Datopotamab deruxtecan improves efficacy outcomes and safety in patients with advanced or metastatic non-squamous non-small cell lung cancer
Datopotamab deruxtecan (dato-DXd) previously showed promising antitumor efficacy in patients with advanced or metastatic non-small cell lung cancer (NSCLC) in the phase I TROPION-PanTumour01 trial. The phase III TROPION-Lung01 trial now reveals improved efficacy outcomes and safety with dato-DXd compared to docetaxel in pretreated patients with advanced or metastatic NSCLC, predominantly benefiting those with non-squamous histology. These findings endorse dato-DXd as a compelling treatment option for previously treated non-squamous NSCLC.
Chemotherapy remains the standard of care in the second-line treatment of patients with metastatic non-small cell lung cancer (NSCL), which is associated with a modest benefit and substantial toxicity. Datopotamab deruxtecan (dato-DXd) is a TROP2-directed antibody-drug conjugate (ADC) that selectively delivers a potent topoisomerase I inhibitor payload directly into the tumour cells. Dato-DXd showed promising antitumour activity in patients with advanced or metastatic NSCLC in the phase I TROPION-PanTumour01 trial, with an overall response rate (ORR) of 26%. Based on these encouraging results, the phase III TROPION-Lung01 trial evaluated the efficacy and safety of dato-DXd compared to docetaxel in pretreated patients with advanced or metastatic NSCLC with or without actionable genomic alternations (AGAs).
Methods
The global phase III TROPION-Lung01 study enrolled patients with previously treated advanced or metastatic NSCLC (stage IIIB, IIIC or IV) ineligible for second-line chemotherapy. These patients were included independently of their histology, AGA status and TROP-2 expression level on the tumour cell surface. In total, 604 patients were randomly assigned (1:1) to receive dato-DXd 6 mg/kg (n=299) or docetaxel 75 mg/m2 Q3W (n=305). Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included ORR, duration of response (DOR), and safety.
Results
After a median follow-up of 13 months, the number of patients continuing treatment in the dato-DXd arm was three times higher than in the docetaxel arm (18% vs. 6%, respectively). Dato-DXd significantly improved PFS, with a median PFS of 4.4 vs. 3.7 months, respectively (HR[95%CI]: 0.75[0.62-0.91]; p=0.004). This improvement in PFS was supported by a higher ORR and a longer duration of response in the Dato-DXd arm compared to docetaxel (ORR: 26.4% vs. 12.8%, DoR: 7.1 vs. 5.6 months). This benefit extended across most subgroups, with the exception of patients with squamous NSCLC. Zooming on the differences based on histology, patients with non-squamous NSCLC (with or without AGAs) clearly benefit from dato-DXd, with a median PFS of 5.6 vs. 3.7 months in the dato-DXd and docetaxel arms, respectively (HR[95%CI]: 0.63[0.51-0.78]). This PFS benefit was supported by ORRs rates of 31.2% vs. 12.8%, and DoR of 7.7 vs. 5.6 months, respectively. Importantly, these patients derived benefit from dato-DXd regardless of the presence/absence of AGAs. In contrast, patients with squamous histology did not benefit from dato-DXd (HR[95%CI]: 1.38[0.94-2.02]), with a median PFS of 2.8 vs. 3.9 months in the dato-DXd and docetaxel arms, respectively. ORR rates were reported at 9.2% vs. 12.7% and DoR at 5.9 vs. 8.1 months. The first interim OS revealed a trend in favour of dato-DXd over docetaxel, with a median OS of 12.4 vs. 11.0 months, respectively (HR[95%CI]: 0.90[0.72-1.13]). Once more, patients with non-squamous NSCLC appeared to derive the greatest benefit from dato-DXd (HR[95%CI]: 0.77[0.59-1.01]), while those with squamous histology experienced no advantage (HR[95%CI]: 1.32[0.87-2.00]). The trial is ongoing, with the final OS analysis to be presented in an upcoming meeting.
Despite a longer median treatment duration with dato-DXd (4.2 vs. 2.8 months in the docetaxel arm), fewer grade≥ 3 treatment-related adverse events (TRAEs) were observed with dato-DXd compared to docetaxel (25% vs. 41%). This translated into a lower number of TRAEs, leading to dose reductions (20% vs. 29%) and discontinuations (8% vs. 12%). The most common treatment-emergent adverse events (TEAEs) observed with dato-DXd were stomatitis (47%,) and nausea (34%), mostly of grades 1-2. Haematologic toxicities were more common with docetaxel, including neutropenia (4% vs. 26% with dato-DXd and docetaxel, respectively) and febrile neutropenia (0.3% vs. 7%). Importantly, no new safety signals were observed with dato-DXd in this trial. Regarding AEs of special interest, stomatitis/oral mucositis associated with dato-DXd resulted in a low rate of discontinuation (0.7%). Dry eye was the most common ocular event seen with dato-DXd (6.1%, primarily grade ≤2), followed by increased lacrimation (5.4%). There were seven associated drug-related grade 5 intestinal lung disease (ILD) events. In four of these patients, the primary cause of death was attributed to disease progression. Infusion-related reactions (IRRs) were observed in 8% of patients in each arm, all with grade ≤2, with the exception of one grade 3 event with Dato-DXd.
Conclusion
Dato-DXd is the first ADC to demonstrate a statistically significant improvement in PFS over docetaxel in patients with previously treated, locally advanced or metastatic NSCLC. Importantly, PFS benefit was primarily driven by patients with non-squamous histology. Dato-DXd exhibited a favourable safety profile with fewer grade ≥3 TRAEs and no new safety signals, though there were some grade ≥3 ILD events, emphasising the need for careful monitoring and adherence to ILD management guidelines. Finally, the interim OS findings showed a positive OS trend for Dato-DXd, and the final analysis is eagerly awaited. These findings suggest that dato-DXd has the potential to become a meaningful therapy for previously treated non-squamous NSCLC patients.
Reference
Lisberg AE. Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): Results of the randomized phase III study TROPION-Lung01. Presented at ESMO 2023; Abstract LBA12.
