Initial results for datopotamab deruxtecan plus pembrolizumab and platinum chemotherapy in advanced NSCLC
This year, the annual WCLC meeting featured the first reported clinical experience of a TROP2 antibody-drug conjugate in combination with a checkpoint inhibitor and platinum chemotherapy in non-small cell lung cancer (NSCLC). Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab with or without platinum chemotherapy demonstrated a tolerable safety profile and has notable activity in frontline and relapsed or refractory settings.
Most patients with advanced/metastatic non-small cell lung cancer (NSCLC) experience disease progression within 8-10 months of starting frontline therapy, highlighting the need for novel therapies. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) composed of a humanised TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. Dato-DXd demonstrated encouraging efficacy and a manageable safety profile as monotherapy in patients with relapsed/refractory advanced/metastatic NSCLC (objective response rate [ORR] of 28% with 6 mg/kg and median response duration of 10.5 months). TROPION-Lung02 is a phase Ib study evaluating Dato-DXd plus pembrolizumab with or without platinum chemotherapy in advanced NSCLC without actionable genomic alterations. At IASLC WCLC 2022, Prof. Levy reported the initial safety and efficacy results of this trial.
Study design
TROPION-Lung02 is a phase 1b, global, dose-escalation and expansion study. Two dose levels of Dato-DXd (4.0 mg/kg and 6.0 mg/kg) were studied in combination with 200 mg fixed-dose pembrolizumab in six study cohorts (see Keyslide 1). Patients in the dose confirmation part of the study could have received a maximum of two prior lines of therapy. Patients in cohort expansion must not have received prior therapy for advanced/metastatic NSCLC (cohorts 3-6, ‘triplets’) or maximum one line of platinum chemotherapy (cohorts 1 and 2, ‘doublets’). The primary objective is to assess tolerability and safety. In this light, it should be noticed that the safety of Data-DXd plus pembrolizumab ‘doublets’ was established prior to evaluation of platinum-containing ‘triplets’. Furthermore, the safety of 4 mg/kg combinations was established prior to evaluation of 6 mg/kg combinations. Secondary objectives are to evaluate efficacy, pharmacokinetics, and antidrug antibodies.
Results
In total, 40 patients were enrolled in the doublet arm and 48 patients in the triplet arm. At the time of the data cut-off (May 2, 2022) for doublet and triplet therapy, study treatment was ongoing in respectively 53% and 77% of patients. Median treatment duration was 4.1 months and 3.0 months and median follow-up was 6.5 and 4.4 months, respectively. Treatment-related adverse events (TRAEs) occurred in 83% of patients receiving the doublet regimen and in 96% of patients receiving the triplet combination. Respectively 35% and 54% of TRAEs were of grade ≥3. Nonetheless, discontinuations due to Dato-DXd occurred in only 15% and 10%, respectively. Treatment-emergent AEs (TEAEs) associated with death were reported for two patients receiving the doublet regimen and for one patient receiving the triplet combination. Four cases of drug-related interstitial lung disease were registered, three in the doublet arm (two of grade 1/2 and 1 of grade 3) and one in the triplet arm (grade 3). The most frequent TEAEs in the doublet and triplet arms of any grade were stomatitis (56% vs. 29%), nausea (41% vs. 48%), and decreased appetite (28% vs. 38%).
In the overall population, ORRs (confirmed and pending) of 37% and 41% were seen with doublet (N= 38) and triplet (N= 37) therapy, respectively. Both groups had a disease control rate of 84%. As first-line therapy, the doublet and triplet yielded ORRs of 62% and 50%, respectively while for second-line and beyond the respective ORRs were 24% and 29%. Responses were observed across all PD-L1 expression levels, although PD-L1 expression levels seemed to predict better responses in both the doublet and triplet arm.
Conclusion
This first reported clinical experience of a TROP2 ADC + a checkpoint inhibitor ± platinum chemotherapy in metastatic NSCLC demonstrated a tolerable safety profile and supported further evaluation of the 6 mg/kg dose of Dato-DXd in immunotherapy combination regimens. Stomatitis and nausea, mostly grade 1/2, were the most frequent TEAEs in patients receiving doublet and triplet therapy, respectively. Interim efficacy results in the overall population and in patients receiving first-line therapy are encouraging. The phase III TROPION-Lung08 trial (NCT05215340) is evaluating Dato-DXd + pembrolizumab vs. pembrolizumab alone as first-line therapy in advanced/metastatic NSCLC with PD-L1 TPS >50%.
Reference
Levy B, Paz-Ares L, Rixe O, et al. TROPION-Lung02: Initial Results for Datopotamab Deruxtecan Plus Pembrolizumab and Platinum Chemotherapy in Advanced NSCLC. Presented at IASLC WCLC 2022; Abstract MA13.07.
