Datopotamab deruxtecan (Dato-DXd) is an antibody–drug conjugate that targets TROP2. It consists of an anti-TROP2 monoclonal antibody that is covalently attached to a highly effective, membrane-permeable topoisomerase I inhibitor. This connection is facilitated by a plasma-stable, tumor-selective cleavable linker based on a tetrapeptide. Brain metastases are frequently observed in patients with non-small cell lung cancer (NSCLC) and are associated with a poor prognosis. The phase 3 TROPION-Lung01 trial (NCT04656652) revealed a statistically significant enhancement in progression-free survival (PFS) when comparing Dato-DXd with docetaxel (DTX) in patients with previously treated advanced NSCLC, particularly among those with nonsquamous histology. A post hoc analysis focusing on patients with nonsquamous NSCLC categorized by their baseline brain metastasis status was presented at ESMO 2024.
TROPION-Lung01 is a phase 3, multicenter, randomized, open-label study that evaluated Dato-DXd versus DTX in patients with previously treated advanced NSCLC with or without actionable genomic alterations. Patients were randomized 1:1 to receive either Dato-DXd at a dosage of 6 mg/kg or DTX at 75 mg/m2 every 3 weeks. Those with clinically stable brain metastases, characterized as asymptomatic and either previously treated or untreated, were considered eligible for the study. The primary end points included PFS by blinded independent central review (BICR) and overall survival, and secondary end points included objective response rate (ORR) by BICR, duration of response by BICR, and safety.
As of the data cutoff on March 29, 2023, a total of 84 of 468 patients with nonsquamous NSCLC presented with brain metastases. Among these, 43 patients were assigned to receive Dato-DXd, while 41 were allocated to DTX. Baseline characteristics were generally comparable across the treatment groups, both for patients with brain metastases and those without. Dato-DXd demonstrated a significant improvement in PFS compared with DTX, irrespective of the presence of brain metastases; the median PFS was 4.9 months versus 3.6 months for patients with brain metastases and 5.7 months versus 3.7 months for those without brain metastases. The ORR was also higher in patients treated with Dato-DXd compared with DTX, regardless of brain metastasis status. The ORR for the Dato-DXd group in those with brain metastasis was 30% versus 12% in the DTX group with brain metastasis. The ORR for the Dato-DXd group in those without brain metastasis was 31% versus 13% in the DTX group without brain metastasis. Additionally, there were fewer instances of grade ≥3 serious treatment-related adverse events and a lower rate of dose reductions or treatment discontinuations in the Dato-DXd group compared with the DTX group, irrespective of brain metastasis status.
Dato-DXd demonstrated enhanced efficacy, and a tolerable safety profile compared with DTX in patients with nonsquamous NSCLC, irrespective of baseline brain metastasis status. The evaluation of Dato-DXd’s intracranial activity in patients with breast cancer is currently in progress. There is a need for further exploration of the cranial activity associated with Dato-DXd in patients who have brain metastasis.
Source: Pons-Tostivint E, Okamoto I, Sands J, et al. Datopotamab deruxtecan (Dato-DXd) vs docetaxel (DTX) in patients (pts) with advanced nonsquamous (NSQ) non-small cell lung cancer (NSCLC) with brain metastases (mets): results from TROPION-Lung01. Barcelona, Spain, & online: presented at ESMO Congress 2024; abstract 1312P.