Treatment strategies for HER2-mutated non-small cell lung cancer (NSCLC) are rapidly advancing, with ongoing research focused on optimizing the use of existing therapies and integrating novel agents. The current treatment paradigm involves platinum-based doublet chemotherapy as the first-line standard of care, followed by fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in the post-chemotherapy setting. However, emerging data from clinical trials are paving the way for potential shifts in treatment sequencing and the introduction of new HER2-directed therapies.
Current Standards and Emerging Strategies
Currently, T-DXd is the only FDA-approved therapy specifically for HER2-mutated NSCLC after chemotherapy. This antibody-drug conjugate (ADC) has demonstrated efficacy in patients who have progressed on prior lines of therapy. Data from the final analysis of the phase 2 DESTINY-Lung02 trial showed a confirmed objective response rate (ORR) of 50.0% (95% CI, 39.9%-60.1%) in patients treated with 5.4 mg/kg of T-DXd, and 56.0% (95% CI, 41.3%-70.0%) in the 6.4 mg/kg arm. The median overall survival (OS) was 19.0 months (95% CI, 14.7-NE) and 17.3 months (95% CI, 13.8-NE) in the respective arms. Given these results, the ongoing phase 3 DESTINY-Lung04 trial is evaluating T-DXd in the first-line setting compared to standard-of-care platinum chemotherapy plus pemetrexed and pembrolizumab.
The Rise of HER2-Directed TKIs
Alongside T-DXd, several tyrosine kinase inhibitors (TKIs) are under development, showing promise in the treatment of HER2-mutated NSCLC. Zongertinib (BI 1810631) is an irreversible TKI that selectively inhibits HER2 while sparing EGFR, potentially reducing off-target toxicities. In the phase 1 Beamion LUNG-1 study, patients with HER2-altered advanced solid tumors treated with 120 mg of zongertinib achieved a confirmed ORR of 71% (95% CI, 60%-80%; P < .0001). The phase 3 Beamion LUNG-2 trial is now enrolling patients to receive zongertinib as first-line therapy for HER2-mutated advanced NSCLC. The FDA has granted fast track and breakthrough therapy designations to zongertinib for pretreated patients with advanced HER2-mutated NSCLC.
Another oral, small molecule TKI, BAY 2927088, has also demonstrated efficacy. Data from the phase 1/2 SOHO-01 trial showed an ORR of 72.1% (95% CI, 56.3%-84.7%) and a median duration of response (DOR) of 8.7 months (95% CI, 4.5-NE) in patients with advanced NSCLC harboring HER2 activating mutations. Notably, patients with HER2 YVMA insertions treated with BAY 2927088 achieved an ORR of 90.0% (95% CI, 73.5%-97.9%) with a median DOR of 9.7 months (95% CI, 5.5-NE). The phase 3 SOHO-02 trial is currently evaluating BAY 2927088 versus standard-of-care therapy in the first-line setting.
Safety and Tolerability Considerations
Balancing efficacy with safety is crucial in treating HER2-mutated NSCLC. The DESTINY-Lung02 trial indicated that the 5.4 mg/kg dose of T-DXd was associated with a more favorable benefit/risk profile compared to the 6.4 mg/kg dose. Zongertinib has shown a manageable safety profile, with most treatment-related adverse events (TRAEs) being low grade. BAY 2927088 was associated with grade 3 TRAEs in 40.9% of patients, with the most common being diarrhea (86.4%) and rash (43.2%).
Ongoing Research and Future Directions
Several other TKIs are under evaluation in phase 3 trials. The PYRAMID-1 study is examining pyrotinib versus docetaxel in patients with advanced nonsquamous NSCLC who have a HER2 exon 20 mutation and have progressed on prior platinum-based chemotherapy. These studies aim to refine treatment strategies and address the unmet needs of patients with HER2-mutated NSCLC.
