PO.CL05.07 · 临床研究

可切除IA-IIIA期非N2 NSCLC中单剂量新辅助atezolizumab：来自PRINCEPS试验的肿瘤浸润分析

Single-dose neoadjuvant atezolizumab in resectable stage IA-IIIA non-N2 NSCLC: Tumor infiltrate analysis from the PRINCEPS trial

编号 7766 展板 26 时间 4/22 09:00–12:00 区域 Section 42 主讲 Antonio Nuccio, MD

分会场 Immune Response to Therapies

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作者与单位 Authors & Affiliations

Antonio Nuccio¹, Lydie Cassard², Nathalie Cozic³, Malek Ben Salah⁴, Vesna Lukic⁴, Julien Adam⁵, Wael Salem Zrafi³, David Planchard⁶, Jordi Remon⁷, Pernelle Lavaud⁷, Anas Gazzah⁸, Vincent Thomas de Montpreville⁹, Maria Rosa Ghigna¹⁰, Patrick Dumont¹¹, Elie Fadel¹², Fabrice Barlesi¹, Caroline Caramella¹³, Filippo Gustavo Dall’Olio⁶, Olaf Mercier¹², Paul-Henry Cournède⁴, Nathalie Chaput¹⁴, Benjamin Besse¹

¹Inserm, U981, F-94805, Université Paris-Saclay, Gustave Roussy, Villejuif, France,², INSERM US23, Laboratoire d’immunomonitoring en Oncologie, F-94805,, Université Paris-Saclay, Gustave Roussy, Villejuif, France,³Service de Biostatistique et d’Épidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France,⁴Lab of Mathematics and Computer Science (MICS), Université Paris-Saclay, CentraleSupélec, Paris, France,⁵Pathology, Hôpital Paris Saint-Joseph, Paris, France,⁶Medical Oncology, Institut Gustave Roussy, Villejuif, France,⁷Institut Gustave Roussy, Villejuif, France,⁸DITEP, F-94805, Université Paris-Saclay, Gustave Roussy, Villejuif, France,⁹Pathology, Hospital Marie Lannelongue, Le Plessis Robinson, Paris, France,¹⁰BIOPATH, F-94805, Université Paris-Saclay, Gustave Roussy, Villejuif, France,¹¹Centre Hospitalier de Chauny, Chauny, France,¹²Department of Thoracic Surgery & Heart-Lung Transplantation, Université Paris-Saclay, Hôpital Marie Lannelongue, Paris, France,¹³Radiology Department, Groupe Hospitalier Paris Saint Joseph, Hôpital Marie Lannelongue, Paris, France,¹⁴INSERM US23, Laboratoire d’immunomonitoring en Oncologie, F-94805, Université Paris-Saclay, Gustave Roussy, Villejuif, France

摘要 Abstract

中文摘要

2期PRINCEPS试验(NCT02994576)显示，单剂量新辅助Atezolizumab(A,1200 mg静脉注射)在30例IA-IIIA期非N2 NSCLC患者(治疗组,T)中是可行的。随后增加了一个比较组(C)。我们报告T组和C组的肿瘤免疫谱和更新的生存数据。 C组包括未经治疗的切除IA-IIIA期非N2 NSCLC患者。对手术样本进行残余存活肿瘤(RVT)和免疫浸润的分析。RVT界值采用最大选择秩检验针对DFS/OS进行定义(表1)。免疫浸润(N=316)采用Mann Whitney U检验在各组间进行比较。从2019年9月至2022年8月，C组共入组30例患者(排除2例非NSCLC)。平均年龄64比66，鳞状组织学13%比26%，PD-L1阴性63%比46%，辅助化疗20%比50%(T比C)。 T组肿瘤富集CD45+白细胞、CD8+T细胞、HLA-DR+CD163+髓系细胞；C组肿瘤显示CD115+CD163+巨噬细胞和CD16Low未成熟中性粒细胞，提示免疫抑制性TME。在T组中，应答者(RVT≤60%)具有更高的淋巴细胞、激活/耗竭PD-1+/TIGIT+T细胞以及成熟/激活CD16+CD11bHigh中性粒细胞比率；非应答者(RVT>60%)显示更多衰老CD57+T细胞和免疫抑制性(CD16-、CD163+)髓系细胞。在C组中，自发消退者(RVT≤95%)具有增殖的Ki67+OX40+T细胞、CD69+NK、耗竭CTLA4+TIGIT+T细胞和促炎CD16+巨噬细胞，而非自发消退者(RVT>95%)富集高度激活的Treg。总之，新辅助单剂量A诱导了一种CD8+/激活髓系细胞谱，可能与持久的生存获益相关。在T组中，应答者显示激活/耗竭T细胞和成熟促炎中性粒细胞，与C组中的自发消退者相似；非应答者富集衰老T细胞和免疫抑制性髓系细胞。这些结果可能表明PD-1+/TIGIT+耗竭T细胞和促炎髓系细胞作为A活性的预测性生物标志物。表1。DFS：无病生存；OS：总生存；MaxStat：最大选择秩检验组别治疗组[N=30] 比较组[N=28] 中位随访月数(95%CI) 80(74.2-94.5) 50.6(40.5-60.7) 总体5年DFS 76.3% 55.6% 总体5年OS 83.3% 58.7% 预测最佳DFS结局的MaxStat RVT界值 60% 95% 预测最佳OS结局的MaxStat RVT界值 60% 95% 达到≤RVT MaxStat界值(DFS)的患者数 13(应答者) 19(自发消退者) ≤RVT MaxStat界值中的5年DFS 84.6% 61.8% >RVT MaxStat界值组中的5年DFS 69.7% 41.7% ≤RVT比>RVT MaxStat界值组的DFS HR(95%CI) 0.47(0.12-1.82) 0.41(0.13-1.37) ≤RVT比>RVT MaxStat界值组的DFS log-rank p值 0.26 0.13 ≤RVT MaxStat界值组中的5年OS 100% 63.7% >RVT MaxStat界值组中的5年OS 70% 44.4% ≤RVT比>RVT MaxStat界值组的OS HR(95%CI) NA(无事件) 0.52(0.14-1.94) ≤RVT比>RVT MaxStat界值组的OS log-rank p值 0.01 0.31

查看英文原文 English abstract

Phase 2 PRINCEPS trial (NCT02994576) showed that single dose neoadjuvant Atezolizumab (A, 1200 mg IV) was feasible in 30 stage IA-IIIA non-N2 NSCLC patients (treated arm, T). A comparative arm (C) was later added. We report tumor immune profiles and updated survival for T and C arms. C arm included untreated resected stage IA-IIIA non-N2 NSCLC patients. Surgery samples were profiled for residual viable tumor (RVT) and immune infiltrates. RVT cutoffs were defined with Maximally Selected Rank Test for DFS/OS (Table1). Immune infiltrates (N=316) were compared across groups by Mann Whitney U test. From 9/2019 to 8/2022, 30 patients were enrolled in C (2 non-NSCLC excluded). Mean age was 64 vs 66, squamous histology 13% vs 26%, PD-L1 neg 63% vs 46%, adjuvant ChT 20% vs 50% (T vs C). T arm tumors were enriched in CD45+ leukocytes, CD8+ T cells, HLA-DR+ CD163+ myeloids; C arm tumors showed CD115+ CD163+ macrophages and CD16Low immature neutrophils suggesting an immunosuppressive TME. In T arm, Responders (RVT≤60%) had higher lymphocyte, activated/exhausted PD-1+/TIGIT+ T cell and mature/activated CD16+ CD11bHigh neutrophil rates; Non-Responders (RVT>60%) showed more senescent CD57+ T cells and immunosuppressive (CD16-, CD163+) myeloids. In C arm, Spontaneous Regressors (RVT≤95%) had proliferating Ki67+ OX40+ T cells, CD69+ NK, exhausted CTLA4+ TIGIT+ T cells and pro-inflammatory CD16+ macrophages vs Non-Spontaneous Regressors (RVT>95%), enriched in highly activated Treg. In conclusion, neoadjuvant single dose A induced a CD8+/activated-myeloid profile that could relate to durable survival benefit. In T arm Responders showed activated/exhausted T cells and mature pro-inflammatory neutrophils, similar to Spontaneous Regressors in C arm; Non-Responders were enriched in senescent T cells and immunosuppressive myeloids. These results may indicate PD-1+/TIGIT+ exhausted T cells and pro-inflammatory myeloids as predictive biomarkers of A activity. Table 1. DFS: Disease-free Survival; OS: Overall Survival; MaxStat: Maximally Selected Rank Test Arm Treated [N=30] Comparative [N=28] Median follow-up months (95%CI) 80 (74.2-94.5) 50.6 (40.5-60.7) Overall 5 years DFS 76.3% 55.6% Overall 5 years OS 83.3% 58.7% MaxStat RVT cutoff predicting best DFS outcome 60% 95% MaxStat RVT cutoff predicting best OS outcome 60% 95% Number of patients achieving ≤RVT MaxStat cutoff for DFS 13 (Responders) 19 (Spontaneous Regressors) 5 years DFS in ≤RVT MaxStat cutoff 84.6% 61.8% 5 years DFS in >RVT MaxStat cutoff group 69.7% 41.7% DFS HR (95% CI) ≤RVT vs >RVT MaxStat cutoff groups 0.47 (0.12-1.82) 0.41 (0.13-1.37) DFS ≤RVT vs >RVT MaxStat cutoff groups log-rang p value 0.26 0.13 5 years OS in ≤RVT MaxStat cutoff group 100% 63.7% 5 years OS in >RVT MaxStat cutoff group 70% 44.4% OS HR (95% CI) ≤RVT vs >RVT MaxStat cutoff groups NA (no events) 0.52 (0.14-1.94) OS ≤RVT vs >RVT MaxStat cutoff groups log-rang p value 0.01 0.31

利益披露 Disclosure

A. Nuccio, None.. L. Cassard, None.. N. Cozic, None.. M. Ben Salah, None.. V. Lukic, None.. J. Adam, None.. W. Zrafi, None.. D. Planchard, None.. J. Remon, None.. P. Lavaud, None.. A. Gazzah, None.. V. de Montpreville, None.. M. Ghigna, None.. P. Dumont, None.. E. Fadel, None. F. Barlesi, Abbvie Other, Institutional financial interest. ACEA Other, Institutional financial interest. Amgen Other, Institutional financial interest. Astra-Zeneca Other, Institutional financial interest. Bayer Other, Institutional financial interest. Bristol-Myers Squibb Other, Institutional financial interest. Boehringer–Ingelheim Other, Institutional financial interest. Eisai Other, Institutional financial interest. Eli Lilly Oncology Other, Institutional financial interest. F. Hoffmann–La Roche Ltd Other, Institutional financial interest. Genentech Other, Institutional financial interest. Ipsen Other, Institutional financial interest. Ignyta Other, Institutional financial interest. Innate Pharma Other, Institutional financial interest. Loxo Other, Institutional financial interest. Novartis Other, Institutional financial interest. Medimmune Other, Institutional financial interest. Merck Other, Institutional financial interest. MSD Other, Institutional financial interest. Pierre Fabre Other, Institutional financial interest. C. Caramella, None.. F. Dall’Olio, None.. O. Mercier, None.. P. Cournède, None.. N. Chaput, None. B. Besse, Abbvie Other, Advisory board. Biontech SE Other, Advisory board. Beijing Avistone Biotechnology Other, Advisory board. BristolMyerSqibb Other, Advisory board. CureVac AG Other, Advisory board. Pharmamar Other, Advisory board. Regeneron Other, Advisory board. Sanofi aventis Other, Advisory board. Eli Lilly Other, Conseil. Ellipses pharma Ltd Other, Conseil. F.Hoffmann-La Roche Ltd Other, Conseil. Foghorn Therapeutics Inc. Other, Conseil. Genmab Other, Conseil. Immunocore Other, Conseil. Owkin Other, Conseil. Astrazeneca Other, Steering committee. Amgen Other, Steering committee. Beigene Other, Steering committee. Janssen Other, Steering committee. MSD Other, Steering committee.

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