, any-grade interstitial lung disease (ILD)/pneumonitis occurred in 14.9% of patients treated with 5.4 mg/kg of T-DXd and 32.0% of those given 6.4 mg/kg of the ADC.
Given the efficacy of T-DXd in this setting, the phase 3 DESTINY-Lung04 study (NCT05048797) is currently enrolling patients with NSCLC and HER2 exon 19 or 20 mutations to receive the agent vs SOC platinum-chemotherapy plus pemetrexed and pembrolizumab (Keytruda) in the frontline setting.4 Read more.
