Advanced Recurrent Ovarian Cancer Research Articles

Oncolytic adenovirus MEM-288 encoding membrane-stable CD40L and IFNβ induces an anti-tumor immune response in high grade serous ovarian cancer

Single agent immune checkpoint inhibitors have been ineffective for patients with advanced stage and recurrent high grade serous ovarian cancer (HGSOC). Using pre-clinical models of HGSOC, we evaluated the anti-tumor and immune stimulatory effects of an oncolytic adenovirus, MEM-288. This conditionally replicative virus encodes a modified membrane stable CD40L and IFNβ. We demonstrated this virus successfully infects HGSOC cell lines and primary human ascites samples in vitro. We evaluated the anti-tumor and immunostimulatory activity in vivo in immune competent mouse models. Intraperitoneal delivery of MEM-288 decreased ascites and solid tumor burden compared to controls, and treatment generated a systemic anti-tumor immune response. The tumor microenvironment had a higher proportion of anti-tumor macrophages and decreased markers of angiogenesis. MEM-288 is a promising immunotherapy agent in HGSOC, with further pre-clinical studies required to understand the mechanism of action in the peritoneal microenvironment and clinical activity in combination with other therapies.

Effects of niraparib dose reduction on short-term outcomes in ovarian cancer patients

ObjectivesDespite the individualized starting dose for maintenance therapy in ovarian cancer, the niraparib dose reduction rate remains high. The aim of this study was to evaluate the impact of niraparib...

Reflections on the changes in ascites and serum VEGF1 levels before and after intraperitoneal infusion of bevacizumab.

e17539 Background: This study analyzes the levels of VEGF1 in ascites and serum before and after intraperitoneal infusion of bevacizumab, aiming to explore the optimal administration route for treating recurrent ovarian cancer accompanied by ascites. Methods: Sixty-seven patients with advanced recurrent ovarian cancer and significant ascites were treated with intraperitoneal infusion of bevacizumab combined with chemotherapy. Under ultrasound guidance, a peritoneal drainage tube was placed, and the volume of ascites was measured before the infusion. The effects of the treatment were assessed by measuring the ascites volume during the 2nd to 3rd treatment (final ascites drainage) and by analyzing and comparing the levels of Vascular Endothelial Growth Factor 1 (VEGF1) in both ascites and serum. Results: The average volumes of ascites before and after treatment were 4229.97 ml and 5.42 ml, respectively (P<0.0001), with an overall response rate (ORR) of 89.6% (60/67). Before and after treatment, the levels of VEGF1 in ascites were 283.86 pg/mL and 18.76 pg/mL, respectively (P<0.0001). Before and after treatment, serum levels of VEGF1 were 80.67 pg/mL and 61.25 pg/mL, respectively (P<0.0001). Before treatment, the level of VEGF1 in ascites at 283.86 pg/mL was significantly higher than in serum, which was 80.67 pg/mL (P<0.0001). The reduction in VEGF1 levels following intraperitoneal infusion was over tenfold greater in serum compared to ascites. When the cutoff value for VEGF1 in ascites was set at 37.12 pg/mL, the sensitivity was 80.28%, and the specificity was 91.55%. Conclusions: The combined treatment of intraperitoneal infusion of bevacizumab with chemotherapy is an effective strategy for controlling ascites in recurrent ovarian cancer. Keywords: Bevacizumab, Intraperitoneal Infusion, Recurrent Ovarian Cancer, Ascites, Vascular Endothelial Growth Factor 1 (VEGF1).

A real-world, patient-reported outcomes study in patients with platinum-sensitive recurrent ovarian cancer receiving long-term maintenance therapy with niraparib.

e23164 Background: Niraparib has been approved for the maintenance treatment of newly diagnosed advanced and platinum-sensitive recurrent ovarian cancer (PSR OC). The phase 3 PRIMA and NOVA studies showed that maintenance niraparib did not worsen quality of life (QoL) compared with placebo. However, no QoL data have been reported for Asian OC patients treated with niraparib. Here, we report patient-reported outcomes (PROs) for PSR OC patients who received niraparib as maintenance therapy for more than two years in a real-world setting. Methods: This prospective, real-world study included OC patients participating in the Niraparib Patient Assistance Program (PAP) in China (NCT06037213). Eligible patients had histologically confirmed PSR epithelial OC, fallopian tube, or primary peritoneal cancer, had been maintained on niraparib for more than two years without disease progression and were still receiving niraparib within 28 days. PROs were assessed every 4-6 weeks for three times using the EQ-5D-5L questionnaire and the FOSI. In addition, a 6-question niraparib medication questionnaire including starting dose, adaptive dose, dose adjustments and reasons, missed doses, concomitant medications was administered at baseline. Results: The PAP enrolled 3154 PSR OC patients, 1151 had been on niraparib for more than two years and could be followed up. From August 2023 to January 2024, 604 eligible patients were recruited and completed at least one assessment. The median age was 58 years (range, 27-82 years). The median duration of treatment with niraparib was 34.8 months (range, 30.5-46.7 months). Among 445 patients with BRCAm status, 104 were BRCAm (23.4%) and 341 were BRCAwt (76.6%). A total of 491 patients (81.3%) received niraparib 200 mg as a starting dose, while 107 (17.7%) required dose adjustments in clinical practice. Presently, 503 (83.3%) were on 200mg. 523 (86.6%) were compliant with the daily oral dose of niraparib, without missing any doses in the previous 6 months. 193 patients (32.0%) had common chronic disease, and 176 (29.1%) were taking concomitant medications during maintenance. The EQ-5D-5L HUI and VAS scores remained stable across the three assessments. The baseline mean EQ-5D-5L HUI and VAS scores were 0.98 (SD 0.05) and 84.31 (SD 10.50), respectively, and the least squares (LS) mean changes from baseline to the third assessment were -0.004 (SE 0.001) and -0.609 (SE 0.248), respectively. A similar situation was observed for the FOSI score. The baseline mean FOSI score was 31.13 (SD 1.37), and the LS mean change from baseline to the third assessment was -0.359 (SE 0.033). Conclusions: In the real world, patients with PSR OC who underwent long-term maintenance treatment with niraparib exhibited a consistently stable QoL. This finding highlights the significant clinical value of niraparib in maintaining QoL in these populations.

The role of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) as second-line debulking in advanced ovarian cancer patients. A meta-analysis

Purpose: Ovarian cancer, as a type of gynecological cancer with one of the highest morbidity and recurrence rates, has been the burning issue for modern research. With new therapeutic methods coming to light, the focus on the promising Hyperthermic Intraperitoneal Chemotherapy (HIPEC) has raised questions about its efficacy on patients’ overall survival (OS) and post-surgical quality of life. Methods: A meta-analysis was performed in order to estimate the role of HIPEC in advanced ovarian cancer, concentrating, among others, on the following quality of life. After thorough research on the PubMed and Cochrane databases, using the terms ‘HIPEC, ovarian cancer’, as well as decoding the results on the last decade, a total of nine articles were selected for this purpose. Results: Data decoding revealed a notorious improvement of OS of the cytoreductive surgery (CRS) plus HIPEC versus the CRS arm at 1, 3, 4 and 5 years respectively; (OR 1.10; 95% CI, 0.85-1.43), (OR 1.53; 95% CI, 1.12-2.10), (OR 1.70; 95% CI, 1.03-2.81), (OR 1.22; 95% CI, 0.77-1.95). At 2 years, the collected data depicted a small worsening in OS (OR 0.92; 95% CI, 0.70-1.19). Conclusion: HIPEC, in spite of its recent innovative nature, has already given positive signs for ovarian cancer therapeutic mapping. Objective of the conducted study focuses on investigating its reflection in advanced stages and recurrent ovarian cancer lesions, respectively.

Factors Effecting on Hyperthermic Intraperitoneal Chemotherapy in Advanced Recurrent Ovarian Cancer

Amaç: Hipertermik intraperitoneal kemoterapi (HİPEK), ileri evre over kanserlerinde uygulanan tedavi yöntemidir. Isı ile birlikte kanser ilaçlarının doğrudan periton içerisine verilerek sitoredüktif cerrahi ile birlikte peritoneal metastazların kontrolünü amaçlar. Çalışmamızda ileri evre over kanseri tanısı alıp primer sitoredüktif cerrahi ile tedavi edilen ve nüks sonrası sekonder sitoredüksiyon + HİPEK uygulaması ile tedavi edilen hastaların ilk tedavi sırasındaki klinikopatolojik özellikleri ile sağkalım arasındaki ilişkiyi incelemeyi amaçlamaktadır
 Gereç ve Yöntem: İleri evre over kanserinin primer tedavisi sonrası nüks tespit edilen ve sekonder sitoredüktif cerrahi ve beraberinde HİPEK ile tedavi edilen hastalar retrospektif olarak incelenmiştir. Hastaların demografik özellikleri, evreleri, laboratuvar ve klinik seyirleri retrospektif olarak incelenmiştir. 
 Bulgular: HİPEK ile tedavi edilen toplam 29 nüks ileri evre over kanseri hastası dahil edilmiştir. Primer cerrahi sırasında sekiz olguda R0, 20 olguda R1 ve bir hastada R2 rezeksiyon mevcuttur.. R0 rezeksiyon uygulanan hastalarda istatistiksel olarak anlamlı şekilde daha yüksek sağkalım oranı gözlenmiştir (p

Cytoreductive surgery and perioperative intraperitoneal chemotherapy in recurrent ovarian cancer: 18 years of experience

AimTo identify the clinical and pathological factors associated with relapse in women who had undergone secondary cytoreductive surgery due to locally advanced recurrent ovarian cancer. MethodsWomen with locally advanced recurrent ovarian cancer who had undergone cytoreduction between 2000 and 2018 were included in this study. Demographic, clinical and biochemical intraoperative findings were recorded for each woman. All factors were assessed in order to identify which correlated with the outcomes of interest (i.e. disease relapse, mortality and morbidity). ResultsIn total, 181 women who had undergone secondary cytoreduction were analysed. The hospital mortality rate was 1.7 % (n = 3) and the morbidity rate was 32.1 % (n = 58). Recurrence was recorded in 101 (55.8 %) women. Infiltration of large bowel lymph nodes was a negative prognostic indicator of morbidity (p = 0.029). A prior surgical score of 1 (PSS-1) [odds ratio (OR) 0.465] and complete cytoreduction (OR 0.518) were found to be significant independent predictors for disease relapse. Median overall survival was greater for patients with PSS-1 (151.3 vs 59.4 vs 44.1 months; p = 0.049) and patients with complete cytoreduction (137.6 vs 36.2 vs 10.0 vs 27.4 months; p < 0.001). ConclusionComplete cytoreduction and PSS-1 are associated with reduced disease relapse and increased overall survival. Infiltration of large bowel lymph nodes is associated with increased morbidity.

Molecular determinants of clinical outcomes of pembrolizumab in recurrent ovarian cancer: Exploratory analysis of KEYNOTE-100

ObjectiveThis prespecified exploratory analysis evaluated the association of gene expression signatures, tumor mutational burden (TMB), and multiplex immunohistochemistry (mIHC) tumor microenvironment–associated cell phenotypes with clinical outcomes of pembrolizumab in advanced recurrent ovarian cancer (ROC) from the phase II KEYNOTE-100 study. MethodsPembrolizumab-treated patients with evaluable RNA-sequencing (n = 317), whole exome sequencing (n = 293), or select mIHC (n = 125) data were evaluated. The association between outcomes (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) and gene expression signatures (T-cell–inflamed gene expression profile [TcellinfGEP] and 10 non-TcellinfGEP signatures), TMB, and prespecified mIHC cell phenotype densities as continuous variables was evaluated using logistic (ORR) and Cox proportional hazards regression (PFS; OS). One-sided p-values were calculated at prespecified α = 0.05 for TcellinfGEP, TMB, and mIHC cell phenotypes and at α = 0.10 for non-TcellinfGEP signatures; all but TcellinfGEP and TMB were adjusted for multiplicity. ResultsNo evidence of associations between ORR and key axes of gene expression was observed. Negative associations were observed between outcomes and TcellinfGEP-adjusted glycolysis (PFS, adjusted-p = 0.019; OS, adjusted-p = 0.085) and hypoxia (PFS, adjusted-p = 0.064) signatures. TMB as a continuous variable was not associated with outcomes (p > 0.05). Positive associations were observed between densities of myeloid cell phenotypes CD11c+ and CD11c+/MHCII−/CD163−/CD68− in the tumor compartment and ORR (adjusted-p = 0.025 and 0.013, respectively). ConclusionsThis exploratory analysis in advanced ROC did not find evidence for associations between gene expression signatures and outcomes of pembrolizumab. mIHC analysis suggests CD11c+ and CD11c+/MHCII−/CD163−/CD68− phenotypes representing myeloid cell populations may be associated with improved outcomes with pembrolizumab in advanced ROC.Clinical trial registration: ClinicalTrials.gov, NCT02674061.

Complications of HIPEC for ovarian cancer surgery: evaluation over two time periods

ObjectiveCytoreductive surgery in conjunction with hyperthermic intraperitoneal chemotherapy (HIPEC) is being explored in the upfront, interval, and recurrent setting in patients with ovarian cancer. The objective of this systematic review...

Abstract 2274: An immune-educating therapy, Maveropepimut-S, elicits a diverse and active anti-tumor T cell response in patients with advanced recurrent ovarian cancer

Abstract Maveropepimut-S (MVP-S) is a T cell activating immunotherapy designed within the novel DPX® immune delivery platform. MVP-S is comprised of 5 HLA class I peptides from the tumor antigen, survivin, along with the A16L T helper peptide, and the innate immune activator, polydIdC. Analysis of PBMCs collected from advanced recurrent ovarian cancer patients treated with MVP-S based therapy in the DeCidE1 trial (NCT02785250) showed robust survivin-specific T cell induction that persisted in some patients up to 420 days. Herein, we analyzed the T cell repertoires of pre- and on-treatment (on-Tx) tumor biopsies from these patients to further investigate the fate of T cells elicited by the MVP-S based therapy. Analysis of the T cell receptor beta (TCRβ) sequences revealed that MVP-S treatment actively promotes the infiltration of a new, diverse T cell repertoire with 51.6% to 94.9% new clones recruited to the on-Tx tumors. These novel clones cumulatively comprise 29.8% to 90.5% of the total intra-tumoral T cell population. Profiling of patients achieving partial response (by RECISTv1.1) versus those achieving only progressive disease indicated an increase in clonal diversity, with reduction in clonal domination, in the on-Tx tumors, suggestive of epitope spreading in these responsive patients. To evaluate frequency of survivin-specific T cells within the tumor tissue, a library of survivin-specific T cell clonotypes was prepared using in vitro expanded and sorted PBMCs. Across 33 patients of various clinical outcomes and timepoints, 309 unique, survivin-specific clones were identified. Clonotypes were found to be strongly subject-specific with very limited overlap across subjects. TCRβ sequences of circulating survivin-specific T cells were compared with TCβ repertoire in the tumor biopsies to determine clonal sequence overlap. Sixty-four of the identified survivin-specific clones (20.7%) were found in tumor samples (pre- and on-treatment); of these, 71.9% (46/64) were detected in on-treatment samples only, compared to 12.5% (8/64) in pre-treatment samples only. Importantly, survivin-specific clones were recurrently found within the top 1-10% of the most frequent clones in the on-treatment tumoral T cell population, suggesting that MVP-S therapy promoted strong enrichment and expansion of survivin-specific T cells within tumour tissue. These data indicate that treatment of advanced recurrent ovarian cancer patients with MVP-S based therapy induced robust, persistent survivin-specific T cells that were detected in circulation up to 420 days. These de novo elicited T cells were demonstrated to migrate into tumor tissues, where MVP-S therapy promoted reinvigoration of the total T cell population with new highly diverse clones including strong expansion of survivin-specific T cells. Citation Format: Kelcey Patterson, Barry Kennedy, Walead Ebrahimizadeh, Aurelio Lobo, Heather Hirsch, Heather Torrey, Valarmathy Kaliaperumal, Lisa MacDonald, Jeremy Graff, Stephan Fiset, Olga Hrytsenko. An immune-educating therapy, Maveropepimut-S, elicits a diverse and active anti-tumor T cell response in patients with advanced recurrent ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2274.

Observation of the therapeutic effect of apatinib in advanced platinum-resistant recurrent epithelial ovarian cancer

BackgroundApatinib is an oral anti-angiogenic drug that mainly targets vascular endothelial growth factor receptor 2 (VEGFR-2) and is widely used in a variety of solid tumours. The purpose of this study is to evaluate the clinical efficacy and safety of apatinib in patients with advanced platinum-resistant relapsed epithelial ovarian cancer (EOC).MethodsA retrospective analysis was performed, the clinical data of patients with stage IIIC-IV platinum-resistant relapsed EOC between January 2014 and May 2018 were collected. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were reviewed and evaluated. The propensity score matching (PSM) method was used to determine the final case data included in this study.ResultsAccording to 1:2 propensity matching, 108 patients were finally taken into account: 36 in the apatinib group and 72 in the control group. The follow-up ended in January 2019, and the median follow-up time was 28 months. In the apatinib group, ORR was 30.56% and DCR was 66.67%, whereas in the control group, ORR was 16.67% and DCR was 44.44%. In the apatinib group, median PFS was 6.0 months (95% CI 3.69–8.31) and median OS was 15.8 months (95% CI 6.99–24.6), while in the control group, median PFS was 3.3 months (95% CI 2.44–4.16) and median OS was 9.2 months (95% CI 6.3–12.06); the difference was statistically significant (P < 0.05). Apatinib was more effective than conventional chemotherapy in reducing the risk of PFS [HR 0.40 (95% CI 0.22–0.76), P = 0.0017] and OS [HR 0.40 (95% CI 0.21–0.73), P = 0.002]. Multivariate Cox analysis showed that the course of treatment and decrease in serum CA125 levels are independent risk factors for PFS in patients, while apatinib, the length of treatment course and the location of the lesion are independent risk factors for recurrence affecting the OS of patients. The main grade 3–4 adverse events in the apatinib group were hypertension, hand-foot syndrome, and oral mucosal ulcers, and all adverse events were controllable.ConclusionApatinib was found to be both safe and effective in patients with advanced platinum-resistant relapsed EOC. More in-depth clinical research and applications should be carried out.

Efficacy and safety of apatinib in the treatment of advanced platinum-resistant recurrent epithelial ovarian cancer: A retrospective study.

e17594 Background: Apatinib is an oral anti-angiogenic drug that mainly targets vascular endothelial growth factor receptor 2 (VEGFR-2) and is widely used in a variety of solid tumours. The purpose of this study is to evaluate the clinical efficacy and safety of apatinib in patients with advanced platinum-resistant relapsed epithelial ovarian cancer (EOC). Methods: This study retrospectively analyzed the clinical data of patients with stage IIIC-IV platinum-resistant relapsed EOC between January 2014 and May 2018. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were reviewed and evaluated. The propensity score matching (PSM) method was used to determine the data included in this study of the final case. Results: This study included 36 patients in the apatinib group and 72 patients in the control group, according to the 1:2 propensity matching. The follow-up ended in January 2019, and the median follow-up time was 28 months. The ORR was 30.56% in the apatinib group and 16.67% in the control group. The DCR in both cohorts was 66.67% and 44.44%, respectively. The median PFS (6.0 vs. 3.3 months) and OS (15.8 vs. 9.2 months) in the apatinib group were significantly longer than that in the control group. In addition, apatinib was more effective than conventional chemotherapy in reducing the risk of PFS [HR 0.40 (95% CI 0.22-0.76), P = 0.0017] and OS [HR 0.40 (95% CI 0.21-0.73), P = 0.002]. Multivariate Cox analysis showed that the course of treatment and decrease in serum CA125 levels are independent risk factors for PFS in patients, while for apatinib, the length of treatment course and the location of the lesion are independent risk factors for recurrence that affects the OS of patients. The most common grade 3/4 toxicities in the apatinib group were hypertension, hand-foot syndrome, and oral mucosal ulcers. Conclusions: Apatinib therapy was an effective treatment for patients with advanced platinum-resistant relapsed EOC. The toxicities were tolerable and manageable.

Optimizing regional chemotherapy for epithelial ovarian cancer.

The response with intravenous chemotherapy using cisplatin and paclitaxel in patients with advanced ovarian cancer is often substantial. However, this regression of the malignancy is not durable, and a majority of patients succumb to this disease process. It is possible that alternative types of chemotherapy and alternative routes of chemotherapy administration can improve the results of treatment and perhaps, reduce the morbidity and mortality that patients experience. Regional chemotherapy treatments previously presented in the ovarian cancer literature were reviewed and critically analyzed. New methods for chemotherapy delivery for both advanced primary and recurrent ovarian cancer were reviewed. This included hyperthermic intraperitoneal chemotherapy (HIPEC), early postoperative intraperitoneal chemotherapy (EPIC), and normothermic intraperitoneal chemotherapy (NIPEC) long-term. An important addition to perioperative chemotherapy delivery is the simultaneous use of heat with intraperitoneal drug delivery after a complete cytoreductive surgery. Drugs to be considered for HIPEC are cisplatin, gemcitabine, and melphalan. For EPIC, chemotherapy agents to consider include paclitaxel, pemetrexed, gemcitabine, and liposomal doxorubicin. For NIPEC, paclitaxel is the drug of choice usually combined with a systemic agent as bidirectional chemotherapy. Also, pemetrexed, gemcitabine, and liposomal doxorubicin are drugs to be considered for NIPEC in phase I/II trials. Innovative regimens of regional chemotherapy may improve the outcome of patients with advanced ovarian cancer. These chemotherapy treatments must be integrated with complete cytoreductive surgery and the availability of peritoneal access for repeated delivery of chemotherapy solutions.

Effects of carboplatin combined with paclitaxel-based intraperitoneal hyperthermic perfusion chemotherapy on serum levels of HE4 and DJ-1 in patients with advanced recurrent ovarian cancer.

Objective:To analyze the effects of carboplatin combined with paclitaxel-based intraperitoneal hyperthermic perfusion chemotherapy (IPCH) on serum levels of human epididymis protein 4 (HE4) and mitogen-dependent oncogene-1 (DJ-1) in patients with advanced recurrent ovarian cancer (OC).Methods:From July 2019 to July 2020, patients with advanced recurrent OC (n=92) treated in Affiliated Hospital of Hebei Engineering University were selected as study subjects. According to the random number table method, patients were divided into control group and observation group. Patients in the control group were treated with carboplatin combined with paclitaxel-based intravenous chemotherapy, and patients in the observation group were treated with carboplatin combined with paclitaxel-based IPCH. The therapeutic effects, serum levels of HE4, DJ-1 and human kallikrein 10 (HK-10), peripheral blood immune indexes and adverse reactions of patients were compared between the two groups.Results:The response rate of the observation group was significantly higher than that of the control group (p<0.05); after treatment, the indexes of HE4, DJ-1 and HK-10 in the two groups were significantly decreased, while the indexes of CD3+CD4+, CD3+CD56+ and CD3+CD4+/CD3+CD8+ were significantly increased; moreover, significantly lower indexes of HE4, DJ-1 and HK-10 and significantly higher indexes of CD3+CD4+, CD3+CD56+ and CD3+CD4+/CD3+CD8+ were found in the observation group when compared with the control group (p<0.05). The severity of myelosuppression, nausea and vomiting in the observation group was significantly lower than that in the control group, and the total tumor metastasis rate in the observation group was significantly lower than that in the control group (p<0.05).Conclusions:Carboplatin combined with paclitaxel IPCH had obvious inhibitory effects on HE4, DJ-1 and other serum tumor markers in patients with advanced recurrent OC, with a more prominent clinical effect, and could further significantly reduce the risk of adverse reactions and metastasis.

733P Bevacizumab (Bev), olaparib (Ola) and durvalumab (Durva) in patients with recurrent advanced ovarian cancer (AOC): The GINECO BOLD study

In high-grade AOC patients, the combination of immunotherapy, PARP inhibitors (PARPi), and antiangiogenic agents, may enhance the efficacy of each treatment. Different chemotherapy-free combinations were previously found to be feasible. A significant activity of the Durva + Ola +/- Bev combination was reported in platinum-sensitive recurrent (PSR) AOC in the MEDIOLA trial. However the efficacy of the triplet in platinum resistant relapse (PRR) has never been assessed.

Phosphoproteomic response mapping to anti-angiogenic agents bevacizumab and cediranib in high-grade serous ovarian and endometrial cancer cell lines

<h3>Objectives:</h3> Antiangiogenics have become a cornerstone of treatment in advanced stage and recurrent high grade serous ovarian cancer. Both cediranib (ICON6) and bevacizumab (ICON7, GOG218) have demonstrated benefit as a maintenance treatment for ovarian cancer patients in clinical trials. Investigators have also explored their role in advanced stage and recurrent endometrial carcinoma (MITO-END 2, Rose 2017, Aghajanian 2011). There have been no head to head trials in gynecologic cancers comparing cediranib to bevacizumab, although in colorectal carcinoma, phase III data suggests equivalent efficacy (HORIZON III). We hypothesize that these drugs, although both categorized as anti-angiogenics, induce unique cellular responses and sought to explore the varying impact of each agent on cell signaling using established serous cell models. <h3>Methods:</h3> CAOV3 ovarian cancer cells and Hec50 endometrial cancer cells were exposed to 1µM bevacizumab or cediranib for 24 hours. Cell lysates were analyzed in duplicate using an antibody-based phosphoproteomic array of 875 phosphoproteins supplied by Kinexus Bioinformatics (Vancouver, BC). Priority signaling effects were defined for each drug and in each cell line as those with a significant (>75%) change from control with an acceptable sum of error (<75%). <h3>Results:</h3> Bevacizumab yielded 13 total leads, and cediranib yielded 9 in CAOV3 ovarian cancer cells (Table 1). Both agents significantly enhanced signaling events on the following epitopes: ABl, EZH2, HGK (2 sites), and IGF1R, indicating that these may be some of the core cellular effects of anti-angiogenic agents. Interestingly, all common leads induced by both agents in CAOV3 cells represent potential pro-oncogenic effects. In Hec50 cells (Table 1), both cediranib and bevacizumab treatment induced a unique set of phosphoproteins compared to the effects of these agents in CAOV3 cells, yet common findings were the phosphorylation of IGFR1 by bevacizumab and the activation of alternative MAP kinases in both cell lines. <h3>Conclusions:</h3> Angiogenesis plays a crucial role in tumor development and metastasis. Blocking angiogenesis using monoclonal antibodies such as bevacizumab or tyrosine kinase inhibitors such as cediranib is a strategy that is proving to be helpful in the care of patients with gynecologic malignancies. These molecular agents have both on-target, therapeutic effects but also may induce pathways of resistance. In these comprehensive phosphoproteomic mapping studies, we noted the activation of signaling pathways which were cell and drug specific. One consistent finding was the enhanced phosphorylation of IGFR1 and alternative MAP kinases that may portend eventual drug resistance.

The use of bevacizumab is correlated with improved post-progression survival in advanced recurrent ovarian cancer.

The recent improvements in anti-cancer therapy following first-line treatment can potentially impact post-progression survival. We evaluated the factors that influence post-progression survival in advanced recurrent ovarian cancer. Eighty-nine patients who underwent first-line treatment between June 2005 and December 2017 were included. The post-progression survival was defined as the difference between overall survival and initial progression-free survival. The effects of age, histology, stage, optimal surgery, secondary debulking surgery, bevacizumab administration, platinum sensitivity, and olaparib maintenance in recurrence were compared and independent risk factors were determined. The median follow-up duration was 60.0months (range: 2-181). Platinum-sensitive recurrence had longer post-progression survival than platinum-resistant (P<0.001). Inclusion of bevacizumab in first-line treatment did not produce a significant difference in post-progression survival (P=0.462). Secondary debulking surgery (P=0.013), bevacizumab administration (P<0.001), and olaparib maintenance (P=0.001) during recurrence increased post-progression survival. In multivariate analysis, histologies other than serous or endometrioid (hazard ratio=2.389; 95% confidence interval=1.200-4.754; P=0.013) and non-bevacizumab usage in recurrence (hazard ratio=4.484; 95% confidence interval=1.939-10.370; P<0.001) were independently correlated with poorer prognosis. Bevacizumab administration beyond progressive disease elicited improved post-progression survival (P<0.001). In patients receiving bevacizumab in first-line treatment, exclusion of bevacizumab in the recurrent therapy (hazard ratio=5.507; 95% confidence interval=2.301-12.124; P<0.001) was independently correlated with poorer prognosis. The continuous use of bevacizumab beyond progressive disease improves post-progression survival suggesting its important role in first-line and recurrence treatment for ovarian cancer.

Anlotinib in combination with TQB2450 in patients with recurrent ovarian cancer (ACTION): A multicenter, single-arm, open-label, phase Ib trial.

5557 Background: Combination of antiangiogenic therapy and immune checkpoint inhibitor therapy is reported as an effective antitumor strategy. TQB2450 is a humanized IgG1 monoclonal antibody against programmed death-ligand 1 (PD-L1). We aimed to assess the activity and safety of TQB2450 plus the antiangiogenic multi-target tyrosine kinase inhibitor anlotinib in patients with recurrent advanced ovarian cancer. Methods: The study with ClinicalTrials.gov identifier NCT04236362 is an open-label, multicohort, and multicenter phase Ib trial evaluating the efficacy and safety of anlotinib combined with TQB2450 in patients with advanced gynecologic cancer. The present study (ACTION study) reports the ovarian cancer cohort. We enrolled patients aged 18–70 years with platinum-resistant or platinum-refractory epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST). Eligible patients received anlotinib 12 mg per day orally on days 1 to 14 and TQB2450 1200 mg intravenously on day 1, every three weeks. Treatment continued until disease progression, unacceptable toxicity, and withdrawal of consent. The primary endpoint was objective response rate (ORR) assessed by investigators according to RECIST version 1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. Results: Between 21 Feb 2020 and 15 Jan 2021, 33 patients with a median age of 55 years (range, 26-71) were enrolled and received study treatment. Patients had received at least once platinum-based chemotherapy, and the median number of previous chemotherapy lines was 3 (range, 1–6). 30.3% patients had bevacizumab therapy before enrollment. At data cutoff (15 Jan 2021), the median follow-up was 5.1 months (range, 0.1–10.8). In the 25 efficacy-evaluable patients, 13 of them achieved partial response, yielding the ORR of 52.0% (95% CI, 30.4%–71.6%). The median PFS was 6.7 months (95% CI, 4.5 months to not reached). The median duration of response and the median OS were not reached. The treatment-related grade 3 or 4 adverse events (AEs) occurred in 54.5% patients, and the most common ones were palmar-plantar erythrodysesthesia syndrome (21.2%) and hypertension (18.2%). The most potential immune-related AEs included grade 1 to 2 hypothyroidism (24.2%) and fatigue (9.1%). No treatment-related death was recorded. Conclusions: Anlotinib plus TQB2450 showed encouraging antitumor activity and tolerable toxicity in patients with recurrent advanced ovarian cancer. Clinical trial information: NCT04236362.

Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer.

BackgroundAs with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment.MethodsPatient data for multiple cardiac‐related treatment‐emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231).ResultsMultivariate analyses on pooled trabectedin data revealed that cardiovascular medical history (risk ratio [RR (95% CI)]: 1.90 [1.24‐2.91]; p = 0.003) and age ≥65 years (RR [95% CI]: 1.78 [1.12‐2.83]; p = 0.014) were associated with increased risk for cTEAEs. Multivariate analyses showed increased risk of experiencing cTEAEs with T+PLD compared to PLD monotherapy (RR [95% CI]: 2.70 [1.75‐4.17]; p < 0.0001) and with history of prior cardiac medication (RR [95% CI]: 1.88 [1.16‐3.05]; p = 0.010).ConclusionsFor patients with STS or ROC who still have limited treatment options, trabectedin may be initiated after carefully considering benefit versus risk. Trial Registration (ClinicalTrials.gov): NCT01343277; NCT00113607; NCT01846611.

Risk factors of pleural effusion after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in late-stage and recurrent ovarian cancer.

Pleural effusion (PE) is one of the most common complications of advanced recurrent ovarian cancer. However, no studies have revealed the risk factors for PE after surgery. The purpose of this study is to observe the incidence and risk factors of PE after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with late-stage and recurrent ovarian cancer. A retrospective analysis of 77 patients with late-stage and recurrent ovarian cancer after CRS + HIPEC was conducted. According to the presence of PE within 7 days after operation, two groups were formed. The basic information, surgical process, and laboratory examinations of the two groups were analyzed and compared to conduct a regression analysis. The incidence of postoperative PE was 57.1% (44/77 patients). Among these patients, the prevalence of grade I-II and grade III-IV PE was 42.8% (33/77 patients) and 14.3% (11/77 patients), respectively. There were statistically significant differences between the two groups in terms of preoperative PE, the duration of surgery, intraoperative blood loss, postoperative level of albumin, intestinal involvement, and diaphragmatic involvement. Among these, preoperative PE and diaphragmatic involvement were identified as independent risk factors of postoperative PE. Patients with late-stage and recurrent ovarian cancer invariably develop postoperative PE after CRS + HIPEC. Preoperative PE and diaphragmatic involvement are independent risk factors of postoperative PE. It is estimated that the incidence of postoperative PE among patients with these two independent risk factors is approximately 100%. Hence, we should promote the prevention and treatment of PE to improve its prognosis.