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Postoperative cisplatin and radiotherapy is the standard of care for high-risk resected locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). The NIVOPOST-OP trial aimed to assess the efficacy and safety of programmed death 1 blockade by nivolumab added to cisplatin and radiotherapy in this setting. This open-label, phase 3 trial evaluated adding nivolumab to cisplatin and radiotherapy after surgery for LA-SCCHN with high-risk pathological features. The main inclusion criteria were age 19–74 years, an Eastern Cooperative Oncology Group performance status 0–1, squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx resected with macroscopic complete resection, and at least one high-risk pathological feature: nodal extracapsular extension, microscopically positive margins, four or more cervical nodal involvements without extracapsular extension, and multiple perineural invasions. 680 participants recruited in 82 sites across six countries (France, Spain, Poland, Belgium, Greece, and Switzerland) were randomly assigned 1:1 to receive cisplatin and radiotherapy (66 Gy, cisplatin 100 mg/m2 intravenously once every 3 weeks, for three cycles); or nivolumab 240 mg intravenously, followed by cisplatin and radiotherapy with three cycles of concomitant nivolumab 360 mg once every 3 weeks, and six cycles of adjuvant nivolumab 480 mg once every 4 weeks. The primary endpoint was disease-free survival as per investigator assessment in the intention-to-treat population. 230 disease-free survival events (relapses or deaths) were required to detect a hazard ratio of 0·65 with 0·05 two-sided α error, with 90% power. The trial is registered at ClinicalTrials.gov (NCT03576417) and is active, but not recruiting. The 680 patients were recruited from Oct 15, 2018, to July 3, 2024. The analysis was based on 666 participants randomly assigned until the cutoff date (April 30, 2024), at which point the required number of events was reached (median follow-up 30·3 months). Disease-free survival was significantly improved with nivolumab, cisplatin, and radiotherapy versus cisplatin and radiotherapy alone, irrespective of programmed death ligand 1 expression (HR 0·76; 95% CI 0·60–0·98; stratified log-rank test p value=0·034). There was an increase in the rate of participants with treatment-related grade 4 adverse events with nivolumab, cisplatin, and radiotherapy compared with cisplatin and radiotherapy (30 [10%] of 312 vs 16 [5%] of 306). Treatment-related deaths occurred in two participants in each group. Nivolumab added to cisplatin and radiotherapy in high-risk resected LA-SCCHN improves disease-free survival with moderate toxic effect increase, and can be proposed as a new standard treatment. Groupe Oncologie Radiotherapie Tete Et Cou (GORTEC) and Bristol Myers Squibb.

Ovarian cancer ranks 18th in terms of incidence and 14th in terms of mortality. Due to a lack of specific symptoms and late diagnosis at an advanced stage, the survival prognosis for these patients is poor. After initial management, the majority of patients will progress. Treatment options will then depend on the speed of progression, and simple, non-intrusive follow-up is essential.Despite the use of the CA-125 blood marker, since the 1980s, the best means of analyzing its decline and prognostic role are poorly quantified.Using individual patient data from the individual patient data meta-analysis initiated by the GCIG, this thesis aims to evaluate the different summaries of CA-125 dynamics over the first few months after the start of treatment to predict patient progression and survival.These summaries include observed and estimated measurements obtained by a linear mixed model (LMM) with splines. Their performance was assessed by cross- validation and adapted scores such as the area under the ROC curve (AUC) and the Brier Score.In our first study, we showed that 3-month monitoring with CA-125 provides individual predictions on overall survival up to 48 months for patients receiving first-line chemotherapy. The second study concludes that a simple CA-125 measurement at 3 months gave a fairly good predictive capacity for detecting platinum-resistant patients, but with a risk of misclassification that would nonetheless lead to a wrong therapeutic orientation,which prompts caution. This thesiscontributes to establishing a framework for the use of CA-125 to guide clinicians in their decision-making for the follow-up of ovarian cancer patients. It also highlights the importance of updating the meta-analysis to include the latest developments in treatment and clinical practice.

(1) Background: Cancer antigen 125 (CA-125) is a protein produced by ovarian cancer cells that is used for patients’ monitoring. However, the best ways to analyze its decline and prognostic role are poorly quantified. (2) Methods: We leveraged individual patient data from the Gynecologic Cancer Intergroup (GCIG) meta-analysis (N = 5573) to compare different approaches summarizing the early trajectory of CA-125 before the prediction time (called the landmark time) at 3 or 6 months after treatment initiation in order to predict overall survival. These summaries included observed and estimated measures obtained by a linear mixed model (LMM). Their performances were evaluated by 10-fold cross-validation with the Brier score and the area under the ROC (AUC). (3) Results: The estimated value and the last observed value at 3 months were the best measures used to predict overall survival, with an AUC of 0.75 CI 95% [0.70; 0.80] at 24 and 36 months and 0.74 [0.69; 0.80] and 0.75 [0.69; 0.80] at 48 months, respectively, considering that CA-125 over 6 months did not improve the AUC, with 0.74 [0.68; 0.78] at 24 months and 0.71 [0.65; 0.76] at 36 and 48 months. (4) Conclusions: A 3-month surveillance provided reliable individual information on overall survival until 48 months for patients receiving first-line chemotherapy.

The Gynecologic Cancer InterGroup (GCIG) recommended that progression-free survival (PFS) can serve as a primary end point instead of overall survival (OS) in advanced ovarian cancer. Evidence is lacking for the validity of PFS as a surrogate marker of OS in the modern era of different treatment types. To evaluate whether PFS is a surrogate end point for OS in patients with advanced ovarian cancer. In September 2016, a comprehensive search of publications in MEDLINE was conducted for randomized clinical trials of systematic treatment in patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer. The GCIG groups were also queried for potentially completed but unpublished trials. Studies with a minimum sample size of 60 patients published since 2001 with PFS and OS rates available were eligible. Investigational treatments considered included initial, maintenance, and intensification therapy consisting of agents delivered at a higher dose and/or frequency compared with that in the control arm. Using the meta-analytic approach on randomized clinical trials published from January 1, 2001, through September 25, 2016, correlations between PFS and OS at the individual level were estimated using the Kendall τ model; between-treatment effects on PFS and OS at the trial level were estimated using the Plackett copula bivariate (R2) model. Criteria for PFS surrogacy required R2 ≥ 0.80 at the trial level. Analysis was performed from January 7 through March 20, 2019. Overall survival and PFS based on measurement of cancer antigen 125 levels confirmed by radiological examination results or by combined GCIG criteria. In this meta-analysis of 17 unique randomized trials of standard (n = 7), intensification (n = 5), and maintenance (n = 5) chemotherapies or targeted treatments with data from 11 029 unique patients (median age, 58 years [range, 18-88 years]), a high correlation was found between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717-0.732), but a low correlation was found at the trial level (R2 = 0.24; 95% CI, 0-0.59). Subgroup analyses led to similar results. In the external validation, 14 of the 16 hazard ratios for OS in the published reports fell within the 95% prediction interval from PFS. This large meta-analysis of individual patient data did not establish PFS as a surrogate end point for OS in first-line treatment of advanced ovarian cancer, but the analysis was limited by the narrow range of treatment effects observed or by poststudy treatment. These results suggest that if PFS is chosen as a primary end point, OS must be measured as a secondary end point.