ASCO Updates NSCLC Guidelines to Include Repotrectinib and Zongertinib
The American Society of Clinical Oncology updated its living clinical practice guideline for stage IV non–small cell lung cancer, adding repotrectinib and zongertinib to its recommended treatment pathways for specific molecular driver alterations.
Expanding Targeted Options in Advanced NSCLC
The updated guidelines, designated version 2026.3.0 and published in the Journal of Clinical Oncology, integrate precision therapies for patients carrying NTRK fusion-positive, ROS1-alterated, or HER2 tyrosine kinase domain-mutated disease. Developed by ASCO’s Expert Panel, the framework aims to refine biomarker-directed treatment selection at both initial diagnosis and subsequent disease progression.
For ROS1 rearrangement-positive stage IV non–small cell lung cancer, the panel incorporated repotrectinib, marketed as Augtyro, alongside existing first-line options like crizotinib and entrectinib. The recommendation builds on data from the phase 1/2 TRIDENT-1 trial. In that study, TKI-naive patients achieved a confirmed objective response rate of 79 percent, alongside a median progression-free survival of 35.7 months.
Clinical Trial Data and Dosing Specifications
The regulatory and clinical footprints of these newly added compounds require precise adherence to dosing regimens and management of distinct toxicity profiles. Repotrectinib carries a starting dose of 160 mg orally once daily for 14 days, followed by 160 mg twice daily. Safety data highlights TRK-related adverse events, including dizziness, dysgeusia, ataxia, and paresthesia.
For HER2 exon 20–mutated non–small cell lung cancer, the panel added zongertinib (Hernexeos) and sevabertinib as second-line choices, including for patients previously treated with trastuzumab deruxtecan. Zongertinib dosing is weight-based, requiring 120 mg daily for patients under 90 kg and 180 mg daily for those at or above that threshold. Labeling for zongertinib includes explicit warnings for hepatotoxicity, left ventricular dysfunction, and interstitial lung disease/pneumonitis.
Implications for Molecular Profiling and Treatment Sequencing
Sonam Puri, MD, cochair of the panel, noted that the expert group will continue monitoring emerging trial data to refine future sequencing strategies, including potential earlier deployment of available agents and novel combinations. The guideline update underscores the emphasis on comprehensive molecular profiling, combining next-generation sequencing with immunohistochemistry for HER2 and MET targets.
Evidence for some newly incorporated agents remains less mature than for established therapies. Outcomes data for repotrectinib in the NTRK fusion-positive population, for instance, are currently less well characterized than data for larotrectinib and entrectinib, pending full manuscript publication. Ongoing trials like the phase 3 Beamion LUNG-2 study will ultimately determine whether zongertinib displaces standard first-line therapies.