Datopotamab Deruxtecan in Advanced or Metastatic Non-Small Cell Lung Cancer With Actionable Genomic Alterations: Results From the Phase II TROPION-Lung05 Study

Abstract

Purpose: Datopotamab deruxtecan (Dato-DXd) is a trophoblast cell-surface antigen-2-directed antibody-drug conjugate with a highly potent topoisomerase I inhibitor payload. The TROPION-Lung05 phase II trial (ClinicalTrials.gov identifier: NCT04484142) evaluated the safety and clinical activity of Dato-DXd in patients with advanced/metastatic non-small cell lung cancer (NSCLC) with actionable genomic alterations progressing on or after targeted therapy and platinum-based chemotherapy.

Patients and methods: Patients received Dato-DXd 6 mg/kg once every 3 weeks. The primary end point was objective response rate (ORR) by blinded independent central review. Secondary end points included duration of response (DOR), safety, tolerability, and survival.

Results: Among 137 patients who received at least 1 dose of Dato-DXd, 71.5% received at least three lines of prior therapies for advanced/metastatic disease. Overall, 56.9% had EGFR mutations and 24.8% had ALK rearrangements. Median treatment duration was 4.4 months (range, 0.7-20.6). The confirmed ORR was 35.8% (95% CI, 27.8 to 44.4) overall, and 43.6% (95% CI, 32.4 to 55.3) and 23.5% (95% CI, 10.7 to 41.2) in those with EGFR mutations and ALK rearrangements, respectively. The median DOR was 7.0 months (95% CI, 4.2 to 9.8), and the overall disease control rate was 78.8% (95% CI, 71.0 to 85.3). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 28.5% of patients. The most common TRAE was stomatitis (preferred term; any grade: 56.2%; grade ≥3: 9.5%). Five (3.6%) patients experienced adjudicated treatment-related interstitial lung disease/pneumonitis, with 1 (0.7%) grade 5 event.

Conclusion: Encouraging and durable antitumor activity was observed with Dato-DXd in this heavily pretreated advanced/metastatic NSCLC population with actionable genomic alterations. The rate of treatment-related grade ≥3 toxicities was comparable with previous observations, and no new safety signals were observed.

FIG 1.

Patient disposition. ^aPatients who signed the informed consent form and who were screened for eligibility. AE, adverse event.

FIG 2.

Antitumor activity of Dato-DXd in the overall cohort. (A) Waterfall plot of best percentage change in the SOD from baseline by BICR (n = 126). Snapshot data cutoff, December 14, 2022. Below the waterfall plot, categories of genomic alterations before treatment with Dato-DXd are identified for each patient. (B) Percentage change from baseline in SOD in target lesions in patients with a confirmed CR/PR (upper panel) or SD (lower panel) by BICR. ^aExon 19 deletion (Ex19Del) or Exon 21 L858R (Ex21 L858R). ^bIncludes Exon 18 G719 (Ex18 G719), Exon 19 insertion (Ex19 Ins), Exon 20 insertion (Ex20 Ins), Exon 20 S768I (Ex 20 S768I), Exon 21 L861G (Ex 21 L861G), V323I p.1759M, G724S, and unknown EGFRm. BICR, blinded independent central review; CR, complete response; Dato-DXd, datopotamab deruxtecan; EGFRm, EGFR mutation; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease; SOD, sum of the diameters.

FIG 3.

Kaplan-Meier estimates of survival. (A) PFS by BICR per RECIST v1.1. (B) OS. BICR, blinded independent central review; NE, not evaluable; OS, overall survival; PFS, progression-free survival.