在既往接受过治疗的携带KRAS G12C突变的晚期/转移性非小细胞肺癌中，索托拉西布与阿达格拉西布的匹配调整间接比较

Matching-Adjusted Indirect Comparison of Sotorasib Versus Adagrasib in Previously Treated Advanced/Metastatic Non-Small Cell Lung Cancer Harboring KRAS G12C Mutation.

作者信息

Chopra Divyan, Lan Zhiyi, Waterhouse David M, Wolf Jürgen, Felip Enriqueta, Moradian Hoora, Karim Nadia, Obiozor Cynthia, Stollenwerk Björn

机构信息

Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA.

Cytel, Inc., 675 Massachusetts Ave, Cambridge, MA, 02139, USA.

出版信息

Adv Ther. 2025 Jun 21. doi: 10.1007/s12325-025-03259-8.

DOI:10.1007/s12325-025-03259-8

PMID:40542959

Abstract

INTRODUCTION

Sotorasib and adagrasib are the only treatments approved in the USA and Europe for advanced/metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC). In the absence of head-to-head trials, a matching-adjusted indirect comparison (MAIC) was conducted to assess the relative efficacy and safety of sotorasib versus adagrasib using phase 3 trials.

METHODS

Patient-level data from CodeBreaK 200 were reweighted to match the baseline characteristics reported in KRYSTAL-12. The analysis evaluated progression free-survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAE). Age, sex, region, prior treatment, brain metastases, and liver metastases were selected for adjustment in the primary analysis per clinical guidance, using an unanchored approach (no common comparator). We conducted sensitivity analyses including additional covariates or anchoring the analysis via common comparator (docetaxel). Additional subgroup analysis was performed in patients with baseline brain metastases, assessing systemic PFS.

RESULTS

Following adjustment, the reweighted patient characteristics from CodeBreaK 200 and KRYSTAL-12 were well balanced. In the primary analysis, sotorasib and adagrasib showed similar efficacy: PFS (HR [hazard ratio] 0.93; 95% confidence interval [CI] 0.70-1.22; p = 0.589) and ORR (odds ratio 0.86; 95% CI 0.53-1.38; p = 0.524). Among patients with brain metastases, sotorasib demonstrated a 39% reduced risk of progression compared with adagrasib (HR 0.61; 95% CI 0.38-0.98; p = 0.040). Sotorasib also demonstrated a more favorable safety profile than adagrasib, with lower odds of TRAEs, TRAEs leading to dose reduction or dose interruption, and all eight individual TRAEs evaluated. Sensitivity analyses supported the robustness of base-case results.

CONCLUSION

In this MAIC, sotorasib and adagrasib showed comparable efficacy in previously treated advanced KRAS G12C-mutated NSCLC. Among patients with baseline brain metastases, PFS point estimates favored sotorasib. Sotorasib also demonstrated a favorable overall safety profile. These findings may help inform payer decisions and clinical practice in the treatment of KRAS G12C-mutated NSCLC.

摘要

简介

索托拉西布和阿达格拉西布是美国和欧洲批准用于治疗晚期/转移性KRAS G12C突变非小细胞肺癌（NSCLC）的仅有的两种疗法。在缺乏头对头试验的情况下，进行了一项匹配调整间接比较（MAIC），以利用3期试验评估索托拉西布与阿达格拉西布的相对疗效和安全性。

方法

对CodeBreaK 200的患者层面数据进行重新加权，以匹配KRYSTAL-12中报告的基线特征。分析评估了无进展生存期（PFS）、客观缓解率（ORR）和治疗相关不良事件（TRAE）。根据临床指南，在初步分析中选择年龄、性别、地区、既往治疗、脑转移和肝转移进行调整，采用非锚定方法（无共同对照）。我们进行了敏感性分析，包括纳入额外的协变量或通过共同对照（多西他赛）对分析进行锚定。对有基线脑转移的患者进行了额外的亚组分析，评估全身PFS。

结果

调整后，CodeBreaK 200和KRYSTAL-12重新加权后的患者特征得到了很好的平衡。在初步分析中，索托拉西布和阿达格拉西布显示出相似的疗效：PFS（风险比[HR]0.93；95%置信区间[CI]0.70-1.22；p=0.589）和ORR（优势比0.86；95%CI 0.53-1.38；p=0.524）。在有脑转移的患者中，与阿达格拉西布相比，索托拉西布的疾病进展风险降低了39%（HR 0.61；95%CI 0.38-0.98；p=0.040）。索托拉西布在安全性方面也比阿达格拉西布更具优势，TRAE、导致剂量减少或剂量中断的TRAE以及所评估全部8种个体TRAE的发生几率更低。敏感性分析支持了基础病例结果的稳健性。

结论

在这项MAIC中，索托拉西布和阿达格拉西布在既往接受治疗的晚期KRAS G12C突变NSCLC中显示出相当的疗效。在有基线脑转移的患者中，PFS点估计值更有利于索托拉西布。索托拉西布在总体安全性方面也表现良好。这些发现可能有助于为KRAS G12C突变NSCLC治疗中的支付方决策和临床实践提供参考。