Desilets Antoine, Lucas Justin, Licitra Lisa F, Lu Sunny, Tse Archie, Tang Tom, Dreyer Kevin, He Nanhai, Birgerson Lars E, Faivre Sandrine, Soulières Denis
Hematology-Oncology Service, Department of Medicine, Centre hospitalier de l'Université de Montréal (CHUM), 1000, rue Saint-Denis, Montreal, QC, Canada.
Adlai Nortye, North Brunswick, NJ, USA.
Target Oncol. 2025 Mar;20(2):299-310. doi: 10.1007/s11523-024-01126-0. Epub 2025 Jan 14.
BERIL-1 was a randomized phase 2 study that studied paclitaxel with either buparlisib, a pan-class I PIK3 inhibitor, or placebo in patients with recurrent or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Considering the therapeutic paradigm shift with immune checkpoint inhibitors (ICIs) now approved in the first-line setting, we present an updated immunogenomic analysis of patients enrolled in BERIL-1, including patients with immune-infiltrated tumors.
The objective of this study was to identify biomarkers predictive of treatment efficacy in the context of the post-ICI therapeutic landscape.
Genomic analyses were performed at baseline on tumor and/or plasma circulating DNA (ctDNA) samples, and immunohistochemistry (IHC) studies, including immune infiltration [tumor-infiltrating lymphocytes (TILs) and CD8 expression], were performed on tumor samples. Immunogenomic biomarkers were correlated to overall survival (OS).
Among 158 patients enrolled in BERIL-1, either tumor (53.2%; n = 84) or ctDNA samples (70.8%; n = 112) were available in 85.4% (n = 135). The most commonly mutated genes were TP53 (57.0%), NOTCH1 (23.7%), and PIK3CA (22.2%). In the IHC studies, 98.6% (n = 68/69) of patients were TILs positive in the buparlisib arm versus 94.4% (n = 68/72) in the placebo arm. In patients with TILs-positive tumors, enrichment for clinical benefit on the buparlisib arm was seen in those with PIK3 pathway activation [25.0% (n = 17/68)] with a hazard ratio (HR) for death of 0.43 [95% confidence interval (CI) 0.21-0.87, p = 0.016]. Similarly, improved OS was seen in patients on the buparlisib arm and NOTCH pathway activation [20.5% (n = 14/68)] with a HR for death of 0.40 (95% CI 0.18-0.90, p = 0.022). Both associations were absent in the placebo group. TP53 and tumor mutational burden (TMB) did not correlate with OS in the buparlisib or placebo arms.
In this immunogenomic analysis of BERIL-1, improved HRs for OS were seen in patients with tumor immune infiltration and selected oncogenic alterations, including PIK3 and NOTCH pathway activation (NCT01852292).
BERIL-1是一项随机2期研究，在复发或转移性（R/M）头颈部鳞状细胞癌（HNSCC）患者中研究了紫杉醇联合泛I类PI3K抑制剂布帕利西布或安慰剂。鉴于免疫检查点抑制剂（ICI）现已被批准用于一线治疗，治疗模式发生了转变，我们对BERIL-1研究中入组的患者进行了更新的免疫基因组分析，包括免疫浸润肿瘤患者。
本研究的目的是在ICI治疗后的背景下确定预测治疗疗效的生物标志物。
在基线时对肿瘤和/或血浆循环DNA（ctDNA）样本进行基因组分析，并对肿瘤样本进行免疫组织化学（IHC）研究，包括免疫浸润[肿瘤浸润淋巴细胞（TILs）和CD8表达]。免疫基因组生物标志物与总生存期（OS）相关。
在BERIL-1研究入组的158例患者中，85.4%（n = 135）的患者可获得肿瘤样本（53.2%；n = 84）或ctDNA样本（70.8%；n = 112）。最常见的突变基因是TP53（57.0%）、NOTCH1（23.7%）和PIK3CA（22.2%）。在IHC研究中，布帕利西布组98.6%（n = 68/69）的患者TILs呈阳性，而安慰剂组为94.4%（n = 68/72）。在TILs阳性肿瘤患者中，PI3K通路激活的患者在布帕利西布组中临床获益增加[25.0%（n = 17/68）]，死亡风险比（HR）为0.43[95%置信区间（CI）0.21-0.87，p = 0.016]。同样，布帕利西布组中NOTCH通路激活的患者OS改善[20.5%（n = 14/68）]，死亡HR为0.40（95%CI 0.18-0.90，p = 0.022）。安慰剂组中不存在这两种关联。在布帕利西布组或安慰剂组中，TP53和肿瘤突变负荷（TMB）与OS均无相关性。
在这项对BERIL-1的免疫基因组分析中，肿瘤免疫浸润且有特定致癌改变（包括PI3K和NOTCH通路激活）的患者OS的HR有所改善（NCT01852292）。
