Vošmik Milan, John Stanislav, Dvořák Josef, Mohelníková-Duchoňová Beatrice, Melichar Bohuslav, Lohynská Radka, Ryška Aleš, Banni Aml Mustafa, Krempová Johana, Sirák Igor
Department of Oncology and Radiotherapy, University Hospital Hradec Králové, Sokolská 581, 50005, Hradec Králové, Czech Republic.
Faculty of Medicine in Hradec Králové, Charles University, Prague, Czech Republic.
Oncol Ther. 2024 Dec;12(4):817-831. doi: 10.1007/s40487-024-00309-z. Epub 2024 Oct 23.
The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) highlights the urgent need for novel therapeutic strategies. Immune checkpoint inhibitors (ICIs) seem to be ineffective in most PDAC studies. Therefore, we conducted an open-label, multicenter phase 1/2 study (CA209-9KH) to evaluate the safety of stereotactic radiotherapy (SRT) and sequential ICI therapy in PDAC, as well as to validate the efficacy of this regimen as a potential activator of antitumor immunity.
Patients aged ≥ 18 years with unresectable non-metastatic PDAC following four FOLFIRINOX induction cycles were included. Treatment comprised SRT (4 × 8 Gy) and sequential nivolumab administration until disease progression or unacceptable toxicity. The primary endpoints were safety and toxicity assessment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), biomarker evaluation, and quality of life (QoL) analysis.
Twenty-two patients were screened, with 15 enrolled. Eleven (median) nivolumab cycles were administered. SRT demonstrated low and clinically nonsignificant toxicity, whereas nivolumab toxicity aligned with prior safety profiles, without grade 4-5 events observed. Three patients discontinued therapy owing to toxicity. Median PFS and OS were 8.1 and 13.0 months, respectively, with 12-month PFS and OS rates of 0% and 66.7%, respectively, and a 24-month OS rate of 8.9%. Biomarker levels correlated with clinical or radiological disease control. Patient-reported QoL remained acceptable, deteriorating with disease progression.
SRT and nivolumab therapy exhibited manageable toxicity profiles consistent with previous findings; however, long-term treatment responses were not achieved with this regimen in locally advanced PDAC. Another strategy to trigger antitumor immunity in PDAC needs to be sought.
EudraCT: 2017-003404-52; ClinicalTrials.gov: NCT04098432.
胰腺导管腺癌（PDAC）的预后不佳，凸显了对新型治疗策略的迫切需求。在大多数PDAC研究中，免疫检查点抑制剂（ICI）似乎无效。因此，我们开展了一项开放标签、多中心1/2期研究（CA209-9KH），以评估立体定向放射治疗（SRT）和序贯ICI治疗在PDAC中的安全性，并验证该方案作为抗肿瘤免疫潜在激活剂的疗效。
纳入年龄≥18岁、在接受四个FOLFIRINOX诱导周期后不可切除的非转移性PDAC患者。治疗包括SRT（4×8 Gy）和序贯纳武单抗给药，直至疾病进展或出现不可接受的毒性。主要终点是安全性和毒性评估。次要终点包括无进展生存期（PFS）、总生存期（OS）、生物标志物评估和生活质量（QoL）分析。
筛选了22例患者，15例入组。给予了11（中位数）个纳武单抗周期。SRT显示出低毒性且临床意义不显著，而纳武单抗毒性与先前的安全性特征一致，未观察到4-5级事件。3例患者因毒性而停药。中位PFS和OS分别为8.1个月和13.0个月，12个月的PFS率和OS率分别为0%和66.7%，24个月的OS率为8.9%。生物标志物水平与临床或放射学疾病控制相关。患者报告的QoL仍可接受，并随疾病进展而恶化。
SRT和纳武单抗治疗显示出与先前研究结果一致的可管理毒性特征；然而，该方案在局部晚期PDAC中未实现长期治疗反应。需要寻求另一种在PDAC中触发抗肿瘤免疫的策略。
欧洲临床试验数据库（EudraCT）：2017-003404-52；美国国立医学图书馆临床试验注册库（ClinicalTrials.gov）：NCT04098432。
