Antiangiogenic Drugs Research Articles

IDO1 Inhibitor RY103 Suppresses Trp-GCN2-Mediated Angiogenesis and Counters Immunosuppression in Glioblastoma.

Glioma is characterized by strong immunosuppression and excessive angiogenesis. Based on existing reports, it can be speculated that the resistance to anti-angiogenic drug vascular endothelial growth factor A (VEGFA) antibody correlates to the induction of novel immune checkpoint indoleamine 2,3-dioxygenase 1 (IDO1), while IDO1 has also been suggested to be related to tumor angiogenesis. Herein, we aim to clarify the potential role of IDO1 in glioma angiogenesis and the mechanism behind it. Bioinformatic analyses showed that the expressions of IDO1 and angiogenesis markers VEGFA and CD34 were positively correlated and increased with pathological grade in glioma. IDO1-overexpression-derived-tryptophan depletion activated the general control nonderepressible 2 (GCN2) pathway and upregulated VEGFA in glioma cells. The tube formation ability of angiogenesis model cells could be inhibited by IDO1 inhibitors and influenced by the activity and expression of IDO1 in condition medium. A significant increase in serum VEGFA concentration and tumor CD34 expression was observed in IDO1-overexpressing GL261 subcutaneous glioma-bearing mice. IDO1 inhibitor RY103 showed positive anti-tumor efficacy, including the anti-angiogenesis effect and upregulation of natural killer cells in GL261 glioma-bearing mice. As expected, the combination of RY103 and anti-angiogenesis agent sunitinib was proved to be a better therapeutic strategy than either monotherapy.

177Lu Anti-Angiogenic Radioimmunotherapy Targeting ATP Synthase in Gastric Cancer Model.

This study investigated a novel radioimmunotherapy strategy for targeting tumor angiogenesis. We developed a radiopharmaceutical complex by labeling an anti-adenosine triphosphate synthase (ATPS) monoclonal antibody (mAb) with the radioisotope 177Lu using DOTA as a chelating agent. 177Lu-DOTA-ATPS mAb demonstrated high labeling efficiency (99.0%) and stability in serum. MKN-45 cancer cells exhibited the highest cellular uptake, which could be specifically blocked by unlabeled ATPS mAb. In mice, 177Lu-DOTA-ATPS mAb accumulated significantly in tumors, with a tumor uptake of 16.0 ± 1.5%ID/g on day 7. 177Lu-DOTA-ATPS mAb treatment significantly reduced the viability of MKN-45 cells in a dose-dependent manner. In a xenograft tumor model, this radioimmunotherapy strategy led to substantial tumor growth inhibition (82.8%). Furthermore, combining 177Lu-DOTA-ATPS mAb with sunitinib, an anti-angiogenic drug, enhanced the therapeutic efficacy of sunitinib in the mouse model. Our study successfully developed 177Lu-DOTA-ATPS mAb, a radioimmunotherapy agent targeting tumor blood vessels. This approach demonstrates significant promise for inhibiting tumor growth, both as a single therapy and in combination with other anti-cancer drugs.

Research progress in tumor angiogenesis and drug resistance in breast cancer.

Angiogenesis is considered a hallmark pathophysiological process in tumor development. Aberrant vasculature resulting from tumor angiogenesis plays a critical role in the development of resistance to breast cancer treatments, via exacerbation of tumor hypoxia, decreased effective drug concentrations within tumors, and immune-related mechanisms. Antiangiogenic therapy can counteract these breast cancer resistance factors by promoting tumor vascular normalization. The combination of antiangiogenic therapy with chemotherapy, targeted therapy, or immunotherapy has emerged as a promising approach for overcoming drug resistance in breast cancer. This review examines the mechanisms associated with angiogenesis and the interactions among tumor angiogenesis, the hypoxic tumor microenvironment, drug distribution, and immune mechanisms in breast cancer. Furthermore, this review provides a comprehensive summary of specific antiangiogenic drugs, and relevant studies assessing the reversal of drug resistance in breast cancer. The potential mechanisms underlying these interventions are discussed, and prospects for the clinical application of antiangiogenic therapy to overcome breast cancer treatment resistance are highlighted.

Coronary Stenosis in a Patient Under Pazopanib Therapy: A Case Study

Tyrosine kinase inhibitors have transformed therapeutic approaches to cancer, marking a major advance in oncology. This article presents the clinical case of a 59-year-old moroccan patient with metastatic clear cell kidney cancer treated with pazopanib, who developed a cardiac vascular accident through coronary stenosis after 24 months of treatment with pazopanib. The main objective of this article is to illustrate the side effects of anti-angiogenic drugs and the crucial importance of monitoring these toxicities, particularly those of vascular origin, in order to prevent serious complications that could compromise the prognosis of a patient, regardless of the cancer disease itself. This case highlights the need for regular assessment of cardiovascular risk factors in patients receiving treatment with pazopanib, as well as increased vigilance for the appearance of signs or symptoms suggesting hematological or hepatic toxicities. Early and appropriate management of toxicities is essential to optimize the safety and effectiveness of renal cancer treatment with pazopanib, while preserving the patient's cardiovascular health.

DIPG-60. OPERATIVE PERFORMANCE OF RAPNO DIPG CRITERIA FOR IMAGING REVIEW- A STUDY FROM THE INTERNATIONAL DIPG/DMG REGISTRY (IDIPGR)

Abstract BACKGROUND The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group for diffuse intrinsic pontine glioma (DIPG) recently published its recommendations. Response criteria incorporate radiologic findings, neurologic status, and use of concurrent steroids and antiangiogenic drugs to define response. To test the operative performance of the imaging component, we retrospectively applied RAPNO DIPG recommendations to a convenience sample of 46 patients enrolled in the International DIPG/DMG Registry(IDIPGR). METHODS MRIs were independently reviewed by 2 pediatric neuro-radiologists. These measurements were analyzed utilizing RAPNO DIPG imaging criteria to categorize the response as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). For PR evaluation, each MRI was compared to the baseline MRI, and for PD evaluation, each MRI was compared to the MRI with the smallest cross-sectional measurement. The response category for each MRI was compared between 2 neuro-radiologists and was classified as concordant if they agreed, minor discordant if one reported SD and the other reported PR or PD, and major discordant if one reported PR and the other reported PD. RESULTS A total of 276 paired MRIs were analyzed. Sixty-seven percent of the time, the analyzed response assessment was concordant. In 33% discordant reads, 26% were minor discordant, and 7% were major discordant. There were no CRs reported. Further analysis of minor discordant cases showed that 62% of these cases were within 10% of the boundary for PR or PD. The median difference between 2 neuro-radiologists’ long axis measurements was 2 mm (range 0-27mm) and short axis measurements was 2mm (range 0-29mm). These small differences in measurements account for all discordant response categories between 2 neuro-oncologists. CONCLUSION This study demonstrated that RAPNO DIPG imaging criteria can be successfully applied with high concordance between readers. When discordant, measurements were largely at the boundaries of response type.

Ornidazole Inhibits the Angiogenesis and Migration Abilities of Non-small Cell Lung Cancer (NSCLC) via Downregulation of VEGFA/VEGFR2/NRP-1 and PI3K/AKT/mTOR Pathways.

Around the world, non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths among all cancers. Despite advancements in new therapeutic approaches over the past few decades, the five-year survival rate still remains disappointing. The lack of effective anti-angiogenic and anti-migration drugs is the biggest obstacle to the treatment of metastatic lung cancer. Therefore, there is a need to develop new and effective therapeutic compounds targeting anti-angiogenic and anti-migration pathways for the treatment of lung cancer. Ornidazole is a nitroimidazole agent widely used in the treatment of parasitic infections such as trichomonas vaginalis, amebiasis and giardiasis. This study aimed to investigate the anti-proliferative, anti-angiogenic and anti-mitotic activities of the anti-parasitic drug Ornidazole in two human lung cancer cell lines (A549, H1299). We determined the effects of Ornidazole, on cell viability, apoptosis, migration, angiogenesis and metastatic ability against NSCLC in lung cancer cell lines. Its action on the mRNA and protein expression levels of VEGFA, VEGFR2, NRP1, Casp9, Casp3, Bax, Bcl-2, PIK3CA, AKT, MTOR, PTEN and FOX3A was assessed. Furthermore, in this study the effects on cell migration, cell viability and proliferation was evaluated through wound healing, MTT and Crystal violet assays. This study demonstrated that Ornidazole effectively reduces cell viability and migration ability, inhibits angiogenesis and metastatic abilities in NSCLC cells. In conclusion, these results may shed light on the treatment of NSCLC, and we suggest the anti-parasitic drug Ornidazole as a new agent with potential anti-angiogenic and anti-mitotic activity by interfering with the molecular pathways that trigger tumor angiogenesis and migration.

The discovery of new potent VEGFR2 inhibitors for potential anti-angiogenesis agent through a combination of structure-based virtual screening, molecular dynamics simulation and ADME-Tox prediction

The discovery of the importance of angiogenesis in the mechanisms of tumor growth has empowered the improvement of new particles that are utilized in the therapy of various cancers. The goal of this research was to identify novel compounds functioning as potent VEGFR2 inhibitors in silico. It is an interesting therapeutic target for developing new anti-angiogenic drugs. In this work, molecular simulation studies of enzyme inhibition was carried out by structure-based virtual screening with FlexX program of VEGFR2. This approach makes it possible to model the interactions between a protein and thousands of small chemical compounds. A collection of 6,000 compounds originating from the ZINC chemical library, were tested against the active site of VEGFR2. The ADME-Tox characteristics and molecular dynamics simulation of the potential compounds were also examined. At the end of this screening, the compounds ZINC01534124 and ZINC00588595 appear as new inhibitors theoretically more active towards VEGFR2. Again, these inhibitors have shown significant binding energy by interacting with important residues in the active site. Furthermore, the in silico prediction of a similar drug positively informs us about the ADME-Tox properties of these new compounds. Finally, the stable binding of VEGFR2 with ZINC01534124 and ZINC00588595 is shown using 100 ns molecular dynamics simulations. These findings point to the chemicals ZINC01534124 and ZINC00588595 as potential candidates for VEGFR2 inhibitor research. They might also act as a starting point for further chemical modifications in order to produce therapeutically relevant anti-angiogenic medications.

A new prognostic tool for metastatic colorectal cancer patients receiving anti-angiogenic treatment, the PALM score: A single-center experience.

e15575 Background: Even if anti-angiogenic agents are crucial for metastatic colorectal cancer (mCRC) patients (pts) treatment, to date, no validated prognostic biomarkers are available. We conducted at our Centre a retrospective research to identify a prognostic tool to be applied in clinical practice in this population. Methods: We retrospectively collected laboratory, radiological and clinical data of mCRC pts treated with anti-angiogenic agents at the Medical Oncology Unit of Cagliari University Hospital (2018- 02/2024) in order to identify a potential prognostic tool. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; cut-off: ROC curves; differences among variables: Chi-square test). Results: Globally, 33 mCRC pts were evaluated in our study (19 male, 14 female; 13 RAS wild-type, 22 left-sided primary). 10 were treated with anti-angiogenic drugs in the 1st-line, 13 in the 2nd-line (bevacizumab and aflibercept) and 10 in 1st-2nd line. Median OS was 39.5 months (m) (95%CI:28.2-41.3), median Progression Free Survival (PFS) was 14.9 m (95%CI:9.5-18.5). Pts with lower platelet to lymphocyte ratio (P; ≤253; p < 0.0001, HR = 0,00000048; 95%CI 24.7-39.5 versus [vs] 95% CI 8.2-10.5), alkaline phosphatase (A; < 136 U/l; p = 0.0001, HR = 0.0001; 95%CI 12-39.5 vs 95% CI 8.2-10.5) and lactate dehydrogenasis (L; < 365 U/l; p < 0.0001, HR = 0.0000004; 95%CI 24.7-39.5 vs 95% CI 8.2-10.5) and higher monocyte count (M; > 0.3x103/μL; p = 0.0093, HR 0.01; 95%CI 26.5-39.5 vs 95%CI 8.2-24.7), showed a statistically improved OS. We created the “PALM score” and separated pts in two prognostic groups: good prognostic group (0 unfavorable variables: PALM = 0) and poor prognostic group (≥1 unfavorable variable, PALM = 1). OS was significantly improved in the good prognostic group (PALM = 0): 31.5 m (95%CI:24.7-39.5) vs 10.5 m (PALM = 1) (p = 0.0031, HR = 0.00006). Chi-square test revealed also a statistically significant correlation of upfront resection of primary tumor with the PALM score (73.9% of patients belonging to the PALM = 0 group had undergone surgery for primary tumor and all patients with resected primary belonged to the PALM = 0 group (p = 0.0352). Conclusions: Our research showed a promising prognostic role of easy-to-use PALM score tool in mCRC patients treated with anti-angiogenic drugs in a limited population at our center. Further prospective studies with larger sample size are needed to confirm our findings.

Immune checkpoint inhibitor retreatment in second-line treatment of esophageal cancer: A real-world study.

e16034 Background: Immunotherapy combined with chemotherapy has been recommended in several guidelines and consensus for the first-line treatment of advanced esophageal cancer(EC), but it is controversial whether to continue immune checkpoint inhibitors (ICIs) after the progress of first-line immunotherapy. Methods: This was a single-center, retrospective, observational, real-world study to collect general conditions and clinical data of EC patients hospitalized in the First Affiliated Hospital of Henan University of Science and Technology between February 2020 and December 2023. All patients received programmed cell death protein 1 (PD-1) or its ligand (PD-L1) inhibitor combination therapy in the first-line and received at least two cycles of PD-1/PD-L1 inhibitor-based therapy in the second-line setting after progression. We evaluated the efficacy and safety including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), grade 3-5 treatment-related adverse effects (TRAE) and immune-related adverse events (irAEs). We also evaluated the relationship between clinical features and outcomes using univariate and multivariate analyses. Results: We enrolled 214 patients, with a median age 67.9 (47 – 87) years, male sex 66.8%, 201(93.9%) ESCC and 11(5.1%) EAC. In all patients, the mOS and mPFS were 9.6 (95%CI 9.1-10.1) months and 4.4 (95%CI 4.1-4.7) months; The ORR was 33.2%, DCR was 65.9%. 162 (75.7%) patients treated with immunochemotherapy(I+C), 37 (17.3%) patients received immunotherapy combined with anti-angiogenic drugs(I+A) and 15 (7.0%) patients treated with immunotherapy combined with chemotherapy and anti-angiogenic drugs(I+C+A). The mOS were 9.1 (95% CI 8.4 – 9.8) months, 10.0 (95% CI 8.7 – 11.3) months and 11.5 (95% CI 10.7 – 12.3) months, respectively. The mPFS were 4.3m (95%CI 4.0-4.6) months, 4.3 (95%CI 4.0-14.6) months and 6.0 (95%CI 4.2-6.4) months. mPFS and mOS did not have significant difference between these groups. Univariate and multivariate analyses showed that PFS more than 6 months on first-line therapy was an independent prognostic factor for PFS and OS in second-line therapy. The incidence of grade ≥ 3 TRAEs and irAEs were 25.7% and 5.6%. No treatment-related deaths occurred. Conclusions: This real-world data showed PD-1 or PD-L1 inhibitors retreatment might have good efficacy and manageable safety in EC patients who progress after first-line immunochemotherapy. [Table: see text]

Surufatinib monotherapy or combined with vinorelbine as a late-line therapy in patients with refractory advanced non–small cell lung cancer (NSCLC).

e20543 Background: Surufatinib (S, a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) has shown synergy mechanism with vinorelbine (V) in lung cancer cell lines (A549 cells and PC9 cells) and nude mice experiment. Here, we evaluated the efficacy and safety of surufatinib with or without vinorelbine in refractory advanced NSCLC patients (pts). Methods: This single center, open label, phase Ⅱ study (NCT04922658) has two cohorts. Eligible pts with stage IIIb/IV NSCLC who progressed after at least two lines of previous therapies were assigned to cohort 1 (S, 250 mg qd, po, q3w plus V, 20 mg, po, once every 2 days, q3w) or cohort 2 (S, 300mg qd, po, q3w). Treatment continued until disease progression, intolerable toxicity, or study withdrawal. Primary endpoint was PFS. Secondary endpoints included ORR, DCR, OS, and safety. Results: Up to Jan 15, 2024, 17 pts were enrolled in cohort 1 (median age 62 years, male 76.47%, TNM stage IV 70.59%, ECOG PS 1 94.12%). 32 pts were assigned to cohort 2 (median age 55 years, male 65.62%, TNM stage IV 87.5%, 71.88% pts failing with at least three lines of previous therapies). In cohort 1, 12 pts had received at least one post-baseline tumor assessment (evaluable), among which ORR was 16.7%, DCR was 100 %. 75% pts had stable or shrinking tumors (based on best of response). Median PFS was not reached in cohort 1. In cohort 2, 32 pts were evaluable, ORR was 3.1%, DCR was 87.5%. 62.5% pts had stable or shrinking tumors. Median PFS was 5.4m (95% CI 3.4, 7.4). In subgroup analysis, compared with pts with distant metastases (mainly bone, liver, and brain metastases), pts without above metastases showed significantly longer PFS (6.9m vs 4.1m, p = 0.0071). Additionally, PFS was significantly prolonged in pts who were anti-angiogenic drugs naïve, in contrast with those who received anti-angiogenic therapies before (8.3m vs 4.1m, p = 0.004). Similar result was observed in pts with enlargement tumors versus stable or shrinking tumors (2.8m vs 6.9m, p<0.0001). Longer PFS was observed in pts with squamous NSCLC (sq vs non-sq, 8.3m vs 4.1m, p = 0.0655) or those who received two lines of previous therapies vs at least three lines (6.2m vs 4.8m, p = 0.0728). The most common treatment-emergent adverse events (Total, Grade≥3) in cohort 1 were proteinuria (25.0%, 0), hypothyroidism (16.67%, 0), and diarrhea (8.33%, 8.33%). The most common adverse events (Total, Grade≥3) in cohort 2 were proteinuria (50.0%, 14.7%), hypothyroidism (44.1%, 0), and hypoproteinemia (35.3%, 5.9%). Conclusions: Surufatinib, or combined with vinorelbine, showed encouraging survival benefits and promising anti-tumor activity with acceptable toxicity in the late-line treatment of refractory advanced NSCLC, especially in patients without distant metastases, never using anti-angiogenic drugs, or with squamous NSCLC. The results warrant further investigations in a large cohort. Clinical trial information: NCT04922658 .

Apatinib and camrelizumab plus hepatic arterial infusion with oxaliplatin and 5-fluorouracil vs. apatinib and camrelizumab as the first-line treatment for hepatocellular carcinoma with portal vein tumor thrombus: A randomized multi-center clinical trial.

TPS4194 Background: The combination of immune checkpoint inhibitors and antiangiogenic drugs has been approved as the first-line treatment for advanced hepatocellular carcinoma (HCC). However, the survival benefit is still limited, especially in patients with high-risk features (Vp4, and/or bile duct invasion and/or tumor occupancy of ≥50% of the liver). Hepatic arterial infusion chemotherapy (HAIC) plus apatinib (an antiangiogenic drug) and camrelizumab (a PD-1 antibody) showed encouraging antitumor activity for these patients in a previous phase 2 study. Herein, we investigated the efficacy and safety of apatinib and camrelizumab plus HAIC compared with apatinib and camrelizumab as the first-line treatment for HCC with portal vein tumor thrombus (PVTT). Methods: In this randomized, open-label, phase 3 trial, eligible patients are ≥18 years with HCC confirmed by radiology, histology, or cytology. Other eligibility criteria were as follows: with PVTT, ECOG PS 0/1, no history of systemic therapy, not amenable to curative treatment approach, Child-Pugh A class liver score, and ≥1 measurable lesion by RECIST v1.1. A total of 214 patients (anticipated) will be randomized (1:1) to receive apatinib (250mg orally once daily) and camrelizumab (200 mg IV Q2W) plus HAIC with FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 20 hours via hepatic artery Q4W) or apatinib (250mg orally once daily) and camrelizumab (200 mg IV Q2W) until disease progression or intolerable toxicity. Stratification will be by patients with or without high-risk features. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, objective response rate per RECIST 1.1 and mRECIST, disease control rate per RECIST 1.1 and mRECIST, time to progression, duration of response, time to response, and safety. Whole-Exome Sequencing and RNA Sequencing of tumor biopsy samples were performed for predictive biomarker exploration. Clinical trial information: NCT05198609 .

Eugenol suppresses VEGF-dependent angiogenesis by JAK2/STAT3 pathway in non-small cell lung cancer

Background: Non-small cell lung cancer (NSCLC) is a highly vascularized solid tumor, and tumor angiogenesis is closely associated with the metastasis and progression of NSCLC. Antiangiogenic drugs can target the tumor microenvironment to degrade existing tumor blood vessels while inhibiting tumor angiogenesis and have become one of the indispensable treatments for patients with advanced NSCLC. Although various new drugs have been tested in different settings of NSCLC, none of them have shown the desired therapeutic effects so far. Therefore, the search for new and effective therapeutic modalities has become a new goal for treating NSCLC. Objective: Eugenol is a phenolic aromatic compound derived from Eugenia caryophyllata, Cinnamomum cassia, etc., which has historically been used for various medical purposes. Studies have shown that eugenol exhibits significant anticancer effects against several types of cancer; however, its therapeutic effect on angiogenesis remains a mystery. In this study, the in vitro and in vivo antiangiogenic effects of eugenol in NSCLC and the underlying molecular mechanism were explored, which could provide a promising strategy for the treatment of NSCLC. Methods: The effects of eugenol on the proliferative capacity of human umbilical vein endothelial cells (HUVECs) and A549 cells were examined by methyl thiazolyl tetrazolium assay. The migration and invasion of eugenol-treated HUVECs were evaluated by wounding-healing and transwell assay, and the angiogenesis was measured by tube formation assay. The expression of angiogenesis-related genes and proteins, as well as the JAK2/STAT3 pathway, was evaluated by real-time quantitative PCR and western blot. Flow cytometry was performed to detect the effect of eugenol on the apoptotic profile of A549 cells. Finally, the A549 tumor-bearing nude mice were constructed to evaluate the in vivo anti-NSCLC activity of eugenol. Results: Eugenol inhibited the migration, invasion, and tube formation of HUVECs. Meanwhile, eugenol blocked the phosphorylation of vascular endothelial growth factor reporter-2 and inhibited the expression of other angiogenesis-related proteins. In addition, eugenol suppressed the expression of p-JAK2 and p-STAT3 in HUVECs and A549 cells. Eugenol also suppressed the proliferation of A549 cells by promoting apoptosis and inhibited tumor growth and microvessel formation in A549 cell xenograft-bearing nude mice. Conclusions: Eugenol could be a potential lead compound for the treatment of NSCLC by blocking the vascular endothelial growth factor/vascular endothelial growth factor reporter-2 and JAK2/STAT3 signaling pathways.

Efficacy and safety of SBRT combined with sintilimab and IBI305 in patients with advanced HCC and previously failed immunotherapy: study protocol of a phase 2 clinical trial

IntroductionHepatocellular carcinoma (HCC) is a leading cause of cancer-related death in China. The combination of immune checkpoint inhibitors (ICIs) and antiangiogenic drugs, such as bevacizumab and tyrosine kinase inhibitors, has...

Atezolizumab plus taxane chemotherapy for the treatment of non-BRAF, non-RAS mutated anaplastic thyroid carcinoma: Final analysis.

e18070 Background: Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy with a historical dismal prognosis. Although BRAF/MEK inhibitors have revolutionized the treatment of BRAF-mutant ATC, treatment options remain limited for those without a BRAF mutation. Single agent immunotherapy showed modest efficacy, while combination of immunotherapy with the anti-VEGF lenvatinib led to marked improvement in survival. Yet, given the locally advanced nature of this disease, many patients have contra-indications to antiangiogenics. We assessed the safety and efficacy of the anti-PD-L1 atezolizumab combined with taxane chemotherapy in patients with non- BRAF, non- RAS/NF mutated ATC with contra-indications to VEGF inhibitors. Methods: We enrolledpatientswith ATC in a single-center phase II prospective trial of atezolizumab plus mutation-determined targeted therapy (NCT03181100). Patients without a BRAF, RAS or NF mutation who had a contra-indication to anti-VEGF therapy (such as high risk for bleeding or fistula) were included in an exploratory cohort and were treated with nab-paclitaxel 100 mg/m2 on days 1, 8 and 15, combined with atezolizumab 1200 mg intravenously every 21 days. Paclitaxel could be substituted for nab-paclitaxel, but the latter was preferred as it does not require prophylactic steroids. Here we present results for this exploratory cohort. Best response to therapy was assessed per RECIST v1.1; survival by the Kaplan-Meier method. Results: Nine patients were enrolled in the exploratory cohort. All were naïve to systemic therapies, and 3/9 (33%) received prior bridging cytotoxic chemotherapy. Prior to study entrance, 6/9 (67%) had radiation therapy to the neck and 4/9 (44%) had surgery to resect the primary tumor. Seven (78%) had distant metastatic disease at time of enrollment. Most frequent baseline mutations were in TP53 (89%), APC (33%), PTEN (33%) and TERT promoter (33%). Median duration of follow-up was 4.4 months. Best response to therapy was partial response in 2 patients (1 confirmed and 1 unconfirmed), stable disease in 3 patients, and progressive disease in 4 patients. Overall response rate was 11 %, while disease control rate was 56%. Median OS was 4.44 months (95% CI, 1.12 –25.33) and median progression-free survival was 2.73 months (95% CI, 1.12 – 7.13). All patients had died at the time of data cut-off. Regarding treatment safety, the combination of atezolizumab plus taxane chemotherapy was overall well tolerated, with most adverse events being grade 2 or lower. Conclusions: Combination of atezolizumab plus taxane chemotherapy, although safe, offers limited additional survival benefit compared to single agent immunotherapy (median OS = 5.9 months) or the historical median OS of 5 months. Additional novel treatment strategies for patients with non- BRAF mutated ATC are warranted, especially when antiangiogenic drugs are contra-indicated. Clinical trial information: NCT03181100 .

Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671)

Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. The RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment-naïve advanced TC. They received ramucirumab, carboplatin and paclitaxel for six cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Centralized radiologic review was carried out. From November 2018 to June 2023, 52 patients were screened and 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. The Eastern Cooperative Oncology Group performance status was 0 in 68.5% and 1 in 31.4% of patients. At the present analysis carried out some months after the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95% confidence interval (CI) 63.1% to 91.6%]. At the centralized radiological review of 33/35 assessable patients, ORR was 57.6% (95% CI 39.2% to 74.5%). After a median follow-up of 31.6 months, median PFS was 18.1 months (95% CI 10.8-52.3 months) and median OS was 43.8 months (95% CI 31.9 months-not reached). Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE ≥ grade 3. In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

Short-course radiotherapy (SCRT) followed by fruquintinib plus adebrelimab and CAPOX in the total neoadjuvant therapy of locally advanced rectal cancer (LARC): A multicenter, single-arm, open-label, phase II study.

TPS3643 Background: For LARC patients (pts), long-course concurrent chemoradiotherapy or SCRT followed by chemotherapy is recommended by the NCCN guidelines (Version 1.2024) as neoadjuvant therapy. Compared with chemoradiotherapy, the addition of immune checkpoint inhibitors (ICIs) or anti-angiogenic drugs could further improve complete response (CR) rate in the neoadjuvant treatment of LARC. Fruquintinib, a highly selective small-molecule inhibitor of VEGFR-1, -2, and -3, has gained FDA approval for pts with metastatic colorectal cancer previously treated. For pts with LARC at high risk of recurrence, the CR rate of SCRT followed by chemotherapy was 29%. There is an urgent need for new therapeutical options to improve the CR rate in these pts. This study introduces an innovative approach, combining SCRT, chemotherapy, Fruquintinib, and ICIs as a total neoadjuvant therapy for high-risk LARC pts. Methods: This is a multicenter, single-arm, open-label, phase II study (NCT06234007) investigating the efficacy and safety of SCRT sequential fruquintinib, combined with adebrelimab (an anti-PD-L1 monoclonal antibody) and CAPOX in pts with LARC. Eligible participants were 18 years or older, with an ECOG PS of 0–1, and a biopsy-proven, newly diagnosed, primary, LARC, classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for surgery. Total neoadjuvant therapy included SCRT (5 × 5 Gy over 5 days, 1-week rest) followed by six cycles of fruquintinib (4mg, qd, po, q3w. For the initial 6 pts in the safety run-in period, dosage was adjusted based on dose-limited toxicities in the 1st cycle) combined with adebrelimab (1200mg, iv, d1, q3w) and CAPOX (q3w). Subsequently, pts who did not reach clinical CR underwent total mesorectal excision, others received the “Watch and Wait” policy or surgery. Primary endpoint was CR rate (including clinical CR & pathologic CR). Secondary endpoints included 3-year event free survival rate, overall survival, R0 resection rate and adverse events (AEs). Exploratory endpoints aimed to evaluate the correlation between potential biomarkers and efficacy. Using PASS 15 software (version 15.0.5.0), in the Tests for One Proportion analysis, with a two-sided α of 5% and to guarantee the power over 80%. The null hypothesis of CR rate was 29%, and the alternative hypothesis was 51%, accounting for a 10% drop-out rate, resulting in a sample size of 39 pts. With the 6 pts in the safety run-in period, a total of 45 pts would be enrolled in the study. Until Feb 1, 2024, 7 of planned 45 pts have been enrolled. Clinical trial information: NCT06234007 .

Updated results from ALTER-S002: A single-arm multicenter trial of the combination of anlotinib with chemotherapy in patients with stage IIB classic osteosarcoma of the extremity.

11529 Background: The overexpression of multiple tyrosine kinase receptors in osteosarcoma indicated a promising therapy targeting these receptors. Anlotinib is a multi-targeted tyrosine kinase inhibitor that potentially inhibits tumor angiogenesis. The combination of anti-angiogenic drugs with chemotherapeutic agents is proposed to act synergistically to achieve favorable tumor control, especially as the neoadjuvant therapy. We had reported the neoadjuvant therapy data of anlotinib in combination with chemotherapy for treatment-naive stage IIB classical osteosarcoma of the extremity in the 2023 ESMO congress. Here we report an update on the effectiveness and safety of the follow-up. Methods: In this open-label, single-arm, multicenter phase II clinical trial. Eligible patients(pts) were aged 12-40 years with histologically confirmed primary localized extremity classic osteosarcoma, stage IIB, operable. Pts received anlotinib (10mg, po, d1-14, q3w), doxorubicin (A) (20-25mg/m2 iv, d1-3, q3w) and cisplatin (P) (70-90mg/m2, iv, d1, q3w) for the first nine weeks. Pts underwent radical surgery after the exclusion of contraindications at week 10. After surgery, pts received A+P at weeks 12-14, and anlotinib plus A+P at weeks 15-20 with the drug dose unchanged. Since week 21, anlotinib (12mg, po, d1-14, q3w) monotherapy was maintained until week 104 or the occurrence of an EFS event. The primary endpoint was 24-month EFS rate, secondary endpoints were 36-month EFS rate, local recurrence rate, lung metastasis rate, 3-year OS rate and safety. Results: From May 2020 to Apr 2022, 52 eligible pts were enrolled, while 51 pts underwent surgery after 3 cycles of neoadjuvant therapy. At the data cut-off date (Oct. 2023), the median EFS was not reached, 12 and 24-month EFS rates were 84.18% (95% CI :70.82, 91.77) and 73.43% (95% CI :57.40, 84.21), respectively. The stratified analysis of EFS showed that the length and diameter of the target lesion are independent prognostic factors. The median OS was not reached, the 24-month OS rate was 95.92% (95% CI :84.65, 98.96). Among the 51 pts who underwent surgical treatment, 12(23.53%, 95% CI: 12.79, 37.49) pts experienced recurrence or metastasis. Most treatment-related adverse events (TRAEs) were grade 1-2. Grade 3/4 TRAEs (≥20%) included neutropenia (51.92%), leukopenia (38.46%), thrombocytopenia (36.54%) and anemia (32.69%). Conclusions: The updated results suggested that anlotinib combined with doxorubicin and cisplatin in the perioperative period showed favorable efficiency and manageable adverse events in Stage IIB classic osteosarcoma of the extremity. Clinical trial information: ChiCTR 2000033298.

Retrospective study of continued immunotherapy in patients with advanced esophageal squamous cell carcinoma after progression on first-line immunotherapy combination chemotherapy.

e16025 Background: Immunotherapy combined with chemotherapy has become the standard first-line treatment for advanced esophageal squamous cell carcinoma. However, the disease progression pattern after first-line immunotherapy resistance and the second-line treatment options are not fully understood. This retrospective study was designed to explore the efficacy of continued immunotherapy in advanced esophageal squamous cell carcinoma patients after progression on first-line immunotherapy combination chemotherapy. Methods: We retrospectively analyzed the efficacy of second-line continued immunotherapy in patients with stage IV esophageal squamous cell carcinoma who experienced disease progression after first-line immunotherapy at Huai 'an First People's Hospital from July 2020 to December 2023. The main outcome were progression-free survival (PFS), 3-and 6-month PFS rates, objective response rate (ORR), disease control rate(DCR)and overall survival (OS). Results: A total of 30 eligible patients were included. Median age was 67 years, 20 (66.7%) patients were male. 14 patients achieved partial response (PR), 8 stable disease (SD), illustrating an ORR of 46.7% and a DCR of 73.3%. Median PFS was 3.85 months. In the second-line treatment regimen, 21 (70%) were immunotherapy combined chemotherapy, and the others were immunomonotherapy or combined anti-angiogenic drugs. Conclusions: The current retrospective data shows that a considerable number of patients still could benefit from second-line immunotherapy after the progress of first-line immunotherapy in patients with advanced ESCC. This result brings new hope for the increasingly large population of immune resistance esophageal cancer patients. [Table: see text]

Ex Vivo Evaluation of Antiangiogenic Drugs in Oral Cancer: Potential Implications for Targeting Vasculogenic Mimicry.

Oral squamous cell carcinoma (OSCC) is characterized by early metastasis, clinical resistance and poor prognosis. Recently, we showed that aggressive OSCC cells co-express endothelial cell markers and can form tube-like structures, known as vasculogenic mimicry (VM), a process associated with poor prognosis in head and neck cancers. Given the limited success of current antiangiogenic therapy in treating OSCC, this study sought to explore the efficiency of these drugs in targeting an ex vivo model of VM. OSCC cell lines from the tongue and floor of the mouth in addition to human endothelial cells were used. The treatments comprised a set of clinically relevant antiangiogenic drugs: sorafenib, sunitinib, and axitinib, which were administered in different doses. Multiple ex vivo approaches including cell tubulogenesis, proliferation, apoptosis, and migration assays were used. Although these drugs inhibited the formation of endothelial cell capillaries, they showed clear differential effects on OSCC cell-derived VM and cell morphology. Sorafenib inhibited the tubulogenesis of aggressive OSCC cells compared with the limited effect of sunitinib and axitinib. Furthermore, our data consistently demonstrated a preferential efficacy of certain drugs over others. Sorafenib and sunitinib exhibited anti-cancer effects on tumor cell proliferation, apoptosis, and cell migration, compared with the limited effect of axitinib. The antiangiogenic drugs, except sorafenib, had limited effect on VM formation in vitro and exhibited varying anti-cancer effects on OSCC cells. These data support the notion that VM formation may in part explain the development of drug resistance in OSCC cells.

Angiogenesis in nasopharyngeal carcinoma: insights, imaging, and therapeutic strategies.

Nasopharyngeal carcinoma (NPC) is a highly prevalent head and neck malignancy in southern China frequently diagnosed at advanced stages owing to subtle early symptoms and associated metastasis. Angiogenesis emerges as a pivotal factor in NPC progression, with numerous angiogenesis-related factors showing aberrant expression and contributing to increased neovascularization within NPC tumors. These abnormal vessels not only nourish tumor growth but also facilitate metastasis, culminating in unfavorable patient outcomes. Multiple studies have demonstrated the applicability of various imaging techniques for assessing angiogenesis in NPC tumors, thus serving as a foundation for personalized treatment strategies and prognostic assessments. Anti-angiogenic therapies have exhibited significant potential for inhibiting NPC angiogenesis and exerting anti-tumor effects. To enhance efficacy, anti-angiogenic drugs are frequently combined with other treatment modalities to synergistically enhance anti-tumor effects while mitigating the side effects associated with single-agent therapies, consequently improving patient prognosis. Identifying the potential mechanisms and key targets underlying NPC angiogenesis and exploring more effective detection and treatment approaches holds promise for shaping the future of NPC diagnosis, treatment, and prognosis, thereby offering new avenues and perspectives for research and clinical practice.