Dr Le on Choosing Between Zongertinib and Sevabertinib in HER2 TKD–Mutant NSCLC

“For patients who are diagnosed with a HER2 TKD domain mutation who are treatment naive, zongertinib is the [go-to] option.”

Xiuning Le, MD, PhD, an associate professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed treatment selection among targeted therapies for HER2-mutant non–small cell lung cancer (NSCLC), a topic covered in the Bridging the Gaps in Lung Cancer meeting.

Le noted that both zongertinib (Hernexeos) and sevabertinib (Hyrnuo) received FDA accelerated approval in 2025 for patients with HER2 TKD activating mutations who had received prior systemic therapy. Both accelerated approvals were based on objective response (ORR) and duration of response (DOR) data. For zongertinib, the ORR was 44% (95% CI, 29%-61%), with 27% of patients who had previously received both platinum-based chemotherapy and a HER2-targeted antibody drug conjugate (n = 34) having a DOR of at least 6 months. For sevabertinib, the ORR was 38% (95% CI, 25%-53%), with 60% of responding patients having a DOR of at least 6 months. Earlier this year, she added, zongertinib also received accelerated approval for frontline use in this population. In this setting, the ORR was 76% (95% CI, 65%-85%), with 64% of responders having a DOR of at least 6 months and 44% having a DOR of at least 12 months.

For patients newly diagnosed with a HER2 TKD mutation who are treatment naive, Le said zongertinib is the option to pursue in the frontline setting. For patients who have already received prior systemic therapy, she noted that either zongertinib or sevabertinib represents a valid option. Le also pointed out that fam-trastuzumab deruxtecan-nxki (Enhertu) shouldn’t be overlooked as another agent available for this patient population.