PO.CL01.06 · 临床研究
HER2表达和肿瘤浸润淋巴细胞可预测HER2阳性转移性结直肠癌对tucatinib联合trastuzumab的疗效（MOUNTAINEER）：一项多中心Ⅱ期试验的探索性分析
HER2 expression and tumor-infiltrating lymphocytes predict response to tucatinib plus trastuzumab in HER2 -positive metastatic colorectal cancer (MOUNTAINEER): Exploratory analysis of a multicenter, Phase II trial
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：HER2靶向双药方案tucatinib联合trastuzumab近期获FDA批准用于既往接受过治疗的HER2阳性转移性结直肠癌（mCRC）。尽管HER2 IHC染色强度和ERBB2扩增已被提出作为潜在的疗效标志物，但我们对肿瘤微环境作用的认识仍然有限。
方法：Ⅱ期MOUNTAINEER试验（NCT03043313）基于HER2阳性（IHC或NGS扩增）入组患者接受tucatinib联合trastuzumab治疗。本分析纳入了队列A中具有可用HER2 IHC和H&E切片的患者。采用既往已验证的基于AI的模型（Lunit SCOPE uIHC和SCOPE IO）量化HER2 3+染色肿瘤细胞的百分比（AI-H3+）以及癌上皮内（iTIL）和间质内（sTIL）肿瘤浸润淋巴细胞（TILs）的密度。
结果：所分析的队列（N=30）客观缓解率（ORR）为43.4%，中位无进展生存期（PFS）为8.0个月。AI-H3+百分比显示出强烈的剂量依赖性关联，AI-H3+≥10%（n=14）、≥25%（n=12）和≥50%（n=10）的肿瘤ORR分别为57.1%、66.6%和80.0%。这一获益延伸至PFS，与AI-H3+<50%的肿瘤相比，≥50%队列的PFS HR为0.17（P=0.002）。iTIL或sTIL低于中位数的肿瘤PFS显著更短。值得注意的是，尽管包含高AI-H3+病例，sTIL密度处于最低分位数的肿瘤ORR为0%，PFS HR为4.40（P=0.002）。TIL密度与AI-H3+百分比无相关性。
结论：这些发现证实AI量化的HER2强度是疗效标志物，并提示TILs的重要性，其可能通过免疫原性细胞死亡发挥作用。随着该方案推进至一线治疗，按HER2和TIL进行分层可能是一种值得考虑的方法。
总体 总体高AI-H3+百分比
低iTIL密度 低sTIL密度 界值 不适用 ≥10% ≥25% ≥50% <2.6 cells/mm2（中位数） <131.8 cells/mm2（中位数） <52.1 cells/mm2（25%分位数） N 30 14 12 10 15 15 8 ORR 43.4% 57.1% 66.6% 80.0% 26.7% 26.7% 0.0% PFS 不适用 HR 0.44 [95% CI 0.18-1.10]，P=0.071 HR 0.31 [95% CI 0.11-0.85]，P=0.017 HR 0.17 [95% CI: 0.05-0.59]，P=0.002 HR 3.14 [95% CI: 1.27-7.73]，P=0.010 HR 3.57 [95% CI: 1.42-9.00]，P=0.005 HR 4.40 [95% CI: 1.55-10.51]，P=0.002
查看英文原文 English abstract
Introduction: The HER2-targeted doublet, tucatinib and trastuzumab, recently received FDA approval for previously treated HER2-positive metastatic colorectal cancer (mCRC). While the intensity of HER2 IHC staining and ERBB2 amplification have been proposed as potential markers of response, our understanding of the role of the tumor microenvironment remains limited.
Methods: The phase II MOUNTAINEER Trial (NCT03043313) enrolled patients for tucatinib plus trastuzumab based on HER2 positivity (IHC or NGS amplification). Patients from cohort A with available HER2 IHC and H&E slides were included in this analysis. Previously validated AI-based models (Lunit SCOPE uIHC and SCOPE IO) were used to quantify the percentage of HER2 3+ stained tumor cells (AI-H3+) and the densities of tumor infiltrating lymphocytes (TILs) in the cancer epithelium (iTIL) and stroma (sTIL).
Results: The analyzed cohort (N=30) had an objective response rate (ORR) of 43.4% and median progression-free survival (PFS) of 8.0 months. AI-H3+ percentage showed a strong, dose-dependent association with an ORR of 57.1%, 66.6%, and 80.0% for tumors with AI-H3+ ≥10% (n=14), ≥25% (n=12), and ≥50% (n=10), respectively. This benefit extended to PFS, with the ≥50% cohort reporting a PFS HR of 0.17 (P=0.002) compared to tumors with AI-H3+ <50%. Tumors with below median iTIL or sTIL had significantly shorter PFS. Notably, tumors with sTIL density in the bottom quantile had an ORR of 0% and PFS HR of 4.40 (P=0.002) despite including cases with high AI-H3+. TIL densities and AI-H3+ percentage were not correlated.
Conclusion: These findings confirm AI-quantified HER2 intensity as a marker of response and suggests the importance of TILs, which may have a role through immunogenic cell death. Stratification by HER2 and TIL may be an approach to consider as this regimen progresses into the first-line setting.
Overall OverallHigh AI-H3+ percentage
Low iTIL density Low sTIL density Cutoff n/a ≧ 10% ≧ 25% ≧ 50% < 2.6 cells/mm 2 (median) < 131.8 cells/mm 2 (median) < 52.1 cells/mm 2 (25% quantile) N 30 14 12 10 15 15 8 ORR 43.4% 57.1% 66.6% 80.0% 26.7% 26.7% 0.0% PFS n/a HR 0.44 [95% CI 0.18-1.10], P=0.071 HR 0.31 [95% CI 0.11-0.85], P=0.017 HR 0.17 [95% CI: 0.05-0.59], P=0.002 HR 3.14 [95% CI: 1.27-7.73], P=0.010 HR 3.57 [95% CI: 1.42-9.00], P=0.005 HR 4.40 [95% CI: 1.55-10.51], P=0.002
利益披露 Disclosure
M. Imai, None.
W. Hwang,
Lunit Inc Employment.
K. Bonneau, None.
J. Park,
Lunit Inc Employment.
C. Ahn,
Lunit Inc Employment.