Endothelial Growth Factor Receptor-tyrosine Kinase Research Articles

Primary resistance to nivolumab plus ipilimumab therapy affects second-line treatment outcomes in patients with metastatic renal cell carcinoma.

Nivolumab plus ipilimumab (NIVO+IPI) has a long-term response rate of 30% for patients with metastatic renal cell carcinoma (mRCC). However, 20% of patients develop primary resistant disease (PRD) to NIVO+IPI and show poor survival outcomes. In this study, we aimed to evaluate the effect of PRD as a second-line treatment in patients with mRCC. The data used in this multi-institutional, retrospective cohort were collected between August 2015 and January 2023. In total, 189 patients with mRCC were treated with NIVO+IPI and then with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor. Associations between PRD and progression-free survival of second-line treatment (PFS), progression-free survival 2 (PFS2), and overall survival (OS) were analyzed. The median age at NIVO+IPI initiation was 67 years in the male-dominant population (n = 140, 74.1%), and most patients had clear cell histology (n = 140, 74.1%). PRD was recorded in 42 (22.2%) of 189 patients during NIVO+IPI therapy. Patients who experienced PRD showed poor PFS (hazard ratio [HR], 1.788; 95% confidence interval [CI], 1.176-2.718; p = 0.007), PFS2 (HR, 4.127; 95% CI, 2.649-6.431; p < 0.001), and OS (HR, 3.330; 95% CI, 2.040-5.437; p < 0.001). Before starting second-line therapy, patients with PRD tended to have a poor performance status compared with non-PRD patients and a higher IMDC risk. Second-line drug therapy was not associated with treatment outcomes in patients with PRD. PRD in patients with mRCC receiving NIVO+IPI as first-line treatment was associated with poor clinical course, even with second-line therapy.

Predicting first-line VEGFR-TKI resistance and survival in metastatic clear cell renal cell carcinoma using a clinical-radiomic nomogram.

This study aims to construct predicting models using radiomic and clinical features in predicting first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) early resistance in metastatic clear cell renal cell carcinoma (mccRCC) patients. We also aim to explore the correlation of predicting models with short and long-term survival of mccRCC patients. In this retrospective study, 110 mccRCC patients from 2009 to 2019 were included and assigned into training and test sets. Radiomic features were extracted from tumor 3D-ROI of baseline enhanced CT images. Radiomic features were selected by Lasso method to construct a radiomic score. A combined nomogram was established using the combination of radiomic score and clinical factors. The discriminative abilities of the radiomic, clinical and combined nomogram were quantified using ROC curve. Cox regression analysis was used to test the correlation of nomogram score with progression-free survival (PFS) and overall survival (OS). PFS and OS were compared between different risk groups by log-rank test. The radiomic, clinical and combined nomogram demonstrated AUCs of 0.81, 0.75, and 0.83 in training set; 0.79, 0.77, and 0.88 in test set. Nomogram score ≥ 1.18 was an independent prognostic factor of PFS (HR 0.22 (0.10, 0.47), p < 0.001) and OS (HR 0.38 (0.20, 0.71), p = 0.002), in training set. PFS in low-risk group were significantly longer than high-risk group in training (p < 0.001) and test (p < 0.001) set, respectively. OS in low-risk group were significantly longer than high-risk group in training (p = 0.003) and test (p = 0.009) set, respectively. A nomogram combining baseline radiomic signature and clinical factors helped detecting first-line VEGFR-TKI early resistance and predicting short and long-term prognosis in mccRCC patients.

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.

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(-).

Zinc supplementation is associated with improvement in hand-foot skin reaction in patients on vascular endothelial growth factor receptor-tyrosine kinase inhibitors: A cohort study

Zinc supplementation is associated with improvement in hand-foot skin reaction in patients on vascular endothelial growth factor receptor-tyrosine kinase inhibitors: A cohort study

NCMP-01. TREATMENT STRATEGIES IN PATIENTS WITH RENAL CELL CANCER AND BRAIN METASTASES

Abstract BACKGROUND Brain metastases (BM) significantly impact quality of life and survival in patients with metastatic renal cell cancer (mRCC). Based on the International Metastatic RCC Database Consortium (IMDC) risk classification, treatment strategies for patients with mRCC vary from systemic treatment with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) and/or immune checkpoint inhibitors (ICIs) to active surveillance (AS). Here, we describe the impact of treatment strategies on survival in patients with RCC and BM. METHODS We conducted a single-center, retrospective cohort study at Erasmus MC Cancer Institute (Rotterdam, Netherlands). All consecutive patients with RCC BM between 2011-2022 were included. Primary outcome was the BM-free survival, i.e. the time between diagnosis of extracranial metastases (ECM) and BM. Secondary outcome was overall survival (OS). RESULTS 46 patients with RCC BM were included: 25 (54.3%) had received prior systemic treatment for ECM, and 21 (45.7%) were treatment naive at diagnosis of BM. IMDC scores (favorable 12% resp. 0%, intermediate 48% resp. 64%, poor 24% resp. 0%, unknown 16% resp. 36%) were not significantly different (p=0.07) between these groups. In 39 (84.8%) of 46 patients, BM were metachronous ( &amp;gt;1 month) after ECM. In these patients (n=39), the median BM-free survival was 22.3 (IQR 5.7-46.7) months and was significantly longer (p=0.02) in previously treated patients (29.0 [IQR 12.6-57.0] months) as compared to treatment naive patients (6.8 [IQR 1.0-7.0] months). However, median OS since ECM diagnosis (39.1 [IQR 16.5-111.5] months) was not significantly different (p=0.62) between previously treated and treatment naive patients. CONCLUSION Patients with RCC who received systemic treatment for ECM prior to BM diagnosis, had a longer BM-free survival as compared to patients without previous systemic treatment. These results emphasize the need for careful evaluation of AS in patients with mRCC, even in patients with a favorable prognostic profile.

The Incidence and Management of Cancer-Related Anorexia During Treatment with Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors.

Cancer-related anorexia is a common complication and frequently occurs in cancer patients treated with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). Anorexia contributes to malnutrition, body weight loss, and cachexia in affected patients. Furthermore, patients who experience anorexia have worse outcomes than those who maintain their appetite, highlighting the importance of managing anorexia and related symptoms. However, as the causes of anorexia are both diverse and interconnected, there have been challenges in evaluating and implementing effective interventions. In this review, we described the contributing factors to cancer-related anorexia and reviewed recent literature for the frequency of anorexia symptoms in patients treated with VEGFR-TKIs. Additionally, we evaluated the evidence for current interventions and the potential benefits of multimodal and multidisciplinary approaches to care. The frequency of anorexia symptoms in patients who received VEGFR-TKIs ranged from 14%-58% for all-grade anorexia and 0%-6% for grade 3 or 4 anorexia. While many of the interventions for cancer-related anorexia have minimal benefit or adverse events, recent advances in our understanding of cancer-related anorexia suggest that multimodal therapy with multidisciplinary care is a promising avenue of investigation. Several studies currently underway are anticipated to further assess the effectiveness of multimodal approaches.

Safety profile of vascular endothelial growth factor receptor tyrosine-kinase inhibitors in pediatrics: a pharmacovigilance disproportionality analysis.

Introduction: existing research on children consists primarily of phase I/II clinical trials for VEGFR-TKI. System reports of safety on the use of VEGFR-TKI in pediatrics are lacking. Aim: to investigate the safety profiles of VEGFR-TKI in pediatrics via the FDA Adverse Event Reporting System (FAERS). Method: data regarding VEGFR-TKIs were extracted from the FAERS between 2004Q1 to 2022Q3 and categorized by the Medical Dictionary for Regulatory Activities (MedDRA). Population characteristics were analyzed, and reporting odds ratio (ROR) was performed to identify risk signals associated with VEGFR-TKI. Results: 53,921 cases containing 561 children were identified in the database from 18 May 2005, to 30 September 2022. Among those in the system organ class, skin, subcutaneous tissue disorders, and blood and lymphatic system disorders in pediatrics contributed to over 140 cases. Palmar-plantar eythrodysesthesia syndrome (PPES) in VEGFR-TKI presented the most significant 340.9 (95% 229.2-507.0). And pneumothorax also gave a high reporting odds ratio of 48.9 (95% 34.7-68.9). For a specific drug, musculoskeletal pain gave a ROR of 78.5 (95% 24.4-252.6) in cabozantinib and oesophagitis in lenvatinib with a ROR of 95.2 (95% 29.5-306.9). Additionally, hypothyroidism presented a high signal, especially sunitinib, with a ROR of 107.8 (95% 37.6-308.7). Conclusion: the present study explored the safety profile of VEGFR-TKI in pediatrics using the FAERS database. Multiple skin and subcutaneous tissue disorders, as well as blood and lymphatic system disorders, were common VEGFR-TKI-related AEs in system organ class. No serious hepatobiliary AEs were detected. For the specific AEs, PPES and pneumothorax were VEGFR-TKI-related AEs that presented significantly higher signals than those in the general population.

Real-world effectiveness of nivolumab and subsequent therapy in Japanese patients with metastatic renal cell carcinoma (POST-NIVO study): 36-month follow-up results of a clinical chart review.

To examine the long-term effectiveness of nivolumab monotherapy and following subsequent therapies for metastatic renal cell carcinoma (mRCC) in Japanese real-world settings. This was a multicenter, retrospective, observational study, with a 36-month follow-up, and conducted in Japanese patients with mRCC who initiated nivolumab monotherapy between 1 Feb 2017 and 31 Oct 2017. Endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Of the 208 patients, 36.5% received nivolumab monotherapy as second-line, 30.8% as third-line, and 31.7% as fourth- or later-line therapy. By 36 months, 12.0% of patients continued nivolumab monotherapy; 88.0% discontinued, mainly because of disease progression (66.7%). The median (m) OS was not reached irrespective of treatment line, with a 36-month OS rate of 54.3% (second-line, 57.4%; third-line, 52.6%; fourth- or later-line, 52.9%). The ORR was 24.2% and five patients achieved complete response. The OS from first-line therapy was 8.9 years. In the 95 patients receiving therapy after nivolumab, 87.4% received vascular endothelial growth factor receptor-tyrosine kinase inhibitors, with mOS and mPFS of 27.4 and 8.1 months, respectively. Irrespective of treatment line, the mOS was not reached in patients with International Metastatic RCC Database Consortium (IMDC) favorable or intermediate risk at mRCC diagnosis. This 36-month real-world follow-up analysis showed a survival benefit of nivolumab monotherapy for patients with mRCC. The long-term effectiveness of sequential therapy from first-line therapy to therapy after nivolumab was also demonstrated. Additionally, nivolumab monotherapy was beneficial for patients with favorable IMDC risk at the time of mRCC diagnosis.

Analysis of Anti-Angiogenesis-Related Adverse Events Associated with Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors (VEGFR-TKIs) in Patients with Metastatic Renal Cell Carcinoma.

Limited studies have evaluated anti-angiogenesis-related adverse events involving oral vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) in metastatic renal cell carcinoma using real-world data. This study aimed to investigate the incidence, patterns, and impact on the dose intensity of anti-angiogenesis-related adverse events associated with the use of VEGFR-TKIs in patients with metastatic renal cell carcinoma using real-world data. This cross-sectional study included patients with a diagnosis of metastatic renal cell carcinoma who received axitinib, cabozantinib, pazopanib, sorafenib, and sunitinib at a tertiary hospital in South Korea. We categorized the patients into those who had not previously received a VEGFR-TKI (VEGFR-TKI-naive) and those who had previously received a VEGFR-TKI (VEGFR-TKI-experienced). Anti-angiogenesis-related adverse events were defined as hypertension, proteinuria, bleeding, thrombosis, hypothyroidism, and left ventricular dysfunction, which were rated "possible" or higher based on a causality assessment scale. Among a total of 988 patients, 674 patients were VEGFR-TKI-naïve and 314 patients were VEGFR-TKI-experienced. Anti-angiogenesis-related adverse events of any grade and severe adverse events occurred in 65.1 and 34.6% of VEGFR-TKI-naïve patients and 54.8 and 36.0% of VEGFR-TKI-experienced patients, respectively. Regardless of treatment history, the most common adverse event was hypertension, with 48.6% in VEGFR-TKI-naïve patients and 35.0% in VEGFR-TKI-experienced patients. For VEGFR-TKI-experienced patients, the overall rate of anti-angiogenesis-related adverse events for sorafenib (24.3%) was lower than that for other VEGFR-TKIs (p < 0.05). Patients experiencing anti-angiogenesis-related adverse events were 1.6 times more likely to receive a low relative dose intensity. More than half and more than one-third of patients with renal cell carcinoma receiving VEGFR-TKIs experienced any and severe anti-angiogenesis-related adverse events, respectively. The relative dose intensity of VEGFR-TKI treatment was associated with anti-angiogenesis-related adverse events.

Using a zebrafish xenograft tumor model to compare the efficacy and safety of VEGFR-TKIs.

We constructed a zebrafish xenograft tumor model to compare and quantify the antiangiogenic efficacy and safety of nine vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), axitinib, lenvatinib, pazopanib, apatinib, cabozantinib, sunitinib, semaxanib, sorafenib, and regorafenib, in parallel. CT26 and GL261 tumor cells were implanted into the perivitelline space of Tg (flk1: eGFP) zebrafish to construct a xenograft tumor model. VEGFR-TKIs' antiangiogenic efficacy was quantified using AngioTool software, and the median effective dose (ED50) was calculated. The toxicity was evaluated by calculating the median lethal dose (LD50) and gross morphological changes. Cardiac toxicity was further assessed by heart rate, heart rhythm, the distance between the sinus venosus (SV) and bulbus arteriosus (BA), and pericardial edema. Using the zebrafish xenograft tumor model, we found that all nine VEGFR-TKIs exhibited antiangiogenic abilities, but the effectiveness of semaxanib was worse than that of other VEGFR-TKIs. Meanwhile, the zebrafish toxicity assay showed that all tested VEGFR-TKIs were associated with cardiac-related toxicity, especially apatinib and axitinib, which caused serious pericardial edema in zebrafish at relatively low concentrations. A narrow therapeutic window was found for most VEGFR-TKIs, and the simultaneous occurrence of toxic effects of semaxanib was recognized. Our findings showed the potential of using a zebrafish xenograft tumor model to accelerate VEGFR-TKI screening and further the development of more efficient and less toxic VEGFR-TKIs.

Natural Compounds Targeting VEGFRs in Kidney Cancer: An In silico Prediction

Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), which target angiogenesis by blocking VEGF signaling, are used in the treatment of many cancers including kidney cancer. Despite their efficacy in cancer, serious adverse effects such as hypertension and cardiovascular toxicities remain a clinical challenge. Natural non-toxic compounds targeting VEGFRs might be an alternative to VEGFR-TKIs. In the current study, we screened databases and literature which recommend natural compounds for kidney cancer and found approximately five hundred natural compounds. After screening for toxicity and drug-likeliness properties, fifteen of these compounds remained. Subsequently, we performed molecular docking studies against VEGFR-1 and VEGFR-2 with Lenvatinib, reported to be the most toxic of TKIs, and the fifteen natural compounds. As a result, Polydatin and Plakortide M gave the closest results to Lenvatinib in the interactions of the compounds with VEGFR-1 and VEGFR-2, respectively.

Toripalimab plus axitinib in patients with metastatic mucosal melanoma: 3-year survival update and biomarker analysis

BackgroundMucosal melanoma is an aggressive melanoma subtype with poor response to antiprogrammed cell death-1 (PD-1) monotherapy. Axitinib in combination with toripalimab, a humanized IgG4 mAb against PD-1, showed a promising...

Cancer-associated fibroblasts in renal cell carcinoma: implication in prognosis and resistance to anti-angiogenic therapy.

To investigate the role of cancer-associated fibroblasts (CAFs) in clear cell renal cell carcinoma (ccRCC) with respect to tumour aggressiveness, metastasis development, and resistance to anti-angiogenic therapy (vascular endothelial growth factor receptor-tyrosine kinase inhibitors [VEGFR-TKI]). Our study involved tissue samples from three distinct and independent cohorts of patients with ccRCC. The presence of CAFs and tumour lymphangiogenesis was investigated, respectively, by transcriptional signatures and then correlated with tumour development and prognosis. The effect of these CAFs on tumour cell migration and VEGFR-TKI resistance was analysed on co-cultures of ccRCC cells with CAFs. Results from our cohorts and from in silico investigations showed that VEGFR-TKI significantly increase the number of CAFs in tumours. In the same populations of patients with ccRCC, the proportion of intra-tumoral CAFs correlated to shorter disease-free and overall survival. The presence of CAFs was also correlated with lymphangiogenesis and lymph node metastasis. CAFs increased the migration and decreased the VEGFR-TKI-dependent cytotoxic effect of tumour cells. Our results show that VEGFR-TKI promote the development of CAFs, and CAFs favour tumour aggressiveness, metastatic dissemination, and resistance to treatment in ccRCC. CAFs could represent a new therapeutic target to fight resistance to treatment of ccRCC. Targeting CAF and immunotherapies combination are emerging as efficient treatments in many types of solid tumours. Our results highlight their relevance in ccRCC.

Outcomes of axitinib versus sunitinib as first-line therapy to patients with metastatic renal cell carcinoma in the immune-oncology era.

Although combination immune checkpoint inhibitor (immuno‐oncology [IO]) therapy is the first‐line treatment for metastatic renal cell carcinoma (mRCC), it mostly causes resistance and tumor regrowth. Therefore, an optimal second‐line therapy is necessary. Such therapy typically comprises vascular endothelial growth factor receptor‐tyrosine kinase inhibitors (VEGFR‐TKIs). This study was aimed at comparing the efficacy of two TKIs—axitinib and sunitinib—in mRCC patients. From January 2008 to October 2018, we registered 703 mRCC patients from 8 Japanese institutes. Of these, 408 patients received axitinib or sunitinib as the first‐line treatment. Thereafter, efficacy and survival rate were compared between the axitinib and sunitinib groups. To reduce the effects of selection bias and potential confounders, propensity score matching analysis was performed. Axitinib and sunitinib were administered in 274 and 134 patients, respectively. More than 25% of the patients received nivolumab sequence therapy. To calculate the propensity scores for each patient, we performed multivariate logistic regression analysis. The objective response rate, progression‐free survival (PFS), cause‐specific survival, and overall survival (OS) were significantly better in the axitinib group than in the sunitinib group. Furthermore, the OS was better in the nivolumab‐treated patients in the axitinib group. Axitinib showed higher efficacy and afforded greater survival benefits than did sunitinib when administered as first‐line therapy in mRCC patients. Thus, from among VEGFR‐TKIs, axitinib might be a possible option for application in the middle of IO drug‐based treatment sequences.

Lenvatinib with or Without Everolimus in Patients with Metastatic Renal Cell Carcinoma After Immune Checkpoint Inhibitors and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapies.

Lenvatinib (Len) plus everolimus (Eve) is an approved therapy for metastatic renal cell carcinoma (mRCC) after first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), but limited data exist on the efficacy of Len ± Eve after progression on immune checkpoint inhibitors (ICIs) and VEGFR-TKIs. We retrospectively reviewed the records of patients with mRCC at our institution who were treated with Len ± Eve after ICI and VEGFR-TKI. A blinded radiologist assessed objective response as defined by RECIST version 1.1. Descriptive statistics and the Kaplan-Meier method were used. Fifty-five patients were included in the analysis. Of these patients, 81.8% had clear-cell histology (ccRCC), and 76.4% had International Metastatic RCC Database Consortium intermediate-risk disease. Median number of prior therapies was four (range, 2-10); all patients had prior ICIs and VEGFR-TKIs, and 80% were previously treated with ICI and at least two VEGFR-TKIs, including cabozantinib. One patient (1.8%) achieved a complete response, and 11 patients (20.0%) achieved a partial response, for an overall response rate (ORR) of 21.8%; 35 patients (63.6%) achieved stable disease. In all patients, median progression-free survival (PFS) was 6.2 months (95% confidence interval [CI], 4.8-9.4) and median overall survival (OS) was 12.1 months (95% CI, 8.8-16.0). In patients with ccRCC, ORR was 24.4%, PFS was 7.1 months (95% CI, 5.0-10.5), and OS was 11.7 months (95% CI, 7.9-16.1). 50.9% of patients required dose reductions and 7.3% discontinued treatment because of toxicity. Len ± Eve demonstrated meaningful clinical activity and tolerability in heavily pretreated patients with mRCC after disease progression with prior ICIs and VEGFR-TKIs. As the therapeutic landscape for patients with metastatic renal cell carcinoma continues to evolve, this single-center, retrospective review highlights the real-world efficacy of lenvatinib with or without everolimus in heavily pretreated patients. This article supports the use of lenvatinib with or without everolimus as a viable salvage strategy for patients whose disease progresses after treatment with immune checkpoint inhibitors and vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies, including cabozantinib.

Biomarker-Oriented Therapy in Bladder and Renal Cancer.

Treatment of patients with urothelial carcinoma (UC) of the bladder or renal cancer has changed significantly during recent years and efforts towards biomarker-directed therapy are being investigated. Immune checkpoint inhibition (ICI) or fibroblast growth factor receptor (FGFR) directed therapy are being evaluated for non-muscle invasive bladder cancer (NMIBC) patients, as well as muscle-invasive bladder cancer (MIBC) patients. Meanwhile, efforts to predict tumor response to neoadjuvant chemotherapy (NAC) are still ongoing, and genomic biomarkers are being evaluated in prospective clinical trials. Currently, patients with metastatic UC (mUC) are usually treated with second-line ICI, while cisplatin-ineligible patients with programmed death-ligand 1 (PD-L1) positive tumors can benefit from first-line ICI. Platinum-relapsed UC patients harboring FGFR2/3 mutations can be treated with erdafitinib, while enfortumab vedotin has emerged as a novel third-line treatment option for mUC. In metastatic (clear cell) renal cell carcinoma (RCC), ICI was first introduced as second-line treatment after vascular endothelial growth factor receptor—tyrosine kinase inhibition (VEGFR-TKI). Currently, ICIs have also been introduced as first-line treatment in metastatic RCC. Although there is no evidence up to now for beneficial adjuvant treatment after surgery with VEGFR-TKIs in high-risk non-metastatic RCC, several trials are underway investigating the potential beneficial effect of ICIs in this setting.

Research Progress of Small Molecule Anti-angiogenic Drugs in Non-small Cell Lung Cancer

肺癌是世界上发病率最高的癌症之一，且尚无二线进展后的标准治疗方案，而肿瘤血管生成目前已被确定为恶性肿瘤的重要治疗靶点，小分子多靶点血管激酶抑制剂可通过抑制血管生成相关信号通路，抑制肿瘤血管的生成。目前已开展多项小分子抗血管生成药物治疗非小细胞肺癌的临床试验，且已有部分血管内皮生长因子受体酪氨酸激酶抑制剂（vascular endothelial growth factor receptor-tyrosine kinase inhibitors, VEGFR-TKIs）获批治疗晚期非小细胞肺癌，本文基于国内外多项小分子抗血管生成药物治疗非小细胞肺癌的发展现状，归纳了多个VEGFR-TKIs及成纤维细胞生长因子受体（fibroblast growth factor receptor, FGFR）-TKI单药或联合[包括分别与化疗、表皮生长因子受体（epidermal growth factor receptor, EGFR）-TKIs、免疫治疗、放疗等联合）]治疗非小细胞肺癌的疗效与安全性研究，同时探讨了VEGFR-TKIs可能存在的耐药机制及疗效预测指标等，并对未来抗血管治疗非小细胞肺癌的发展趋势以及存在的潜在问题进行展望，同时为肺癌后续的精准治疗及个体化治疗提供新的思路。

First-line axitinib therapy is less effective in metastatic renal cell carcinoma with spindle histology

Axitinib, a vascular endothelial growth factor receptor-tyrosine kinase inhibitor, will be used in combination first-line therapies against metastatic renal cell carcinoma (mRCC), but its effects as a first-line monotherapy are unclear. Thus, we aimed to elucidate pretreatment clinical factors that predict the prognosis of patients with mRCC receiving first-line axitinib therapy. We enrolled 63 patients with mRCC treated with axitinib as first-line therapy between Nov. 2003 and Jul. 2018. Progression-free survival (PFS) and overall survival (OS) were assessed using the Wald χ2 statistic in Cox proportional hazards regression. Median patient age was 67 (range: 25–85) years. Seven (11.1%) patients were classified as being at favorable risk, 33 (52.4%) at intermediate risk, and 23 (36.5%) at poor risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification system. Median follow-up duration after axitinib initiation was 14 (range: 1–72) months. Median PFS and OS were 18 months and 65 months, respectively. Cox regression analyses of clinical predictors revealed that high C-reactive protein (CRP) levels were significantly correlated with shorter PFS [hazard ratio (HR), 1.63; 95% confidence interval (CI) 1.7–4.0)], whereas spindle cells and poor IMDC risk scores were related to worse OS (HR, 2.87 and 2.88, respectively; 95% CI 1.4–11.0 and 1.1–8.5, respectively). Thus, patients with mRCC and spindle histology or poor IMDC risk scores had worse OS, and those with high CRP levels had shorter PFS in first-line axitinib treatment. Other therapies might be more suitable for initial management of such patients.

Exploratory Pilot Study of Circulating Biomarkers in Metastatic Renal Cell Carcinoma.

Simple SummaryThe identification of biomarkers in response to therapeutic treatment is one of the main objectives of personalized oncology. Predictive biomarkers are particularly relevant for oncologists challenged by the busy scenario of possible therapeutic options in mRCC patients, including immunotherapy and TKIs. In fact the activation of the immune system can determine the outcome and success of the different therapeutic strategies. In this study we evaluated changes in the immune system of TKI mRCC-treated patients defining immunological profiles related to response characterized by specific biomarkers. The validation of the proposed immune portrait to an extended number of patients could allow characterization and selection of responsive and non-responsive patients from the beginning of the therapeutic process.With the introduction of immune checkpoint inhibitors (ICIs) and next-generation vascular endothelial growth factor receptor–tyrosine kinase inhibitors (VEGFR–TKIs), the survival of patients with advanced renal cell carcinoma (RCC) has improved remarkably. However, not all patients have benefited from treatments, and to date, there are still no validated biomarkers that can be included in the therapeutic algorithm. Thus, the identification of predictive biomarkers is necessary to increase the number of responsive patients and to understand the underlying immunity. The clinical outcome of RCC patients is, in fact, associated with immune response. In this exploratory pilot study, we assessed the immune effect of TKI therapy in order to evaluate the immune status of metastatic renal cell carcinoma (mRCC) patients so that we could define a combination of immunological biomarkers relevant to improving patient outcomes. We profiled the circulating levels in 20 mRCC patients of exhausted/activated/regulatory T cell subsets through flow cytometry and of 14 immune checkpoint-related proteins and 20 inflammation cytokines/chemokines using multiplex Luminex assay, both at baseline and during TKI therapy. We identified the CD3+CD8+CD137+ and CD3+CD137+PD1+ T cell populations, as well as seven soluble immune molecules (i.e., IFNγ, sPDL2, sHVEM, sPD1, sGITR, sPDL1, and sCTLA4) associated with the clinical responses of mRCC patients, either modulated by TKI therapy or not. These results suggest an immunological profile of mRCC patients, which will help to improve clinical decision-making for RCC patients in terms of the best combination of strategies, as well as the optimal timing and therapeutic sequence.