After the failure of targeted therapies, immunotherapy, and platinum-based chemotherapy, there are currently few treatment options with limited benefits available for patients with advanced NSCLC. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a TROP-2-directed monoclonal antibody linked to a topoisomerase I inhibitor via a peptide cleavable linker.

Results from the Phase II ICARUS-LUNG01 study of Daiichi Sankyo's Dato-DXd, focusing on patients with previously treated metastatic NSCLC were featured in the ASCO 2024 meeting. Data from the study evaluating activity, safety, and biomarkers of response/resistance to Dato-DXd in pretreated patients with advanced NSCLC was as follows:

• In this pretreated population, Dato-DXd showed similar efficacy and safety results to those reported in TROPION-Lung01

• Patients with non-squamous histology appeared to derive the greatest benefit (ORR: 30.5%, mPFS: 4.8 months)

• Patients with a wide range of TROP2 expression may benefit from Dato-DXd. In this study, patients with TROP2 of H-Score ≥ 100 seem to derive the greatest clinical benefit (H-score <100: n=13)

However, the study had a few limitations. With the limitation of the small sample size, no genomic driver alterations at baseline seem associated with response/resistance to Dato-DXd, activation of DNA repair and suppression of immune-related pathways after 1-2 cycles of Dato- DXd could be associated with treatment resistance

Further biomarker analyses are ongoing, genomic analysis at progression, TROP-2 spatial distribution (Al-digital pathology), immune modulation, and Dato-DXd internalization (IMC), along with CTC, ctDNA

KOL insights

“Two new studies support the hypothesis that patients with EGFR mutated NSCLC are the best population for TROP-2 ADCs: EVOKE-01 (EGFR is in the ‘AGA’ subgroup in the forest plot) and ICARUS-LUNG” – Expert Opinion. 

“ICARUS Lung 01 trial from GustaveRoussy focused on resistance mechanisms to ADCs seems to confirm different Dato-Deruxtecan according to histology but no driver alteration identified as a potential predictive factor”– Expert Opinion.

Conclusion

DATO-DxD targets TROP2-expressing malignancies, not HER2-expressing ones, and utilizes half as many chemotherapy agents as ENHERTU, along with the same linker and payload. Its advantages in treating non-small cell lung cancer (NSCLC), particularly its higher efficacy in early-stage studies, position it as a potential top TROP2 ADC for NSCLC, surpassing other therapy approaches currently under investigation.

Phase II ICARUS-Lung01 for DATO-DxD focuses on the same NSCLC setting as EVOKE-01 and TROPION-Lung01 but is designed with a biomarker and translation-rich intent. However, recent data readouts indicate that both EVOKE-01 and TROPION-Lung01 have not performed well. TRODELVY, for instance, failed to meet the primary endpoint of overall survival in previously treated metastatic NSCLC in the Phase III EVOKE-01 study. Similarly, while the TROPION-Lung01 Phase III trial initially met the dual primary endpoint of progression-free survival (PFS), the survival results did not achieve statistical significance in the overall trial population.

Datopotamab deruxtecan is currently under review by the US FDA and European Medicines Agency for locally advanced or metastatic nonsquamous NSCLC in patients who have received prior systemic therapy, with an FDA action date set for December 20.

Overall, the Phase II ICARUS-Lung01 study suggests that patients with EGFR-mutated NSCLC may be the best population for TROP-2 ADCs.