Anti-angiogenesis Therapy Research Articles

Real-world effectiveness of first- and second-line anti-angiogenesis therapy in RCC: analysis of a UK-based population.

Aim: Renal cell carcinoma (RCC) is the seventh commonest cancer in the UK, where first-line (1L) sunitinib and second-line (2L) axitinib are treatment options.Methods: Retrospective, non-interventional data from the Christie NHS Foundation Trust (Manchester, UK). The primary end point was median progression-free survival (mPFS).Results: For 1L sunitinib (n=622) and 2L axitinib (n=121), mPFS (95% CI) was 8.4 (7.6, 9.9) and 6.2 (4.9, 9.3) months, respectively. In 1L, Karnofsky performance status, lactate dehydrogenase (LDH), neutrophils, hemoglobin, time from diagnosis to treatment and age were predictors (p<0.05) of PFS. In 2L, LDH and platelets were predictors of PFS (p<0.05).Conclusion: Sunitinib and axitinib were effective treatments for RCC. PFS predictors varied between 1L and 2L; LDH was a predictor for both.Clinical Trial Registration: NCT04033991 (ClinicalTrials.gov).

P4.11E.09 The Efficacy of PD-1/PD-L1 Inhibitors Combined with Chemotherapy and Anti-Angiogenesis Therapy in Driver Gene-Negative NSCLC Brain Metastases

P4.11E.09 The Efficacy of PD-1/PD-L1 Inhibitors Combined with Chemotherapy and Anti-Angiogenesis Therapy in Driver Gene-Negative NSCLC Brain Metastases

Patterns of failure and the subsequent treatment after progression on first-line immunotherapy monotherapy in advanced non-small cell lung cancer: a retrospective study

BackgroundImmune checkpoint inhibitors (ICIs) have become the recommended first-line treatment for advanced non-small cell lung cancer (NSCLC) without driver gene mutations. However, data on the failure patterns of first-line ICIs monotherapy is limited, and the optimal strategy for subsequent treatment remains controversial.MethodsAdvanced NSCLC patients receiving first-line ICIs monotherapy at Guangdong Lung Cancer Institute between December 2017 and October 2021 were identified. The progressive sites were recorded to analyze failure patterns. Post-progression survival (PPS) was compared between different treatment regimens.ResultsA total of 121 patients receiving first-line ICIs monotherapy were identified, with a median progression-free survival of 8.6 months. Sixty-five patients had available imaging at diagnosis as well as progressive disease, with 56.9% showing oligoprogression. For those with progression in existing lesions, the most common sites were the liver (77.8%) and lung parenchyma (62.5%), while progression with new lesions frequently occurred in the liver (32.0%). Fifty patients with recorded subsequent treatment were included in the analysis of subsequent treatment patterns. Patients treated with anti-angiogenesis therapy could get better PPS (HR: 0.275, P = 0.013). Isolated oligoprogression occurred most often in the lung parenchyma and intracranial lesions. More than half of these patients continued immunotherapy after local treatment, with a 2.5-year PPS rate of 51.4%.ConclusionThe liver was the most common site of progression on first-line ICIs monotherapy. Anti-angiogenesis-based therapy might be an optimal regimen at the time of progression. Patients with isolated oligoprogressive could still benefit from immunotherapy after local treatment.

Enhancing outcomes in extensive-stage small cell lung cancer brain metastases: a retrospective study on the synergistic effects of immune checkpoint inhibitor, brain radiotherapy, and chemotherapy.

Brain metastasis is a frequent complication in small cell lung cancer (SCLC), and there is an urgent need for new treatment modalities, given the limited success of traditional approaches. This study evaluates the combined efficacy and safety of brain radiotherapy (BRT), chemotherapy, and immune checkpoint inhibitors (ICIs) in the treatment of brain metastases in patients with extensive-stage SCLC (ES-SCLC). Additionally, it seeks to identify prognostic factors in these cases. A retrospective analysis was performed on 187 patients with ES-SCLC and brain metastases treated at Zhejiang Cancer Hospital from January 2017 to October 2023. Patients were divided into three groups based on their initial treatment: BRT alone, ICI alone, and a combined ICI + BRT approach, with chemotherapy included in all regimens. Variables such as age, number of brain metastases, symptoms, comorbidities, Karnofsky Performance Status (KPS) scores, smoking history, Graded Prognostic Assessment (GPA) scores, survival time, and treatment-related adverse events (TRAEs), including hematologic and hepatic toxicities were evaluated. Prognostic factors were assessed using univariate and multivariate analyses via Cox's proportional hazards model. The study also compared outcomes and TRAEs between patients undergoing synchronous treatment (ICI and BRT within four weeks) versus those with asynchronous therapy (more than four weeks apart). Median overall survival (OS) times differed significantly across the groups: 11.6 months for BRT, 11.6 months for ICI, and 20.9 months for ICI + BRT (P<0.001). The ICI + BRT group also exhibited notably better progression-free survival (PFS) and intracranial PFS (iPFS), with medians of 12.6 and 14.9 months, respectively (P<0.001). This group demonstrated significantly improved systemic and intracranial objective response rates (ORR) and disease control rates (DCR). No significant differences in acute radiation injury rates were observed between the BRT and ICI + BRT groups. Multivariate analysis identified several factors influencing OS, including treatment regimen, number of chemotherapy and ICI cycles, presence of bone and multiple brain metastases, and antiangiogenesis therapies and extracranial radiotherapy. Both atezolizumab and serplulimab ICIs, in combination with various radiotherapy regimens [whole BRT (WBRT), WBRT with boost], were effective. Notably, asynchronous ICI and BRT treatment demonstrated advantages in PFS and iPFS over concurrent therapy, with no significant differences in other therapeutic indices or TRAE incidence rates. For ES-SCLC patients with synchronous brain metastases, combined ICI and BRT, alongside chemotherapy, surpasses the efficacy of either treatment alone with manageable TRAEs. Importantly, asynchronous ICI and BRT therapy showed superior outcomes compared to synchronous treatment modalities.

A new perspective on antiangiogenic antibody drug resistance: Biomarkers, mechanisms, and strategies in malignancies.

Drug resistance of malignant tumor leads to disease progression be the bottleneck in clinical treatment. Antiangiogenic therapy, which aims to "starve" the tumor by inhibiting angiogenesis, is one of the key strategies in clinical oncology treatments. Recently, dozens of investigational antibody drugs and biosimilars targeting angiogenesis have obtained regulatory approval for the treatment of various malignancies. Moreover, a new generation of bispecific antibodies based on the principle of antiangiogenesis are being advanced for clinical trial to overcome antiangiogenic resistance in tumor treatment or enhance the efficacy of monotherapy. Tumors often develop resistance to antiangiogenesis therapy, presenting as refractory and sometimes even resistant to new therapies, for which there are currently no effective management strategies. Thus, a detailed understanding of the mechanisms mediating resistance to antiangiogenesis antibodies is crucial for improving drug effectiveness and achieving a durable response to antiangiogenic therapy. In this review, we provide a novel perspective on the tumor microenvironment, including antibody structure, tumor stroma, and changes within tumor cells, to analyze the multifactorial reasons underlying resistance to antiangiogenesis antibodies. The review also enumerates biomarkers that indicate resistance and potential strategies for monitoring resistance. Furthermore, based on recent clinical and preclinical studies, we summarize potential strategies and translational clinical trials aimed at overcoming resistance to antiangiogenesis antibodies. This review provides a valuable reference for researchers and clinical practitioners involved in the development of new drugs or therapeutic strategies to overcome antiangiogenesis antibodies resistance.

Research Progress on Anti-angiogenesis Drugs in Hepatocellular Carcinoma

Primary liver cancer is the sixth most prevalent cancer worldwide and ranked in third for cancer-related mortality rate. Hepatocellular carcinoma (HCC) accounts for about 90% of all primary liver cancers. High vascularization of HCC implies the significance of angiogenesis in the development and pathogenesis of HCC. Several angiogenic pathways have been identified as being dysregulated in HCC, highlighting potential therapeutic targets for the treatment of HCC. In 2007, sorafenib was approved as the standard first-line treatment for advanced HCC, catapulting the therapeutic approach of HCC into the avenue of targeted therapy. In recent years, the approval of several novel targeted drugs and the progress in combination of immunotherapy and targeted therapies provide more alternatives for the treatment of HCC. The progress of anti-angiogenesis therapies in HCC over the past few decades is reviewed and the future prospect of anti-angiogenesis therapy for HCC is also discussed.

Targeted anti-angiogenesis therapy for advanced osteosarcoma.

To date, despite extensive research, the prognosis of advanced osteosarcoma has not improved significantly. Thus, patients experience a reduced survival rate, suggesting that a reevaluation of current treatment strategies is required. Recently, in addition to routine surgery, chemotherapy and radiotherapy, researchers have explored more effective and safer treatments, including targeted therapy, immunotherapy, anti-angiogenesis therapy, metabolic targets therapy, and nanomedicine therapy. The tumorigenesis and development of osteosarcoma is closely related to angiogenesis. Thus, anti-angiogenesis therapy is crucial to treat osteosarcoma; however, recent clinical trials found that it has insufficient efficacy. To solve this problem, the causes of treatment failure and improve treatment strategies should be investigated. This review focuses on summarizing the pathophysiological mechanisms of angiogenesis in osteosarcoma and recent advances in anti-angiogenesis treatment of osteosarcoma. We also discuss some clinical studies, with the aim of providing new ideas to improve treatment strategies for osteosarcoma and the prognosis of patients.

Efficacy of FERscore in predicting sensitivity to ferroptosis inducers in breast cancer

Recent studies have highlighted the potential of ferroptosis in treating breast cancer. However, the efficacy of ferroptosis induction in the most common subtype, estrogen receptor-positive (ER + ) breast cancer, remains inadequately explored. This study unveils that both short-term and long-term treatment with ER-targeted endocrine agents sensitizes ER+ breast cancer cells to ferroptosis inducers, particularly the GPX4 inhibitor, revealing a non-mutational sensitization mechanism. Based on this finding, we introduce a 55-gene signature score (FERscore) tailored to assess ferroptosis susceptibility in breast cancer. Data from cell lines and primary tumors demonstrate significant lower FERscores in ER+ breast cancer compared to other subtypes; however, FERscores dramatically increase in endocrine-resistant ER+ tumor cells and residual tumors post-endocrine therapy. Furthermore, FERscore correlates positively with mesenchymal traits, stemness, immune cell infiltration, and cancer-associated fibroblasts enrichment, while inversely correlating with estrogen responsiveness and DNA repair capacity. Additionally, the FERscore proves effective in predicting therapeutic responses to anti-ER, anti-HER2, poly (ADP-ribose) polymerase inhibitor, and anti-angiogenesis therapies in breast cancer. In summary, ferroptosis induction emerges as a promising avenue in breast cancer therapy. The FERscore offers an innovative tool for identifying patients who may benefit from ferroptosis-inducing therapies, especially those responsive to GPX4 inhibitors.

ATM Activation is Key in Vasculogenic Mimicry Formation by Glioma Stem-like Cells

Objective Vasculogenic mimicry (VM) is a novel vasculogenic process integral to glioma stem cells (GSCs) in glioblastoma (GBM). However, the relationship between VM and ataxia-telangiectasia mutated (ATM) serine/threonine kinase activation, which confers chemoradiotherapy resistance, remains unclear.Methods We investigated VM formation and phosphorylated ATM (pATM) levels by CD31/GFAPperiodic acid-Schiff dual staining and immunohistochemical staining in 145 GBM specimens. Glioma stem-like cells (GSLCs) derived from the formatted spheres of U87 and U251 cell lines and their pATM level and VM formation ability were examined using western blot and three-dimensional culture. For the examination of the function of pATM in VM formation by GSLCs, ATM knockdown by shRNAs and deactivated via ATM phosphorylation inhibitor KU55933 were studied.Results VM and high pATM expression occurred in 38.5% and 41.8% of tumors, respectively, and were significantly associated with reduced progression-free and overall survival. Patients with VM-positive GBMs exhibited higher pATM levels (rs = 0.425, P = 0.01). The multivariate analysis established VM as an independent negative prognostic factor (P = 0.002). Furthermore, GSLCs expressed high levels of pATM and formed vascular-like networks in vitro. ATM inactivation or knockdown hindered VM-like network formation concomitant with the downregulation of pVEGFR-2, VE-cadherin, and laminin B2.Conclusion VM may predict a poor GBM prognosis and is associated with pATM expression. We propose that pATM promotes VM through extracellular matrix modulation and VE-Cadherin / pVEGFR-2 activation, thereby highlighting ATM activation as a potential target for enhancing anti-angiogenesis therapies for GBM.

Single-cell RNA-seq reveals heterogeneity in metastatic renal cell carcinoma and effect of anti-angiogenesis therapy in the pancreas metastatic lesion

Metastatic clear cell renal cell carcinoma has heterogenous tumor microenvironment (TME). Among the metastatic lesions, pancreas metastasis is rare and controversy in treatment approaches. Here, extensive primary and metastatic lesion samples were included by single-cell RNA-seq to decipher the distinct metastasis TME. The hypoxic and inflammatory TME of pancreas metastasis was decoded in this study, and the activation of PAX8-myc signaling, and metabolic reprogramming were observed. The active components including endothelial cells, fibroblasts and T cells were profiled. Meanwhile, we also evaluated the effect of anti-angiogenesis treatment in the pancreas metastasis patient. The potential mechanisms of pancreatic tropism, instability of genome, and the response of immunotherapy were also discussed in this work. Taken together, our findings suggest a clue to the heterogeneity in metastasis TME and provide evidence for the treatment of pancreas metastasis in renal cell carcinoma patients.

M6A modification of VEGFA mRNA by RBM15/YTHDF2/IGF2BP3 contributes to angiogenesis of hepatocellular carcinoma.

Vascular endothelial growth factor A (VEGFA) plays a critical role as a potent angiogenesis factor and is highly expressed in hepatocellular carcinoma (HCC). Although the expression of VEGFA has been strongly linked to the aggressive nature of HCC, the specific posttranscriptional modifications that might contribute to VEGFA expression and HCC angiogenesis are not yet well understood. In this study, we aimed to investigate the epitranscriptome regulation of VEGFA in HCC. A comprehensive analysis integrating MeRIP-seq, RNA-seq, and crosslinking-immunprecipitation-seq data revealed that VEGFA was hypermethylated in HCC and identified the potential m6A regulators of VEGFA including a m6A methyltransferase complex component RBM15 and the two readers, YTHDF2 and IGF2BP3. Through rigorous cell and molecular biology experiments, RBM15 was validated as a key component of methyltransferase complex responsible for m6A methylation of VEGFA, which was subsequently recognized and stabilized by IGF2BP3 and YTHDF2, leading to enhanced VEGFA expression and VEGFA-related functions such as human umbilical vascular endothelial cells (HUVEC) migration and tube formation. In the HCC xenograft model, knockdown of RBM15, IGF2BP3, or YTHDF2 resulted in reduced expression of VEGFA, accompanied by significant inhibition of tumor growth closely associated with VEGFA expression and angiogenesis. Furthermore, our analysis of HCC clinical samples identified positive correlations between the expression levels of VEGFA and the regulators RBM15, IGF2BP3, and YTHDF2. Collectively, these findings offer novel insights into the posttranscriptional modulation of VEGFA and provide potential avenues for alternative approaches to antiangiogenesis therapy targeting VEGFA.

Pericytes recruited by CCL28 promote vascular normalization after anti-angiogenesis therapy through RA/RXRA/ANGPT1 pathway in lung adenocarcinoma

BackgroundIt has been proposed that anti-angiogenesis therapy could induce tumor "vascular normalization" and further enhance the efficacy of chemotherapy, radiotherapy, target therapy, and immunotherapy for nearly twenty years. However, the detailed molecular mechanism of this phenomenon is still obscure.MethodOverexpression and knockout of CCL28 in human lung adenocarcinoma cell line A549 and murine lung adenocarcinoma cell line LLC, respectively, were utilized to establish mouse models. Single-cell sequencing was performed to analyze the proportion of different cell clusters and metabolic changes in the tumor microenvironment (TME). Immunofluorescence and multiplex immunohistochemistry were conducted in murine tumor tissues and clinical biopsy samples to assess the percentage of pericytes coverage. Primary pericytes were isolated from lung adenocarcinoma tumor tissues using magnetic-activated cell sorting (MACS). These pericytes were then treated with recombinant human CCL28 protein, followed by transwell migration assays and RNA sequencing analysis. Changes in the secretome and metabolome were examined, and verification of retinoic acid metabolism alterations in pericytes was conducted using quantitative real-time PCR, western blotting, and LC–MS technology. Chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) was employed to validate the transcriptional regulatory ability and affinity of RXRα to specific sites at the ANGPT1 promoter.ResultsOur study showed that after undergoing anti-angiogenesis treatment, the tumor exhibited a state of ischemia and hypoxia, leading to an upregulation in the expression of CCL28 in hypoxic lung adenocarcinoma cells by the hypoxia-sensitive transcription factor CEBPB. Increased CCL28 could promote tumor vascular normalization through recruiting and metabolic reprogramming pericytes in the tumor microenvironment. Mechanistically, CCL28 modified the retinoic acid (RA) metabolism and increased ANGPT1 expression via RXRα in pericytes, thereby enhancing the stability of endothelial cells.ConclusionWe reported the details of the molecular mechanisms of "vascular normalization" after anti-angiogenesis therapy for the first time. Our work might provide a prospective molecular marker for guiding the clinical arrangement of combination therapy between anti-angiogenesis treatment and other therapies.

Combination Nanomedicine Strategy for Preventing High-Risk Corneal Transplantation Rejection.

High-risk (HR) corneal transplantation presents a formidable challenge, with over 50% of grafts experiencing rejection despite intensive postoperative care involving frequent topical eyedrop administration up to every 2 h, gradually tapering over 6-12 months, and ongoing maintenance dosing. While clinical evidence underscores the potential benefits of inhibiting postoperative angiogenesis, effective antiangiogenesis therapy remains elusive in this context. Here, we engineered controlled-release nanomedicine formulations comprising immunosuppressants (nanoparticles) and antiangiogenesis drugs (nanowafer) and demonstrated that these formulations can prevent HR corneal transplantation rejection for at least 6 months in a clinically relevant rat model. Unlike untreated corneal grafts, which universally faced rejection within 2 weeks postsurgery, a single subconjunctival injection of the long-acting immunosuppressant nanoparticle alone effectively averted graft rejection for 6 months, achieving a graft survival rate of ∼70%. Notably, the combination of an immunosuppressant nanoparticle and an anti-VEGF nanowafer yielded significantly better efficacy with a graft survival rate of >85%. The significantly enhanced efficacy demonstrated that a combination nanomedicine strategy incorporating immunosuppressants and antiangiogenesis drugs can greatly enhance the ocular drug delivery and benefit the outcome of HR corneal transplantation with increased survival rate, ensuring patient compliance and mitigating dosing frequency and toxicity concerns.

The anti-angiogenic and anti-vasculogenic mimicry effects of GN25 in endothelial and glioma cells

Background and purposeScientists have been exploring anti-angiogenic strategies to inhibit angiogenesis and prevent tumor growth. Vasculogenic mimicry (VM) in glioblastoma multiforme (GBM) poses a challenge, complicating anti-angiogenesis therapy. A novel drug, GN25 (3-[{1,4-dihydro-5,8-dimethoxy-1,4-dioxo-2-naphthalenyl}thio]-propanoic acid), can inhibit tumor formation. This study aims to investigate the microenvironmental effects and molecular mechanisms of GN25 in anti-angiogenesis and anti-VM. Experimental approachMTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay was used to evaluate the cell viability of different concentrations of GN25 in human umbilical vein endothelial cells (HUVEC) and Uppsala 87 malignant glioma (U87MG) cells. Functional assays were used to investigate the effects of GN25 on angiogenesis-related processes, whereas gelatin zymography, enzyme-linked immunosorbent assays, and Western blotting were utilized to assess the influence on matrix metalloproteinase (MMP)-2 and vascular endothelial growth factor (VEGF) secretion and related signaling pathways. Key resultsGN25 suppressed migration, wound healing, and tube formation in HUVECs and disrupted angiogenesis in a rat aorta ring and zebrafish embryo model. GN25 dose-dependently reduced phosphatidylinositol 3-kinase/AKT and inhibited MMP-2/VEGF secretion in HUVECs. In U87MG cells, GN25 inhibited migration, wound healing, and VM, accompanied by a decrease in MMP-2 and VEGF secretion. The results indicate that GN25 effectively inhibits angiogenesis and VM formation in HUVECs and U87MG cells without affecting preexisting vascular structures. Conclusion and implicationsThis study elaborated GN25's potential as an anti-angiogenic agent by elucidating its inhibitory effects on classical angiogenesis. VM provides valuable insights for developing novel therapeutic strategies against tumor progression and angiogenesis-related diseases. These results indicate the potential of GN25 as a promising candidate for angiogenesis-related diseases.

Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC (‘EC alone’; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607.

Anti-angiogenesis and anti-immunosuppression gene therapy through targeting COUP-TFII in an in situ glioblastoma mouse model.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer; angiogenesis and immunosuppression exacerbate GBM progression. COUP-TFII demonstrates pro-angiogenesis activity; however, its role in glioma progression remains unclear. This study revealed that COUP-TFII promotes angiogenesis in gliomas by inducing transdifferentiation of glioma cells into endothelial-like cells. Mechanistic investigation suggested that COUP-TFII as a transcription factor exerts its function via binding to the promoter of TXNIP. Interestingly, COUP-TFII knockdown attenuated tumorigenesis and tumor progression in an immunocompetent mouse model but promoted tumor progression in an immuno-deficient mouse model. As an explanation, repression of COUP-TFII induces cellular senescence and activates immune surveillance in glioma cells in vitro and in vivo. In addition, we used heparin-polyethyleneimine (HPEI) nanoparticles to deliver COUP-TFII shRNA, which regulated tumor angiogenesis and immunosuppression in an in situ GBM mouse model. This study provides a novel strategy and potential therapeutic targets to treat GBM.

Cadonilimab safety and efficacy in recurrent or metastatic cervical cancer: First real-world experience from a Chinese multicenter study.

e17510 Background: Cadonilimab, a bi-specific antibody that simultaneously targets PD-1 and CTLA-4, was approved on 29 June 2022 in China for the treatment of recurrent or metastatic cervical cancer (R/M CC) in patients who have progressed following platinum-based chemotherapy. The COMPASSION-03 trial recently demonstrated promising tumor response rates with cadonilimab in R/M CC patients. This study aims to assess the efficacy and safety of cadonilimab in a real-world clinical setting in China. Methods: This multicenter retrospective study enrolled 102 patients with R/M CC, who received at least one cycle of cadonilimab at seven medical centers from July 2022 to October 2023. Among these, 94 patients were administered 10 mg/kg of cadonilimab once every 3 weeks on day 1, while 8 patients received 6 mg/kg every 2 weeks on day 1. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and the disease control rate (DCR) of the overall patients, as well as toxicity, were evaluated. Results: The study included patients with squamous cell carcinoma (73 patients), adenocarcinoma (20), adenosquamous carcinoma (5), and small cell neuroendocrine carcinoma (4). The median age was 54 years, ranging from 28 to 83. Initially, most patients presented with advanced disease: stage IIIB (8 patients), stage IIIC (24), and stage IV (43). The Eastern Cooperative Oncology Group (ECOG) performance status was 0, 1, 2, and 3 for 150, 12, 6, and 3 patients, respectively. Cadonilimab was administered as first, second, and third line or beyond in 35 (34.3%), 31 (30.4%), and 36 (35.3%) patients, respectively. Treatment regimens included cadonilimab monotherapy (13.7%), combined with chemotherapy (33.3%), chemoradiotherapy (19.6%), anti-angiogenesis therapy (11.8%), chemotherapy and anti-angiogenesis therapy (7.8%), chemoradiotherapy and anti-angiogenesis therapy (10.8%), and surgery plus chemoradiotherapy (2.9%). After a median follow-up of 10.2 months, median PFS and OS were not reached. Among the 93 patients (88.2%) with evaluable efficacy, 8 were CR, 32 were PR, 32 were SD, and 22 were PD. The ORR reached 43.0% and the DCR reached 77.4%. Adverse events were reported by 88.2% of patients, with 31 (30.4%) experiencing grade 3-4 immunotherapy-related adverse effects, mainly decreased white blood cell count(21 patients, 20.6%),, anaemia (6, 5.9%), infection (4, 3.9%), and increased alanine aminotransferase (3, 2.9%). Treatment discontinuation or reduction due to toxicity occurred in 17 patients (16.7%). There were no treatment-related deaths. Conclusions: Cadonilimab demonstrates efficacy and safety for patients with recurrent/metastatic cervical cancer in a real-world setting.

Efficacy and safety of SHR-2554 in advanced epithelioid sarcoma: A phase 2 trial.

11549 Background: Epithelioid sarcoma (ES) is a rare and aggressive subtype of soft-tissue sarcoma. The loss of SMARCB1 (INI1) expression which leads to oncogenic dependence on the transcriptional repressor EZH2 has been observed in over 90% of ES. Patients (pts) with metastatic ES have a poor prognosis. We investigated the efficacy and safety of SHR-2554, an oral selective EZH2 inhibitor, in pts with refractory ES. Methods: To be eligible for inclusion, pts had to fulfill the following criteria: 8 years or older; histologically confirmed advanced or metastatic ES with loss of INI1 or upregulated mRNA level of EZH2; progressive disease after at least one line of doxorubicin-containing chemotherapy; the presence of measurable disease according to RECIST 1.1; an ECOG performance status of 0-1. Pts received SHR2554 (350 mg, bid, po) until disease progression or unacceptable toxicity. The primary endpoint was progression-free rate at 12 weeks. A Simon two-stage design was applied. If there were 3 pts remaining progression-free at 12 weeks within the first 9 pts, the cohort would expand to 17 pts and the outcome would be positive if more than 7 pts remained progression-free at 12 weeks. Results: Between Jul 2021 and Dec 2023, a total of 17 pts were enrolled and received at least 1 dose of SHR-2554. The median age was 32 years (range 8-57) and 41.2% were males. 9 (52.9%) pts had received immunotherapy targeting PD-1/L1 and 6 (35.3%) pts had received anti-angiogenesis therapy before enrollment. The median line of previous treatment was 2 (range 1-4). Loss of INI1 was confirmed in 14 (82.4%) pts. Tumor response was evaluated in 14 pts at data cutoff. 9 (64.3%) of 14 pts remained progression-free at 12 weeks. The primary endpoint was met. Based on investigator assessment, 3 (21.4%) of 14 pts achieved partial response and 8 (57.1%) pts had stable disease as best response. Adverse events (AEs) were generally mild. The most common treatment-related hematological AEs were anaemia, platelet count decreased and hyperuricaemia. Conclusions: SHR-2554 showed promising efficacy and an acceptable safety profile in pts with refractory ES, warranting further investigation. Clinical trial information: ChiCTR2100046099.

Landscape of Endometrial Cancer: Molecular Mechanisms, Biomarkers, and Target Therapy.

Endometrial cancer is one the most prevalent gynecological cancers and, unfortunately, has a poor prognosis due to low response rates to traditional treatments. However, the progress in molecular biology and understanding the genetic mechanisms involved in tumor processes offers valuable information that has led to the current classification that describes four molecular subtypes of endometrial cancer. This review focuses on the molecular mechanisms involved in the pathogenesis of endometrial cancers, such as genetic mutations, defects in the DNA mismatch repair pathway, epigenetic changes, or dysregulation in angiogenic or hormonal signaling pathways. The preclinical genomic and molecular investigations presented allowed for the identification of some molecules that could be used as biomarkers to diagnose, predict, and monitor the progression of endometrial cancer. Besides the therapies known in clinical practice, targeted therapy is described as a new cancer treatment that involves identifying specific molecular targets in tumor cells. By selectively inhibiting these targets, key signaling pathways involved in cancer progression can be disrupted while normal cells are protected. The connection between molecular biomarkers and targeted therapy is vital in the fight against cancer. Ongoing research and clinical trials are exploring the use of standard therapy agents in combination with other treatment strategies like immunotherapy and anti-angiogenesis therapy to improve outcomes and personalize treatment for patients with endometrial cancer. This approach has the potential to transform the management of cancer patients. In conclusion, enhancing molecular tools is essential for stratifying the risk and guiding surgery, adjuvant therapy, and cancer treatment for women with endometrial cancer. In addition, the information from this review may have an essential value in the personalized therapy approach for endometrial cancer to improve the patient's life.

Prognostic significance of pan-immune-inflammation value in hepatocellular carcinoma treated by curative radiofrequency ablation: potential role for individualized adjuvant systemic treatment

Background This study aimed to explore the prognostic role of pan-immune-inflammation value (PIV) and develop a new risk model to guide individualized adjuvant systemic treatment following radiofrequency ablation (RFA) for early-stage hepatocellular carcinoma (HCC). Materials and methods Patients with early-stage HCC treated by RFA were randomly divided into training cohort A (n = 65) and testing cohort B (n = 68). Another 265 counterparts were enrolled into external validating cohort C. Various immune-inflammatory biomarkers (IIBs) were screened in cohort A. Prognostic role of PIV was evaluated and validated in cohort B and C, respectively. A nomogram risk model was built in cohort C and validated in pooled cohort D. Clinical benefits of adjuvant anti-angiogenesis therapy plus immune checkpoint inhibitor (AA-ICI) following RFA was assessed in low- and high-risk groups. Results The cutoff point of PIV was 120. High PIV was an independent predictor of unfavorable recurrence-free survival (RFS) and overall survival (OS). RFS and OS rates of patients with high PIV were significantly lower than those with low PIV both in cohort B (P RFS=0.016, P OS=0.011) and C (P RFS<0.001, P OS<0.001). The nomogram model based on PIV, tumor number and BCLC staging performed well in risk stratification in external validating cohort C. Adjuvant AA-ICI treatment showed an added benefit in OS (p = 0.011) for high-risk patients. Conclusions PIV is a feasible independent prognostic factor for RFS and OS in early-stage HCC patients who received curative RFA. The proposed PIV-based nomogram risk model could help clinicians identify high-risk patients and tailor adjuvant systemic treatment and disease follow-up scheme.