Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Research Articles

Retrospective study assessing the role of theandrogen receptor in clear cell renal cell cancer patients treated with VEGFR inhibitors in monotherapy.

Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading tothe question ofwhether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions. We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis. Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC. AR-overexpression and its association with other genes could favor a transcriptomic signature set to aidin identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.

Repeated treatment with VEGF receptor inhibitors induces phenotypic changes in endothelial cells and pericytes in the rat retina

Abnormal ocular angiogenesis is a major cause of visual impairment and vision loss in neovascularization-related diseases. Currently, anti-vascular endothelial growth factor (VEGF) drugs are used to treat ocular neovascularization, but repeated injections are needed to maintain their therapeutic effects. However, repeated injection of anti-VEGF drugs may affect the retinal blood vessel phenotype and diminish therapeutic effects. In this study, we aimed to investigate the phenotypic changes in endothelial cells and pericytes caused by the repeated interruption of the VEGF receptor signaling pathway in neonatal rats. KRN633 (10 mg/kg), a VEGF receptor tyrosine kinase inhibitor, was subcutaneously administered on postnatal day (P)-7 and P8 (first round), P14 and P15 (second round), and P21 and P22 (third round). The rat eyes were collected on P7, P9, P14, P16, P21, P23, P28, and P35. Using retinal flat-mount specimens stained with specific markers for vascular endothelial cells, basement membranes, and pericytes, the arteriolar tortuosity, capillary area density, and distribution of pericytes were evaluated. Significant loss of capillaries was observed the day after the first round of KRN633 treatment, after which aggressive angiogenesis occurred, leading to the formation of tortuous arterioles. Rats that completed second and third rounds of KRN633 treatment showed more severe abnormalities in the retinal vasculature than those that only completed first round treatment. Repeated treatment with KRN633 decreased the anti-angiogenic effects but increased the immunoreactivity of α-smooth muscle actin in the pericytes on veins and capillaries. α-Smooth muscle actin expression was inversely correlated to anti-angiogenic effects. Overall, these results revealed that repeated interruption of VEGF receptor signaling pathway altered the phenotypes of endothelial cells and pericytes and induced anti-VEGF drug resistance. Therefore, careful follow-up is necessary when using anti-VEGF drugs to treat abnormal angiogenesis-associated ocular diseases.

Hypertension toxicity of VEGFR-TKIs in cancer treatment: incidence, mechanisms, and management strategies.

Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are a class of targeted anticancer agents that include pazopanib, sunitinib, axitinib, and others. Currently, VEGFR-TKIs are widely used in the clinical treatment of various tumors, which can prolong patients' survival and even cure tumors. However, the use of VEGFR-TKIs is frequently associated with the occurrence of cardiovascular adverse events, with hypertension being the most prevalent. Hypertension and its complications can significantly impact the prognosis of patients, potentially jeopardizing their lives and resulting in the reduction or even cessation of treatment in severe cases. This review addresses the incidence of hypertension due to VEGFR-TKIs, mechanisms of toxicity, management strategies, and future research directions. In addition, hypertension due to VEGFR-TKIs may be associated with salt sensitivity, and possible mechanisms of hypertensive side effects are vasodilator imbalance, decreased capillary density, renal injury, impaired endothelial function due to oxidative stress, decreased lymphatic vascular density, and "off-target effect". A comprehensive understanding of hypertension toxicity due to cancer treatment with VEGFR-TKIs, can enhance clinical practice, thereby improving the prognostic outcomes of VEGFR-TKIs in oncology patients.

Pembrolizumab and Cabozantinib in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Long-term Survival Update with a Biomarker Analysis.

Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent and/or metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) have immunomodulatory properties and improve clinical outcomes in combination with anti-PD-1 therapy in different malignancies. We report the long-term efficacy and safety of pembrolizumab and cabozantinib in patients with RMHNSCC and include a correlative biomarker analysis. This open-label, single-arm, multicenter, phase 2 study screened 50 patients with RMHNSCC, of whom 36 received pembrolizumab and cabozantinib. The primary endpoint was overall response rate (ORR), safety, and tolerability. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and correlative studies of tissue and blood. We report the long-term PFS, OS, and safety of treated patients and describe correlative biomarkers evaluating p-MET expression and tumor immune microenvironment (TIME) using multiplex immunohistochemistry. With median follow-up of 22.4 months, the median PFS was 12.8 months with a 2-year PFS of 32.6% (95% CI, 18.8%-56.3%) and the median OS was 27.7 months with a 2-year OS of 54.7% [95% confidence interval (CI), 38.9%-76.8%]. The median duration of response was 12.6 months with a 2-year rate of 38.5% (95% CI, 30.8%-81.8%). Long-term treatment-related adverse events included manageable hypothyroidism (5.5%) and grade 1 elevated aspartate aminotransferase and alanine aminotransferase (2.8%). Baseline tumor p-MET expression correlated with ORR (P = 0.0055). Higher density of CD8+, CD103+, and CSF1-R+ cells at baseline correlated with improved OS [hazard ratio (HR) = 5.27, P = 0.030; HR = 8.79, P = 0.017; HR = 6.87, P = 0.040, respectively]. Pembrolizumab and cabozantinib provided prolonged encouraging long-term disease control and survival with a maintained favorable safety profile. The prognostic significance of higher density of CD8+, CD103+, and CSF1-R+ cells in TIME deserve further evaluation in similar clinical settings.

Baseline neutrophil-to-eosinophil-ratio and outcome in metastatic clear-cell renal cell carcinoma treated with nivolumab or ipilimumab/nivolumab.

This study aims to evaluate neutrophil-to-eosinophil ratio (NER) as a prognostic and/or predictive biomarker in metastatic clear cell renal cell carcinoma (m-ccRCC) treated with nivolumab or ipilimumab/nivolumab. We performed a retrospective study on m-ccRCC patients treated with nivolumab or ipilimumab/nivolumab (2012-2022). Baseline NER was calculated and correlated with clinical outcomes: response rate (RR), progression free survival (PFS) and overall survival (OS). Corresponding transcriptomic data were analysed. We included 201 m-ccRCC patients, 76 treated with ipilimumab/nivolumab and 125 with nivolumab. Baseline NER was statistically significantly associated with International Metastatic RCC Database Consortium (IMDC) risk groups. Increased NER was associated with shorter PFS and OS in the total patient series and nivolumab-treated patients. In patients treated with ipilimumab/nivolumab, increased NER was only statistically significantly associated with shorter OS. The impact of baseline NER on PFS and OS was independent of IMDC risk stratification. No clear correlation was found between baseline NER and RECIST response or maximal tumour shrinkage. In two additional databases, NER was also associated with PFS and OS in first-line vascular-endothelial-growth-factor-receptor tyrosine-kinase-inhibitors (VEGFR-TKIs), but not to disease-free survival in the post-nephrectomy setting. Lower NER was associated with intratumoural molecular features possibly associated with better outcome on immune checkpoint inhibitors. Lower baseline NER is associated with better PFS and OS, independent of IMDC risk score, in m-ccRCC patients treated with ipilimumab/nivolumab or nivolumab. It correlates with intratumoural molecular features possibly associated with better outcome on immune checkpoint inhibitors. The predictive power of this biomarker is probably limited and insufficient for patient selection.

Predicting Survival of Metastatic Clear Cell Renal Cell Cancer Treated with VEGFR-TKI-Based Sequential Therapy.

(1) Objective: To develop a clinically useful nomogram that may provide a more individualized and accurate estimation of cancer-specific survival (CSS) for patients with clear-cell (CC) metastatic renal cell carcinoma (mRCC) treated with nephrectomy and vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI)-based sequential therapy. (2) Methods: A prospectively maintained database of 145 patients with mRCC treated between 2008 and 2018 was analyzed to predict the CSS of patients receiving sunitinib and second- and third-line therapies according to current standards of practice. A nomogram based on four independent clinical predictors (Eastern Cooperative Oncology Group status, International Metastatic RCC Database Consortium score, the Morphology, Attenuation, Size and Structure criteria and Response Evaluation Criteria in Solid Tumors response criteria) was calculated. The corresponding 1- to 10-year CSS probabilities were then determined from the nomogram. (3) Results: The median age was 60 years (95% CI 57.9-61.4). The disease was metastatic at diagnosis in 59 (40.7%), and 86 (59.3%) developed metastasis during follow-up. Patients were followed for a median 48 (IQR 72; 95% CI 56-75.7) months after first-line VEGFR-TKI initiation. The concordance probability estimator value for the nomogram is 0.778 ± 0.02 (mean ± SE). (4) Conclusions: A nomogram to predict CSS in patients with CC mRCC that incorporates patient status, clinical risk classification and response criteria to first-line VEGFR-TKI at 3 months is presented. This new tool may be useful to clinicians assessing the risk and prognosis of patients with mRCC.

Advanced Renal Cell Cancer Combination Immunotherapy Clinical Trial (ARCITECT; HCRN GU 22-587)

Abstract Background First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods ARCITECT is a phase II, multicenter study evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has > 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR > 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806. Results

The Efficacy and Safety of Apatinib and Anlotinib in Advanced Non-Small Cell Lung Cancer.

Anlotinib and apatinib, both vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), are clinically established in the treatment of advanced non-small cell lung cancer (NSCLC) in China, with anlotinib emerging as a standard treatment strategy. This study was conducted to evaluate the efficacy and safety of apatinib and anlotinib, and to compare their differences in treating patients with advanced NSCLC. We retrospectively analyzed the data of patients with advanced NSCLC treated with apatinib or anlotinib at a hospital in Eastern China from January 2017 to December 2021. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profile. A total of 145 patients were included in this study. Median PFS (mPFS) was 3.53 months for the apatinib group and 5.3 months for the anlotinib group (HR = 0.59, 95% CI: 0.41-0.84; P = 0.004), and median OS (mOS) was 7.6 months versus 15.6 months (HR = 0.68, 95% CI: 0.46-1.00; P = 0.048), which all showed significant differences after adjusting for confounders (P < 0.05). Subgroup analysis revealed that the presence or absence of bone metastases significantly influenced PFS in both treatment groups. The ORR was 3.03% in the anlotinib group versus 10.13% in the apatinib group (P = 0.12), the DCR was 72.73% versus 51.90% (P = 0.21). No unanticipated adverse events (AEs) were observed. The incidence of grade 3-4 AEs was significantly higher in the apatinib group (31.65% vs 13.64%, P < 0.05). Anlotinib demonstrated greater efficacy and safety compared to apatinib in the treatment of advanced NSCLC, particularly in patients with bone metastases and EGFR(-).

STELLAR-303: randomized phase III study of zanzalintinib+atezolizumab in previously treated metastatic colorectal cancer.

Most patients with metastatic colorectal cancer (mCRC) have limited treatment options following standard-of-care therapy. VEGFR-tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity in mCRC in combination with immune checkpoint inhibitors (ICIs), particularly in patients without liver metastases. The TKI zanzalintinib (XL092) targets VEGFR, MET and TAM kinases, proteins that are involved in tumor growth, angiogenesis, metastasis and immunosuppression. Zanzalintinib has immunomodulatory properties that may enhance response to ICIs. Presented is the design of STELLAR-303, a global, phase III, open-label, randomized study evaluating zanzalintinib plus atezolizumab versus regorafenib in patients with non-MSI-H mCRC who progressed during/after or are refractory/intolerant to standard-of-care therapy. The primary end point is overall survival in patients without liver metastases.Clinical Trial Registration: NCT05425940 (ClinicalTrials.gov).

Concomitant Administration of VEGFR Tyrosine Kinase and Proton Pump Inhibitors May Impair Clinical Outcome of Patients With Metastatic Renal Cancer

IntroductionThe administration of proton pump inhibitors (PPIs) is a common practice to reduce gastro-esophageal adverse events associated with drug treatments but may impair absorption and exposure to oncology drugs. This study investigated the effect of concomitant administration of PPIs and pazopanib, sunitinib and cabozantinib on survival of patients with metastatic clear cell renal carcinoma (mRCC). Patients and MethodsTotal 451 patients receiving pazopanib, sunitinib and cabozantinib as first line treatment were enrolled in this retrospective study. Patients were defined as “no concomitant PPIs (PPI−)” if no PPIs were administered during TKIs, and as “concomitant PPIs (PPI+)” if the administration of PPIs was at least 75% of the time during which TKIs were given. ResultsEighty patients administered pazopanib were PPI− and 86 PPI+; no difference in PFS was observed (10.7 vs. 11.9 months, P = .79). If patients were stratified as short (n = 89) and long (n = 77) responders, there was a significant difference in terms of PFS in PPI+ (n = 47) versus PPI− (n = 30) in long responders, being 24.7 versus 38 months (P = .04), respectively. In the sunitinib cohort, no significant difference of PFS in PPI+ (n = 102) versus PPI− (n = 131) was found, being 11.3 versus 18.1 months, respectively (P=0.15). In the cabozantinib cohort, there was a statistically significant difference in PFS of PPI+ versus PPI− (6 months vs. not reached, P = .04). No correlation with adverse events was found. ConclusionsThis study demonstrates an association between PPIs and impaired PFS in mRCC patients given pazopanib and cabozantinib and recommends caution on their concomitant use.

Identification of naturally occurring flavonoids as anticancer agents: In silico studies

It is recognized that flavonoids have a variety of functions in nature, including anti-inflammatory, antibacterial, antioxidant, anticancer, anti-HIV and neuroprotective properties. In the present study, molecular docking experiment was performed on 15 naturally occurring flavonoids as anticancer agents. The analysis of results was performed on the basis of docking score, glide energy and interaction with amino acids. Each flavonoid showed a specific interaction with target protein. Naringin showed interactions with amino acids GLN131, ASP145, PHE80, VAL83, GLU8, ILE10, THR89 (docking score −12.48) involved with the protein PDB ID: 1gij (inhibitor of cyclin-dependent kinase 4). Naringin further showed interactions with THR887, THR886, LYS833, ASP836 amino acids (docking score −15.078) involved with PDB ID: 5jhb (inhibitor of PI3K and tubulin). Orientin showed interactions with amino acids ASN150, ASP163, LYS43, VAL101 (docking score −13.89) with PDB ID: 2euf as inhibitor of cyclin-dependent kinase 6. Quercetin showed interactions with amino acids PHE1047, LEU840, CYS919, GLU917 (docking score −11.7) with PDB ID: 4agd as inhibitor of VEGF receptor tyrosine kinase inhibitor. Epigallocatechin gallate showed interactions with amino acids LYS868, GLU885, THR916, ASP1046 using protein PDB ID: 3ewh (docking score −10.004) as inhibitor of Tie-2 kinase. The given flavonoid drugs interaction with cancer targets shows their possible potential against various forms of cancer. Epigallocatechin gallate when docked with 3ewh showed best docking score with important interaction required for anticancer activity. In molecular dynamic study, Epigallocatechin gallate in complex with VEGFR2 kinase protein (PDB ID: 3ewh) with RMSD indicates the protein remained stable through the simulation of 100ns with fluctuation in the range of 1.5–3.5 Å. The provided docking results may be useful for the development of novel drug candidate for anticancer targets.

Increase in blood pressure in patients with metastatic kidney cancer treated with combination checkpoint inhibitor and vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy.

e24128 Background: The combination therapy of an immune checkpoint inhibitor (ICI) with a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) is considered a first line treatment option for patients with metastatic clear cell renal cell carcinoma (ccRCC). TKI-induced hypertension is a well-known potential side effect with VEGFR-TKIs however little is known about the real-world increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with and without underlying hypertension treated with this combination therapy. Methods: A retrospective study was performed that included patients with metastatic ccRCC who were treated at the University of Florida Health Cancer Center between June 2019 and September 2022 who received treatment with the combination of an ICI and VEGFR-TKI. The data collected included history of hypertension, patients use of anti-hypertensive therapy at baseline, SBP and DBP prior to initiation of therapy and at approximately one month after initiation of treatment. Results: We identified a total of 29 patients who met the inclusion criteria for our study. The median age was 68 years old (IQR 61-72) while 25 patients (86%) were male and 4 (14%) were females. There were 27 patients (93%) who were treated with axitinib with pembrolizumab, while 1 (3%) was treated with cabozantinib with nivolumab, and 1 (3%) was treated with lenvatinib with pembrolizumab. Out of the 29 patients, 11 (38%) did not have hypertension prior to therapy while 18 (62%) did have baseline hypertension and were receiving at least one anti-hypertensive treatment. In those patients without baseline hypertension, the median baseline SBP was 113 and the median SBP after one month of treatment was 144 (p = 0.01). Conversely, those patients with baseline hypertension, the median baseline SBP was 122 and median SBP after one month of treatment was 148 (p = 0.003). In those without hypertension at baseline, the mean SBP increase after one month was 27.3% while in those with baseline hypertension the mean increase in SBP of 17.0%. Conclusions: Our study demonstrates that in a real-world population of patients with metastatic ccRCC there is a statistically significant elevation of both SBP and DBP when treated with the combination of an ICI and VEGFR-TKI and that in those patients without baseline hypertension and not on anti-hypertensive therapy at baseline, there is a more pronounced increase in blood pressure. This data should reinforce the need to have close monitoring of SBP and DBP during therapy, regardless of whether the patient has underlying hypertension or not, and may help guide anti-hypertensive therapy during kidney cancer treatment.

Efficacy and safety of fruquintinib across different subgroups of patients with previously treated metastatic colorectal cancer: A meta-analysis.

e15589 Background: Most patients with mCRC eventually develop disease progression or intolerance to first- and second-line therapy. Fruquintinib, a selective oral tyrosine kinase inhibitor of VEGFRs 1, 2, and 3, has emerged as a novel treatment option for refractory mCRC. We conducted a meta-analysis to assess the safety and efficacy of Fruquintinib for the treatment of refractory mCRC compared to placebo in specific patient subgroups of interest. Methods: We systematically searched PubMed, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) reporting Fruquintinib efficacy. The data extraction followed PRISMA guidelines and our protocol was registered in PROSPERO (CRD42023477783). Summary hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were calculated using a random-effects model. The likelihood of Fruquintinib being associated with adverse events (AEs) was expressed by odds ratios (ORs). Results: Of the 1138 studies yielded by the search, three were included, totaling 1178 patients, of whom 786 (67%) received Fruquintinib. This meta-analysis of three randomized trials assessed the clinical outcomes of Fruquintinib in the intervention group compared with placebo in refractory mCRC. Pooled results from all three studies suggested the superiority of Fruquintinib in PFS (HR: 0.29 [0.25, 0.34], 95% CI, I² = 10%, p &lt; 0.01) and OS (HR: 0.66 [0.57, 0.76], 95% CI, p &lt; 0.01). Notably, subgroup analysis showed that Fruquintinib was associated with improved PFS in patients with prior use of VEGF inhibitors (HR: 0.32 [0.27, 0.38], 95% CI, p &lt; 0.01) and those with more than three prior lines of treatment (HR: 0.37 [0.25, 0.53], 95% CI, p &lt; 0.01), RAS wild-type status (HR: 0.25 [0.13, 0.35], 95% CI, p &lt; 0.01), or RAS mutated (HR: 0.33 [0.28, 0.40], 95% CI, p &lt; 0.01). In the safety analysis, fruquintinib and placebo showed no significant differences in serious AEs; nonetheless, the VEGFR inhibitor was associated with more frequent grade ≥ 3 AEs (OR: 3.13 [1.15, 8.53], 95% CI, p = 0.03). Conclusions: This meta-analysis supports the efficacy of Fruquintinib for refractory mCRC regardless of previous use of VEGF inhibitors, the number of previous treatment lines, and gene RAS mutational status, without a significant increase in serious adverse events. [Table: see text]

Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).

TPS4614 Background: First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods: ARCITECT is a phase II, multicenter investigator initiated trial evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has &gt; 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR &gt; 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806 .

Role of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte-ratio (PLR) in unresectable hepatocellular carcinoma (uHCC): Subgroup analysis of patients treated with camrelizumab (cam) + rivoceranib (rivo) in the CARES-310 trial.

e16197 Background: CARES-310 (NCT03764293) evaluated the combination of the PD-1 inhibitor, cam, and the VEGFR-2 tyrosine kinase inhibitor, rivo, compared to sorafenib (sor) for the treatment of 543 patients (pts) with uHCC. Cam + rivo significantly improved mOS (22.1 months [mo] [95% CI 19.1-27.2] vs 15.2 mo [13.0-18.5] HR 0.62 [95% CI 0.49-0.80]; one-sided p &lt; 0.0001) and mPFS (5.6 mo [95% CI 5.5-6.3] vs 3.7 mo [2.8-3.7]; HR 0.54 [95% CI 0.44-0.67]; one-sided p &lt; 0.0001) compared to sor. The most common (≥20%) grade ≥3 treatment-related adverse events (TRAEs) for cam + rivo were hypertension (37.5%) and increased AST (16.5%) vs palmar-plantar erythrodysesthesia syndrome (15.2%) for sor. An elevated level of inflammation, including NLR and PLR, have been associated with poor survival outcomes in pts with HCC (Lin S, et al. Trans Cancer Res. 2021). Here, we present a subgroup analysis of the CARES-310 trial evaluating the impact of baseline (BL) NLR and PLR status on pt outcomes. Methods: The subgroup of pts treated with cam+rivo and BL NLR &lt; 5 or ≥5 and PLR &lt; 300 or ≥300 were evaluated for mOS, mPFS, overall response rate (ORR), disease control rate (DCR), and safety. Results: Of 272 pts treated with cam+rivo, 64.3% of pts had extrahepatic spread, median AFP was 84.1 ng/mL, 86.8% were Child-Pugh (CP) class A5, 13.2% were CP class A6, 73.5% were ALBI grade 1, 26.5% were ALBI grade 2. Additionally, 249 pts had NLR &lt; 5, 10 pts had NLR ≥5, 252 pts had PLR &lt; 300, and 7 pts had PLR ≥300. Pts with BL NLR &lt; 5 and PLR &lt; 300 demonstrated improved outcomes in mOS, mPFS, ORR, and DCR vs pts with BL NLR ≥5 and PLR ≥300 (Table). Rates of any grade TRAEs and grade ≥ 3 TRAEs were comparable between pts with BL NLR &lt; 5 and ≥5 and PLR &lt; 300 and ≥300 (Table). Conclusions: These results suggest that NLR and PLR may serve as a prognostic marker in patients with uHCC, but larger studies are needed to validate these findings. Clinical trial information: NCT03764293 . [Table: see text]

STELLAR-305: A randomized phase 2/3 study of zanzalintinib plus pembrolizumab versus pembrolizumab alone in patients with previously untreated PD-L1 positive recurrent/metastatic head and neck squamous cell carcinoma.

TPS6114 Background: VEGFR, MET, and the TAM kinase AXL are overexpressed in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC); their activation contributes to increased tumor aggressiveness and poor prognosis. The immune checkpoint inhibitor (ICI) pembrolizumab, as monotherapy or in combination with chemotherapy, is a standard of care in patients with PD-L1 expressing R/M HNSCC. However, the response rate and survival benefit with pembrolizumab monotherapy are unsatisfactory, and addition of chemotherapy results in unfavorable toxicity. Zanzalintinib is a novel, multi-targeted tyrosine kinase inhibitor (TKI) of VEGFR, MET, and the TAM kinases (TYRO3, AXL, MER). Preclinical data suggest zanzalintinib-mediated inhibition of these kinases may suppress tumor growth and angiogenesis, while simultaneously promoting an immune-permissive tumor microenvironment that may enhance response to ICIs. Zanzalintinib + ICI combination has shown promising antitumor activity and manageable safety in a phase 1 study in solid tumors. To further support the TKI-ICI combination, phase 2 clinical activity was observed in R/M HNSCC with the multi-targeted TKI cabozantinib (inhibits VEGFR, MET, and TAM kinases) in combination with pembrolizumab. The present study, STELLAR-305, will evaluate the efficacy and safety of zanzalintinib + pembrolizumab vs pembrolizumab alone in previously untreated, PD-L1-positive, R/M HNSCC. Methods: STELLAR-305 (NCT06082167) is a randomized, double-blind, phase 2/3 study. Eligible patients are adults (≥18 years) with histologically or cytologically confirmed R/M HNSCC that is incurable with local therapy. Patients may not have been treated with systemic therapy, unless given as part of multimodal treatment for locally advanced disease and completed &gt;6 months before randomization. Patients must have a primary tumor location of the oropharynx (HPV testing required), oral cavity, hypopharynx, or larynx; those with nasopharynx, salivary gland, or occult primary sites are excluded. Other eligibility criteria include a PD-L1 CPS ≥1, measurable disease per RECIST v1.1, and an ECOG performance status of 0–1. Patients with prior treatment with ICIs or zanzalintinib are not eligible. Patients will be randomized 1:1 to zanzalintinib + pembrolizumab, or placebo + pembrolizumab. The dual primary endpoints are PFS per RECIST v1.1 by blinded independent radiology committee and overall survival. Secondary endpoints include safety, PFS per RECIST v1.1 by investigator, objective response rate, and duration of response. If minimum efficacy requirements are met in phase 2, the study will proceed to phase 3 with approximately 500 patients enrolled across both phases. STELLAR-305 is currently enrolling, with 200 sites estimated for global expansion. Clinical trial information: NCT06082167 .

Expression of the receptor tyrosine kinase AXL and clinical outcomes to cabozantinib and everolimus in patients with metastatic renal cell carcinoma enrolled in the METEOR trial.

4543 Background: High expression of the receptor tyrosine kinase AXL has been associated with resistance to targeted agents and anti-PD-1 therapy in multiple tumor types, including metastatic clear cell Renal Cell Carcinoma (mccRCC). Cabozantinib (cabo), a multitargeted tyrosine kinase inhibitor (TKI) active against VEGFR, MET, and AXL, is approved for the treatment of mccRCC, but no predictive biomarkers are available. Here, we analyzed tumor samples from the METEOR trial to assess whether AXL expression predicts improved clinical outcomes with cabo relative to everolimus (evero, mTOR inhibitor) in patients (pts) with mccRCC. Methods: Double immunohistochemistry staining for AXL and CD45/CD163 (immune cell/ macrophage markers) was performed on 278 pretreatment tumor tissues from the METEOR trial (cabo=147; evero=131). Image analysis algorithms were used to assess the % of AXL+ tumor cells (TC), % of AXL+ immune cells (IC), and combined % of AXL+ TC and IC (TC/IC). Optimal cutoffs, based on the minimum p-value approach, were determined at the 17th, 30th, and 22nd percentile for TC, IC, and TC/IC, respectively. The association with progression-free survival (PFS) was assessed using Cox regression adjusted for IMDC risk groups, the presence of bone metastases, and the number of previous VEGFR TKI treatments. The association with objective response rate (ORR) (cabo arm only due to low response rate in evero arm) was reported descriptively. Results: We observed a strong correlation between % AXL+ TC and % AXL+ IC (Spearman correlation coefficient 0.85; p-value &lt;0.001). In the evero arm, high % AXL+ TC and high % AXL+ TC/IC were significantly associated with shorter PFS (median 1.9 vs. 4.1 months and 1.9 vs 4.2 months, respectively); a similar trend was observed for % AXL+ IC. In the cabo arm, % AXL+ TC, % AXL+ IC, and % AXL+ TC/IC were not associated with PFS or ORR (Table). The magnitude of increase in PFS for pts receiving cabo versus evero was larger in pts with high % AXL+ TC compared to pts with low % AXL+ TC (HR: 0.30 vs. 0.51, p-interaction=0.18) and in pts with high % AXL+ TC/IC compared to pts with low % AXL+ TC/IC (HR: 0.30 vs 0.53, p-interaction=0.12). Conclusions: Our finding that the improvement in outcome with cabo relative to evero is more evident in pts with high levels of AXL expression supports that the antitumor activity of cabo in mccRCC is mediated, in part, by AXL inhibition. Our work identifies AXL expression as a potential predictive biomarker for cabo-based therapies in mccRCC. [Table: see text]

Preliminary data of a phase Ib/II trial evaluating the efficacy and safety of adebrelimab, camrelizumab plus apatinib as first-line therapy in patients with advanced hepatocellular carcinoma.

e16221 Background: The CARES-310 study has demonstrated that the combination of the anti-PD-1 antibody camrelizumab and the VEGFR2 tyrosine kinase inhibitor apatinib exhibits improved progression-free survival (PFS) and overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC). We conducted this study to investigate whether the addition of the anti-PD-L1 antibody adebrelimab to camrelizumab and apatinib would further improve clinical outcomes. Methods: This is a prospective, phase 1b/2 clinical trial employing the i3 + 3 dose escalation design. Eligibility includes adults with unresectable or metastatic HCC, a ECOG PS of 0 or 1, a Child-Pugh score ≤ 7, and at least one measurable lesion per RECIST v 1.1. In phase 1b, patients (pts) received adebrelimab (10 mg/kg or 20 mg/kg, I.V., D1, Q3W), camrelizumab (200mg, I.V., D1, Q3W), and apatinib (250 mg orally daily). Phase 2 is a single arm, open-label trial in the first-line setting. The primary objective were dose-limiting toxicity (DLT), maximal tolerated dose (MTD), and recommended phase II dose (RP2D). With α = 0.05 and 80% power, the pts needed for stage I and total of the Simon 2-stage design was 17 and 41 pts, respectively. Results: As of 4 February 2024, 6 HCC pts progressed after or were intolerant to first-line treatment (systemic therapy ± surgical resection) were treated in 1 dose cohorts. 1 DLT occurred (Grade 3 elevated blood bilirubin increased). The RP2D was adebrelimab (10 mg/kg), camrelizumab (200mg), and apatinib (250 mg). The most common drug-related AEs were Hypertension (83.3%) and Rash (50%); and Serum amylase increased, Itching, ALT/AST increased, and Hypothyroidism (each 33.3%). Immune-related AEs were similar to those seen with other checkpoint blockade agents. No drug-related AEs led to death. 1 pts (16.7%) discontinued due to drug-related AEs. Conclusions: The combination of Adebelimumab, Camrelizumab, and Apatinib demonstrated manageable safety for unresectable HCC. Enrollment in the phase II trial is ongoing and updated clinical data will be presented. Clinical trial information: NCT05924997 .

The efficacy of subsequent therapy after failure of anti-PD-1 antibody in metastatic renal cell carcinoma.

The optional regimens of subsequent therapy after failure of anti-programmed cell death protein-1 (PD-1) antibody in metastatic renal cell carcinoma (mRCC) remain to be explored. There are reports of the efficacy of single-agent vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) in patients with mRCC after failure of anti-PD-1 antibody therapy. However, it is not clear whether it is beneficial for patients to receive anti-PD-1 antibody as post-progression treatment. It has great significance to explore whether continuous application of anti-PD-1 antibody is beneficial for patients with mRCC whose diseases progressed to the state of pre-anti-PD-1 therapy. The purposes of this study are to explore the efficacy and safety of subsequent treatment on whether to continue using anti-PD-1 antibody therapy for patients who have progressive mRCC after prior treatment with anti-PD-1 antibody. The clinical data of patients with mRCC from the Department of Immunotherapy in the Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital from February 1, 2019 to December 31, 2021 were analyzed retrospectively. The primary endpoints were the objective response rate (ORR) and progression-free survival (PFS). The ORR and disease control rate (DCR) were estimated with Fisher's exact test. PFS and overall survival (OS) were assessed using the Kaplan-Meier method and log-rank tests. The associations between potential prognostic variables and PFS were evaluated with univariate and multivariate Cox regression analyses. A P value of less than or equal to 0.05 was deemed as statistically significant. A total of 35 patients were included in this study, during which 19 received VEGFR-TKI monotherapy and 16 received the VEGFR-TKI plus anti-PD-1 antibody therapy. Until the last follow-up on June 30, 2022, 19 patients experienced progressive disease (PD), five were in remission, and 11 kept stable disease (SD). After a median follow-up of 28.7 [95% confidence interval (CI): 17.0-35.6] months, the median PFS (mPFS) was 11.6 months for the VEGFR-TKI group and 9.1 months for the VEGFR-TKI plus anti-PD-1 antibody group [hazard ratio (HR) =0.81, 95% CI: 0.32-1.03, P=0.44]. Median OS (mOS) were 16.9 and 11.2 months respectively (HR =0.99, 95% CI: 0.44-2.27, P=0.90). The ORRs were 26.3% and 0% (P=0.049), and the DCRs were 47.4% and 43.8% (P=0.55) respectively. Treatment-related adverse events (TRAEs) occurred in 14 patients (73.7%) in the VEGFR-TKI group and 14 patients (87.5%) in the VEGFR-TKI plus anti-PD-1 antibody group (P=0.42); grade 3/4 TRAEs occurred in two patients (10.5%) and six patients (37.5%) respectively (P=0.11). VEGFR-TKI monotherapy is an efficacious regimen for patients with mRCC whose diseases progressed on previous anti-PD-1 antibody therapy, and continuous anti-PD-1 therapy after failure of anti-PD-1 antibody could not provide additional clinical benefit but increased the incidence of TRAEs.

Characterization of a polysaccharide from Amauroderma rugosum and its proangiogenic activities in vitro and in vivo

Amauroderma rugosum (AR), also known as “Blood Lingzhi” in Chinese, is a basidiomycete belonging to the Ganodermataceae family. Four polysaccharide fractions were systematically isolated and purified from AR. Subsequently, their compositions were examined and analyzed via high-performance gel permeation chromatography (HPGPC), analysis of the monosaccharide composition, Fourier-transform infrared spectroscopy (FT-IR), and 1H nuclear magnetic resonance (NMR). The zebrafish model was then used to screen for proangiogenic activities of polysaccharides by inducing vascular insufficiency with VEGF receptor tyrosine kinase inhibitor II (VRI). The third fraction of AR polysaccharides (PAR-3) demonstrated the most pronounced proangiogenic effects, effectively ameliorating VRI-induced intersegmental vessel deficiency in zebrafish. Concurrently, the mRNA expression levels of vascular endothelial growth factor (VEGF)-A and VEGF receptors were upregulated by PAR-3. Moreover, the proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs) were also stimulated by PAR-3, consistently demonstrating that PAR-3 possesses favorable proangiogenic properties. The activation of the Akt, ERK1/2, p38 MAPK, and FAK was most likely the underlying mechanism. In conclusion, this study establishes that PAR-3 isolated from Amauroderma rugosum exhibits potential as a bioresource for promoting angiogenesis.