Datopotamab Deruxtecan in EGFR- and ALK-Mutant Lung Cancer

Non-small cell lung cancer (NSCLC) is now regarded as a diverse group of diseases with many genetic characteristics. In nearly half of patients, various mutations are closely linked to cancer development and are also amenable to targeted treatment. This expands options but complicates care. Although patients may live for many years, treatment options become much more limited when resistance develops and cancer progresses. Effective later-line treatments are therefore greatly needed for patients with targetable alterations.

Published on January 6, 2025, in Journal of Clinical Oncologyby Sands and colleagues, the Phase II TROPION-Lung05 study reported encouraging findings for datopotamab deruxtecan (Dato-DXd) in advanced NSCLC progressing after targeted treatment and platinum chemotherapy.

What Is Datopotamab Deruxtecan?

Dato-DXd is an antibody–drug conjugate targeting trophoblast cell-surface antigen-2 (TROP2), carrying a topoisomerase I inhibitor payload. TROP2 is highly expressed in many cancers, allowing Dato-DXd to target TROP2-expressing tumor cells and provide effective treatment.

Although being tested in many cancers, this drug has not yet received FDA (United States Food and Drug Administration) approval for any indication.

• Related topic: Longer PFS with Dato-DXd in Breast Cancer: The TROPION-Breast01 Study

Details of TROPION-Lung05

This multinational Phase II study enrolled patients between March 2021 and December 2022, totaling 137 patients . All received Dato-DXd 6 mg/kg every 3 weeks until progression or unacceptable toxicity.

71.5% had received three or more treatment lines for advanced/metastatic disease.

Among patients, 56.9% had EGFR mutations and 24.8% had ALK rearrangements . The primary endpoint, assessed by blinded independent central review, was the objective response rate.

Key Findings

• The confirmed objective response rate in all patients was 35.8% (confidence interval [CI]: 27.8%–44.4%).

• In patients with EGFR mutations, the response rate was 43.6% (CI: 32.4%–55.3%), while for ALK rearrangements it was 23.5% (CI: 10.7%–41.2%).

• The disease control rate among all patients was 78.8% , compared with 82,1% in EGFR-mutant patients and 73.5% in patients with ALK alterations.

Duration of Response

Median duration of response among all responders was 7.0 months (CI: 4.2–9.8 months). It was 7.0 months (CI: 4.2–10.2 months) in EGFR-mutant patients and 7.0 months (CI: 2.8–8.4 months) in those with ALK rearrangements.

The plots below show durable tumor shrinkage in many patients continuing datopotamab deruxtecan, with responses across different genetic profiles.

(A) Waterfall Plot:

• Y-axis: Percentage change in tumor diameter from baseline (%).

• X-axis: Individual patients are arranged in sequence.

• Bars show the extent of each patient's response:

  • CR (Complete Response) – Red: Patients whose tumors disappeared completely.
  • PR (Partial Response) – Blue: Patients with substantial tumor shrinkage (more than 30%).
  • SD (Stable Disease) – Orange: Patients without marked tumor shrinkage or growth.
  • PD (Progressive Disease) – Gray: Patients with disease progression.
  • NE (Not Evaluable) – Light blue: Patients whose response could not be evaluated.
  • Plus (+) sign: Represents patients still receiving treatment.

• Genetic Alteration Categories: Colored blocks beneath the plot show pretreatment genomic alterations (e.g., EGFR mutations or ALK rearrangements).

(B) Wrestling Graph (Changes Over Time):

• Upper panel: Patients with CR or PR (complete or partial response) and their tumor shrinkage over time.
• Lower panel: Patients with SD (stable disease) and their measurements over time.
• Y-axis: Percentage change in tumor diameter from baseline.
• X-axis: Treatment duration (months).
• Yellow arrows indicate patients still receiving treatment.

These plots show durable tumor shrinkage with datopotamab deruxtecan in many patients continuing treatment and responses across different genetic profiles. Promising responses are particularly seen in patients with targetable alterations such as EGFR and ALK changes.

Treatment-Related Side Effects

Treatment-related side effects were reported as follows:

• The most common side effects of any grade:

  • Mouth sores (56.2%)

  • Nausea (54.7%)

  • Hair loss (49.6%)

  • Loss of appetite (20.4%)

  • Fatigue (19.0%)

• Grade ≥ 3 treatment-related side effects occurred in 28.5%, most commonly:

  • Mouth sores (9.5%)

  • Nausea (2.2%)

  • Loss of appetite (2.2%)

• Seven patients (5.1%) discontinued treatment because of treatment-related side effects.

• Treatment-related interstitial lung disease/pneumonitis occurred in five patients (3.6%), causing one death.

Commentary

The researchers reported encouraging, durable antitumor activity in these heavily pretreated advanced/metastatic NSCLC patients. Treatment-related grade ≥ 3 adverse-event rates were consistent with prior studies, with no new safety signal. The findings suggest Dato-DXd could be a promising new option for NSCLC with targetable genetic alterations. However, potentially serious effects such as treatment-related interstitial lung disease require careful monitoring.

These findings represent an important advance in advanced NSCLC treatment. Phase III studies in larger populations are needed to better establish effectiveness and safety. Nevertheless, the potential clinical impact is already attracting considerable interest, and the promising results are a step toward an important option for these patients.