Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial,Nature Medicine

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Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial
Nature Medicine ( IF 82.9 ) Pub Date : 2022-06-03 , DOI: 10.1038/s41591-022-01829-9
Lacey J Padrón ₁ , Deena M Maurer ₁ , Mark H O'Hara ₂ , Eileen M O'Reilly ₃ , Robert A Wolff ₄ , Zev A Wainberg ₅ , Andrew H Ko ₆ , George Fisher ₇ , Osama Rahma ₈ , Jaclyn P Lyman ₁ , Christopher R Cabanski ₁ , Jia Xin Yu ₁ , Shannon M Pfeiffer ₁ , Marko Spasic ₁ , Jingying Xu ₁ , Pier Federico Gherardini ₁ , Joyson Karakunnel ₁ , Rosemarie Mick ₂ , Cécile Alanio _{2,

9,

10,

11} , Katelyn T Byrne _{2,

9} , Travis J Hollmann ₃ , Jonni S Moore ₂ , Derek D Jones ₂ , Marco Tognetti ₁₂ , Richard O Chen ₁₃ , Xiaodong Yang ₁₄ , Lisa Salvador ₁₅ , E John Wherry _{2,

9,

10,

11} , Ute Dugan ₁ , Jill O'Donnell-Tormey ₁₆ , Lisa H Butterfield ₁ , Vanessa M Hubbard-Lucey ₁₆ , Ramy Ibrahim ₁ , Justin Fairchild ₁ , Samantha Bucktrout ₁ , Theresa M LaVallee ₁ , Robert H Vonderheide _{2,

9,

11}

Affiliation

Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
University of California, Los Angeles, Los Angeles, CA, USA.
University of California, San Francisco, San Francisco, CA, USA.
Stanford University, Stanford, CA, USA.
Dana-Farber Cancer Institute, Boston, MA, USA.
Parker Institute of Cancer Immunotherapy at the University of Pennsylvania, Philadelphia, PA, USA.
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
Biognosys AG, Schlieren, Switzerland.
Personalis, Inc., Menlo Park, CA, USA.
Apexigen, Inc., San Carlos, CA, USA.
Bristol Myers Squibb, New York, NY, USA.
Cancer Research Institute, New York, NY, USA.

Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC (NCT03214250). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.

中文翻译：

Sotigalimab 和/或 nivolumab 联合化疗一线转移性胰腺癌：来自随机 2 期 PRINCE 试验的临床和免疫学分析

化疗联合免疫疗法改善了某些实体瘤的治疗，但对胰腺导管腺癌 (PDAC) 的有效治疗方案仍然难以捉摸。我们进行了一项随机 2 期试验，评估纳武单抗（nivo；抗 PD-1）和/或 sotigalimab（sotiga；CD40 激动性抗体）与吉西他滨/白蛋白结合型紫杉醇（化疗）在一线转移性 PDAC 患者中的疗效（ NCT03214250）。在分析疗效的 105 名患者中，nivo/化疗达到了 1 年总生存期 (OS) 的主要终点（57.7%，P = 0.006，与历史上 35% 的 1 年 OS 相比，n = 34），但未达到满足 sotiga/chemo (48.1%, P = 0.062, n = 36) 或 sotiga/nivo/chemo (41.3%, P = 0.223,n = 35). 次要终点是无进展生存期、客观缓解率、疾病控制率、缓解持续时间和安全性。各组与治疗相关的不良事件发生率相似。多组学循环和肿瘤生物标志物分析确定了与 nivo/chemo 和 sotiga/chemo 生存相关的不同免疫特征。nivo/chemo 后的存活率与抑制性较低的肿瘤微环境和较高数量的基线时活化的、抗原经历过的循环 T 细胞相关。sotiga/化疗后的存活与更大的瘤内 CD4 T 细胞浸润和循环分化的 CD4 T 细胞和抗原呈递细胞相关。未确定受益于 sotiga/nivo/chemo 的患者子集。总的来说，

更新日期：2022-06-06

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