Dr Le on the Clinical Significance of the FDA Approval of Sevabertinib for Locally Advanced/Metastatic HER2+ NSCLC

“When patients have HER2-mutated lung cancer and receive sevabertinib, the response is really great, and the duration is great. This is shown in multiple cohorts.”

Xiuning Le, MD, PhD, associate professor in the Department of Thoracic/Head and Neck Medical Oncology, Division of Internal Medicine, at The University of Texas MD Anderson Cancer Center in Houston, Texas, discussed the clinical significance of the FDA’s accelerated approval of sevabertinib (Hyrnuo) for adult patients with locally advanced or metastatic, nonsquamous non–small cell lung cancer (NSCLC) harboring activating HER2 (ERBB2) tyrosine kinase domain (TKD) mutations who have received prior systemic therapy.

The November 2025 regulatory decision expands targeted treatment options for a genomically defined NSCLC subset in which durable disease control has historically been challenging.

Le contextualized the approval within the evolving HER2-mutant NSCLC landscape, emphasizing that HER2 TKD mutations represent a distinct oncogenic driver that is biologically and therapeutically different from HER2 amplification or overexpression paradigms in other tumor types. Prior HER2-directed approaches in NSCLC have been constrained by either limited efficacy signals, insufficient biomarker specificity, or tolerability limitations, Le stated. Sevabertinib is an oral, next-generation HER2-directed TKI designed to more selectively inhibit HER2-driven signaling in tumors with HER2 TKD activating mutations.

The accelerated approval was supported by efficacy and safety data from the phase 1/2 SOHO-01 trial (NCT05099172), a multicohort study evaluating sevabertinib in patients with HER2-mutated advanced NSCLC across multiple treatment cohorts. Le noted that the patient population in SOHO-01 was representative of those seen in clinical practice. Many of thse patients progressed following prior systemic therapy, including platinum-based chemotherapy and, frequently, immunotherapy. In that setting, the observed antitumor activity supported sevabertinib as an effective option following progression on standard regimens.

Le emphasized that the characterization and management of adverse effects is vital to determine the real-world feasibility of targeted therapies intended for continuous administration in metastatic NSCLC. In SOHO-01, the adverse effects (AEs) profile of sevabertinib was consistent with expectations for HER2 kinase inhibition, and most AEs were manageable with standard supportive care and dose-modification strategies. This is particularly relevant for patients who may have cumulative toxicity from prior therapies or baseline comorbidities. Le stressed that familiarity with class-associated toxicities, early recognition, and proactive supportive management are important for maintaining dose intensity and minimizing treatment interruptions.

From an implementation perspective, Le stated that the approval further reinforces the importance of comprehensive molecular profiling in NSCLC. Identification of HER2 TKD activating mutations using an FDA-approved test now directly informs post–first-line treatment selection, and patients now have the option to receive targeted therapy rather than defaulting exclusively to additional cytotoxic options.