Clinical and Molecular Characteristics and Best Response in All Patients Included With (A) Various Malignancies (n=34) and (B) Ewing Sarcoma (n=36)

Comparison of Homologous Recombination Deficiency (HRD) Scores and Tumor Mutational Burden (TMB) Between Treatment Responders and Non-Responders.

Somatic Driver Mutations (A), Focal Amplification/deletions (B) or Gene Fusions (C) and Germline Mutations (D) Detected in 65 Patients Explored in the Molecular Analysis.

Chimeric Antigen Receptor (CAR)-T cell is an immunotherapy which revolutionised the treatment of relapsed/refractory lymphoma and leukaemia. It is shown to have a higher response rate, higher mid-to-long term overall survival, and lower toxicity than standard treatments. However, due to a lack of dose-limiting toxicity (DLT) and unclear dose-effect relationship, traditional phase I designs of clinical trials cannot lead to accurate selections of the optimal dose (OD). Beside clinical outcomes, the CAR-T cell expansion from serial blood samples is measured at various time points. We propose a novel early phase dose-finding design for CAR-T cells, using both toxicity and activity endpoints to locate the OD. The number of CAR-T cells measured in the peripheral blood is used to indicate activity, which is more sensitive than the short-term clinical responses traditionally used. A Bi-Exponential model is used for the repeated measures of the number of cells for each patient, and is estimated under a Bayesian framework. The model is motivated by biological concerns and is flexible enough to accommodate different shapes of the cell-expansion curve. Three criteria for activity are considered: (1) the number of cells at specific time points, (2) the duration before all cells are eliminated, (3) the area under the cell-expansion curve. Simulation studies show that the OD can be selected with high accuracy even under small sample sizes.

Dose Levels of Arm D and Probabilities of Toxicity at the End of Dose Escalation (n=24 Patients Evaluable for DLT) and after the Whole Study (n=65 Patients Evaluable for DLT)

Duration of Treatment Overall and per Dose Level: 66 Patients Receiving a Total of 348 Cycles

Oncoplot of Somatic Variants Across Patient Cohorts.

Objective Response Rates in 66 Patients Treated Overall and per Dose Escalation or Dose Expansion in Other Malignancies and Ewing Sarcoma.

5510 Background: OSE2101 is a neo-epitope vaccine targeting 5 tumor-associated antigens (TP53, MAGE2, MAGE3, CEA and HER2) modified to increase both HLA-A2 and TCR affinity, designed to turn immunogenic ‘cold’ ovarian cancer (OC) to ‘hot’ tumors. Patients with platinum sensitive OC (PSOC) relapsing post-PARP inhibitor (PARPi) and bevacizumab (BEV) represent an area of unmet medical need. Methods: This international multicenter GINECO-sponsored phase II study randomized PSOC patients in CR, PR, or SD after platinum therapy to best supportive care (BSC, arm A), or maintenance treatment with OSE2101 ((SC, q3w until week 18, then q6w to week 48, then q12w, arm B) or OSE2101+pembrolizumab (IV q6w, Arm C) (1:1:2) for up to 2 years. Eligible pts were HLA-A2 positive and previously treated with, or ineligible for, BEV and a PARPi. Primary endpoint was PFS and randomization was stratified for best response to platinum (CR/PR vs SD). Sample size was calculated to provide 90% power to detect an improved PFS in arm C vs A with HR=0.57. Subsequent hierarchical testing then compared arms C vs B, and arms B vs A. Results: 185 pts were randomized to BSC (N=48), OSE2101 (N=46) or OSE+PEMBRO (N=91). Histology was mainly high grade (93%) and serous (93%), 20% harbored a BRCA1/2 mutation, 51% of pts were in CR/PR and 49% in SD at randomization, 85% and 83% of pts were PARPi and BEV-exposed, respectively. Baseline characteristics were balanced between arms. With a median follow up of 22 months, PFS was significantly improved with OSE2101+Pembro vs BSC (4.1 vs 2.8mo in arms C vs A; HR=0.53, 95%CI, 0.36-0.78; p<0.001), especially among pts in CR/PR to platinum (HR=0.31, 95% CI, 0.17-0.53; p<0.01; test for interaction p=0.02). For OSE2101+Pembro vs OSE2101, HR was 0.72 (p=0.074) and for OSE2101 vs BSC, HR was 0.70 (p=0.099). Treatment emergent AEs were increased in arm C vs B with most common being injection site reaction (57% vs 35%), cytokine release syndrome (CRS, mainly G1/2: 28% vs 9%), arthralgia (21% vs 17%) and >G2 immune related events (18% vs 4%). Conclusions: This is the 1 st trial demonstrating a significant improvement in PFS with a combination of a neo-epitope vaccine and an anti-PD1 as maintenance after platinum for patients with platinum sensitive relapsed OC progressing post-PARPi and bevacizumab. Clinical trial information: 2024-516096-32-00.

INTRODUCTION:In high-grade serous ovarian carcinoma (HGSOC), time to first recurrence is a major prognostic factor guiding therapeutic management. However, this parameter remains poorly studied in low-grade serous ovarian carcinoma (LGSOC), a rare subtype characterized by indolent progression and marked chemoresistance. Moreover, AGO criteria for selecting candidates for secondary cytoreductive surgery appear poorly applicable to LGSOC, highlighting the need for specific prognostic markers. METHODS:We conducted a multicenter retrospective study using the national LGSC database from the French Rare Malignant Gynaecologic Tumor Network. Patients with recurrent LGSOC were included. Associations between time to first recurrence, post-relapse survival (PRS), and post-relapse progression-free survival (PR-PFS) were assessed using Cox proportional hazards models adjusted for established prognostic factors. The association between time to recurrence and completeness of secondary cytoreduction was evaluated using multivariable logistic regression. RESULTS:Among 211 patients, the median time to first recurrence was 32 months (IQR 19-63). Longer recurrence intervals were associated with improved outcomes. In multivariable analysis, patients relapsing at 24-48 months (PRS: HR 0.50; 95% CI 0.25-0.97) and ≥48 months (PRS: HR 0.25; 95% CI 0.11-0.58) had significantly better survival compared with the 12-24 month group. Similar results were observed for PR-PFS, with a significant benefit for ≥48 months (HR 0.36; 95% CI 0.19-0.70). Incorporating time to recurrence improved model discrimination. Time to recurrence was not associated with completeness of secondary cytoreduction. CONCLUSION:Time to first recurrence is an independent prognostic factor in LGSOC. Its integration into prognostic models may improve patient stratification and refine selection for secondary cytoreductive surgery.

OBJECTIVE:Growing evidence suggests potential ethnic and geographical variations in chemotherapy efficacy. The CA125 ELIMination rate constant K score is a pragmatic and reproducible indicator of tumor chemosensitivity in newly diagnosed ovarian cancer. We compared ELIMination rate constant K distributions and prognostic performances between patients enrolled in Japanese and Western trials who had stage III/IV serous ovarian cancer from the Gynecologic Cancer InterGroup individual-patient-data Meta-Analysis in OVarian cancer. METHODS:The ELIMination rate constant K values were previously estimated for 5884 women receiving first-line chemotherapy for ovarian cancer. Data from 246 women enrolled in the Japanese JGOG-3016 trial were compared to 2561 patients from Western trials. ELIMination rate constant K was analyzed as a binary variable (favorable ≥1.0 vs unfavorable <1.0). Prognostic value for progression-free survival and overall survival was assessed using univariable and multi-variable models. A standardization cut-off specific to patients enrolled in the Japanese trial was explored using maximally selected rank statistics. RESULTS:KELIM was significantly higher in patients enrolled in the Japanese trial (median 0.071 day-1 vs 0.056 day-1; p <.0001). Using the standard cut-off, favorable ELIMination rate constant K was independently associated with improved progression-free survival (hazard ratio 0.59, 95% confidence interval 0.43 to 0.83) and overall survival (hazard ratio 0.53, 95% confidence interval 0.36 to 0.79) in patients from the Japanese trial. Applying the exploratory cut-off of 0.07 day-1 strengthened prognostic discrimination (progression-free survival: hazard ratio 0.35, 95% confidence interval 0.25 to 0.49, p <.0001; overall survival: hazard ratio 0.40, 95% confidence interval 0.26 to 0.61, p <.0001). CONCLUSIONS:Potential higher ELIMination rate constant K-assessed chemosensitivity is suggested in patients from Japan with advanced serous ovarian cancer, warranting further prospective validation and investigation into underlying biological and environmental determinants and implications for personalized therapeutic strategies.

Oncoplot of Germline Cancer Risk Variants Across Patient Cohorts.

Representativeness of Study Participants

Progression Free Survival (PFS) and Overall Survival (OS) in Patients Treated in Arm D.

AcSé-ESMART Platform Trial Overview

Pharmacogenetic Study Evaluating the Association Between 5 Genetic Variants and Dose-limiting Toxicity (DLT) (N=41).

PURPOSE:Arm D of the AcSé-ESMART proof-of-concept phase I/II platform trial aimed to define the recommended phase II dose (RP2D), pharmacokinetics, activity, and biomarkers of the PARP inhibitor olaparib with irinotecan in pediatric patients with recurrent/refractory malignancies. PATIENTS AND METHODS:Olaparib was administered orally twice daily on days 1 to 10 and irinotecan intravenously on days 4 to 8 of a 21-day cycle. Dose escalation followed the continuous reassessment method; activity was assessed in diverse tumor types (cohort 1) and Ewing sarcoma (cohort 2) according to a minimax Simon 2-stage design. Cohorts were enriched for alterations in homologous recombination repair (HRR) pathways. RESULTS:Seventy patients (median age, 14.9 years; range, 5.0-23.8) were included, 34 with diverse tumor types (25 with HRR gene alterations) and 36 with Ewing sarcoma. Sixty-six patients received 348 treatment cycles (median, 2; range, 1-51) over four dose levels. Main toxicities were gastrointestinal and myelosuppression; the RP2D was olaparib 90 mg/m2 twice daily and irinotecan 20 mg/m2/day. Olaparib exposure in children was equivalent to that in adults. The overall response rate was 9.1% (cohort 1, 11.8%; cohort 2, 6.3%). Four patients with osteosarcoma, pineoblastoma, choroid plexus carcinoma, and neuroblastoma experienced a partial response and were treated for nine to 51 cycles. Two patients with Ewing sarcoma experienced a complete and a partial response for 10 and 42 cycles, respectively. Genetic analyses suggest a high aneuploidy score possibly associated with objective response and prolonged stable disease. CONCLUSIONS:Olaparib combined with irinotecan demonstrated activity in pediatric tumors, which was enriched among tumors that exhibited aneuploidy.

The implementation and spread of new radiation therapy (RT) techniques are often rushed through before or without high-quality proof of a clinical benefit. The framework for phase 1, 2 and 3 trials, ideally designed for pharmaceutical evaluation, is not always appropriate for RT interventions. The IDEAL framework is a five-step process initially developed to enable the rapid implementation of surgical innovations while limiting risks for patients. IDEAL was subsequently adapted to RT. Proton-minibeam radiation therapy (pMBRT) is an innovative RT approach, using an array of parallel thin beams resulting in an outstanding increase in the therapeutic ratio. Cumulative preclinical evidence showed pMBRT was superior to standard RT regarding brain tolerance and provided equivalent or better local control in several glioblastoma models. We decided to adapt IDEAL to pMBRT to accelerate the implementation of this promising new technique in clinical care and present here some examples of possible upcoming studies.

INTRODUCTION:To assess the prognostic impact of residual disease (RD) after primary cytoreductive surgery (PCS) and to compare survival outcomes between PCS and neoadjuvant chemotherapy followed by interval debulking surgery (NAC-IDS) in patients with advanced-stage low-grade serous ovarian cancer (LGSOC). METHODS:A systematic search of PubMed and Scopus databases was conducted to identify relevant studies published from January 2005 to January 2024. We included retrospective cohort studies reporting progression-free survival (PFS) and/or overall survival (OS) in patients with FIGO stage III-IV LGSOC, stratified by the extent of residual disease after cytoreductive surgery and/or the timing of surgery (PCS vs NAC-IDS). Case reports, reviews, and non-English studies were excluded. Two reviewers independently screened articles and extracted data. Hazard ratios (HRs) for PFS and OS were pooled using a random-effects meta-analysis model. Residual disease was categorized using the Completeness of Cytoreduction (CC) score: CC0/CC1 (no or minimal RD) versus CC2 (macroscopic RD). Statistical heterogeneity was assessed using the I2 statistic. RESULTS:Nineteen studies encompassing 3361 patients were included. PCS was performed in 89.1 % of patients. The presence of macroscopic RD (CC2) after PCS was associated with significantly poorer PFS (HR = 2.71, 95 % CI: 2.27-3.23) and OS (HR = 3.06, 95 % CI: 2.44-3.82) compared to CC0/CC1. PCS was associated with superior PFS (HR = 1.72, 95 % CI: 1.19-2.48) and OS (HR = 2.06, 95 % CI: 1.47-2.89) compared to NACT-IDS. Heterogeneity across studies was moderate to high but consistent in direction. CONCLUSIONS:Complete or near complete cytoreduction (CC0/CC1) is a key prognostic factor in advanced LGSOC. Whenever feasible, PCS should be prioritized over neoadjuvant strategies to improve survival outcomes in this chemoresistant ovarian cancer subtype. PROSPERO REGISTRATION:Registration number: CRD420250621053. https://www.crd.york.ac.uk/PROSPERO/view/CRD420250621053.