Pembrolizumab in patients with rare ovarian cancers : analysis from AcSé Pembrolizumab phase II multicentric basket trial

Pembrolizumab in patients with rare ovarian cancers : analysis from AcSé Pembrolizumab phase II multicentric basket trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Pembrolizumab in patients with rare ovarian cancers : analysis from AcSé Pembrolizumab phase II multicentric basket trial Laetitia Collet, Isabelle Ray-Coquard, Nicolas Penel, Sylvie Chevret, and 22 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7752410/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Rare ovarian cancer is a heterogeneous group of diseases with significant unmet medical needs and low chemotherapy sensitivity. In this context, the AcSé Pembrolizumab (NCT03012620) multicentric, non-randomized, phase II basket trial, assessing pembrolizumab monotherapy in rare tumors has been conducted. We report here the results from the rare ovarian cancer cohort. Primary outcome was the objective response rate (ORR) at week 12. Secondary endpoints included best ORR, clinical benefit rate, survival and safety. ORR at week 12 was 3.2% (95%CI, 0.4% to 11.2%), with one partial (PR) and one complete response (CR) in a patient with a teratoma with malignant transformation remaining in CR six years after initiating pembrolizumab. Stable disease (SD) was observed in 34% of patients, including one patient with carcinosarcoma maintaining a SD for 33 months. No new safety concerns and no deaths related to pembrolizumab were observed. Pembrolizumab in rare ovarian tumor subtypes showed limited ORR but promising long-term benefit in selected patients were observed. Health sciences/Oncology Health sciences/Oncology/Cancer Biological sciences/Cancer/Gynaecological cancer/Ovarian cancer Figures Figure 1 Figure 2 Figure 3 Introduction Ovarian cancer is a highly heterogeneous disease with a high mortality rate 1 . Rare ovarian cancers are defined by an incidence of fewer than 6 cases per 100,000 but collectively account for approximately half of all ovarian malignancies. They encompass several distinct ‘rare’ histotypes, including clear-cell, endometrioid and mucinous tumors, low-grade serous and carcinosarcoma, as well as non-epithelial ovarian cancers, mainly represented by germ-cell, sex cord-stromal and small-cell carcinomas 2 , 3 . Due to their rarity, clinical research remains challenging 4 , 5 and clinical trials dedicated to rare ovarian cancers often close prematurely because of slow and insufficient patient recruitment 6 . As a result, therapeutic strategies are primarily extrapolated from the management of more common subtypes, such as high-grade serous ovarian cancers 7 , 8 , with surgery and platinum-based chemotherapy remaining the cornerstone of first line treatment. Nevertheless, recent collaborative efforts have significantly advanced the molecular understanding of rare ovarian cancers, and, in specific cases, led to new and innovative therapeutic strategies 5 , 9 , 10 . Despite these advances, a high unmet medical still persists, due to lower chemotherapy sensitivity, including platinum-based chemotherapy 11 , resulting in poor patient outcomes. A decade ago, immune checkpoint inhibitors (ICIs) dramatically changed the therapeutic landscape for several cancer types 12 , 13 . However, immunotherapy in ovarian carcinoma has shown disappointing results, with an overall response rate (ORR) of barely 10% with ICIs are used as monotherapy 14 , and several negative randomized phase III trials exploring immunotherapy in combination with the standard of care in first-line or relapse setting 15 – 18 . Whereas high grade serous ovarian cancers are characterized by high genomic instability and angiogenesis, both of which can impair immunosurveillance, it is noteworthy that neither combination with PARP inhibitors 10 nor with bevacizumab 16 improved the benefits of immunotherapy in ovarian cancer patients. Notably, the phase III KEYNOTE-B96 clinical trial was recently reported, via press release, to demonstrate an improvement in both progression-free survival and overall survival with the combination of pembrolizumab and paclitaxel compared to placebo and paclitaxel in patients with platinum-resistant ovarian cancer 19 . However, as patients with rare ovarian cancer accounted for only 5 to 10% of the population in these large phase III trials, drawing conclusions for this subgroup is difficult. Nevertheless, subgroup analyses and data from smaller early-phase trials have indicated a potential benefit for some patients, including those with clear cell carcinoma 20 – 22 . In this context, AcSé Pembrolizumab basket study, an innovative strategy initiated in 2017, evaluated the response to pembrolizumab, a PD-1 monoclonal antibody, in patients with rare tumors, including a cohort of rare ovarian cancer patients, the results of which are presented here. Results Patients Between August 23, 2017, and January 12, 2020, a total of 62 patients with rare ovarian cancer were enrolled from 22 French hospitals (Supplementary Table 1, Supplementary Fig. 1). The median age was 53.5 years old [IQR, 36.25;64.75] and 52% has a ECOG Performance Status 0. The median number of prior lines of therapy was 2 [IQR, 1;4] (Table 1). The most common histotype was low-grade serous carcinoma (N = 23, 37%), followed by sex cord-stromal tumors (N = 14, 23%), clear cell carcinoma (N = 10, 16%) and mucinous carcinoma (N = 5, 8%). Other tumor types included carcinosarcoma (n = 4), small-cell carcinoma (n = 4) and germ-cell tumors (n = 2). As of the data cut-off in June 2024, the median follow-up was 13.9 months (IQR, 6.1–17; range 39–36.9 months). At that time, only one (1.6%) patient remained on treatment while 61 patients (98%) had discontinued therapy due to disease progression (N = 47, 76%), toxicities (N = 5, 8%), completion of protocol treatment duration (N = 3, 5%), death (N = 2, 3%), and patient or physician decision (N = 2, 3%, each) (Supplementary Table 2). The median number of pembrolizumab cycles administered was 5 [IQR 4–8]. Efficacy At the time of first radiologic assessment (week-12), the ORR was 3.2% (95%CI, 1.8 to 15.7) with one PR (1.6%) in a patient with a low-grade serous ovarian cancer and one CR (1.6%) in a patient with a germ cell tumor (a teratoma with malignant transformation) (Table 2). Twenty-one patients (33.8%) achieved stable disease (SD) at week 12, resulting in a disease control rate of 37% (N = 23). Response was not evaluable in nine patients, due to death (N = 2) or progression (N = 4) before week 12, treatment discontinuation after two cycles due to adverse events (N = 1), physician decision for wrong histology (N = 1) or an unreported reason (N = 1). Two additional PRs were observed after the first radiologic assessment (week 12) in two patients with clear cell carcinoma (2/10, 20%), leading to a best response rate of 6.4% (95%CI, 1.8 to 15.7) and a disease control rate of 40.3% (Table 2). ORR and best response varied by histotypes (Table 2, Supplementary Table 3, Fig. 1A-B). One CR was observed in a patient with germ-cell tumor (50%) corresponding to a teratoma with malignant transformation. Best response was PR for two patients with clear cell carcinoma (20%) and one patient with low-grade serous ovarian cancer (4.3%). Median duration of CR and PR was 7.6 months and 20.7 months, respectively. Best response was SD for 21 patients, including patients with low-grade serous ovarian cancer (n = 11/23, 47.8%), clear cell carcinoma (n = 3/10, 30%), mucinous carcinoma (n = 2/5, 40%), carcinosarcoma (n = 1/4, 25%), and sex cord-stromal tumors (n = 4/14, 28.6%) according to investigators assessment. The median duration of SD was 2.8 months (range: 0-34.4 months). Notably, one patient with carcinosarcoma maintained SD for 33.4 months. In addition, one patient with clear cell carcinoma, one with low-grade serous ovarian carcinoma and one with mucinous carcinoma remained progression-free for 12.0, 11.0 and 10.9 months, respectively (Supplementary Fig. 2). These patients were heavily pretreated and had poor prognosis features: the carcinosarcoma case had stage IVB disease, no cytoreductive surgery, and progressed after two lines of platinum-based chemotherapy; the low-grade serous case had unresectable stage IVA disease and already received three prior lines of treatment; finally, the mucinous carcinoma and clear cell carcinoma cases had stage IIIA and IIIC disease, with four and two prior lines of therapy, respectively. Of note, tumor burden tended to be lower in patients with prolonged SD compared to those with progressive disease or SD with progression before 10 months (median total size of target lesions 73 mm [IQR 32.0-120.5] versus 89 mm [IQR 59.5-134.2], p-value = 0.59) and in responders than in non-responders (median total size of tumor lesions 63.50mm [IQR 43.8–82.0] versus 89.0mm [IQR 57.5–134.2], p-value = 0.25) (Supplementary Fig. 3). Among the four patients who achieved PR or CR, one patient with low-grade serous ovarian cancer and one with clear cell carcinoma (both PR) experienced progressions after 20.7 and 7.6 months, respectively. The remaining two responders, a patient with clear cell and a patient with germ cell tumor, remained disease-free at 33.1 months and 34 months, respectively (Supplementary Fig. 2), each having received only one prior line of therapy. Of importance, the patient with a germ cell tumor (teratoma with malignant transformation) remained in CR in December 2024, six years after initiating pembrolizumab. Thirty-six patients (58%) experienced disease-progression as best response. All four patients with small cell carcinoma progressed (Fig. 1B). At data cut-off, 32 (51.6%) patients had died. In the intention to treat population, OS rates at 6 and 12 months were 77.3% (95%CI, 67.5–88.5) and 60.5% (95% CI, 49.4–74.2), respectively, with a median OS of 18.8 months (Fig. 2A). Median OS for patients with clear cell carcinoma, low-grade serous carcinoma and sex-cord tumors was 13.0 (2.33 – Non-reached (NR)), NR (14.62 - NR) and NR (12.98 - NR), respectively (Fig. 3A). A total of 61 (98.4%) patients had a PFS event, including 54 progressions and seven deaths before progression, all related to cancer. The PFS rate at 6 months was 22.6% (95%CI, 14.2–35.8) (Fig. 3A),. Median PFS was 2.5months (1.67-NR) for patients with clear cell carcinoma, 3.02 (2.36–5.25) months for low-grade serous carcinoma, and 2.3 months (2.16–8.26) for sex-cord tumors (Fig. 3B). Safety The most common grade 3–5 AEs were bowel obstruction (29%), anemia (21%), abdominal pain (16%), vomiting (15%) and hypomagnesemia (10%) (Supplementary Table 3). The most frequently reported AEs of any grade included fatigue, anemia, lymphopenia and abdominal pain. Three grade 5 AEs were reported (one bowel obstruction, one sub-occlusive syndrome and one renal failure), none of which were deemed related to treatment. Overall, no new safety concerns were identified. Discussion We present for the first time, the results of a phase II, non-randomized clinical basket trial assessing pembrolizumab monotherapy in a cohort of heavily pretreated patients with rare ovarian tumors. At the time the study was launched, very few data were available regarding ICI in rare tumors and in ovarian cancers. Our aim was to provide and expand the limited knowledge on these rare and heterogeneous tumors, addressing the substantial unmet medical need of this patient population. Sixty-two patients with rare ovarian cancers were enrolled in the ACSé Pembrolizumab study. Notably, patient recruitment was efficient, despite the challenges posed by rarity of these tumors and the COVID-19 pandemic at the time. This achievement was facilited by the support of the TMRG network 25 and the involvement of the French National Institute of Cancer (INCa) collaborative networks, which pooled resources and expertise to improve the management of rare tumors. As excepted from known incidence patterns, most cases involved low-grade serous and clear cell carcinoma. One complete and three PR were observed as best response, yielding a best response rate of 6.4% and a best clinical benefit rate of 40.3% in the overall cohort. In addition, four patients, including one with carcinosarcoma, experienced a prolonged disease control. Of interest, three patients with durable PR or CR had received only one or two prior lines of chemotherapy, and tumor burden tended to be lower in responders and in patients with prolonged disease control. These findings support the concept that immune-checkpoint blockade may be more effective earlier in the disease course, before further progression, increasing heterogeneity and volume, or cumulative chemotherapy-induced impairment of T-cell function 26 . Furthermore, responses differed significantly between histological subtypes. As expected, patients with clear cell carcinoma benefited most from ICI, with an ORR of 20% and a clinical benefit rate of 50%, consistent with previous findings 4 , 20 . The recent PEACOCC phase II trial assessing pembrolizumab monotherapy in recurrent clear cell gynecological cancers, reported similar results, with a 25% ORR and a median PFS of 12.2 weeks 20 . Although these findings are encouraging, ICIs combination may be more effective, as suggested by the the BruOG 354 phase II trial, showing an ORR of 33.3% with nivolumab and ipilimumab compared to 14.3% with nivolumab monotherapy in ovarian clear cell carcinoma cohort 4 . We also observed one PR in a patient with low-grade serous ovarian cancer, a subtype for which data on immunotherapy remain scarce. The biomarker-based ENGOT-GYN2/GOG-3051/BOUQUET trial reported an ORR of 13.3% and a disease control rate of 80%, in patients with low-grade serous ovarian cancer treated with atezolizumab and bevacizumab 10 . Importantly, we also reported a CR with ICI in a patients with an ovarian germ-cell tumor 27 . The patient’s response was sustained, remaining disease-free after 33 months of follow-up and still free from disease six years after starting pembrolizumab. Of note, the teratoma had undergone malignant transformation into an epidermoid carcinoma, a subtype associated ICI responsiveness in other cancers 28 . SD was also observed in 21 additional patients (33.9%), including one with stage IVB carcinosarcoma, a highly aggressive tumor with median OS typically less than 8 months 29 , who achieved exceptional disease control for over 33 months. Early results from the ROCSAN trial, assessing durvalumab with or without rucaparib or chemotherapy in carcinosarcoma, have shown an improved ORR with combination therapy 30 . SD in other tumor types, particularly low-grade serous ovarian cancer, might partly reflect their indolent nature. Nevertheless, prolonged disease control has been reported with pembrolizumab in ovarian sex cord-stromal tumor, specifically in granulosa cell tumors, where it ranked among the systemic therapies providing the longest disease control 31 . All four patients with small cell carcinoma in our study experienced PD as their best response. While ICI have shown benefit in rare small-cell carcinoma cases, durable benefits have been observed with combination involving targeted therapy 32 , 33 or dual-immunotherapy 34 . The PembroSCCOHT phase II trial is evaluating pembrolizumab plus the standard PAVEP polychemotherapy in ovarian small-cell carcinoma. Overall, the PFS rate of 22.6% at 6 months in the intention to treat population, underscores the limited efficacy of ICI monotherapy in rare ovarian cancer patients. The median OS of 18.8 months likely reflects the heterogeneity in survival outcomes, longer in low-grade serous ovarian cancers and worse is aggressive histologies such as carcinosarcoma or small-cell ovarian carcinoma 35 . From a safety perspective pembrolizumab’s toxicity profile was comparable to previous reports 16 , 36 . Is it noteworthy that ORR at 12 weeks might not be the most efficacy endpoint for ICI 37 . The two PRs observed after 12 weeks support extending efficacy assessments over a longer period. Furthermore, PFS should be interpreted in the context of histology-specific natural histories. Additionally, several clinical trials are now investigating immunotherapy combinations in rare ovarian cancers, including dual ICIs, and combination with chemotherapy, anti-angiogenic agents, or targeted therapies 4 , 38 . The biological determinants of ICI response remain unclear. Upcoming translational research from the AcSé Pembrolizumab study will explore predictive biomarkers. In particular, common immunotherapy biomarkers are present in a significant proportion of rare ovarian tumors, including tumor infiltrating lymphocytes 39 , alteration in the Switch/Sucrose-Nonfermentable (mSWI/SNF) chromatin-remodeling complexes, such as ARID1A (clear cell carcinoma) and SMARCA4 mutations (small cell carcinoma), and microsatellite instability in endometriosis-associated tumors 40 . Recent studies have also highlighted new ICI resistance mechanisms in ovarian cancer underscoring the role of the tumor microenvironment in both primary and metastasis 41 , and the contribution of macrophage and regulatory T-cells 42 , 43 . These factors, alongside established biomarkers, should be integrated into the design of future clinical trials and the development of innovative combination strategies. In summary, this study demonstrated the feasibility of conducting a clinical trial in rare ovarian cancers, with an acceptable toxicity profile and evidence of potential activity of pembrolizumab, where existing data are scarce. Importantly, international collaborations are essential to evaluate ICIs in a more homogeneous population, enabling robust conclusions that could ultimately inform clinical practice and improve patient outcomes. Methods Study design and participants AcSé Pembrolizumab is a French, single-arm, phase 2, multicohort basket study investigating the activity and safety of pembrolizumab in patients with rare, advanced cancers. For the rare ovarian tumor sub-study cohort, patients were recruited from 22 hospitals in France (Supplementary Table 1). The rare ovarian cancer cohort included 18 years and older women with recurrent or relapsed advanced sex cord-stromal tumor, germ cell tumor (immature teratoma, non seminomatous germ cell and dysgerminoma), low-grade serous carcinoma, mucinous carcinoma, clear cell adenocarcinoma, small cell carcinoma, and carcinosarcoma. Histological confirmation by expert pathologists from the French Rare Gynecological Tumor Group (TMRG) network 23 was realized by central review. Other key inclusion and exclusion criteria are fully detailed in supplementary methods and reported in details previously 24 . The trial was sponsored by Unicancer and was approved by French regulatory authorities (April 3, 2017) and the French ethics committee CPP Est IV (March 14, 2017). All patients provided written informed consent. Procedures All patients received 200 mg intravenous infusion of pembrolizumab every 21 days for a maximum of 24 months (or 35 cycles, whichever was longer), or until disease progression. Early treatment discontinuation or interruption was permitted at the discretion of the investigator or by patient’s initiation for any reason that would have been beneficial to the patient. Treatment was interrupted in the event of any of the toxicities listed in the supplementary methods, intercurrent illness, or changes in the patient’s condition preventing further treatment. Disease assessments were performed by radiologic imaging (CT scan, MRI, or any other appropriate radiological assessments) every 84 (+/- 7) days. Tumor response treatment according to RECIST v.1.1 was assessed by each investigator. Frequency and severity of adverse events (AEs) were assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for AE (CTCAE). And reported irrespective of their association with pembrolizumab therapy. Outcomes Primary endpoint was the ORR defined as the proportion of patients with a complete (CR) or partial response (PR) measured at week 12 (+/-7 days) following study treatment initiation. Secondary endpoints included best response to treatment (measured at any disease assessment during the course of the study), response duration (time from first observation of objective response until disease progression or death from any cause), overall survival (OS; time from inclusion until death due to any cause), progression-free survival (PFS; time from inclusion until documented disease progression or death due to any cause, whichever occurred first), and safety evaluation according to the NCI CTCAE v4. Patients alive who had not progressed at the time of analysis were censored at the time of their latest visit. Statistical analysis Given the rarity of the disease, the number of patients to be included was not prespecified and no hypotheses were postulated regarding potential predictors of treatment response. Full details of the statistical analysis are provided in the supplementary methods. The trial used a two-stage Bayesian enrichment design, specifically intended to guide decision-making within a drug development program. Analyses were conducted both in the whole rare ovarian cancer cohort and for each histotype subgroup. Frequencies and percentages (qualitative variables), median and interquartile range (IQR) (quantitative variables) were used for the descriptive analyses. Duration of response, OS and PFS estimate, along with their 95% confidence intervals were obtained using the Kaplan-Meier method, with comparisons performed using the log-rank test. Activity and safety analyses were conducted on an intention-to-treat basis. Patients with non-evaluable disease at week 12, withdrew from the study, or evaluated only before the 12-week timepoint were included in the analysis and considered to be non-responders. All evaluation criteria are reported with a 95% CI computed using the Clopper-Pearson exact method. All p-values are two-sided, with values below 0.05 considered statistically significant. Statistical analyses were performed using SAS version 9.4 and R version 4.0.4 (https ://www.R-project.org/) software packages. Declarations Data availability The datasets that support the findings of this study are not publicly available due to information that could compromise research participant consent. According to French and European regulations, any reuse of the data must be approved by the ethical committee CPP Est IV. Each request for access to the dataset will be granted upon reasonable request sent to Unicancer.. Role of the funding source The study sponsor (Unicancer) had a role in study design, data collection, data analysis, data interpretation, and writing of the report. The funders of the study (Ligue contre le Cancer, INCa, and MSD) had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Acknowledgments We thank the Ligue contre le cancer, INCa, and MSD for their support in the funding of the study. The supply of pembrolizumab was kindly provided by MSD (MSD International, trading as MSD Ireland, Ballydine, County Tipperary, Ireland). We thank all the patients who participated in the study, the investigators who recruited patients, and the clinical and research staff of the Immuno-oncology team at Unicancer (Paris, France) Authors’ Contributions L. Collet: Formal analysis, validation, investigation, methodology, writing–original draft, writing–review and editing. Nicolas Penel: Resources, data curation, writing–review and editing. Sylvie Chevret: Conceptualization, resources, formal analysis, validation, investigation, methodology, writing–review and editing. Camille Moreau-Bachelard: resources, data curation, writing–review and editing François Cherifi: resources, data curation, writing–review and editing Patrick Soulie: resources, data curation, writing–review and editing Diego Tosi: resources, data curation, writing–review and editing Francois Bertucci: resources, data curation, writing–review and editing Sophie Cousin: resources, data curation, writing–review and editing Esma Saada Bouzid: resources, data curation, writing–review and editing Laurence Gladieff: resources, data curation, writing–review and editing Jérôme Alexandre: resources, data curation, writing–review and editing Thibault de la Motte Rouge: resources, data curation, writing–review and editing Camille Petrau: resources, data curation, writing–review and editing François Ghiringhelli: resources, data curation, writing–review and editing Jean-Christophe Eymard: resources, data curation, writing–review and editing Carole Soussain: resources, data curation, writing–review and editing Fabien Calcagno: resources, data curation, writing–review and editing Mathieu Larroquette: resources, data curation, writing–review and editing Valérie Lebrun Ly: resources, data curation, writing–review and editing Heba Dawood: resources, data curation, writing–review and editing Hélène Marijon: resources, data curation, writing–review and editing Clotilde Simon: resources, data curation, writing–review and editing Assia Lamrani-Ghaouti: resources, data curation, writing–review and editing Caroline Even: resources, data curation, writing–review and editing Isabelle Ray-Coquard: Conceptualization, resources, validation, investigation, methodology, writing–review and editing. 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Nat Med . 2020;26(4):475-484. doi:10.1038/s41591-020-0829-0 Bernard L. Treatment of recurrent ovarian germ cell tumours: Is there a role for immune checkpoint inhibitors? Gynecologic Oncology Reports . 2024;56:101502. doi:10.1016/j.gore.2024.101502 Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer | New England Journal of Medicine. Accessed June 18, 2024. https://www.nejm.org/doi/full/10.1056/NEJMoa2112435 Collet L, González López AM, Romeo C, et al. Gynecological carcinosarcomas: Overview and future perspectives. Bulletin du Cancer . 2023;110(11):1215-1226. doi:10.1016/j.bulcan.2023.07.005 Ray-Coquard IL, Bellesoeur A, Fabbro M, et al. 34O ROCSAN: A multicentric randomized phase II/III evaluating dostarlimab in combination with niraparib versus niraparib alone compared to chemotherapy in the treatment of endometrial/ovarian carcinosarcoma after at least one line of platinum-based chemotherapy – Preliminary results. ESMO Open . 2024;9. doi:10.1016/j.esmoop.2024.103534 How JA, Jazaeri A, Westin SN, et al. The clinical efficacy and safety of single-agent pembrolizumab in patients with recurrent granulosa cell tumors of the ovary: a case series from a phase II basket trial. Invest New Drugs . 2021;39(3):829-835. doi:10.1007/s10637-020-01043-9 Lee EK, Esselen KM, Kolin DL, Lee LJ, Matulonis UA, Konstantinopoulos PA. Combined CDK4/6 and PD-1 Inhibition in Refractory SMARCA4-Deficient Small-Cell Carcinoma of the Ovary, Hypercalcemic Type. JCO Precis Oncol . 2020;4:PO.20.00063. doi:10.1200/PO.20.00063 Li G, Jiang Y. Case Report: A Durable Response to Camrelizumab and Apatinib Combination Therapy in a Heavily Treated Small Cell Carcinoma of the Ovary, Hypercalcemic Type. Front Oncol . 2022;12. doi:10.3389/fonc.2022.916790 Chae YK, Ryan CW, Aung N, et al. Abstract CT162: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the clear cell ovarian, endometrial, cervical cancer cohorts. Cancer Research . 2023;83(8_Supplement):CT162. doi:10.1158/1538-7445.AM2023-CT162 Tischkowitz M, Huang S, Banerjee S, et al. Small-Cell Carcinoma of the Ovary, Hypercalcemic Type–Genetics, New Treatment Targets, and Current Management Guidelines. Clinical Cancer Research . 2020;26(15):3908-3917. doi:10.1158/1078-0432.CCR-19-3797 Ray-Coquard IL, Savoye AM, Schiffler C, et al. Neoadjuvant and adjuvant pembrolizumab in advanced high-grade serous carcinoma: the randomized phase II NeoPembrOV clinical trial. Nat Commun . 2024;15(1):5931. doi:10.1038/s41467-024-46999-x Borcoman E, Kanjanapan Y, Champiat S, et al. Novel patterns of response under immunotherapy. Annals of Oncology . 2019;30(3):385-396. doi:10.1093/annonc/mdz003 Lee JY, Tan DSP, Ray-Coquard IL, et al. A three-arm randomized phase II study of dostarlimab alone or with bevacizumab versus nonplatinum chemotherapy in recurrent gynecological clear cell carcinoma: DOVE (APGOT-OV7/ENGOT-ov80 study). JCO . 2024;42(16_suppl):TPS5627-TPS5627. doi:10.1200/JCO.2024.42.16_suppl.TPS5627 Ovarian Tumor Tissue Analysis (OTTA) Consortium. Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer. JAMA Oncology . 2017;3(12):e173290. doi:10.1001/jamaoncol.2017.3290 Hollis RL, Thomson JP, Stanley B, et al. Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome. Nat Commun . 2020;11(1):4995. doi:10.1038/s41467-020-18819-5 Collet L, Ardin M, Venet D, et al. Unravelling the tumor microenvironment and PD-L1 expression across tissue type in high-grade serous ovarian cancer in the NeoPembrOV/GINECO phase II randomized trial. Clinical Cancer Research . Published online 2025. Le Saux O, Ardin M, Berthet J, et al. Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma. Nat Commun . 2024;15(1):5932. doi:10.1038/s41467-024-47000-5 Collet L, Noël JC, Catteau X, et al. Tumor-stroma proportion on primary tumor as a prognostic biomarker in advanced ovarian cancer patients receiving chemo-immunotherapy as first-line therapy: analyses from the NeoPembrOV/GINECO phase II randomized trial. ESMO Open . 2025;10(6):105104. doi:10.1016/j.esmoop.2025.105104 Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryFigure1.pdf Supplementary Figure 1 SupplementaryFigure2.pdf Supplementary Figure 2 SupplementaryFigure3.pdf Supplementary Figure 3 SupplementaryTable1.pdf Supplementary Table 1 SupplementaryTable2.pdf Supplementary Table 2 SupplementaryTable3.pdf Supplementary Table 3 SupplementaryTable4.pdf Supplementary Table 4 NICEUC01051612v8.020200907.pdf Informed Consent Form (ICF) AcSePEMBROLIZUMABprotocolv10.0Amdt920211122clean.pdf Protocol Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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1","display":"","copyAsset":false,"role":"figure","size":38679,"visible":true,"origin":"","legend":"\u003cp\u003eReduction of tumor size at week according to rare ovarian cancer subtype\u003c/p\u003e\n\u003cp\u003eA. Swimmer plot showing the reduction of tumor size at week 12 and B. the maximum reduction of tumor size\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7752410/v1/21303e1b17e28a76ef6246ad.png"},{"id":92802699,"identity":"4ce7f09c-7093-461a-a2c3-6902657f1fdd","added_by":"auto","created_at":"2025-10-05 11:42:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":32497,"visible":true,"origin":"","legend":"\u003cp\u003eMedian overall survival and progression-free survival in the intention to treat population.\u003c/p\u003e\n\u003cp\u003eA.Overall survival and B. Progression-free Survival in the intention to treat population\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7752410/v1/6aa33cbde55226cdd0844a78.png"},{"id":92803057,"identity":"0b5facdc-5b4a-43bf-a11f-72caf516a27b","added_by":"auto","created_at":"2025-10-05 11:50:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":67533,"visible":true,"origin":"","legend":"\u003cp\u003eMedian overall survival and progression free survival in the intention to treat population according to the histological subgroups\u003c/p\u003e\n\u003cp\u003eA.Overall survival and B. Progression-free Survival accoding to histological subgroups *median overall survival and progression free survival is given for histological subgroup with more than 10 patients\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7752410/v1/b1945364ea4b8aef9a80c44f.png"},{"id":97376588,"identity":"3ced8bfa-6c1a-48c1-84a5-ffd4046e0ee0","added_by":"auto","created_at":"2025-12-03 16:41:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":708964,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7752410/v1/5ceb0029-d949-4a8f-8697-66d58a4792ca.pdf"},{"id":92802703,"identity":"114a47b4-0f43-41ec-a3ee-1d21c213d85b","added_by":"auto","created_at":"2025-10-05 11:42:34","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":31712,"visible":true,"origin":"","legend":"Supplementary Figure 1","description":"","filename":"SupplementaryFigure1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7752410/v1/6df7831d0b1d382d3a903d23.pdf"},{"id":92802701,"identity":"273c89d1-8eb9-4e5b-9ad4-720137259b37","added_by":"auto","created_at":"2025-10-05 11:42:34","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":30282,"visible":true,"origin":"","legend":"Supplementary Figure 2","description":"","filename":"SupplementaryFigure2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7752410/v1/73af257e7a2aa9be4a7da7c8.pdf"},{"id":92802707,"identity":"3d3db35d-a786-4cbb-aac8-692fea429a39","added_by":"auto","created_at":"2025-10-05 11:42:34","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":55651,"visible":true,"origin":"","legend":"Supplementary Figure 3","description":"","filename":"SupplementaryFigure3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7752410/v1/ea7afebf873d6c4388b9f3bd.pdf"},{"id":92802708,"identity":"a9042f7d-202d-46f5-8c59-5a91242fa5ce","added_by":"auto","created_at":"2025-10-05 11:42:34","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":33444,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 1\u003c/p\u003e","description":"","filename":"SupplementaryTable1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7752410/v1/8f0a705ba2db938f459a8ba5.pdf"},{"id":92803058,"identity":"83b1c458-71df-43b2-bc4d-fe26e034af17","added_by":"auto","created_at":"2025-10-05 11:50:34","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":23180,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 2\u003c/p\u003e","description":"","filename":"SupplementaryTable2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7752410/v1/5691af06d2e008e24e0ca721.pdf"},{"id":92802705,"identity":"f868c311-4610-491d-a371-0d0a0b6e785a","added_by":"auto","created_at":"2025-10-05 11:42:34","extension":"pdf","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":27423,"visible":true,"origin":"","legend":"Supplementary Table 3","description":"","filename":"SupplementaryTable3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7752410/v1/baf111577ee4ab2dfd6b4a04.pdf"},{"id":92802709,"identity":"eeacd054-9a87-4d31-8125-eb5d414e375e","added_by":"auto","created_at":"2025-10-05 11:42:34","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":60271,"visible":true,"origin":"","legend":"Supplementary Table 4","description":"","filename":"SupplementaryTable4.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7752410/v1/dce24aea02b5aecf3210f957.pdf"},{"id":92803060,"identity":"90dc1c75-a43c-4597-b0e1-d99701b3b43d","added_by":"auto","created_at":"2025-10-05 11:50:34","extension":"pdf","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":374061,"visible":true,"origin":"","legend":"Informed Consent Form (ICF)","description":"","filename":"NICEUC01051612v8.020200907.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7752410/v1/d19e4d69916c8c22c5a08981.pdf"},{"id":92802714,"identity":"c8445614-100f-4242-ac98-ab5141475469","added_by":"auto","created_at":"2025-10-05 11:42:34","extension":"pdf","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":1994017,"visible":true,"origin":"","legend":"Protocol","description":"","filename":"AcSePEMBROLIZUMABprotocolv10.0Amdt920211122clean.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7752410/v1/a8ac57c7843b7560e8b0ea70.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"\u003cp\u003e\u003cstrong\u003ePembrolizumab in patients with rare ovarian cancers : analysis from AcSé Pembrolizumab phase II multicentric basket trial\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOvarian cancer is a highly heterogeneous disease with a high mortality rate \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Rare ovarian cancers are defined by an incidence of fewer than 6 cases per 100,000 but collectively account for approximately half of all ovarian malignancies. They encompass several distinct \u0026lsquo;rare\u0026rsquo; histotypes, including clear-cell, endometrioid and mucinous tumors, low-grade serous and carcinosarcoma, as well as non-epithelial ovarian cancers, mainly represented by germ-cell, sex cord-stromal and small-cell carcinomas \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Due to their rarity, clinical research remains challenging \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e and clinical trials dedicated to rare ovarian cancers often close prematurely because of slow and insufficient patient recruitment \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. As a result, therapeutic strategies are primarily extrapolated from the management of more common subtypes, such as high-grade serous ovarian cancers \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, with surgery and platinum-based chemotherapy remaining the cornerstone of first line treatment. Nevertheless, recent collaborative efforts have significantly advanced the molecular understanding of rare ovarian cancers, and, in specific cases, led to new and innovative therapeutic strategies \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Despite these advances, a high unmet medical still persists, due to lower chemotherapy sensitivity, including platinum-based chemotherapy\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, resulting in poor patient outcomes.\u003c/p\u003e\u003cp\u003eA decade ago, immune checkpoint inhibitors (ICIs) dramatically changed the therapeutic landscape for several cancer types\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. However, immunotherapy in ovarian carcinoma has shown disappointing results, with an overall response rate (ORR) of barely 10% with ICIs are used as monotherapy\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, and several negative randomized phase III trials exploring immunotherapy in combination with the standard of care in first-line or relapse setting \u003csup\u003e\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Whereas high grade serous ovarian cancers are characterized by high genomic instability and angiogenesis, both of which can impair immunosurveillance, it is noteworthy that neither combination with PARP inhibitors\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e nor with bevacizumab\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e improved the benefits of immunotherapy in ovarian cancer patients. Notably, the phase III KEYNOTE-B96 clinical trial was recently reported, via press release, to demonstrate an improvement in both progression-free survival and overall survival with the combination of pembrolizumab and paclitaxel compared to placebo and paclitaxel in patients with platinum-resistant ovarian cancer\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. However, as patients with rare ovarian cancer accounted for only 5 to 10% of the population in these large phase III trials, drawing conclusions for this subgroup is difficult. Nevertheless, subgroup analyses and data from smaller early-phase trials have indicated a potential benefit for some patients, including those with clear cell carcinoma \u003csup\u003e\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn this context, AcS\u0026eacute; Pembrolizumab basket study, an innovative strategy initiated in 2017, evaluated the response to pembrolizumab, a PD-1 monoclonal antibody, in patients with rare tumors, including a cohort of rare ovarian cancer patients, the results of which are presented here.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003eBetween August 23, 2017, and January 12, 2020, a total of 62 patients with rare ovarian cancer were enrolled from 22 French hospitals (Supplementary Table\u0026nbsp;1, Supplementary Fig.\u0026nbsp;1). The median age was 53.5 years old [IQR, 36.25;64.75] and 52% has a ECOG Performance Status 0. The median number of prior lines of therapy was 2 [IQR, 1;4] (Table\u0026nbsp;1). The most common histotype was low-grade serous carcinoma (N\u0026thinsp;=\u0026thinsp;23, 37%), followed by sex cord-stromal tumors (N\u0026thinsp;=\u0026thinsp;14, 23%), clear cell carcinoma (N\u0026thinsp;=\u0026thinsp;10, 16%) and mucinous carcinoma (N\u0026thinsp;=\u0026thinsp;5, 8%). Other tumor types included carcinosarcoma (n\u0026thinsp;=\u0026thinsp;4), small-cell carcinoma (n\u0026thinsp;=\u0026thinsp;4) and germ-cell tumors (n\u0026thinsp;=\u0026thinsp;2). As of the data cut-off in June 2024, the median follow-up was 13.9 months (IQR, 6.1\u0026ndash;17; range 39\u0026ndash;36.9 months). At that time, only one (1.6%) patient remained on treatment while 61 patients (98%) had discontinued therapy due to disease progression (N\u0026thinsp;=\u0026thinsp;47, 76%), toxicities (N\u0026thinsp;=\u0026thinsp;5, 8%), completion of protocol treatment duration (N\u0026thinsp;=\u0026thinsp;3, 5%), death (N\u0026thinsp;=\u0026thinsp;2, 3%), and patient or physician decision (N\u0026thinsp;=\u0026thinsp;2, 3%, each) (Supplementary Table\u0026nbsp;2). The median number of pembrolizumab cycles administered was 5 [IQR 4\u0026ndash;8].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEfficacy\u003c/h3\u003e\n\u003cp\u003eAt the time of first radiologic assessment (week-12), the ORR was 3.2% (95%CI, 1.8 to 15.7) with one PR (1.6%) in a patient with a low-grade serous ovarian cancer and one CR (1.6%) in a patient with a germ cell tumor (a teratoma with malignant transformation) (Table\u0026nbsp;2). Twenty-one patients (33.8%) achieved stable disease (SD) at week 12, resulting in a disease control rate of 37% (N\u0026thinsp;=\u0026thinsp;23). Response was not evaluable in nine patients, due to death (N\u0026thinsp;=\u0026thinsp;2) or progression (N\u0026thinsp;=\u0026thinsp;4) before week 12, treatment discontinuation after two cycles due to adverse events (N\u0026thinsp;=\u0026thinsp;1), physician decision for wrong histology (N\u0026thinsp;=\u0026thinsp;1) or an unreported reason (N\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e\u003cp\u003eTwo additional PRs were observed after the first radiologic assessment (week 12) in two patients with clear cell carcinoma (2/10, 20%), leading to a best response rate of 6.4% (95%CI, 1.8 to 15.7) and a disease control rate of 40.3% (Table\u0026nbsp;2).\u003c/p\u003e\u003cp\u003eORR and best response varied by histotypes (Table\u0026nbsp;2, Supplementary Table\u0026nbsp;3, Fig.\u0026nbsp;1A-B). One CR was observed in a patient with germ-cell tumor (50%) corresponding to a teratoma with malignant transformation. Best response was PR for two patients with clear cell carcinoma (20%) and one patient with low-grade serous ovarian cancer (4.3%). Median duration of CR and PR was 7.6 months and 20.7 months, respectively. Best response was SD for 21 patients, including patients with low-grade serous ovarian cancer (n\u0026thinsp;=\u0026thinsp;11/23, 47.8%), clear cell carcinoma (n\u0026thinsp;=\u0026thinsp;3/10, 30%), mucinous carcinoma (n\u0026thinsp;=\u0026thinsp;2/5, 40%), carcinosarcoma (n\u0026thinsp;=\u0026thinsp;1/4, 25%), and sex cord-stromal tumors (n\u0026thinsp;=\u0026thinsp;4/14, 28.6%) according to investigators assessment. The median duration of SD was 2.8 months (range: 0-34.4 months). Notably, one patient with carcinosarcoma maintained SD for 33.4 months. In addition, one patient with clear cell carcinoma, one with low-grade serous ovarian carcinoma and one with mucinous carcinoma remained progression-free for 12.0, 11.0 and 10.9 months, respectively (Supplementary Fig.\u0026nbsp;2). These patients were heavily pretreated and had poor prognosis features: the carcinosarcoma case had stage IVB disease, no cytoreductive surgery, and progressed after two lines of platinum-based chemotherapy; the low-grade serous case had unresectable stage IVA disease and already received three prior lines of treatment; finally, the mucinous carcinoma and clear cell carcinoma cases had stage IIIA and IIIC disease, with four and two prior lines of therapy, respectively. Of note, tumor burden tended to be lower in patients with prolonged SD compared to those with progressive disease or SD with progression before 10 months (median total size of target lesions 73 mm [IQR 32.0-120.5] versus 89 mm [IQR 59.5-134.2], p-value\u0026thinsp;=\u0026thinsp;0.59) and in responders than in non-responders (median total size of tumor lesions 63.50mm [IQR 43.8\u0026ndash;82.0] versus 89.0mm [IQR 57.5\u0026ndash;134.2], p-value\u0026thinsp;=\u0026thinsp;0.25) (Supplementary Fig.\u0026nbsp;3).\u003c/p\u003e\u003cp\u003eAmong the four patients who achieved PR or CR, one patient with low-grade serous ovarian cancer and one with clear cell carcinoma (both PR) experienced progressions after 20.7 and 7.6 months, respectively. The remaining two responders, a patient with clear cell and a patient with germ cell tumor, remained disease-free at 33.1 months and 34 months, respectively (Supplementary Fig.\u0026nbsp;2), each having received only one prior line of therapy. Of importance, the patient with a germ cell tumor (teratoma with malignant transformation) remained in CR in December 2024, six years after initiating pembrolizumab. Thirty-six patients (58%) experienced disease-progression as best response. All four patients with small cell carcinoma progressed (Fig.\u0026nbsp;1B).\u003c/p\u003e\u003cp\u003eAt data cut-off, 32 (51.6%) patients had died. In the intention to treat population, OS rates at 6 and 12 months were 77.3% (95%CI, 67.5\u0026ndash;88.5) and 60.5% (95% CI, 49.4\u0026ndash;74.2), respectively, with a median OS of 18.8 months (Fig.\u0026nbsp;2A). Median OS for patients with clear cell carcinoma, low-grade serous carcinoma and sex-cord tumors was 13.0 (2.33 \u0026ndash; Non-reached (NR)), NR (14.62 - NR) and NR (12.98 - NR), respectively (Fig.\u0026nbsp;3A).\u003c/p\u003e\u003cp\u003eA total of 61 (98.4%) patients had a PFS event, including 54 progressions and seven deaths before progression, all related to cancer. The PFS rate at 6 months was 22.6% (95%CI, 14.2\u0026ndash;35.8) (Fig.\u0026nbsp;3A),. Median PFS was 2.5months (1.67-NR) for patients with clear cell carcinoma, 3.02 (2.36\u0026ndash;5.25) months for low-grade serous carcinoma, and 2.3 months (2.16\u0026ndash;8.26) for sex-cord tumors (Fig.\u0026nbsp;3B).\u003c/p\u003e\n\u003ch3\u003eSafety\u003c/h3\u003e\n\u003cp\u003eThe most common grade 3\u0026ndash;5 AEs were bowel obstruction (29%), anemia (21%), abdominal pain (16%), vomiting (15%) and hypomagnesemia (10%) (Supplementary Table\u0026nbsp;3). The most frequently reported AEs of any grade included fatigue, anemia, lymphopenia and abdominal pain. Three grade 5 AEs were reported (one bowel obstruction, one sub-occlusive syndrome and one renal failure), none of which were deemed related to treatment. Overall, no new safety concerns were identified.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe present for the first time, the results of a phase II, non-randomized clinical basket trial assessing pembrolizumab monotherapy in a cohort of heavily pretreated patients with rare ovarian tumors. At the time the study was launched, very few data were available regarding ICI in rare tumors and in ovarian cancers. Our aim was to provide and expand the limited knowledge on these rare and heterogeneous tumors, addressing the substantial unmet medical need of this patient population.\u003c/p\u003e\u003cp\u003eSixty-two patients with rare ovarian cancers were enrolled in the ACS\u0026eacute; Pembrolizumab study. Notably, patient recruitment was efficient, despite the challenges posed by rarity of these tumors and the COVID-19 pandemic at the time. This achievement was facilited by the support of the TMRG network\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e and the involvement of the French National Institute of Cancer (INCa) collaborative networks, which pooled resources and expertise to improve the management of rare tumors. As excepted from known incidence patterns, most cases involved low-grade serous and clear cell carcinoma. One complete and three PR were observed as best response, yielding a best response rate of 6.4% and a best clinical benefit rate of 40.3% in the overall cohort. In addition, four patients, including one with carcinosarcoma, experienced a prolonged disease control. Of interest, three patients with durable PR or CR had received only one or two prior lines of chemotherapy, and tumor burden tended to be lower in responders and in patients with prolonged disease control. These findings support the concept that immune-checkpoint blockade may be more effective earlier in the disease course, before further progression, increasing heterogeneity and volume, or cumulative chemotherapy-induced impairment of T-cell function\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eFurthermore, responses differed significantly between histological subtypes. As expected, patients with clear cell carcinoma benefited most from ICI, with an ORR of 20% and a clinical benefit rate of 50%, consistent with previous findings\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. The recent PEACOCC phase II trial assessing pembrolizumab monotherapy in recurrent clear cell gynecological cancers, reported similar results, with a 25% ORR and a median PFS of 12.2 weeks \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Although these findings are encouraging, ICIs combination may be more effective, as suggested by the the BruOG 354 phase II trial, showing an ORR of 33.3% with nivolumab and ipilimumab compared to 14.3% with nivolumab monotherapy in ovarian clear cell carcinoma cohort \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. We also observed one PR in a patient with low-grade serous ovarian cancer, a subtype for which data on immunotherapy remain scarce. The biomarker-based ENGOT-GYN2/GOG-3051/BOUQUET trial reported an ORR of 13.3% and a disease control rate of 80%, in patients with low-grade serous ovarian cancer treated with atezolizumab and bevacizumab\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Importantly, we also reported a CR with ICI in a patients with an ovarian germ-cell tumor \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. The patient\u0026rsquo;s response was sustained, remaining disease-free after 33 months of follow-up and still free from disease six years after starting pembrolizumab. Of note, the teratoma had undergone malignant transformation into an epidermoid carcinoma, a subtype associated ICI responsiveness in other cancers\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. SD was also observed in 21 additional patients (33.9%), including one with stage IVB carcinosarcoma, a highly aggressive tumor with median OS typically less than 8 months\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, who achieved exceptional disease control for over 33 months. Early results from the ROCSAN trial, assessing durvalumab with or without rucaparib or chemotherapy in carcinosarcoma, have shown an improved ORR with combination therapy\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. SD in other tumor types, particularly low-grade serous ovarian cancer, might partly reflect their indolent nature. Nevertheless, prolonged disease control has been reported with pembrolizumab in ovarian sex cord-stromal tumor, specifically in granulosa cell tumors, where it ranked among the systemic therapies providing the longest disease control \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. All four patients with small cell carcinoma in our study experienced PD as their best response. While ICI have shown benefit in rare small-cell carcinoma cases, durable benefits have been observed with combination involving targeted therapy \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e or dual-immunotherapy \u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. The PembroSCCOHT phase II trial is evaluating pembrolizumab plus the standard PAVEP polychemotherapy in ovarian small-cell carcinoma.\u003c/p\u003e\u003cp\u003eOverall, the PFS rate of 22.6% at 6 months in the intention to treat population, underscores the limited efficacy of ICI monotherapy in rare ovarian cancer patients. The median OS of 18.8 months likely reflects the heterogeneity in survival outcomes, longer in low-grade serous ovarian cancers and worse is aggressive histologies such as carcinosarcoma or small-cell ovarian carcinoma\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. From a safety perspective pembrolizumab\u0026rsquo;s toxicity profile was comparable to previous reports\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIs it noteworthy that ORR at 12 weeks might not be the most efficacy endpoint for ICI \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. The two PRs observed after 12 weeks support extending efficacy assessments over a longer period. Furthermore, PFS should be interpreted in the context of histology-specific natural histories. Additionally, several clinical trials are now investigating immunotherapy combinations in rare ovarian cancers, including dual ICIs, and combination with chemotherapy, anti-angiogenic agents, or targeted therapies\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. The biological determinants of ICI response remain unclear. Upcoming translational research from the AcS\u0026eacute; Pembrolizumab study will explore predictive biomarkers. In particular, common immunotherapy biomarkers are present in a significant proportion of rare ovarian tumors, including tumor infiltrating lymphocytes \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e, alteration in the Switch/Sucrose-Nonfermentable (mSWI/SNF) chromatin-remodeling complexes, such as \u003cem\u003eARID1A\u003c/em\u003e (clear cell carcinoma) and \u003cem\u003eSMARCA4\u003c/em\u003e mutations (small cell carcinoma), and microsatellite instability in endometriosis-associated tumors \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Recent studies have also highlighted new ICI resistance mechanisms in ovarian cancer underscoring the role of the tumor microenvironment in both primary and metastasis\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, and the contribution of macrophage and regulatory T-cells \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. These factors, alongside established biomarkers, should be integrated into the design of future clinical trials and the development of innovative combination strategies.\u003c/p\u003e\u003cp\u003eIn summary, this study demonstrated the feasibility of conducting a clinical trial in rare ovarian cancers, with an acceptable toxicity profile and evidence of potential activity of pembrolizumab, where existing data are scarce. Importantly, international collaborations are essential to evaluate ICIs in a more homogeneous population, enabling robust conclusions that could ultimately inform clinical practice and improve patient outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cu\u003eStudy design and participants\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAcSé Pembrolizumab is a French, single-arm, phase 2, multicohort basket study investigating the activity and safety of pembrolizumab in patients with rare, advanced cancers. For the rare ovarian tumor sub-study cohort, patients were recruited from 22 hospitals in France (Supplementary Table 1). The rare ovarian cancer cohort included 18 years and older women with recurrent or relapsed advanced sex cord-stromal tumor, germ cell tumor (immature teratoma, non seminomatous germ cell and dysgerminoma), low-grade serous carcinoma, mucinous carcinoma, clear cell adenocarcinoma, small cell carcinoma, and carcinosarcoma.\u0026nbsp;Histological confirmation by expert pathologists from the French Rare Gynecological Tumor Group (TMRG) network\u0026nbsp;\u003csup\u003e23\u003c/sup\u003e was realized by central review. Other key inclusion and exclusion criteria are fully detailed in supplementary methods and reported in details previously\u0026nbsp;\u003csup\u003e24\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe trial was sponsored by Unicancer and was approved by French regulatory authorities (April 3, 2017) and the French ethics committee CPP Est IV (March 14, 2017). All patients provided written informed consent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eProcedures\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAll patients received 200 mg intravenous infusion of pembrolizumab every 21 days for a maximum of 24 months (or 35 cycles, whichever was longer), or until disease progression. Early treatment discontinuation or interruption was permitted at the discretion of the investigator or by patient’s initiation for any reason that would have been beneficial to the patient. Treatment was interrupted in the event of any of the toxicities listed in\u0026nbsp;the supplementary methods,\u0026nbsp;intercurrent illness, or changes in the patient’s condition preventing further treatment. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDisease assessments were performed by radiologic imaging (CT scan, MRI, or any other appropriate radiological assessments) every 84 (+/- 7) days. Tumor response treatment according to RECIST v.1.1 was assessed by each investigator. Frequency and severity of adverse events (AEs) were assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for AE (CTCAE). And reported irrespective of their association with pembrolizumab therapy.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eOutcomes\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003ePrimary endpoint was the ORR defined as the proportion of patients with a complete (CR) or partial response (PR) measured at week 12 (+/-7 days) following study treatment initiation.\u003c/p\u003e\n\u003cp\u003eSecondary endpoints included best response to treatment (measured at any disease assessment during the course of the study), response duration (time from first observation of objective response until disease progression or death from any cause), overall survival \u0026nbsp;(OS; time from inclusion until death due to any cause), progression-free survival (PFS; time from inclusion until documented disease progression or death due to any cause, whichever occurred first), and safety evaluation according to the NCI CTCAE v4. Patients alive who had not progressed at the time of analysis were censored at the time of their latest visit.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eStatistical analysis\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eGiven the rarity of the disease, the number of patients to be included was not prespecified and no hypotheses were postulated regarding potential predictors of treatment response. Full details of the statistical analysis are provided in the supplementary methods.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe trial used a two-stage Bayesian enrichment design, specifically intended to guide decision-making within a drug development program.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnalyses were conducted both in the whole rare ovarian cancer cohort and for each histotype subgroup.\u003c/p\u003e\n\u003cp\u003eFrequencies and percentages (qualitative variables), median and interquartile range (IQR) (quantitative variables) were used for the descriptive analyses. Duration of response, OS and PFS estimate, along with their 95% confidence intervals were obtained using the Kaplan-Meier method, with comparisons performed using the log-rank test. Activity and safety analyses were conducted on an intention-to-treat basis. Patients with non-evaluable disease at week 12, withdrew from the study, or evaluated only before the 12-week timepoint were included in the analysis and considered to be non-responders.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll evaluation criteria are reported with a 95% CI computed using the Clopper-Pearson exact method. All p-values are two-sided, with values below 0.05 considered statistically significant. Statistical analyses were performed using SAS version 9.4 and R version 4.0.4 (https ://www.R-project.org/) software packages.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets that support the findings of this study are not publicly available due to information that could compromise research participant consent. According to French and European regulations, any reuse of the data must be approved by the ethical committee CPP Est IV. Each request for access to the dataset will be granted upon reasonable request sent to Unicancer..\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRole of the funding source\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study sponsor (Unicancer) had a role in study design, data collection, data analysis, data interpretation, and writing of the report. The funders of the study (Ligue contre le Cancer, INCa, and MSD) had no role in study design, data collection, data analysis, data interpretation, or writing of the report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the Ligue contre le cancer, INCa, and MSD for their support in the funding of the study. The supply of pembrolizumab was kindly provided by MSD (MSD International, trading as MSD Ireland, Ballydine, County Tipperary, Ireland). We thank all the patients who participated in the study, the investigators who recruited patients, and the clinical and research staff of the Immuno-oncology team at Unicancer (Paris, France)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL. Collet: Formal analysis, validation, investigation, methodology, writing–original draft, writing–review and editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNicolas Penel: Resources, data curation, writing–review and editing.\u003c/p\u003e\n\u003cp\u003eSylvie Chevret: Conceptualization, resources, formal analysis, validation, investigation, methodology, writing–review and editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCamille Moreau-Bachelard: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eFrançois Cherifi: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003ePatrick Soulie: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eDiego Tosi: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eFrancois Bertucci: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eSophie Cousin: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eEsma Saada Bouzid: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eLaurence Gladieff: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eJérôme Alexandre: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eThibault de la Motte Rouge: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eCamille Petrau: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eFrançois Ghiringhelli: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eJean-Christophe Eymard: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eCarole Soussain: resources, data curation, writing–review and editing\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFabien Calcagno: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eMathieu Larroquette: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eValérie Lebrun Ly: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eHeba Dawood: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eHélène Marijon: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eClotilde Simon: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eAssia Lamrani-Ghaouti: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eCaroline Even: resources, data curation, writing–review and editing\u003c/p\u003e\n\u003cp\u003eIsabelle Ray-Coquard: Conceptualization, resources, validation, investigation, methodology, writing–review and editing.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSung H, Ferlay J, Siegel RL, et al. 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Tumor-stroma proportion on primary tumor as a prognostic biomarker in advanced ovarian cancer patients receiving chemo-immunotherapy as first-line therapy: analyses from the NeoPembrOV/GINECO phase II randomized trial. \u003cem\u003eESMO Open\u003c/em\u003e. 2025;10(6):105104. doi:10.1016/j.esmoop.2025.105104\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7752410/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7752410/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRare ovarian cancer is a heterogeneous group of diseases with significant unmet medical needs and low chemotherapy sensitivity. In this context, the AcSé Pembrolizumab (NCT03012620) multicentric, non-randomized, phase II basket trial, assessing pembrolizumab monotherapy in rare tumors has been conducted. We report here the results from the rare ovarian cancer cohort. Primary outcome was the objective response rate (ORR) at week 12.\u003cstrong\u003e \u003c/strong\u003eSecondary endpoints included best ORR, clinical benefit rate, survival and safety. ORR at week 12 was 3.2% (95%CI, 0.4% to 11.2%), with one partial (PR) and one complete response (CR) in a patient with a teratoma with malignant transformation remaining in CR six years after initiating pembrolizumab. Stable disease (SD) was observed in 34% of patients, including one patient with carcinosarcoma maintaining a SD for 33 months. No new safety concerns and no deaths related to pembrolizumab were observed. Pembrolizumab in rare ovarian tumor subtypes showed limited ORR but promising long-term benefit in selected patients were observed.\u003c/p\u003e","manuscriptTitle":"Pembrolizumab in patients with rare ovarian cancers : analysis from AcSé Pembrolizumab phase II multicentric basket trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-05 11:42:29","doi":"10.21203/rs.3.rs-7752410/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"599c4e54-3819-4fd5-8b98-db7696ed64a0","owner":[],"postedDate":"October 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":55714005,"name":"Health sciences/Oncology"},{"id":55714006,"name":"Health sciences/Oncology/Cancer"},{"id":55714007,"name":"Biological sciences/Cancer/Gynaecological cancer/Ovarian cancer"}],"tags":[],"updatedAt":"2025-12-03T16:39:39+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-05 11:42:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7752410","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7752410","identity":"rs-7752410","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}