Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study

Abstract

Purpose: The randomized, open-label, global phase III TROPION-Lung01 study compared the efficacy and safety of datopotamab deruxtecan (Dato-DXd) versus docetaxel in patients with pretreated advanced/metastatic non-small cell lung cancer (NSCLC).

Methods: Patients received Dato-DXd 6 mg/kg or docetaxel 75 mg/m² once every 3 weeks. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Objective response rate, duration of response, and safety were secondary end points.

Results: In total, 299 and 305 patients were randomly assigned to receive Dato-DXd or docetaxel, respectively. The median PFS was 4.4 months (95% CI, 4.2 to 5.6) with Dato-DXd and 3.7 months (95% CI, 2.9 to 4.2) with docetaxel (hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.91]; P = .004). The median OS was 12.9 months (95% CI, 11.0 to 13.9) and 11.8 months (95% CI, 10.1 to 12.8), respectively (HR, 0.94 [95% CI, 0.78 to 1.14]; P = .530). In the prespecified nonsquamous histology subgroup, the median PFS was 5.5 versus 3.6 months (HR, 0.63 [95% CI, 0.51 to 0.79]) and the median OS was 14.6 versus 12.3 months (HR, 0.84 [95% CI, 0.68 to 1.05]). In the squamous histology subgroup, the median PFS was 2.8 versus 3.9 months (HR, 1.41 [95% CI, 0.95 to 2.08]) and the median OS was 7.6 versus 9.4 months (HR, 1.32 [95% CI, 0.91 to 1.92]). Grade ≥3 treatment-related adverse events occurred in 25.6% and 42.1% of patients, and any-grade adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8.8% and 4.1% of patients, in the Dato-DXd and docetaxel groups, respectively.

Conclusion: Dato-DXd significantly improved PFS versus docetaxel in patients with advanced/metastatic NSCLC, driven by patients with nonsquamous histology. OS showed a numerical benefit but did not reach statistical significance. No unexpected safety signals were observed.

Trial registration: ClinicalTrials.gov NCT04656652.

FIG 1.

CONSORT diagram. Data cutoff: March 1, 2024. ^aOne patient in the docetaxel treatment group was randomly assigned twice; treatment was not initiated under the first patient identifier, and only the second patient identifier was included. A total of 305 unique patients were allocated to docetaxel. AE, adverse event; Dato-DXd, datopotamab deruxtecan; PD, progressive disease.

FIG 2.

PFS by treatment and key subgroups. Data cutoff: March 29, 2023. (A) Kaplan-Meier curves for PFS in the full analysis set, (B) HRs of PFS in key subgroups, (C) Kaplan-Meier curves for PFS in patients with nonsquamous histology, and (D) Kaplan-Meier curves for PFS in patients with squamous histology. PFS was assessed by blinded independent central review. Tick marks in the Kaplan-Meier curves represent censored data. HRs and CIs in the forest plot were calculated on the basis of the patient data in the electronic case report forms for the histology and actionable genomic alteration subgroups. ^aRegardless of histology. Dato-DXd, datopotamab deruxtecan; HR, hazard ratio; PFS, progression-free survival.

FIG 3.

OS by treatment and key subgroups. Data cutoff: March 1, 2024. (A) Kaplan-Meier curves for OS in the full analysis set, (B) HRs of OS in key subgroups, (C) Kaplan-Meier curves for OS in patients with nonsquamous histology, and (D) Kaplan-Meier curves for OS in patients with squamous histology. Tick marks in the Kaplan-Meier curves represent censored data. HRs and CIs in the forest plot were calculated on the basis of the patient data in the electronic case report forms for the histology and actionable genomic alteration subgroups. ^aRegardless of histology. Dato-DXd, datopotamab deruxtecan; HR, hazard ratio; OS, overall survival.

FIG A1.

Study design of TROPION-Lung01. Pretreated patients with advanced or metastatic NSCLC received Dato-DXd 6 mg/kg IV once every 3 weeks or docetaxel 75 mg/m² IV once every 3 weeks. ^aFor patients with actionable genomic alterations, previously treated with one to two lines of approved alteration-targeted therapy, with platinum-based chemotherapy as the only previous line of cytotoxic therapy, with or without not more than one anti–PD-1/PD-L1 monoclonal antibody alone or in combination with a cytotoxic agent. For patients without actionable genomic alterations, previously treated with platinum-based chemotherapy and anti–PD-1/PD-L1 immunotherapy, either in combination as the only previous line of therapy or sequentially as the only two previous lines of therapy. For all patients, no previous docetaxel was permitted. ^bPatients with known KRAS mutations, in the absence of any driver genomic alterations, were eligible and had to meet previous therapy requirements for patients without actionable genomic alterations. ^cDay 1 of each 3-week cycle. ^dRadiographic disease progression, clinical progression, death, unacceptable toxicity, loss to follow-up, or withdrawal of patient consent. ^ePer RECIST v1.1. ^fAssessed by BICR and investigator per RECIST v1.1. BICR, blinded independent central review; CR, complete response; Dato-DXd, datopotamab deruxtecan; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; NSCLC, non–small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease; TTR, time to response.