TACTC-2 trial: Efficacy of pembrolizumab ± chemotherapy first-line therapy in advanced non-small cell lung cancer patients with PD-L1 expression ≥50% adjusting in accordance with CtDNA

BackgroundPembrolizumab is approved as first-line therapy in advanced non-small cell lung cancer (NSCLC) patients(pts) with programmed cell death ligand-1 (PD-L1) expression ≥50%. However, not all pts could achieve durable benefit due to early resistance and primary resistance. Pembrolizumab combined with chemotherapy may enhance therapeutic efficacy but increase adverse effects. Circulating tumor DNA (ctDNA) is an emerging strategy to identify the resistant pts early. The rapid decrease of the maximum allelic fraction (MaxAF) of somatic mutations correlates with longer progression-free survival (PFS) and overall survival (OS). This study is evaluating the feasibility of ctDNA-based intervention first-line therapy in advanced NSCLC pts with PD-L1 expression ≥50% by dynamic monitoring of ctDNA to early predict the efficacy of Pembrolizumab monotherapy.Trial designThis is a randomized, single-center, open-label phase II study that enrolls pts with treatment-naive, no actionable EGFR, ALK, or ROS1 mutations advanced NSCLC with PD-L1 expression≥50%. Plasma samples are collected at baseline for a cancer-associated 168-gene panel detection by next-generation sequencing. All pts receive pembrolizumab monotherapy (200 mg) at the first treatment. The first post-treatment ctDNA assessment is performed 3 weeks after treatment, and pts are stratified into arms based on changes in maximum allelic fraction (MaxAF). Arm A (MaxAF decreases more than 50%) continues pembrolizumab every 3 weeks. Arm B (MaxAF decreases to 50% or less) is randomized (1:1) into pembrolizumab monotherapy or pembrolizumab combined chemotherapy (carboplatin plus pemetrexed or paclitaxel every 3 weeks for 4 cycles), followed by maintenance therapy with pembrolizumab. Subsequent post-treatment ctDNA assessments will be conducted 1 month after stratification and disease progression. The primary endpoint is median PFS in intervention arm. Secondary endpoints include median OS, one-year PFS rate, ORR, DCR. Exploratory analysis of the mechanism of drug resistance across different immunotherapy modes. Enrollment of up to 94 pts is planned.Clinical trial identificationChiCTR2100052222.Legal entity responsible for the studyRuijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.FundingHas not received any funding.DisclosureAll authors have declared no conflicts of interest.