WCLC 2025 - Posters & ePosters-PT2.11.03 Phase I Study of Trametinib, Anlotinib, and Tislelizumab in KRAS-Mutant NSCLC: Safety, RP2D, and Preliminary Efficacy

PT2.11.03 Phase I Study of Trametinib, Anlotinib, and Tislelizumab in KRAS-Mutant NSCLC: Safety, RP2D, and Preliminary Efficacy

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This Phase I clinical trial (NCT06456138) evaluated the safety, recommended phase 2 dose (RP2D), and preliminary efficacy of a triple combination therapy—trametinib, anlotinib, and tislelizumab—in patients with advanced KRAS-mutant non-small cell lung cancer (NSCLC) who had received prior treatments, including immunotherapy. Twelve patients harboring various KRAS mutations (G12C, G12D, G12V, G12R) were enrolled between June and December 2024. The dosing involved a trametinib and anlotinib crossover ramp-up in four groups with varying dosages, followed by the addition of tislelizumab starting from the third treatment cycle.<br /><br />Adverse events (AEs) were generally manageable, including rash, diarrhea, hypertension, pneumonia, bleeding, nausea, and elevated creatine kinase, with severity ranging from Grade 1 to 3 across dose groups. No unexpected toxicities were reported. The median progression-free survival (PFS) was 171 days, with median overall survival (OS) not reached at data cutoff. The objective response rate (ORR) was 33.3%.<br /><br />The study identified the RP2D as 2 mg trametinib and 8 mg anlotinib combined with tislelizumab 200 mg every three weeks. This regimen shows promise as a potential therapeutic strategy for refractory KRAS-mutant NSCLC patients, particularly those previously treated with immunotherapy. Background translational research indicated that the trametinib and anlotinib combination may enhance PD-L1 expression and natural killer cell infiltration, potentially augmenting immunotherapy efficacy.<br /><br />This trial addresses the clinical challenge of treating later-line KRAS-mutant NSCLC, suggesting that combining targeted therapies with immune checkpoint blockade is a feasible and effective approach warranting further investigation. The study was sponsored by Novartis, Beigene, Chia Tai Tianqing, and Shanghai Chest Hospital.

Asset Subtitle

Baohui Han

Meta Tag

Speaker Baohui Han

Topic Metastatic Non-small Cell Lung Cancer – Immunotherapy

Keywords

Phase I clinical trial

KRAS-mutant NSCLC

trametinib

anlotinib

tislelizumab

triple combination therapy

recommended phase 2 dose (RP2D)

immune checkpoint blockade

progression-free survival (PFS)

objective response rate (ORR)