PD-1抗体用于浆液性卵巢癌:肿瘤突变负荷与疗效相关
  • 截止2017年1月,18例HGSOC患者(16例为铂类耐药患者)参与Pembro单抗抗肿瘤实验;
  • 14例可评估(RECIST 1.1标准),5例SD,9例PD,可能相关AE(3-4级):疲劳和低钠血症(22%),无患者死亡;
  • 肿瘤缩小患者(3例)比PD患者(2例)CD4/CD8 T细胞中PD-1的表达更高;
  • 对于肿瘤CD4/CD8 T细胞PD-1水平和基线突变负荷更高的患者,Pembro的疗效更好;
  • POLE突变很罕见,可能与检查点抑制剂活性相关。
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Immunologic and genomic characterization of high grade serous ovarian cancer (HGSOC) in patients (pts) treated with pembrolizumab (Pembro) in the phase II INSPIRE trial

一项二期INSPIRE研究:Pembro单抗治疗的高级别浆液性卵巢癌(HGSOC)免疫学和基因特征

2017-06-03

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Background: Checkpoint inhibitors have shown to be effective in different tumors and are under investigation in HGSOC.
Methods: INSPIRE (NCT02644369) is a prospective multi-cohort study investigating tumor genomic and immune landscapes in pts treated with Pembro at 200 mg IV Q3W. Patients underwent tumor biopsy pre, on-treatment and at progression for DNA/RNA sequence, immune-profile, and PD-L1 expression by immunohistochemistry (IHC). Serial blood samples for immunophenotyping were collected. Correlative data are available for 6 pts: 3 with shrinkage in target lesion and 3 with progressive disease (PD).
Results: At interim analysis as of January 2017, 18 pts with HGSOC have been enrolled and 16 have platinum-resistant disease, with median 3 prior lines of treatment (range 1-7). Of 14 evaluable pts, best response by RECIST 1.1 was stable disease (SD) in 5 (36%) and PD in 9 (64%). Mean Tumor Proportion Score of PD-L1 by IHC (Qualtek) was 6.4% (range 0-30%). Grade 3/4 adverse events possibly related to Pembro were observed in 4/18 (22%) pts; none was fatal and the most common were fatigue and hyponatremia. Preliminary correlative data showed no significant change in CD4, CD8 and myeloid-derived suppressor cells in peripheral blood after Pembro treatment. Mean PD-1 expression on CD4 and CD8 T cells on baseline tumor tissue (measured as product of PD-1+ cells and the per cell expression of PD-1 [% of mean fluorescence intensity]) was significantly higher in pts with tumor shrinkage compared to pts with PD (CD4: 2658 vs 678, p = .02; CD8: 1999 vs 451, p = .048). Genomic analysis of baseline tumor tissue was available for 3 pts with tumor shrinkage and 2 with PD. Mean mutation burden was higher for pts with tumor shrinkage (2.38 vs 1.0 mutations/Mb covered). The pt with the longest SD in our cohort (6 months) had the highest mutation burden (2.72), including somatic POLE (c.6331-6C > G) and germline BRCA2mutations.
Conclusions: In HGSOC, pts with higher PD-1 level on tumor CD4 and CD8 T cells and higher mutation burden at baseline may have a better outcome following treatment with Pembro. POLE mutation is rare in HGSOC but may correlate with checkpoint inhibitor activity.

All Authors:
Ilaria Colombo

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