Zamulko Olga, Karivedu Vidhya, Riaz Muhammad Kashif, Monroe Ilaina, Romano Audrey, Mulanda Rachel, Kurtzweil Nicky, Forsythe Allie, Allen Casey L, Harun Nusrat, Pan Jianmin, Rai Shesh, El-Gamal Dalia, Wise-Draper Trisha M
Division of Hematology Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio.
Division of Hematology/Oncology, Duke University Medical Center, Durham, North Carolina.
Cancer Res Commun. 2025 Jun 1;5(6):939-944. doi: 10.1158/2767-9764.CRC-25-0192.
PURPOSE: Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) portends a poor prognosis. DNA pathway repair mutations in HNSCC are associated with higher tumor mutational burden rates and immune checkpoint inhibitor response. PARP inhibitors (PARPi) induce ssDNA breaks and are efficacious in cancers with DNA repair defects. Thus, we designed a single-arm, open-label, phase II clinical trial to evaluate the combination of niraparib and dostarlimab in patients with R/M HNSCC. PATIENTS AND METHODS: Patients with R/M HNSCC were treated with niraparib and dostarlimab until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate and clinical benefit assessed by RECIST version 1.1. Using Simon's two-step minimax design, 14 patients were planned to enroll in the first stage with a goal of overall clinical benefit of 50%. RESULTS: Ten patients were enrolled. The majority were White males with a median age of 62.5. One patient had a PD-L1 combined positive score >20, a high tumor mutational burden, a BRCA1 rearrangement, and an ATRX splice site mutation. Nine patients previously failed anti-PD-1/PD-L1 therapy. The best overall response rate was 10%, with a 20% clinical benefit (1 partial response, 1 stable disease). The trial was terminated early for futility as the goal clinical benefit could not be reached. At a median follow-up of 10.13 months, the median progression-free survival was 3.8 months, and the median overall survival was 10.1 months. The most common grade 3 or higher treatment-related adverse events were thrombocytopenia and hypertension. CONCLUSIONS: The combination of niraparib and dostarlimab did not achieve the primary endpoint of clinical benefit, but activity may be improved with biomarker-driven treatment and selected patients. SIGNIFICANCE: Patients with R/M HNSCC that progress on PD-1 inhibitors have poor prognoses. PARPis cause ssDNA breaks that accumulate in cells with mutations in DNA damage repair pathways, leading to synthetic lethality. However, PARPi also inhibits glycogen synthase kinase-3β activity, leading to upregulated PD-L1, which is abrogated by PD-1 inhibitors. In this study, we combine niraparib (PARPi) with dostarlimab (anti-PD-L1) to evaluate clinical benefit in patients with R/M HNSCC.
目的：复发/转移性头颈部鳞状细胞癌（R/M HNSCC）预后较差。HNSCC中的DNA通路修复突变与较高的肿瘤突变负荷率和免疫检查点抑制剂反应相关。PARP抑制剂（PARPi）可诱导单链DNA断裂，对存在DNA修复缺陷的癌症有效。因此，我们设计了一项单臂、开放标签的II期临床试验，以评估尼拉帕利和多斯塔利单抗联合治疗R/M HNSCC患者的疗效。 患者与方法：R/M HNSCC患者接受尼拉帕利和多斯塔利单抗治疗，直至疾病进展或出现不可接受的毒性。主要终点是根据RECIST 1.1版评估的总缓解率和临床获益。采用西蒙两步最小最大设计，计划在第一阶段纳入14例患者，目标是总体临床获益率达到50%。 结果：共纳入10例患者。大多数为白人男性，中位年龄为62.5岁。1例患者的PD-L1联合阳性评分>20，肿瘤突变负荷高，存在BRCA1重排和ATRX剪接位点突变。9例患者先前抗PD-1/PD-L1治疗失败。最佳总缓解率为10%，临床获益率为20%（1例部分缓解，1例病情稳定）。由于未达到目标临床获益，该试验因无效而提前终止。中位随访10.13个月时，中位无进展生存期为3.8个月，中位总生存期为10.1个月。最常见的3级或更高等级的治疗相关不良事件是血小板减少和高血压。 结论：尼拉帕利和多斯塔利单抗联合治疗未达到临床获益的主要终点，但通过生物标志物驱动的治疗和选择合适的患者，活性可能会得到改善。 意义：在PD-1抑制剂治疗中进展的R/M HNSCC患者预后较差。PARPi会导致单链DNA断裂，这些断裂会在DNA损伤修复途径发生突变的细胞中积累，从而导致合成致死。然而，PARPi也会抑制糖原合酶激酶-3β的活性，导致PD-L1上调，而PD-1抑制剂可消除这种上调。在本研究中，我们将尼拉帕利（PARPi）与多斯塔利单抗（抗PD-L1）联合使用，以评估R/M HNSCC患者的临床获益。
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