*November 2025*
On November 6, 2025, The National Comprehensive Cancer Network (NCCN) released their updated Clinical Practice Guidelines in Oncology for non–small cell lung cancer (NSCLC).1 Key updates in the newly released version 1.2026 from version 8.2025 include the addition of datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) as a preferred second-line regimen for patients with EGFR-mutated NSCLC following disease progression on frontline therapy with osimertinib (Tagrisso) plus chemotherapy, and as a third-line therapy following all other preferred first-line regimens.
The decision follows the June 2025 accelerated approval by the FDA for Dato-DXd for the treatment of patients with locally advanced or metastatic, EGFR-mutated NSCLC who have received previous EGFR-directed therapy and platinum-based chemotherapy.2 The approval was supported by pooled data from the phase 2 TROPION-Lung05 (NCT04484142) and phase 3 TROPION-Lung01 (NCT04656652) studies, which revealed that patients who received Dato-DXd (n = 114) experienced an overall response rate of 45% (95% CI, 35%-54%) and a median duration of response of 6.5 months (95% CI, 4.2-8.4).
The recommended dose of Dato-DXd in this setting is 6 mg/kg, with a maximum of 540 mg for patients weighing at least 90 kg. The agent is administered once every 3 weeks until disease progression or unacceptable toxicity.
Safety findings from a pooled analysis of the 2 clinical trials showed that patients with EGFR-mutated NSCLC who received the antibody-drug conjugate (n = 117) experienced any-grade and grade 3 or higher treatment-related adverse effects (TRAEs) at respective rates of 95% and 23%. TRAEs associated with dose reduction (22%), delay (23%), and discontinuation (5%) were all reported. No patients died due to TRAEs, and serious TRAEs occurred at a rate of 8%. Any-grade TRAEs that occurred in at least 10% of patients in the EGFR-mutated population included stomatitis (59%), alopecia (49%), nausea (46%), fatigue (18%), decreased appetite (16%), constipation (15%), vomiting (12%), rash (11%), and pruritus (10%).
Any-grade adverse effects of special interest included stomatitis/oral mucositis (69%), ocular surface events (32%), and adjudicated drug-related interstitial lung disease (4%). These events occurred at grade 3 severity at respective rates of 9%, 3%, and 1%.
Dato-DXd is listed in version 1.2026 as a subsequent therapy option for the treatment of patients with NSCLC harboring EGFR exon 19 deletions or L858R mutations, EGFR S768, L861Q, and/or G79X mutations, as well as EGFR exon 20 insertion mutations.1
