KEYNOTE-495/KeyImPaCT：生物标志物导向、基于帕博利珠单抗的非小细胞肺癌联合治疗

Biomarker-directed, pembrolizumab-based combination therapy in non-small cell lung cancer: phase 2 KEYNOTE-495/KeyImPaCT trial interim results

(Nat Med, IF: 87.241)

Gutierrez Martin,Lam Wei-Sen,Hellmann Matthew D et al. Biomarker-directed, pembrolizumab-based combination therapy in non-small cell lung cancer: phase 2 KEYNOTE-495/KeyImPaCT trial interim results.[J] .Nat Med, 2023, 29: 1718-1727.

Although pembrolizumab confers clinical benefit in non-small cell lung cancer (NSCLC), only a subset of patients will respond due to a heterogenous tumor microenvironment. KEYNOTE-495/KeyImPaCT  is an ongoing biomarker-directed, adaptively randomized phase 2  study investigating first-line pembrolizumab (200 mg every 3 weeks) +  lenvatinib (20 mg daily), anti-CTLA-4 quavonlimab (25 mg every 6 weeks) or anti-LAG-3 favezelimab (200 mg or 800 mg every 3 weeks) in advanced NSCLC. Patients were categorized by T-cell-inflamed gene expression profile (TcellinfGEP) and tumor mutational burden (TMB) status and randomly assigned 1:1:1 to receive pembrolizumab + lenvatinib, pembrolizumab + quavonlimab or pembrolizumab + favezelimab. The primary outcome was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 using pre-specified efficacy thresholds for each biomarker-defined subgroup (>5% (TcellinfGEPlowTMBnon-high (group I)), >20% (TcellinfGEPlowTMBhigh (group II) and TcellinfGEPnon-lowTMBnon-high (group III)) and >45% (TcellinfGEPnon-lowTMBhigh (group IV))). Secondary outcomes were progression-free survival, overall survival and safety. At data cutoff, ORR ranges were 0–12.0% in group I, 27.3–33.3% in group II, 13.6–40.9% in group III and 50.0–60.0% in group IV. ORR with pembrolizumab + lenvatinib in group III met the pre-specified efficacy threshold. The safety profile of each treatment arm was consistent with the known safety profile of each combination. These data demonstrate the feasibility of prospective TcellinfGEP and TMB assessment to study the clinical activity of first-line pembrolizumab-based combination therapies in advanced NSCLC. ClinicalTrials.gov registration: NCT03516981.

尽管pembrolizumab在非小细胞肺癌(NSCLC)中具有临床疗效，但由于肿瘤微环境异质性，只有一小部分患者会产生反应。KEYNOTE-495/KeyImPaCT是一项正在进行的生物标志物导向、随机适应的2期研究，研究晚期NSCLC的一线pembrolizumab(200mg/3周)+ lenvatinib (20mg/每天)，抗CTLA-4 quavonlimab (25mg / 6周)或抗LAG-3 favezelimab (200mg或800mg/3周)。根据T细胞炎症基因表达谱(TcellinfGEP)和肿瘤突变负担(TMB)状态对患者进行分类，随机按1:1:1分配接受pembrolizumab+lenvatinib、pembrolizumab+ quavonlimumab或pembrolizumab+favezelimab治疗。主要结局是研究者评估的客观缓解率(ORR)，每个生物标志物定义的亚组使用预先指定的疗效阈值(>5% (TcellinfGEPlowTMBnon-high(I组))，>20%(TcellinfGEPlowTMBhigh (II组)和TcellinfGEPnon-lowTMBnon-high (III组))和>45% (TcellinfGEPnon-lowTMBhigh (IV组))))。次要终点为无进展生存期、总生存期和安全性。截止数据时，I组的ORR范围为0-12.0%，II组为27.3-33.3%，III组为13.6-40.9%，IV组为50.0-60.0%。III组pembrolizumab+lenvatinib的ORR达到预定的疗效阈值。每个治疗组的安全性与每个组合的已知安全性一致。这些数据证明了前瞻性TcellinfGEP和TMB评估研究一线pembrolizumab联合治疗晚期NSCLC临床活性的可行性。ClinicalTrials.gov注册号：NCT03516981。

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