Carrot Aurore, Corbaux Pauline, Colomban Olivier, Lebreton Coriolan, Gladieff Laurence, Tredan Olivier, Selle Frédéric, Abdeddaim Cyril, Leary Alexandra, D'Hondt Véronique, Dubot Coraline, Reverdy Thibaut, You Benoit, Freyer Gilles
EA UCBL/HCL 3738, Centre Pour l'lnnovation en Cancérologie de Lyon (CICLY), Faculty of Medicine Lyon-Sud, Claude Bernard University Lyon 1, Lyon, France.
Service de Biostatistiques-Bioinformatiques, Hospices Civils de Lyon, Lyon, France.
CPT Pharmacometrics Syst Pharmacol. 2025 Aug;14(8):1310-1321. doi: 10.1002/psp4.70025. Epub 2025 Jul 7.
In patients with recurrent advanced ovarian cancer, there is a need for companion tests to guide the development of innovative chemotherapy-free treatments. The modeled longitudinal CA-125 ELIMination rate constant K KELIM-B was a major prognostic factor for progression-free survival (PFS) and overall survival (OS) in recurrent advanced ovarian cancer patients treated with bevacizumab, olaparib, and durvalumab in the BOLD trial. The objective was to determine if a joint semi-mechanistic model with tumor size and CA-125 kinetics would increase KELIM-B accuracy/prognostic value. The BOLD phase II trial (NCT04015739) investigated the triplet regimen in 74 patients with recurrent platinum-sensitive/resistant advanced ovarian cancer. Two kinetic-pharmacodynamic models were developed to fit the data collected during the first 100 treatment days: (1) a CA-125 longitudinal kinetics model, and (2) a joint model integrating both CA-125 kinetics and tumor size. The prognostic value of KELIM-B and KELIM-joint was assessed using univariate/multivariate analyses (PFS/OS). The modeling of CA-125 and tumor size dynamics was feasible with adequate quality checks. The prognostic value of the categorical KELIM-joint, binarized by the median (PFS, HR = 0.29, 95% CI [0.12-0.72]; OS, HR = 0.24, 95% CI [0.08-0.74]), was not clinically different from that of KELIM-B (PFS, HR = 0.35, 95% CI [0.14-0.84]; OS, HR = 0.34, 95% CI [0.12-0.99]). Interactions between tumor size changes and CA-125 kinetics could be assessed in the joint model. However, the improvement in prognostic value was not sufficient to justify the higher complexity of the joint model. Assessing early longitudinal CA-125 kinetics alone remains the best pragmatic strategy for future development.
在复发性晚期卵巢癌患者中，需要有伴随检测来指导创新的无化疗治疗方案的开发。在BOLD试验中，用贝伐单抗、奥拉帕利和度伐单抗治疗的复发性晚期卵巢癌患者，模拟的纵向CA-125消除率常数K KELIM-B是无进展生存期（PFS）和总生存期（OS）的主要预后因素。目的是确定一个结合肿瘤大小和CA-125动力学的联合半机制模型是否会提高KELIM-B的准确性/预后价值。BOLD II期试验（NCT04015739）研究了74例复发性铂敏感/耐药晚期卵巢癌患者的三联方案。开发了两个动力学-药效学模型来拟合前100个治疗日收集的数据：（1）一个CA-125纵向动力学模型，以及（2）一个整合CA-125动力学和肿瘤大小的联合模型。使用单变量/多变量分析（PFS/OS）评估KELIM-B和KELIM-joint的预后价值。通过充分的质量检查，对CA-125和肿瘤大小动态进行建模是可行的。以中位数进行二值化的分类KELIM-joint的预后价值（PFS，HR = 0.29，95%CI [0.12 - 0.72]；OS，HR = 0.24，95%CI [0.08 - 0.74]）与KELIM-B在临床上无差异（PFS，HR = 0.35，95%CI [0.14 - 0.84]；OS，HR = 0.34，95%CI [0.12 - 0.99]）。在联合模型中可以评估肿瘤大小变化与CA-125动力学之间的相互作用。然而，预后价值的改善不足以证明联合模型更高的复杂性是合理的。仅评估早期纵向CA-125动力学仍然是未来发展的最佳实用策略。
