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For patients with advanced/metastatic non-small-cell lung cancer (NSCLC) without actionable genomic alterations and low (<50%) PD-L1 expression, pembrolizumab plus pemetrexed and platinum chemotherapy is a preferred first-line treatment. These patients have comparatively worse outcomes than those with higher PD-L1 expression, underscoring the need for new combination strategies. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, has demonstrated encouraging antitumor activity and safety in this patient population. We describe the rationale and design of TROPION-Lung07, a randomized, open-label Phase III study assessing Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pembrolizumab plus pemetrexed and platinum-based chemotherapy in patients with advanced/metastatic non-squamous NSCLC without actionable genomic alterations and <50% PD-L1 expression. Primary study objectives are progression-free survival and overall survival. Clinical Trial Registration:NCT05555732 (ClinicalTrials.gov) Plain Language Summary Most patients discover they have non-small-cell lung cancer (NSCLC) after it has already spread beyond the lungs (metastasized) making it more challenging to treat. If patients with NSCLC also lack specific genetic changes, called "actionable genomic alterations", or have low levels of a protein called PD-L1 (which cancer cells use to avoid attack from the immune system and continue to grow), current treatments may not fully help, or only help for a while. However, newer approaches are being investigated that may benefit these patients with fewer side effects than traditional chemotherapy. Datopotamab deruxtecan (Dato-DXd) is an investigational drug which combines an antibody with a chemotherapy agent to specifically target and kill cancer cells. The antibody in Dato-DXd attaches to a protein called TROP2, which is widely expressed in NSCLC tumors, and delivers chemotherapy directly into cancer cells to kill them. The TROPION-Lung07 study will assess the potential benefits and side effects of adding Dato-DXd to other drugs, including pembrolizumab (an immunotherapy which attaches to PD-1 on immune cells and triggers the death of cancer cells) and chemotherapy. Three treatment groups will be compared: pembrolizumab with chemotherapy; Dato-DXd with pembrolizumab; and Dato-DXd with pembrolizumab and chemotherapy. The study will help us to understand if adding Dato-DXd to other anticancer drugs allow patients to live longer without their disease getting worse. Article highlights Background NSCLC accounts for 80–85% of all new lung cancer diagnoses, with most patients diagnosed at an advanced or metastatic stage and thus having a poor prognosis. For patients with advanced/metastatic NSCLC without actionable genomic alterations and with low PD L1 expression (<50%), pembrolizumab combined with pemetrexed and cisplatin or carboplatin is a preferred first-line treatment option. Data suggest that outcomes with immunotherapy in patients with lower PD-L1 expression are comparatively worse than in those with higher PD-L1 expression, resulting in lower quality of life for these patients. Thus, new combination strategies, which have the potential to replace standard-of-care treatments without compromising safety or efficacy, are needed to improve outcomes. Datopotamab deruxtecan Dato-DXd is a novel TROP2-directed ADC that consists of a humanized anti-TROP2 immunoglobulin G1 monoclonal antibody covalently linked to a highly potent topo I inhibitor payload via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker. In the ongoing TROPION-PanTumor01 study, Dato-DXd as monotherapy demonstrated promising antitumor activity and a manageable safety profile in heavily pretreated patients with NSCLC. In the Phase Ib TROPION-Lung02 combination study, Dato-DXd plus pembrolizumab with or without platinum-based chemotherapy also showed favorable tolerability and encouraging efficacy, regardless of PD-L1 expression, in patients with advanced/metastatic NSCLC. The TROPION-Lung04 Phase Ib study is evaluating the safety, tolerability and antitumor activity of Dato-DXd plus immunotherapy with or without carboplatin in patients with advanced/metastatic NSCLC. TROPION-Lung07 study TROPION-Lung07 is a global, multicenter, randomized, open-label Phase III study assessing the safety and efficacy of Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pemetrexed in combination with platinum-based chemotherapy in patients with no prior therapy for advanced/metastatic non-squamous NSCLC, without actionable genomic alterations and with low PD-L1 expression (TPS <50%). Patients will be randomized in a 1:1:1 ratio into the following treatment arms: Dato-DXd 6.0 mg/kg plus pembrolizumab 200 mg IV plus platinum-based chemotherapy, Dato-DXd 6.0 mg/kg plus pembrolizumab 200 mg IV, and pembrolizumab 200 mg IV plus pemetrexed 500 mg/m2 plus platinum-based chemotherapy. Objectives The primary objectives of this study are to compare the efficacy of Dato-DXd in combination with pembrolizumab with or without platinum-based chemotherapy versus pembrolizumab plus pemetrexed and platinum-based chemotherapy, as measured by PFS and OS. The key secondary objective is to evaluate the efficacy of treatment in each arm as measured by ORR by BICR. Other secondary objectives include PFS, duration of response, time to response, disease control rate and PFS2. PROs, including time to deterioration in cough, dyspnea, or chest pain and treatment-emergent adverse events will be evaluated, and other safety parameters and Dato-DXd immunogenicity will be assessed. Exploratory objectives include evaluation of biomarkers and pharmacogenetics and pharmacokinetic exposures for potential association with efficacy and safety, and exploring how changes in biomarkers may relate to exposure, AEs and clinical outcomes. Biomarkers of interest include the proportion of tumor cells expressing TROP2. Conclusion The TROPION-Lung07 study will assess the safety and efficacy of Dato-DXd in combination with pembrolizumab with/without platinum-based chemotherapy versus pemetrexed in combination with platinum-based chemotherapy as a first-line treatment option in patients with advanced/metastatic non-squamous NSCLC without actionable genomic alterations and with low PD-L1 expression (TPS <50%). The outcomes of this study will help establish whether the Dato-DXd doublet and/or triplet regimens may replace the platinum doublet and/or the platinum partner in combination with pembrolizumab therapy as first-line treatment for patients with advanced/metastatic NSCLC. [ABSTRACT FROM AUTHOR] |
