Olivier Colomban

Prognostic Value of a Joint K‐PD Model With Tumor Size Dynamics and CA‐125 Kinetics in Recurrent Ovarian Cancer Patients: BOLD Phase II GINECO Study

ABSTRACTIn 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.

KELIM score predicts outcome in patients with platinum-resistant/refractory recurrent ovarian cancer

Confirmation of the utility of the CA-125 elimination rate (KELIM) as an indicator of the chemosensitivity in advanced-stage ovarian cancer in a “real-life setting”

The modeled CA-125 ELIMination rate constant K (KELIM) has been validated as a marker of response to chemotherapy in >12,000 patients with advanced epithelial ovarian carcinoma (EOC) treated in first-line setting enrolled in >12 clinical trials. Patient KELIM is calculable online https://www.biomarker-kinetics.org/presentation. The objective was to investigate the prognostic value of KELIM in a large real-life national cancer registry with non-selected patients. We investigated 4,025 EOC patients from the Netherlands Cancer Registry treated with neoadjuvant chemotherapy (NACT) ± followed by interval debulking surgery (IDS). Patient KELIM values were calculated in patients with ≥ 3 CA-125 measurements during NACT. KELIM was standardized with a pre-specified cut-off and scored as unfavorable/favorable (<1.0/≥1.0). KELIM's prognostic value regarding radiological response, completeness of IDS, progression-free survival (PFS), and overall survival (OS) was assessed using univariate/multivariate analyses. The data from 1,582 patients treated with heterogeneous chemotherapy regimens and sequences were assessable. KELIM was prognostic for radiological response and the likelihood of complete IDS after NACT (odds ratio=2.59; 95% confidence interval [CI]=2.04-3.29). Moreover, KELIM was independently associated with PFS (hazard ratio [HR]=0.76; 95% CI=0.66-0.87), and OS (HR=0.79; 95% CI=0.69-0.91). Combining KELIM with the completeness of the IDS resulted in 3 prognostic groups (satisfactory, intermediate, and poor) with significant OS differences, namely a good, intermediate, and poor survival respectively. The value of KELIM, as a pragmatic indicator of response to chemotherapy, was maintained in a large real-life population-based cohort, highlighting its applicability in routine conditions.

Mathematical modeling of the early modeled CA-125 longitudinal kinetics (KELIM-PARP) as a pragmatic indicator of rucaparib efficacy in patients with recurrent ovarian carcinoma in ARIEL2 &amp; STUDY 10

PARP inhibitors (PARPi) have revolutionized the management of advanced ovarian carcinoma, and were investigated as forefront treatment in recurrent disease. The objective was to explore if mathematical modeling of the early longitudinal CA-125 kinetics could be used as a pragmatic indicator of the subsequent rucaparib efficacy, like it is for platinum-based chemotherapy. The datasets of ARIEL2 and Study 10 involving recurrent HGOC patients treated with rucaparib were retrospectively investigated. The same strategy as those successfully developed for platinum chemotherapy, based on CA-125 ELIMination rate constant K (KELIM™), was implemented. Individual values of rucaparib-adjusted KELIM (KELIM-PARP) were estimated based on the longitudinal CA-125 kinetics during the first 100 treatment days, and then scored as favorable (KELIM-PARP ≥1.0) or unfavorable (KELIM-PARP <1.0). The prognostic value of KELIM-PARP regarding treatment efficacy (radiological response, and progression-free survival (PFS)) was assessed using univariable/multivariable analyses, with respect to platinum-sensitivity and homologous recombination deficiency (HRD) status. The data from 476 patients were assessed. The CA-125 longitudinal kinetics during the first 100-treatment days could be accurately assessed using the KELIM-PARP model. In patients with platinum-sensitive diseases, BRCA mutational status KELIM-PARP score and were associated with subsequent complete/partial radiological responses (KELIM-PARP: odds-ratio = 2.81, 95% CI 1.86-4.52), and PFS (KELIM-PARP: hazard-ratio = 0.67, 95% CI 0.50-0.91). The patients with BRCA-wild type cancer and favorable KELIM-PARP experienced long PFS with rucaparib regardless of HRD. In platinum-resistant disease patients, KELIM-PARP was associated with subsequent radiological response (odds-ratio = 2.80, 95% CI 1.82-4.72). This proof-of-concept study confirms the early CA-125 longitudinal kinetics during rucaparib in recurrent HGOC patients are assessable by mathematical modeling, to generate individual a KELIM-PARP score associated with the subsequent efficacy. This pragmatic strategy might be useful for selecting the patients for PARPi-based combination regimens, when identifying efficacy biomarker is challenging. Further assessment of this hypothesis is warranted. The present study was supported by Clovis Oncology with a grant to academic research association.

Survival and modelled cancer antigen-125 ELIMination rate constant K score in ovarian cancer patients in first-line before poly(ADP-ribose) polymerase inhibitor era: A Gynaecologic Cancer Intergroup meta-analysis

In patients with advanced ovarian cancer, the modelled CA-125 ELIMination rate constant K (KELIM) is an early indicator of the tumour intrinsic chemosensitivity. We assessed the prognostic and surrogate values of KELIM with respect to those of surgery outcome (based on post-operative residual lesions) in the Gynaecologic Cancer Intergroup (GCIG) individual patient data meta-analysis MAOV (Meta-Analysis in OVarian cancer) built before the emergence of poly(ADP-ribose) polymerase (PARP) inhibitors. The dataset was split into learning and validation cohorts (ratio 1:2). The individual modelled KELIM values were estimated, standardised by the median value, then scored as unfavourable (<1.0) or favourable (≥1.0). Overall survival (OS) and progression-free survival (PFS) analyses were performed with a two-step meta-analytic approach and surrogacy through a two-level meta-analytic model. KELIM was assessed in 5884 patients from eight first-line trials (learning, 1962; validation, 3922). A favourable KELIM score was significantly associated with longer OS (validation set, median, 78.8 versus 28.4 months, hazard-ratios [HR] 0.46, 95% confidence interval [CI], 0.41-0.50, C-index 0.68), and longer PFS (validation set, median 30.5 versus 9.8 months, HR 0.49, 95% CI, 0.45-0.54, C-index 0.68), as were International Federation of Gynaecology and Obstetrics (FIGO) stage and debulking surgery outcome. Three prognostic groups were identified based on the surgery outcome and KELIM score, with large differences in OS (105.1, ∼45.0, and 22.1 months) and PFS (58.1, ∼15.0, and 8.0 months). Surrogacy for OS and for PFS was not established. KELIM is an independent prognostic biomarker for survival, complementary to surgery outcome, representing a new determinant of first-line treatment success.

Benefit From Fractionated Dose-Dense Chemotherapy in Patients With Poor Prognostic Ovarian Cancer: ICON-8 Trial

PURPOSE An international meta-analysis identified a group of patients with advanced epithelial ovarian cancer (EOC) with a very poor survival because of two unfavorable features: (1) a poor chemosensitivity defined by an unfavorable modeled CA-125 ELIMination rate constant K (KELIM) score &lt;1.0 with the online calculator CA-125—Biomarker Kinetics, and (2) an incomplete debulking surgery. We assumed that patients belonging to this poor prognostic group would benefit from a fractionated densified chemotherapy regimen. METHODS The data set of ICON-8 phase III trial (ClinicalTrials.gov identifier: NCT01654146 ), where patients with EOC were treated with the standard three-weekly, or the weekly dose-dense, carboplatin-paclitaxel regimens and debulking primary surgery (immediate primary surgery [IPS] or delayed primary [or interval] surgery [DPS]), was investigated. The association between treatment arm efficacy, standardized KELIM (scored as favorable ≥1.0, or unfavorable &lt;1.0), and surgery completeness was assessed by univariate/multivariate analyses in IPS and DPS cohorts. RESULTS Of 1,566 enrolled patients, KELIM was calculated with the online model in 1,334 with ≥3 CA-125 available values (85%). As previously reported, both KELIM and surgery completeness were complementary prognostic covariates, and could be combined into three prognostic groups with large OS differences: (1) good if favorable KELIM and complete surgery; (2) intermediate if either unfavorable KELIM or incomplete surgery; and (3) poor if unfavorable KELIM and incomplete surgery. Weekly dose-dense chemotherapy was associated with PFS/OS improvement in the poor prognostic group in both the IPS cohort (PFS: hazard ratio [HR], 0.50; 95% CI, 0.31 to 0.79; OS: HR, 0.58; 95% CI, 0.35 to 0.95) and the DPS cohort (PFS: HR, 0.53; 95% CI, 0.37 to 0.76; OS: HR, 0.57; 95% CI, 0.39 to 0.82). CONCLUSION Fractionated dose-dense chemotherapy might be beneficial for patients belonging to the poor prognostic group characterized by lower tumor chemosensitivity assessed with the online calculator CA-125—Biomarker Kinetics and incomplete debulking surgery. Further investigation in the future SALVOVAR trial is warranted.

CA-125 ELIMination Rate Constant K (KELIM) Is a Marker of Chemosensitivity in Patients with Ovarian Cancer: Results from the Phase II CHIVA Trial

Abstract Purpose: In patients with ovarian cancer receiving neoadjuvant chemotherapy, the first-line treatment success will depend on both the tumor-primary chemosensitivity and the completeness of interval debulking surgery (IDS). The modeled CA-125 ELIMination rate constant K (KELIM), calculated with the CA-125 longitudinal kinetics during the first 100 chemotherapy days, is a validated early marker of tumor chemosensitivity. The objective was to investigate the role of the chemosensitivity relative to the success of first-line medical–surgical treatment. Experimental Design: The CA-125 concentrations were prospectively measured in the randomized phase II trial CHIVA (NCT01583322, carboplatin–paclitaxel regimen ± nintedanib, and IDS, n = 188 patients). The KELIM predictive value regarding the tumor response rate, likelihood of complete IDS, risk of subsequent platinum-resistant relapse (PtRR), progression-free survival (PFS), and overall survival (OS) was assessed using univariate and multivariate tests. Results: The data from 134 patients were analyzed. KELIM was an independent and major predictor of subsequent PtRR risk, and of survivals. The final logistic regression model, including KELIM [OR = 0.13; 95% confidence interval (CI), 0.03–0.49] and complete IDS (no vs. yes, OR = 0.30; 95% CI, 0.11–0.76) highlights the preponderant role of chemosensitivity on the success of the first-line treatment. In patients with highly chemosensitive diseases, the patient prognosis was driven more by the chemotherapy-induced antitumor effects than by the surgery. Conclusions: The tumor-primary chemosensitivity, assessed by the modeled CA-125 KELIM calculated during neoadjuvant chemotherapy (http://www.biomarker-kinetics.org/CA-125-neo), may be a major parameter to consider for decision-making regarding IDS attempt, and selecting patients for treatments meant to reverse the primary chemoresistance. See related commentary by May and Oza, p. 4432

Identifying high-risk relapse in early-stage I to II ovarian cancer using the CA125 ELIMination rate constant K (KELIM) score: a Gynecologic Cancer InterGroup individual patient-data meta-analysis

Despite curative surgery and adjuvant chemotherapy, a significant number of early stage I to II ovarian cancers relapse. The CA125 ELIMination rate constant K (KELIM) is a pragmatic indicator of tumor intrinsic chemosensitivity in advanced epithelial ovarian cancer. We assessed the prognostic value of KELIM in patients with early-stage ovarian cancer, with respect to 5-year recurrence-free survival and overall survival, using the Meta-Analysis in Ovarian Cancer, which is the Gynecologic Cancer InterGroup individual patient-data meta-analysis of randomized trials evaluating different adjuvant chemotherapy regimens. Individual patient KELIM values were previously estimated in 5884 patients from the Meta-Analysis in Ovarian Cancer. The prognostic value of KELIM was assessed using univariable & multivariable analyses in patients with resected International Federation of Gynecology and Obstetrics stage I and II disease. Overall, 1143 patients were identified, including clear cell (46.7%); serous (23.7%); endometrioid (12.4%); and mucinous carcinomas (3.9%). In multivariable analyses, a favorable KELIM score (≥1.0) was associated with higher 5-year recurrence-free survival (68.3% vs 55.9%; HR 0.61, 95% CI 0.48 to 0.77) and 5-year overall survival (80.7% vs 72.8%; HR 0.50, 95% CI 0.36 to 0.68), as was the histological sub-type. In exploratory analyses, KELIM score was a prognostic factor regarding 5-year recurrence-free survival and overall survival across all sub-types (especially clear cell carcinoma and serous, with HR ranging from 0.45 to 0.63) with baseline CA125 ≥15 IU/L, except for mucinous histology. The pragmatic KELIM score is an independent prognostic factor in patients with a non-mucinous stage I to II ovarian cancer optimally resected and treated with adjuvant chemotherapy. KELIM may help identify the patients at higher risk of relapse and death requiring closer follow-up or treatment intensification.