Datopotamab Deruxtecan Shows Promise for Heavily Pretreated Patients With Advanced Non-Small Cell Lung Cancer With Actionable Mutations

According to results from the phase 2 TROPION-Lung05 trial, datopotamab deruxtecan (Dato-DXd) demonstrated promising antitumor activity among heavily pretreated patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring actionable mutations. 

“A considerable unmet need remains for patients with non-small cell lung cancer and actionable genomic alterations who progress on front-line targeted therapies,” stated Jacob Sands, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, and coauthors. They went on, “In the first-in-human TROPION-PanTumor01 study, Dato-Dxd showed promising efficacy and manageable safety in patients with NSCLC, including those with actionable genomic alterations.”

In this open-label study, researchers enrolled patients with advanced or metastatic NSCLC harboring EGFR (n = 78), ALK (n = 34), ROS1 (n = 10), RET (n = 8), MET exon 14 (n = 5), and BRAF (n = 4) mutations who had received prior lines of cytotoxic therapies in the metastatic setting and targeted therapies for the actionable genomic alteration. In 21-day cycles, 137 patients received 6 mg/kg of datopotamab deruxtecan once every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) by blinded independent central review. Key secondary end points included duration of response, disease control rate, progression-free survival (PFS), overall survival (OS), and safety. 

At analysis, the confirmed ORR was 35.8% in the overall population. The confirmed ORR was 43.6% for patients with EGFR mutations and 23.5% for patients with ALK rearrangements. The median duration of response was 7 months, and the disease control rate was 78.8%. The median PFS was 5.4 months, and the median OS was 13.6 months. Grade ≥3 treatment-related adverse events occurred in 28.5% of patients, the most common including stomatitis (9.5%), amylase increase (5.1%), anemia (2.9%), nausea (2.2%), and decreased appetite (2.2%). Adjudicated treatment-related interstitial lung disease or pneumonitis was reported by 5 patients and resulted in 1 death. 

“These findings suggest that this novel TROP2-directed [antibody-drug conjugate] may provide clinically meaningful benefit in a difficult-to-treat population with poor prognosis and lack of effective therapies,” concluded Dr Sands et al. 

“Based upon these results, a phase III trial of Dato-DXd compared to platinum-based chemotherapy in patients with actionable genomic alterations with disease progression on targeted therapies is warranted,” added Journal of Clinical Oncology Associate Editor Thomas Stinchcombe, MD, Duke Cancer Center, Durham, North Carolina. 

Source: 

Sands J, Ahn MJ, Lisberg A, et al. Datopotamab deruxtecan in advanced or metastatic non–small cell lung cancer with actionable genomic alterations: Results from the phase II TROPION-Lung05 study. J Clin Oncol. Published online: January 6, 2025. doi: 10.1200/JCO-24-01349