Datopotamab Deruxtecan Shows Promising Antitumor Activity in Advanced Pretreated NSCLC

Most lung cancers are non-small cell lung cancer (NSCLC) and mainly diagnosed at an advanced stage. Although recent advances have been made in the treatment landscape for advanced NSCLC, including PD-L1 agents and targeted therapies, the disease inevitably progresses. Current treatments in the second-line setting and beyond offer limited clinical benefit and often have substantial toxicity. Therefore, more effective and tolerable options that prolong survival and improve quality of life are needed.

Trophoblast cell-surface antigen 2 (TROP2), a transmembrane glycoprotein, is expressed in many solid tumors, including NSCLC, making it an attractive antigen for antibody-drug conjugate (ADC) binding. Datopotamab deruxtecan (Dato-DXd) is a novel, investigational, anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload through a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker. Toshio Shimizu, MD, PhD, and colleagues evaluated the safety, tolerability, and antitumor activity of Dato-DXd from the advanced NSCLC cohort of the phase 1, first-in-human, dose-escalation, and dose-expansion TROPION-PanTumor01 study. Results were reported in the Journal of Clinical Oncology [2023;41(29):4678-4687; doi:10.1200/JCO.23.00059].

TROPION-PanTumor01 is an ongoing, multicenter, two-part, open-label study of Dato-DXd conducted in the United States and Japan in heavily pretreated patients with advanced NSCLC. The study included patients aged 20 years and older (Japan) or 18 years and older (United States) with unresectable locally advanced/metastatic NSCLC who relapsed or progressed after available treatments or without standard treatment available. Patients had an Eastern Cooperative Oncology Group performance status score of 0-1 and measurable disease based on Response Evaluation Criteria in Solid Tumors v1.1. Exclusion criteria included a history of malignancy other than NSCLC, clinically significant/suspected lung disease other than underlying NSCLC, clinically active brain metastases, and clinically significant corneal disease.

The primacy outcome measures were safety and tolerability. Secondary outcome measures included objective response rate (ORR) and survival.

A total of 210 patients received Dato-DXd 0.27 mg/kg to 10.00 mg/kg once every 3 weeks during escalation or Dato-DXd 4, 6, or 8 mg/kg (n=180) once every 3 weeks during expansion. The maximum tolerated dose was 8 mg/kg once every 3 weeks; the recommended dose for further development was 6 mg/kg once every 3 weeks. In patients receiving Dato-DXd 4, 6, or 8 mg/kg, the median duration on study was 15.9, 13.3, and 20.6 months and the median exposure was 4.1, 3.5, and 3.3 months, respectively.

In patients receiving 6 mg/kg (n=50), median duration on study, including follow-up, and median exposure were 13.3 and 3.5 months, respectively. Of the patients in the Dato-DXd 4-mg/kg to 8-mg/kg cohort, 54% to 64% had three or more lines of therapy and 20% to 24% had five or more lines. Across dose cohorts, 76% to 88% of patients received previous immunotherapy and 96% to 98% received previous platinum-based chemotherapy. Premedication was not allowed before the initial dose of Dato-DXd during the dose-limiting toxicity evaluation period. Patients received Dato-DXd until acceptable toxicity, progressive disease, or withdrawal of consent.

Dato-DXd showed encouraging antitumor activity, and responses were observed regardless of TROP2 expression level. “The unique ADC platform characteristics and emerging clinical profile in advanced NSCLC support further development of Dato-DXd in NSCLC and other tumors,” the researchers said.

Among patients who received Dato-DXd 4 mg/kg, the confirmed ORR was 22% (95% CI, 11.5-36.0), the median duration of response (DOR) was 12.7 months, the disease control rate (DCR) was 76% (95% CI, 61.8-86.9), and the median progression-free survival (PFS) was 4.3 months (95% CI, 2.9-6.9). In the group of patients who received Dato-DXd 6 mg/kg, confirmed ORR was 26% (95% CI, 14.6-40.3), the median DOR was 10.5 months (95% CI, 5.6-26.5), the DCR was 70% (95% CI, 55.4-82.1), and the median PFS was 6.9 months (95% CI, 2.7-8.8). For patients who received Dato-DXd 8 mg/kg, the ORR was 23.8% (95% CI, 14.9-34.6), the median DOR was 9.6 months, the DCR was 78.8% (95% CI, 68.2-87.1), and the PFS was 5.2 months (95% CI, 4.1-7.1).

Dato-DXd demonstrated a manageable safety profile, with treatment-emergent adverse events (TEAEs) observed across dose escalation and expansion. The most common TEAEs of any grade were nausea, alopecia, and stomatitis. Although stomatitis was predominantly grade 1 or 2, the researchers noted that an ongoing TROPION-PanTumor01 substudy is focused on providing further insight into potential mechanisms of stomatitis and appropriate prevention strategies and clinical management.

Infusion-related reactions occurred in 24%, 20%, and 25% of patients receiving Dato-DXd 4, 6, or 8 mg/kg, respectively. The most common grade ≥3 TEAEs were pneumonia, anemia, and decreased lymphocyte count. Serious TEAEs occurred in 20.0%, 48.0%, and 48.8% of patients receiving Dato-DXd 4, 6, or 8 mg/kg, respectively. TEAEs associated with discontinuation occurred in 16.0% (n=8), 14.0% (n=7), and 23.8% (n=19) of patients receiving Dato-DXd 4, 6, or 8 mg/kg, respectively; TEAEs associated with dose reduction occurred in 2.0%, 10.0%, and 27.5% of patients, respectively.

Drug-related interstitial lung disease (ILD) was reported in five patients (10.0%) receiving Dato-DXd
4 mg/kg, three patients (6.0%) receiving 6 mg/kg, and 11 patients (13.8%) receiving 8 mg/kg. These events were primarily grade 1 or 2 (7.2%). Grade ≥3 events occurred in six patients (two grade 3, two grade 4, and three grade 5). All grade 5 events occurred in the 8-mg/kg arm. Because ILD is an important risk with DXd ADCs, it is being closely monitored in ongoing studies.

“Dato-DXd demonstrated a manageable profile and promising antitumor activity, with durable responses in heavily pretreated patients with advanced NSCLC,” concluded the researchers. “On the basis of the dose-response relationship and optimal benefit-risk profile, the 6-mg/kg once every 3 weeks dose was selected for further development. Multiple randomized, confirmatory studies are further evaluating Dato-DXd as a treatment for NSCLC in first-line and later settings.”