FDA Approves Dato-DXd for Patients With EGFR-Mutated NSCLC

Jacob Sands, MD Dana-Farber Cancer Institute | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• The FDA approved datopotamab deruxtecan (Dato-DXd) for patients with EGFR-mutated lung cancer based on pooled analysis of the TROPION-Lung01 and TROPION-Lung05 studies.

• Dato-DXd is the first TROP2-directed antibody drug conjugate (ADC) approved in lung cancer.

• The ADC can be used in the second line for patients previously treated with anti-EGFR and platinum-based chemotherapy.

Dato-DXd Approved for NSCLC With EGFR Mutations

In June 2025, the FDA granted accelerated approval to the ADC, Dato-DXd, for previously treated patients with EGFR-mutated non-small cell lung cancer (NSCLC). Jacob Sands, MD, of Dana-Farber Cancer Institute, joined Rahul Gosain, MD, MBA, and Rohit Gosain, MD, of the Oncology Brothers podcast to discuss Dato-DXd for their Journal Club series. 

Dato-DXd was evaluated in the phase 3 TROPION-Lung01 and phase 2 TROPION-Lung05 trials. The doctors discussed the two studies and the pooled analysis of the EGFR-mutated subpopulation from both studies that led to the approval.

Findings From the TROPION Studies

The randomized TROPION-Lung01 trial  compared Dato-DXd and docetaxel in patients with squamous or non-squamous NSCLC with or without actionable genomic alterations. Compared with docetaxel, Dato-DXd significantly improved median progression-free survival (PFS) and median overall survival (OS) for all patients with non-squamous NSCLC, regardless of actionable genomic alteration status. The separation was more substantial for patients with actionable genomic alterations, which were predominantly EGFR mutations, according to Dr. Sands. Notably, Dato-DXd was not superior to docetaxel for patients with squamous NSCLC.

In the single-arm TROPION-Lung05 study, only patients with actionable genomic alterations were enrolled (n=117). In both trials, patients with actionable alterations had previously received both targeted therapy and platinum-based therapy. 

In the pooled analysis of patients with actionable EGFR mutations from TROPION-Lung01 and TROPION-Lung05, Dato-DXd yielded a median PFS of 5.8 months (95% CI, 5.4-8.2) and median OS of 15.6 months (95% CI, 13.1-19.0).

TRAE Clinical Pearls

Although Dato-DXd has a favorable safety profile, the doctors discussed management strategies for potential treatment-related adverse events (TRAEs). The most common TRAE was stomatitis, with grade 1 or 2 events occurring in 50% of patients and grade 3 events occurring in 9%. The primary recommendations for management are use of a soft toothbrush and avoidance of food or substances that irritate the mucous membrane. Ice chips at the time of infusion may also help reduce the impact of Dato-DXd in the mouth. 

Steroid mouth rinses were implemented as a prophylaxis in the trial, but not until the end, so their efficacy may not be reflected in the data, Dr. Sands said. Previous studies that evaluated Dato-DXd in breast cancer implemented steroid rinses earlier and reported lower rates of stomatitis. However, more data are needed to determine their prophylactic value.

Before beginning the next dose of Dato-DXd, Dr. Sands recommended letting the stomatitis resolve. If it remains an issue, he advised a dose reduction over discontinuation of Dato-DXd, as lower doses still showed efficacy signals.

Interstitial lung disease (ILD) is a more critical TRAE that has been seen with deruxtecan-based ADCs. In the pooled analysis cohort, ILD was reported in 4% of patients, including one patient with grade 3. Physicians should be aware of this possibility in patients, but limited inflammatory findings may not immediately indicate ILD, Dr. Sands said. Each case should be approached individually with adequate workup before settling on drug-related ILD.

How to Sequence Dato-DXd Amidst Approved Therapies

Dato-DXd is now available to patients who received EGFR-directed and platinum-based therapies, but there is some nuance in what the preceding treatment lines may look like, Dr. Sands said. 

Several regimens are currently approved in the frontline setting. For instance, in patients with NSCLC with common sensitizing EGFR mutations, osimertinib with or without chemotherapy and amivantamab plus lazertinib (ami-laz) can be used. In addition, amivantamab plus chemotherapy is approved as a frontline treatment for NSCLC with EGFR exon 20 insertion. 

Patients who received frontline ami-laz or osimertinib monotherapy could both go on to chemotherapy, then Dato-DXd. However, more patients may receive upfront osimertinib plus chemotherapy if data from the ongoing FLAURA2 study are positive. In this case, it may be possible to follow up with amivantamab plus chemotherapy in select patients before moving on to Dato-DXd, Dr. Sands said. “It’s hard to be broadly specific with recommendations for this population,” he said. 

Future Research Avenues in NSCLC

Closing the conversation, Dr. Sands highlighted a presentation at the 2024 World Conference of Lung Cancer on an experimental biomarker in NSCLC. The study evaluated the TROPION-Lung01 population, and found that normalized membrane ratio of TROP2 was predictive for response to Dato-DXd in patients with non-squamous metastatic NSCLC without actionable genetic alterations. While the biomarker was prognostic based on the analysis, Dr. Sands said it was an area for further study.