Datopotamab deruxtecan plus durvalumab demonstrates manageable safety and encouraging antitumour activity in advanced NSCLC

Initial results from the phase 1b TROPION-Lung04 trial demonstrated that Datopotamab deruxtecan plus durvalumab showed promising clinical activity in the first-line advanced non-small cell lung cancer setting. The combination of datopotamab deruxtecan plus durvalumab, with or without chemotherapy, demonstrated objective response rates of 77% and 50%, respectively.

Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanised anti-TROP2 IgG1 monoclonal antibody that is covalently linked to a highly potent topoisomerase-I inhibitor payload via a plasma-stable, tumour-selective, tetrapeptide-based cleavable linker. Preclinical data already demonstrated that Dato-DXd can enhance the antitumour response to PD-1/PD-L1 inhibitors. Furthermore, Dato-DXd showed encouraging early efficacy and safety as monotherapy (TROPION-PanTumor01) and combined with anti-PD-1 ± platinum-based chemotherapy (TROPION-Lung02). Finally, in the phase III TROPION-Lung01 study, Dato-DXd 6 mg/kg monotherapy demonstrated a statistically significant improvement in progression-free survival versus docetaxel in previously treated advanced or metastatic NSCLC. TROPION-Lung04 is now investigating Dato-DXd in combination with different immunotherapy agents ± carboplatin across 11 cohorts. The first data from an interim analysis on Cohorts 2 and 4 were recently presented at WCLC.

Study design

In order to be eligible for TROPION-Lung04, patients must be ≥18-years-old with ECOG PS 0/1 and histologically or cytologically confirmed advanced mNSCLC without actionable genomic alterations. Patients in Cohort 1 and one patient in Cohort 2 had received ≥1 platinum-based chemotherapy regimen and anti-PD-1/PD-L1 therapy as per an earlier version of the clinical study protocol. Subsequent patients were treatment-naïve or had ≤1 prior line of systemic chemotherapy without concomitant immune checkpoint inhibitors (ICIs). Patients received Dato-DXd (4 mg/kg in Cohorts 1 and 3; 6 mg/kg, in Cohorts 2 and 4) + durvalumab (1.120 mg, all cohorts) + up to 4 cycles of carboplatin (AUC 5, Cohorts 3 and 4) Q3W until disease progression (RECIST v1.1) or unacceptable toxicity.

Part 1 (dose escalation) was conducted sequentially using a modified toxicity probability interval-2 (mTPI-2) design with 3‒6 patients. Dependent on observed dose-limiting toxicities (DLTs), Part 2 (dose expansion) was opened. Cohort 3 was an as-needed de-escalation cohort but this cohort was skipped as there were sufficient data available from the Dato-DXd development program to conclude that 4 mg/kg Dato-DXd in combination with immunotherapy and carboplatin has an acceptable safety profile. Primary endpoint of the study was safety and tolerability. Secondary endpoints included objective response rate (ORR) and disease control rate by investigator assessment (RECIST v1.1).

Results

At the time of data cut-off for Cohort 2 and Cohort 4, respectively, study treatment was ongoing in 31.6% and 50.0% of patients. Median study treatment duration was 6.0 months and 6.2 months. There were no DLTs in Cohort 1 or Cohort 2 during the dose escalation part. Two patients reported DLTs in Cohort 4 (one patient with grade 3 febrile neutropenia and one patient with both grade 3 stomatitis and grade 3 maculo-papular rash). Dose expansion subsequently occurred in Cohort 2 (doublet regimen) and Cohort 4 (triplet regimen). Importantly, there were no grade 5 adjudicated interstitial lung disease (ILD) events. There was one grade 4 adjudicated ILD event in a patient in Cohort 2. Treatment-emergent adverse events (TEAEs) of all-grade (grade ≥3) occurred in 100% (42.1%) of patients in Cohort 2 and in 100% (71.4%) of patients in Cohort 4. Most frequent TEAEs of all-grade (grade ≥3) in Cohort 2 were constipation in 57.9% (0%), stomatitis in 52.6% (10.5%), alopecia in 52.6% (0%) and nausea in 42.1% (0%). For Cohort 4 these were stomatitis in 64.3% (7.1%), alopecia in 57.1% (0%), nausea in 57.1% (0%) and anaemia in 50.0% (35.7%). In Cohorts 2/4, TEAEs leading to treatment discontinuations and Dato-DXd dose reductions occurred in respectively 21.1%/21.4% and 15.8%/35.7% of patients. There were no treatment-related deaths.

In the first-line setting, ORRs were 50.0% for Cohort 2 and 76.9% for Cohort 4. In the overall population, ORRs were 47.4% for Cohort 2 (N=19) and 71.4% for Cohort 4 (N=14). Responses were numerically higher with the triplet versus doublet combination and were observed across all PD-L1 expression levels.

Conclusion

No new safety signals were observed in Cohort 2 and Cohort 4 investigating Dato-DXd in combination with durvalumab ± carboplatin, throughout dose escalation and dose expansion. The most frequent TEAEs of any grade were stomatitis, alopecia and nausea. In general, grade ≥3 TEAEs were more frequently observed with the triplet versus the doublet combination. There were four cases of drug-related ILD; three cases were grade 1 or 2 and none were grade 5. In addition, the interim efficacy analyses demonstrated promising ORRs with durable responses for both the doublet and triplet combination, both in the first-line setting and the overall population.

Reference

Papadopoulos, et al. Datopotamab Deruxtecan (Dato-DXd) + Durvalumab ± Carboplatin in Advanced/mNSCLC: Initial Results from Phase 1b TROPION-Lung04. Presented at WCLC 2023; Abstract OA05.06.