The November 6, 2025 update to the NCCN Clinical Practice Guidelines in Oncology for non–small cell lung cancer (NSCLC) introduces datopotamab deruxtecan (Dato-DXd) as a key new option for EGFR-mutated disease. Dato-DXd is now a preferred second-line regimen for patients who progress on frontline osimertinib plus chemotherapy, and a preferred third-line option after other first-line regimens. Its FDA accelerated approval in June 2025 was based on pooled data from TROPION-Lung05 and TROPION-Lung01, showing an overall response rate of 45% and a median duration of response of 6.5 months in previously treated EGFR-mutated NSCLC. The recommended dose is 6 mg/kg (capped at 540 mg for patients ≥90 kg) every 3 weeks until progression or unacceptable toxicity, with a safety profile characterized mainly by stomatitis, alopecia, gastrointestinal symptoms, fatigue, and infrequent but notable events such as ocular surface toxicity and low-rate treatment-related interstitial lung disease.
Beyond Dato-DXd, the guidelines strengthen the role of targeted combinations and refine sequencing across several molecular subsets. For EGFR-mutated NSCLC identified before first-line therapy, osimertinib plus platinum/pemetrexed and amivantamab plus lazertinib have been moved to category 1 preferred frontline regimens, with amivantamab/lazertinib also listed as useful in certain circumstances after progression on osimertinib in specific scenarios. For ROS1-positive NSCLC with brain metastases, repotrectinib and taletrectinib are now preferred subsequent therapies, while no ROS1 regimens retain preferred status in the frontline setting.
Reference: Doherty K. NCCN Releases NSCLC Guideline Update, Dato-DXd Designated as a Preferred Second-Line Regimen in EGFR-Mutated Disease. OncLive. Published November 10, 2025. Accessed December 1,2025. https://www.onclive.com/view/nccn-releases-nsclc-guideline-update-dato-dxd-designated-as-a-preferred-second-line-regimen-in-egfr-mutated-disease
