背景：IMpassion130 是第一個顯示在未經治療的 PD-L1+mTNBC 的癌症免疫治療（CIT）中有臨床獲益的 3 期隨機研究。在免疫 TME 較豐富的患者中，與安慰劑（P）+nP相比，A+nP有效性增強，但限於 PD-L1 IC+的患者（PD-L1 一表達免疫細胞在≥1%的腫瘤區域；Emens JNCI 2021）。雖然 TNBC 分子亞型和 CD8 定位對早期 TNBC 有預測作用，但這些特征是否與 mTNBC 的 CIT獲益有關尚不清楚。這項探索性分析的目的是確定在 IMpassion130 中 TME 成分與A+nP的獲益有關。
Background: IMpassion130 was the first randomized phase 3 study to show clinical benefit of cancer immunotherapy (CIT) in untreated PD-L1+ mTNBC. Enhanced A + nP efficacy vs placebo (P) + nP was seen in pts with a richer immune TME but was confined to PD-L1 IC+ pts (PD-L1–expressing immune cells on ≥1% of tumor area; Emens JNCI 2021). While TNBC molecular subtyping and CD8 localization are prognostic in early TNBC, it is unknown whether these features are associated with CIT benefit in mTNBC. This exploratory analysis aimed to identify TME components associated with A + nP efficacy in IMpassion130.
方法：采用 IHC 檢測 PD-L1 狀態（VENTANA SP142）和免疫表型（炎症型/排除型/沙漠型 依 CD8在間質/瘤內的定位;Mariathasan Nature 2018）。RNA-seq 用於分子亞型分析（Burstein CCR 2015）和通路分析（MSigDB-Hallmark）。Cox 回歸用於比較 A + nP 與 P + nP 的 PFS/OS，先前用過紫杉類藥物、肝髒轉移的進行了校正。
Methods: IHC was used to assess PD-L1 status (VENTANA SP142) and immune phenotypes (inflamed/excluded/desert per CD8 stromal/intratumoral localization; Mariathasan Nature 2018). RNA-seq was used for molecular subtyping (Burstein CCR 2015) and pathway analyses (MSigDB Hallmark). Cox regression was used to compare PFS/OS between A + nP vs P + nP, adjusted for prior taxanes, liver mets.
結果：樣本分類和 PD-L1 分布如表所示。在 PD-L1 IC+炎症型和排除型腫瘤中，A+nP與P+nP比較，PFS 改善，但 OS 改善僅限於 PD-L1 IC+炎症型腫瘤。PD-l1 IC+基底樣免疫激活（BLIA）和免疫抑製（BLIS）亞組有 PFS 獲益，而 OS 獲益僅限於 PD-l1 IC+BLIA 亞組。在 PD-L1 IC+患者中，通路分析確定 增殖/DNA 損傷修複（基底樣腫瘤特征）和 血管生成/ER 反應（管腔雄激素受體[LAR]/間充質[MES]腫瘤中較高）分別與 PFS 的改善和降低相關。
Results: Sample classification and PD-L1 distribution are shown (Table). Improved PFS with A + nP vs P + nP was seen in PD-L1 IC+ inflamed and excluded tumors, but improved OS was limited to PD-L1 IC+ inflamed tumors. PD-L1 IC+ basal-like immune activated (BLIA) and immune suppressed (BLIS) subgroups derived PFS benefit, but OS benefit was limited to PD-L1 IC+ BLIA subgroups. In PD-L1 IC+ pts, pathway analysis identified proliferation/DNA damage repair (basal-like tumor features) and angiogenesis/ER response (higher in luminal androgen receptor [LAR]/ mesenchymal [MES] tumors) were associated with improved and reduced PFS, respectively.
|
Subgroup (% of biomarker-evaluable pts) |
All |
PD-L1 IC+ |
PD-L1 IC– |
|||||
|
PFS HR |
OS HR |
% PD-L1 IC+ |
PFS HR |
OS HR |
% PD-L1 |
PFS HR |
OS HR |
|
|
Immune phenotype (n=802): |
0.63 |
0.71 |
63 |
0.58 |
0.61 |
37 |
0.74 |
0.94 |
|
Inflamed (36) |
||||||||
|
Excluded (47) |
0.76 |
0.86 |
41 |
0.72 |
0.72 |
59 |
0.80 |
0.97 |
|
Desert (16) |
1.10 |
1.10 |
8 |
0.25 |
0.14 |
92 |
1.20 |
1.10 |
|
Molecular subtype (n=836): |
0.54 |
0.61 |
74 |
0.49 |
0.54 |
26 |
0.59 |
0.91 |
|
BLIS (42) |
0.85 |
0.99 |
32 |
0.66 |
0.92 |
68 |
0.98 |
1.00 |
|
LAR (26) |
0.86 |
0.90 |
31 |
0.91 |
0.75 |
69 |
0.86 |
1.00 |
|
MES (5) |
1.10 |
1.00 |
28 |
3.40 |
0.70 |
72 |
0.93 |
0.98 |
|
ITT N=902 |
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結論：PD-l1 IC+免疫炎症型腫瘤和 PD-l1 IC+ BLIA 腫瘤對 CIT 的敏感性最高，LAR 腫瘤可能對CIT 抵抗，值得進一步研究和驗證。
Conclusions: PD-L1 IC+ immune-inflamed tumors and PD-L1 IC+ BLIA tumors show highest CIT sensitivity, and LAR tumors may be resistant to CIT. These data warrant further study and validation.
