Benoit You

Early Clinical and Molecular Biomarkers in Patients With Advanced Ovarian Cancer Undergoing Neoadjuvant Chemotherapy: CHIVA Phase II GINECO Trial

PURPOSE Platinum-based chemotherapy and surgery are pivotal in managing ovarian cancer (OC), yet prognosis remains poor, and early biomarkers for platinum resistance are needed. The neoadjuvant setting provides an opportunity to evaluate tumor responsiveness to platinum chemotherapy in vivo. This study evaluated whether early measures of platinum response combined with molecular alterations could predict surgical outcomes and survival in patients with OC treated with neoadjuvant chemotherapy (NACT). METHODS The CHIVA study enrolled stage III/IV OC patients eligible for three cycles NACT with or without nintedanib, followed by interval debulking surgery. Archival samples underwent extensive sequencing to detect clinically relevant variants and copy number alterations and calculate genomic instability (GIS). Early chemotherapy response measures—cancer antigen 125 kinetics by KELIM, major pathologic response, GIS status, tumor infiltrating lymphocytes (TILs) abundance, and genomic alterations—were correlated with surgery completeness and survival. RESULTS Among 127 patients, the overall response rate was 44%, and the complete cytoreduction (CC0) rate was 54.8%. Homologous recombination deficiency (HRD) was identified in 56% of patients and was associated with better survival. The median progression-free survival was 21.4, 20.5, and 14.4 months in the BRCAmut , BRCAwt /GIS-high, and BRCAwt /GIS-low subgroups, respectively ( P = .001). Unfavorable KELIM predicted lower objective response rate, CC0, and shorter survival, while low intraepithelial TILs (ieTILs) correlated with poor outcomes. Multivariate analysis confirmed KELIM, HRD status, and ieTILs as independent biomarkers. CCNE1 amplifications, observed in 20% of patients, were associated with moderate chemotherapy sensitivity. CONCLUSION HRD status, KELIM, and TILs are key independent biomarkers in advanced OC. CCNE1 amplifications, although typically associated with platinum resistance, were linked to moderate chemotherapy sensitivity, defining an intermediate prognostic subgroup.

SALVOVAR: a pragmatic randomized phase III trial comparing the SALVage weekly dose-dense regimen to the standard 3-weekly regimen in patients with poor prognostic OVARian cancers

Background: Patients with epithelial ovarian cancer (EOC) receiving neoadjuvant platinum-based chemotherapy (NACT) who remain ineligible for complete interval cytoreductive surgery (ICS) due to poor chemosensitivity (CA-125 KELIM™ score <1.0) have a poor prognosis (~20% 5-year survival). A weekly dose-dense carboplatin–paclitaxel regimen may improve outcomes in this high-risk subgroup. Objectives: To demonstrate the superiority of a salvage weekly dose-dense carboplatin–paclitaxel regimen over continuation of the standard 3-weekly regimen in poor-prognosis EOC patients after 3–4 cycles of standard NACT. Design: SALVOVAR is a pragmatic, open-label, multicenter, international, randomized phase III trial. Methods and analysis: Patients with stages III–IV high-grade EOC are eligible if they present (1) an unfavorable standardized KELIM score <1.0, and (2) a disease not amenable to complete ICS after 3–4 cycles of standard 3-weekly carboplatin–paclitaxel. Patients are randomized (1:1) to either the experimental arm (dose-dense carboplatin AUC5 day 1 plus paclitaxel 80 mg/m 2 on days 1, 8, and 15, every 3 weeks) or the control arm (continuation of the standard regimen) for 3 cycles. Bevacizumab use is allowed at investigator discretion. Stratification factors include planned bevacizumab administration, BRCA mutation status, and KELIM strata. The two co-primary endpoints are (1) improvement in late complete cytoreduction rates (from 5% in the control arm to 20% in the experimental arm), and (2) overall survival (target hazard-ratio, 0.61). Total 250 patients will be randomized. Secondary endpoints include objective response rate, progression-free survival, and safety. Additional planned analyses include quality-of-life, cost-effectiveness, surgical standardization, human sciences, and biology studies. Ethics: The protocol was approved by the national ethics committee and health authorities. Discussion: SALVOVAR will evaluate whether chemotherapy densification improves outcomes in poorly chemosensitive advanced EOC. If positive, this pragmatic strategy could be implemented in large-scale studies, independent of resource setting. Trial registration: ClinicalTrials.gov NCT06476184 (June-2024). Available at: https://clinicaltrials.gov/study/NCT06476184

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

Intraperitoneal Nivolumab after Debulking Surgery and Hyperthermic Intraperitoneal Chemotherapy in Advanced Ovarian Cancer: A Phase I Study with Expansion Cohort

Abstract Purpose: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are expected to be synergistic with intraperitoneal (IP) immunotherapy by increasing tumor antigen expression and mutational load. We assessed the feasibility and safety of IP nivolumab following complete CRS and HIPEC in pretreated patients with recurrent ovarian cancer (ClinicalTrials.gov identifier: NCT03959761). Patients and Methods: Patients received IP nivolumab (0.5, 1, or 3 mg/kg) using a 3 + 3 dose-escalation design, starting 5 to 7 days after CRS and HIPEC. Four IP Q2W (once every 2 weeks) nivolumab infusions were planned. The primary objective was to demonstrate the feasibility of IP nivolumab based on dose-limiting toxicity. Secondary objectives were to assess changes in tolerance of CRS and HIPEC. Results: A total of 17 patients were enrolled including 10 patients in the dose escalation and 7 patients in the expansion phase. No dose-limiting toxicity was observed at any dose level in the 9 evaluable patients. Six of the 17 patients (35%) did not complete all planned infusions: 4 (23.5%) due to peritoneal catheter complications and 2 (11.8%) due to early progression. No procedure-related deaths occurred. Eleven patients (65%) experienced serious adverse events (SAE), mainly transitory grade 3 to 4 transaminase elevations (6/11) and surgery-related (9/11). Four SAEs were related to the peritoneal catheter and two to HIPEC. No SAEs/grade 3 to 4 adverse events related to IP nivolumab occurred. Conclusions: This is the first study demonstrating the feasibility of IP nivolumab in patients with relapsed advanced ovarian cancer. Further investigation at 3 mg/kg is warranted.

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.

Maintenance olaparib after platinum-based chemotherapy for advanced/metastatic endometrial cancer: GINECO randomized phase IIb UTOLA trial

Single-agent maintenance poly(ADP-ribose) polymerase (PARP) inhibition may represent an effective strategy in patients with advanced/metastatic endometrial cancer responding to platinum-based chemotherapy, including for molecular subtypes with suboptimal options. To explore this approach, we initiated the randomized phase IIb UTOLA trial (NCT03745950). Female patients without progression following front-line platinum-based chemotherapy for advanced/metastatic endometrial cancer were randomized 2:1 to twice-daily maintenance oral olaparib 300 mg or placebo until progression or intolerance, stratified by p53 status, mismatch repair status, and response to initial chemotherapy. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Secondary endpoints were PFS in subgroups, time to second progression or death, time to first and second subsequent therapy, objective response rate, overall survival, patient-reported outcomes, and safety. In the intention-to-treat population (n = 145), there was no PFS difference between olaparib and placebo (median 5.6 vs. 4.0 months, respectively; hazard ratio 0.94, 95% confidence interval 0.65-1.35; p = 0.74). However, intriguing numerical PFS effects were observed in exploratory analyses of pre-specified subgroups (p53-abnormal, complete response to initial chemotherapy, chromosomal instability). There was no overall survival difference between treatments. Grade 3/4 adverse events occurred in 36% versus 10% of olaparib- versus placebo-treated patients and were consistent with the olaparib safety profile in other cancers. Maintenance olaparib did not improve PFS, but promising numerical effects in subsets of patients warrant prospective evaluation.

Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial

Endometrial cancers are characterized by frequent alterations in the PI3K-AKT-mTor, IGF1 and DNA repair signaling pathways. Concomitant inhibition of these pathways was warranted. ENDOLA phase I/II trial (NCT02755844) was designed to assess the safety/efficacy of the triplet combination of the PARP inhibitor olaparib, metronomic cyclophosphamide (50 mg daily), and PI3K-AKT-mTor inhibitor metformin (1500 mg daily) in women with recurrent endometrial carcinomas. Olaparib dose-escalation (100-300 mg twice-a-day (bid)) was used to determine the recommended-phase II-trial-dose (RP2D, primary endpoint), followed by an expansion cohort to determine the non-progression rate at 10 weeks (NPR-10w, secondary endpoint). 31 patients were treated. Olaparib RP2D was defined as 300 mg bid. The tolerability was acceptable, and grade 3-4 adverse events (51% patients) were mainly hematological. The NPR-10w was 61.5%, and the median progression-free survival (mPFS) was 5.2 months. In a post-hoc analysis, when explored by molecular subtypes/alterations, longer PFS were observed in patients with tumors characterized by a non-specific-molecular-profile (NSMP, n = 4; mPFS, 9.1 months), and by both TP53 altered & high number of large genomic alterations (LGA ≥ 8)(n = 10, mPFS, 8.6 months)). The analyses about kinetics of circulating biomarkers and pharmacodynamic effects are not reported here. In total, the benefit/toxicity ratio of the all-oral olaparib/cyclophosphamide/metformin regimen was favorable in heavily pretreated patients with recurrent endometrial cancer.

Utility of CA125 KELIM in predicting benefit from hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer: pooled analysis of KGOG3042 and KOV-HIPEC-01

Hyperthermic intraperitoneal chemotherapy (HIPEC) administered during interval cytoreductive surgery has shown survival benefits in advanced ovarian cancer. However, predictive biomarkers to guide patient selection for HIPEC are lacking. We evaluated the prognostic and predictive value of the modeled CA125 elimination rate constant K (KELIM), a surrogate marker of tumor chemosensitivity, in relation to the benefit of HIPEC. This pooled analysis included patients from the KOV-HIPEC-01 phase III trial and the KGOG3042 cohort study. KELIM values were estimated using CA125 kinetics during neoadjuvant chemotherapy. Patients were stratified by KELIM score as favorable (≥1.0) or unfavorable (60 years, and stage IV disease. HIPEC may provide survival benefit primarily in patients with an unfavorable KELIM score. KELIM may be a clinically useful biomarker to guide patient selection for HIPEC during interval cytoreductive surgery in advanced ovarian cancer.

ADAGIO: A Phase IIb, Open-Label, Single-Arm, Multicenter Study Assessing the Efficacy and Safety of Adavosertib (AZD1775) as Treatment for Recurrent or Persistent Uterine Serous Carcinoma

PURPOSE This phase IIb, single-arm, multicenter, global study (ADAGIO; ClinicalTrials.gov identifier: NCT04590248 ) assessed the efficacy and safety of adavosertib in patients with recurrent/persistent uterine serous carcinoma (USC) who had previously received platinum-based chemotherapy. METHODS Eligible patients were age 18 years and older and had histologically confirmed recurrent/persistent USC, previously treated with at least one platinum-based chemotherapy regimen, and with evidence of measurable disease. Adavosertib was administered orally at 300 mg once daily on days 1-5 and 8-12 of a 21-day cycle until discontinuation criteria were met. The primary end point was objective response rate (ORR) by blinded independent central review (BICR). Secondary end points included duration of response (DoR), progression-free survival (PFS), safety, and tolerability. Biomarkers previously associated with adavosertib response in other settings were assessed in archival tissue samples. RESULTS In 104 evaluable patients, one complete response and 26 partial responses were observed, for an ORR by BICR of 26.0% (95% CI, 17.9 to 35.5). Median DoR was 4.7 months (95% CI, 3.8 to 8.3); median PFS was 2.8 months (95% CI, 2.6 to 3.9). Biomarker analysis identified no single predictive alteration for adavosertib response, although a trend was observed for CCNE1 amplification or high cyclin E1 protein expression. Most patients (97.2%) experienced treatment-related adverse events (TRAEs), most frequently diarrhea (59.6%), nausea (59.6%), and anemia (58.7%). Grade ≥3 TRAEs occurred in 60.6% of patients, with neutropenia (21.1%) and fatigue (13.8%) most common. 17.4% of patients discontinued adavosertib due to AEs (treatment-related in 14.7%). CONCLUSION Adavosertib showed some antitumor activity in patients with recurrent/persistent USC. However, at 300 mg once daily dosing, it was not well tolerated in this population. Exploratory biomarker studies suggest CCNE1 /cyclin E1 expression may enrich for response to Wee1 inhibition in USC.

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

Identification of Patients With Ovarian Cancer Experiencing the Highest Benefit From Bevacizumab in the First-Line Setting on the Basis of Their Tumor-Intrinsic Chemosensitivity (KELIM): The GOG-0218 Validation Study

PURPOSE In patients with high-grade ovarian cancer, predictors of bevacizumab efficacy in first-line setting are needed. In the ICON-7 trial, a poor tumor intrinsic chemosensitivity (defined by unfavorable modeled cancer antigen-125 [CA-125] ELIMination rate constant K [KELIM] score) was a predictive biomarker. Only the patients with high-risk disease (suboptimally resected stage III, or stage IV) exhibiting unfavorable KELIM score &lt; 1.0 had overall survival (OS) benefit from bevacizumab (median: 29.7 v 20.6 months; hazard ratio [HR], 0.78). An external validation study in the GOG-0218 trial was performed. METHODS In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel ± concurrent-maintenance bevacizumab/placebo. Patient KELIM values were calculated with CA-125 kinetics during the first 100 chemotherapy days by the Lyon University team. The association between KELIM score (favorable ≥ 1.0, or unfavorable &lt; 1.0) and bevacizumab benefit for progression-free survival (PFS)/OS was independently assessed by NGR-GOG using univariate/multivariate analyses. RESULTS KELIM was assessable in 1,662 patients with ≥ 3 CA-125 available values. An unfavorable KELIM score was associated with bevacizumab benefit compared with placebo (PFS: HR, 0.70; 95% CI, 0.59 to 0.82; OS: HR, 0.87; 95% CI, 0.73 to 1.03), whereas a favorable KELIM was not (PFS: HR, 0.96; 95% CI, 0.79 to 1.17; OS: HR, 1.11; 95% CI, 0.89 to 1.39). The highest benefit was observed in patients with a high-risk disease exhibiting unfavorable KELIM, for PFS (median: 9.1 v 5.6 months; HR, 0.64; 95% CI, 0.53 to 0.78), and for OS (median: 35.1 v 29.1 months; HR, 0.79; 95% CI, 0.65 to 0.97). CONCLUSION This GOG-0218 trial investigation validates ICON-7 findings about the association between poor tumor chemosensitivity and benefit from concurrent-maintenance bevacizumab, suggesting that bevacizumab may mainly be effective in patients with poorly chemosensitive disease. Bevacizumab may be prioritized in patients with a high-risk and poorly chemosensitive disease to improve their PFS/OS (patient KELIM score calculator available on the Biomarker Kinetics website).

CA-125 KELIM as a Potential Complementary Tool for Predicting Veliparib Benefit: An Exploratory Analysis From the VELIA/GOG-3005 Study

PURPOSE In VELIA trial, veliparib combined with carboplatin-paclitaxel, followed by maintenance (veliparib-throughout) was associated with improved progression-free survival (PFS) compared with carboplatin-paclitaxel alone in patients with high-grade ovarian carcinomas. We explored the prognostic value of the modeled cancer antigen (CA)-125 elimination rate constant K (KELIM), which is known to be an indicator of the intrinsic tumor chemosensitivity (the faster the rate of CA-125 decline, the higher the KELIM and the higher the chemosensitivity), and its association with benefit from veliparib. PATIENTS AND METHODS Individual KELIM values were estimated from longitudinal CA-125 kinetics. Patients were categorized as having favorable (≥ median) or unfavorable (&lt; median) KELIM. The prognostic value of KELIM for veliparib-related PFS benefit was explored in cohorts treated with primary or interval debulking surgery, according to the surgery completeness, the disease progression risk group, and the homologous recombination (HR) status ( BRCA mutation, HR deficiency [HRD], or HR proficiency [HRP]). RESULTS The data from 854 of 1,140 enrolled patients were analyzed (primary debulking surgery, n = 700; interval debulking surgery, n = 154). Increasing KELIM values were associated with higher benefit from veliparib in HRD cancer, as were decreasing KELIM values in HRP cancer. The highest PFS benefit from veliparib was observed in patients with both favorable KELIM and BRCA mutation (hazard ratio, 0.28; 95% CI, 0.13 to 0.61) or BRCA wild-type HRD cancer (hazard ratio, 0.43; 95% CI, 0.26 to 0.70), consistent with the association between poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy and platinum sensitivity. In contrast, seventy-four percent of patients with a BRCA mutation and unfavorable KELIM progressed within 18 months while on veliparib. The patients with HRP cancer and unfavorable KELIM might have benefited from the veliparib chemosensitizing effect. CONCLUSION In addition to HRD/ BRCA status, the tumor primary chemosensitivity observed during the first-line chemotherapy might be another complementary determinant of poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy.

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.

Germline BRCA1/2 status and chemotherapy response score in high-grade serous ovarian cancer

Abstract Background High-grade serous ovarian cancer (HGSOC) can be treated with platinum-based neoadjuvant chemotherapy (NACT) and delayed primary surgery (DPS). Histopathological response to NACT can be assessed using Böhm’s chemotherapy response score (CRS). We investigated whether germline BRCA1/2 (gBRCA1/2) genotype associated with omental CRS phenotype. Methods A retrospective study of patients with newly diagnosed FIGO stage IIIC/IV HGSOC prescribed NACT and tested for gBRCA1/2 pathogenic variants (PVs) between September 2017 and December 2022 at The Christie Hospital. The Cox proportional hazards model evaluated the association between survival and key clinical factors. The chi-square test assessed the association between CRS3 (no/minimal residual tumour) and gBRCA1/2 status. Results Of 586 eligible patients, 393 underwent DPS and had a CRS reported. Independent prognostic factors by multivariable analysis were gBRCA1/2 status (PV versus wild type [WT]), CRS (3 versus 1 + 2), surgical outcome (complete versus optimal/suboptimal) and first-line poly (ADP-ribose) polymerase-1/2 inhibitor maintenance therapy (yes versus no) (all P &lt; 0.05). There was a non-significant trend for tumours with a gBRCA2 PV having CRS3 versus WT (odds ratio [OR] = 2.13, 95% confidence intervals [CI] 0.95–4.91; P = 0.0647). By contrast, tumours with a gBRCA1 PV were significantly less likely to have CRS3 than WT (OR = 0.35, 95%CI 0.14–0.91; P = 0.0291). Conclusions Germline BRCA1/2 genotype was not clearly associated with superior omental CRS. Further research is required to understand how HGSOC biology defines CRS.

Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study

Abstract Purpose: Early results from the phase II MEDIOLA study (NCT02734004) in germline BRCA1- and/or BRCA2-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) showed promising efficacy and safety with olaparib plus durvalumab. We report efficacy and safety of olaparib plus durvalumab in an expansion cohort of women with gBRCAm PSROC (gBRCAm expansion doublet cohort) and two cohorts with non-gBRCAm PSROC, one of which also received bevacizumab (non-gBRCAm doublet and triplet cohorts). Patients and Methods: In this open-label, multicenter study, PARP inhibitor-naïve patients received olaparib plus durvalumab treatment until disease progression; the non-gBRCAm triplet cohort also received bevacizumab. Primary endpoints were objective response rate (ORR; gBRCAm expansion doublet cohort), disease control rate (DCR) at 24 weeks (non-gBRCAm cohorts), and safety (all cohorts). Results: The full analysis and safety analysis sets comprised 51, 32, and 31 patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively. ORR was 92.2% [95% confidence interval (CI), 81.1–97.8] in the gBRCAm expansion doublet cohort (primary endpoint); DCR at 24 weeks was 28.1% (90% CI, 15.5–43.9) in the non-gBRCAm doublet cohort (primary endpoint) and 74.2% (90% CI, 58.2–86.5) in the non-gBRCAm triplet cohort (primary endpoint). Grade ≥ 3 adverse events were reported in 47.1%, 65.6%, and 61.3% of patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively, most commonly anemia. Conclusions: Olaparib plus durvalumab continued to show notable clinical activity in women with gBRCAm PSROC. Olaparib plus durvalumab with bevacizumab demonstrated encouraging clinical activity in women with non-gBRCAm PSROC. No new safety signals were identified.

ctDNA for Prognostication and Monitoring in Patients with Metastatic Endometrial Carcinoma Treated with Olaparib: Validation in the GINECO-UTOLA Trial

Abstract Purpose: ctDNA may offer a noninvasive means to evaluate tumor response and anticipate disease dynamics before radiologic changes in advanced endometrial carcinoma. Experimental Design: This ancillary analysis included patients from the multicenter, randomized, phase II GINECO-UTerin OLAparib (UTOLA) trial (NCT03745950) evaluating olaparib/placebo as maintenance after first-line platinum-based chemotherapy. Plasma samples were collected at screening after chemotherapy (baseline), 3 months (M3), and progression. ctDNA detection was assessed by a validated methylation-based Droplet Digital PCR (MethddPCR) assay targeting DNA positions universally methylated in endometrial carcinoma. Results: Among 130 evaluable patients, ctDNA was detected in 25 of 129 (19%, 1 technical fail) at baseline, 15 of 80 (19%) at M3, and 33 of 52 (63%) at progression. Baseline ctDNA positivity was independently associated with poorer progression-free survival (PFS) [median 1.81 vs. 7.39 months; adjusted HR = 5.33 (3.17–8.97)] and overall survival (OS) [10.3 vs. 24.7 months; adjusted HR = 3.98 (2.28–6.91); adjusted for age, stage IV at diagnosis, p53abn subgroup, and residual measurable lesions after chemotherapy]. Patients with baseline ctDNA had median OS of 9.36 months under olaparib versus 19.6 months under placebo (log-rank P = 0.05). Patients with increasing ctDNA at M3 had median PFS of 1.67 months, versus 9.64 months without, and median OS of 18.8 versus 25.8 months. ctDNA rising was predictive of poor postprogression OS under olaparib but not under placebo (interaction test, P &amp;lt; 0.001). Conclusions: MethddPCR-ctDNA is an independent prognostic biomarker for OS in advanced/metastatic endometrial carcinoma. MethddPCR-ctDNA may identify patients unlikely to benefit from PARP inhibition, guide therapeutic decisions, and should be further evaluated as a new stratification parameter in future endometrial carcinoma trials.

Utility of Adjusting Chemotherapy Dose & Dosing Schedule With the SALVage Weekly Dose-dense Regimen in Patients With Poor Prognostic OVARian Cancers Based on the Tumor Unfavorable Primary Chemosensitivity and Incomplete Debulking Surgery

SALVOVAR will be a pragmatic open-label multicenter randomized phase III trial (ratio 1:1) comparing the efficacy of the salvage weekly dose-dense regimen with those of the continuation of the standard regimen.

Tolerance of Intraperitoneal (IP) Nivolumab After Extensive Debulking Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Patients With Advanced Ovarian Carcinoma

Spread pattern, the lack of alternative treatments, and emerging data on the activity of anti-Programmed death ligand 1 (PDL1) targeted checkpoint inhibitor therapy in gynecological cancers provide the rationale for this investigation. Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) are likely to increase the tumor-antigen expression and the mutational load. As a result, it would be interesting to combine this approach with immunotherapy. Moreover, Intraperitoneal (IP) infusion will directly target the peritoneal cavity and potentially enhance the immune response. Indeed some recent papers indicate that the peritoneum could be considered as a lymphoid organ, involving "milky spots", thus able to produce a better immune response when immunotherapy is given by IP route rather than intravenous (IV) route. The investigating team in Lyon, France is one of the major groups for HIPEC research in Europe (Pr O. Glehen et al) - Reference center for the tumors of the peritoneum (French National Cancer Institute). The aim of this study is to assess in this I/II phase study, the feasibility of extensive debulking surgery and HIPEC followed by Intraperitoneal (IP) nivolumab dose escalation in patients with advanced ovarian carcinoma.

Safety and Efficacy of Metronomic Cyclophosphamide, Metformin and Olaparib in Endometrial Cancer Patients

Endometrial cancer ranks 11th in terms of incidence (7275 / year) and mortality (2025 deaths/ year). The 5-year overall survivals of patients at diagnosis with locally advanced and metastatic carcinomas are about 50% and 15% respectively. Beyond first line treatment with platinum-based chemotherapy, there is lack of effective drug in this disease, which explains the poor prognosis of patients. The prognosis of metastatic endometrial cancer patients is poor, and few drugs have been shown to be effective beyond first chemotherapy line. Endometrial carcinomas are characterized by frequent alterations of PI3K-AKT-mTor; IGF1R and of DNA repair pathways. Phosphatase and tensin homologue (PTEN)-phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTor) and DNA repair pathways interact, and inhibition of PI3K-AKT-mTor signaling pathway may alter DNA damage repair. Metronomic cyclophosphamide regimen may increase the anti-proliferative effects of olaparib because it is an alkylating agent, and it exerts anti-angiogenic effects, with a favorable toxicity profile. Metformin may increase the anti-proliferative effects of olaparib because it downregulates IGF1R and PI3K-AKT-mTor pathways, with no additive toxicity.

ICON8: Weekly Chemotherapy in Ovarian Cancer

The purpose of this study is to determine if weekly chemotherapy (i.e. giving paclitaxel or carboplatin at a lower dose every week) is more effective than standard chemotherapy (paclitaxel and carboplatin given once every three weeks over 18 weeks) in treating ovarian cancer. The investigators also want to see if weekly chemotherapy causes more or fewer side-effects than standard chemotherapy.

Carboplatin and Paclitaxel With or Without Bevacizumab in Treating Patients With Stage III or Stage IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

This randomized phase III trial studies carboplatin, paclitaxel, and bevacizumab to see how well they work compared to carboplatin, paclitaxel, and placebo in treating patients with stage III or stage IV ovarian epithelial, primary peritoneal, or fallopian tube cancer. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether carboplatin, paclitaxel, and bevacizumab are more effective than carboplatin, paclitaxel, and placebo in treating ovarian epithelial, primary peritoneal, or fallopian tube cancer.