NCCN Releases NSCLC Guideline Update, Dato-DXd Designated as a Preferred Second-Line Regimen in EGFR-Mutated Disease

November 10, 2025

The NCCN has released their updated Clinical Practice Guidelines in Oncology for NSCLC.

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

Key Updates to NCCN Clinical Practice Guidelines in Oncology NSCLC Version 1.2026

The National Comprehensive Cancer Network released updated Clinical Practice Guidelines in Oncology for non–small cell lung cancer on November 6, 2025.
Changes to version 1.2026 included slotting in Dato-DXd as a preferred second-line regimen for the treatment of patients with EGFR-mutated NSCLC who received first-line osimertinib plus chemotherapy. It is a preferred third-line regimen for patients who have received any other preferred first-line treatment.
Other updates included moving osimertinib/carboplatin or cisplatin/pemetrexed as well as amivantamab plus lazertinib from other recommended to category 1 preferred regimens for the frontline treatment of patients with EGFR-mutated NSCLC whose mutations were discovered prior to first-line systemic therapy.

What Were the Other Notable Updates to the NCCN Guidelines?

Key updates to version 1.2026 of the NCCN Clinical Practice Guidelines in Oncology for NSCLC included moving osimertinib/carboplatin or cisplatin/pemetrexed as well as amivantamab-vmjw (Rybrevant) in combination with lazertinib (Lazcluze) from the other recommended category to category 1 as a preferred regimen for the frontline treatment of patients with EGFR-mutated NSCLC whose mutations were discovered prior to first-line systemic therapy. Lazertinib was also designated as useful in certain circumstances in this setting.

Amivantamab plus lazertinib was also added to the useful in certain circumstances category if not previously given as a subsequent therapy for patients with NSCLC harboring EGFR exon 19 deletions or L858R mutations with multiple lesions following disease progression on osimertinib.

Moreover, for the frontline treatment of patients with NSCLC with a ROS1 fusion discovered during first-line systemic therapy, the guidelines were updated to remove preferred status for all regimens. Repotrectinib (Augtyro) or taletrectinib (Ibtrozi) were added as preferred subsequent therapy options if not previously given for patients with ROS1-positive disease and brain metastases.

For the treatment of patients with ERBB/HER2-mutated disease who experienced disease progression following frontline therapy, ado-trastuzumab emtansine (Kadcycla) was moved from the other recommended category to the useful in certain circumstances category.

References

NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 1.2026. Accessed November 10, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. FDA. June 23, 2025. Accessed November 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer
Ahn M-J, Sands J, Lisberg AE, et al. Efficacy and safety of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously-treated EGFR-mutated advanced non-small cell lung cancer (NSCLC): a pooled analysis of TROPION-Lung01 and TROPION-Lung05. Ann Oncol. 2024;35(suppl 4):S1630-S1631. doi:10.1016/j.annonc.2024.10.656