Vascular Endothelial Growth Factor-targeted Therapy Research Articles

Cabozantinib and Axitinib After Vascular Endothelial Growth Factor Therapy in Patients with Advanced Renal Cell Carcinoma: A Retrospective Cohort Study from England.

The tyrosine kinase inhibitors cabozantinib and axitinib have been widely used in England to treat advanced renal cell carcinoma following prior vascular endothelial growth factor-targeted therapy, but data on real-world usage remain limited. Our objective was to describe the real-world treatment patterns and outcomes of patients with advanced renal cell carcinoma who received second-line or later-line (≥2L) cabozantinib or axitinib after vascular endothelial growth factor-targeted therapy in clinical practice in England. This retrospective cohort study used clinical practice data (collected 2011-20) from the English Cancer Analysis System database. Patient characteristics, treatment sequence and duration, and overall survival (time from initiation of cabozantinib/axitinib treatment to death) were evaluated. Data from 1485 eligible adults with advanced renal cell carcinoma were analyzed: 440 received ≥ 2L cabozantinib (2L for 88.6% of them); 1045 received ≥ 2L axitinib (2L for 89.5%). The most common first-line treatments were sunitinib (2L cabozantinib subcohort, 48%; 2L axitinib subcohort, 46%) and pazopanib (46% and 54%, respectively); nivolumab was the most common third-line treatment (18% and 19%, respectively). Median (interquartile range) 2L therapy duration was 5.52 (2.73-11.74) months for cabozantinib and 4.60 (1.45-12.36) months for axitinib. Following adjustment for potential confounders using inverse probability weighting, overall survival (median [interquartile range]) was longer for ≥ 2L cabozantinib (11.2 [5.7-28.0] months) than for ≥ 2L axitinib (10.4 [4.7-22.0] months; log-rank p = 0.0034). The Cancer Analysis System database is a valuable research resource providing extensive real-world clinical data. Real-world overall survival was longer with ≥ 2L cabozantinib than with axitinib. ClinicalTrials.gov, NCT04637204; registered November 2020.

Deep Learning Can Predict Bevacizumab Therapeutic Effect and Microsatellite Instability Directly from Histology in Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) remains a significant cause of mortality among gynecologic cancers, with the majority of cases being diagnosed at an advanced stage. Before targeted therapies were available, EOC treatment relied largely on debulking surgery and platinum-based chemotherapy. Vascular endothelial growth factors have been identified as inducing tumor angiogenesis. According to several clinical trials, anti–vascular endothelial growth factor-targeted therapy with bevacizumab was effective in all phases of EOC treatment. However, there are currently no biomarkers accessible for regular therapeutic use despite the importance of patient selection. Microsatellite instability (MSI), caused by a deficiency of the DNA mismatch repair system, is a molecular abnormality observed in EOC associated with Lynch syndrome. Recent evidence suggests that angiogenesis and MSI are interconnected. Developing predictive biomarkers, which enable the selection of patients who might benefit from bevacizumab-targeted therapy or immunotherapy, is critical for realizing personalized precision medicine. In this study, we developed 2 improved deep learning methods that eliminate the need for laborious detailed image-wise annotations by pathologists and compared them with 3 state-of-the-art methods to not only predict the efficacy of bevacizumab in patients with EOC using mismatch repair protein immunostained tissue microarrays but also predict MSI status directly from histopathologic images. In prediction of therapeutic outcomes, the 2 proposed methods achieved excellent performance by obtaining the highest mean sensitivity and specificity score using MSH2 or MSH6 markers and outperformed 3 state-of-the-art deep learning methods. Moreover, both statistical analysis results, using Cox proportional hazards model analysis and Kaplan-Meier progression-free survival analysis, confirm that the 2 proposed methods successfully differentiate patients with positive therapeutic effects and lower cancer recurrence rates from patients experiencing disease progression after treatment (P < .01). In prediction of MSI status directly from histopathology images, our proposed method also achieved a decent performance in terms of mean sensitivity and specificity score even for imbalanced data sets for both internal validation using tissue microarrays from the local hospital and external validation using whole section slides from The Cancer Genome Atlas archive.

Outcomes for International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Groups in Contemporary First-line Combination Therapies for Metastatic Renal Cell Carcinoma

BackgroundThe combination of immuno-oncology (IO) agents ipilimumab and nivolumab (IPI-NIVO) and vascular endothelial growth factor targeted therapies (VEGF-TT) combined with IO (IO-VEGF) are current standard of care first-line treatments for metastatic renal cell carcinoma (mRCC). ObjectiveTo establish real-world clinical benchmarks for IO combination therapies based on the International mRCC Database Consortium (IMDC) criteria. Design, setting, and participantsPatients with mRCC who received first-line IPI-NIVO, IO-VEGF, or VEGF-TT from 2002 to 2021 were identified using the IMDC database and stratified according to IMDC risk groups. Outcome measurements and statistical analysisOverall survival (OS), time to next treatment (TTNT), and treatment duration (TD) were calculated using the Kaplan-Meier method and compared between IMDC risk groups within each treatment cohort by the log-rank test. The overall response rate (ORR) was calculated by physician assessment of the best overall response. The primary outcome was OS at 18 mo. Results and limitationsIn total, 728 patients received IPI-NIVO, 282 IO-VEGF, and 7163 VEGF-TT. The median follow-up times for patients remaining alive were 14.3 mo for IPI-NIVO, 14.9 mo IO-VEGF, and 34.4 mo for VEGF-TT. OS at 18 mo for favorable, intermediate, and poor risk was, respectively, 90%, 78%, and 50% for those receiving IPI-NIVO; 93%, 83%, and 74% for IO-VEGF; and 84%, 64%, and 28% for VEGF-TT. ORRs in favorable-, intermediate-, and poor-risk groups were 41.3%, 40.6%, and 33.0% for those receiving IPI-NIVO; 60.3%, 56.8%, and 40.9% for IO-VEGF; and 39.3%, 33.5%, and 20.9% for VEGF-TT, respectively. The IMDC model stratified patients into statistically distinct risk groups for the three endpoints of OS, TTNT, and TD within each treatment cohort. Limitations of this study were the retrospective design and short follow-up. ConclusionsThis study demonstrated that the IMDC model continues to risk stratify patients with mRCC treated with contemporary first-line IO combination therapies and provided real-world survival benchmarks. Patient summaryThe International Metastatic Renal Cell Carcinoma Database Consortium model continues to stratify patients with metastatic renal cell carcinoma receiving modern combination treatments in the real-world setting.

Immune Checkpoint Therapy Combinations in Adult Advanced MiT Family Translocation Renal Cell Carcinomas.

There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC). This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods. There were 29 patients identified with median age of 38 (21-70) years, and F:M ratio 0.9:1. FISH revealed TFE3 and TFEB translocations in 22 and 7 patients, respectively. Dual ICT and ICT + VEGF TT were used in 18 and 11 patients, respectively. Seventeen (59%) patients received ICT combinations as first-line therapy. ORR was 1/18 (5.5%) for dual ICT and 4/11 (36%) for ICT + VEGF TT. At a median follow-up of 12.9 months, median PFS was 2.8 and 5.4 months in the dual ICT and ICT + VEGF TT groups, respectively. Median OS from metastatic disease was 17.8 and 30.7 months in the dual ICT and ICT + VEGF TT groups, respectively. In this retrospective study of advanced tRCC, limited response and survival were seen after frontline dual ICT combination therapy, while ICT + VEGF TT therapy offered some efficacy. Due to the heterogeneity of tRCC, insights into the biological underpinnings are necessary to develop more effective therapies.

Is Cytoreductive Nephrectomy Still Beneficial for Patients With Metastatic Renal Cell Carcinoma in the Contemporary Immunotherapy Era?

Cytoreductive nephrectomy (CN) has long been the standard of care for patients with metastatic renal cell carcinoma (mRCC) since 2 clinical trials revealed its role during the cytokines era. With discovery of novel and effective drugs, such as vascular endothelial growth factor-targeted therapies, the role of CN started to be challenged. The 2 recent prospective randomized trials Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques (CARMENA) and Immediate Surgery or Surgery After Sunitinib in Treating Patients with Metastatic Kidney Cancer trial (SURTIME) have changed the therapy paradigm for patients with mRCC. The CARMENA trial was performed to reveal whether CN is required in the targeted therapy, whereas SURTIME evaluated whether initial sunitinib can aid in the selection of patients who are most likely to benefit from subsequent CN or identify patients with innate resistance to targeted therapy. These trials suggest that CN does not provide a survival benefit for patients with poor‑risk disease. Especially, current evolutions in systemic therapies have demonstrated improved oncological outcomes from immunotherapy (IO) such as immune checkpoint inhibitor, particularly in its combination or combination with tyrosine kinase inhibitor. Accordingly, the role of CN continues to be questioned. Taken together, these findings reinforce the concept that the ultimate impact of CN on oncologic outcomes of mRCC patients in the era of IO still needs further investigation to represent a key for unmet clinical need.

Characterizing IMDC prognostic groups in contemporary first-line combination therapies for metastatic renal cell carcinoma (mRCC).

308 Background: The combination of immuno-oncology agents (IO) ipilimumab and nivolumab (IPI-NIVO) and combinations of IO with vascular endothelial growth factor targeted therapies (IOVE) have demonstrated efficacy in clinical trials for the first-line treatment of mRCC. This study seeks to establish real-world clinical benchmarks based on the International mRCC Database Consortium (IMDC) criteria using vascular endothelial growth factor targeted therapy (VEGF-TT) treated patients for context. Methods: The IMDC database (IMDConline.com) was used to identify patients with mRCC who received first-line IPI-NIVO, IOVE (axitinib/pembrolizumab, lenvatinib/pembrolizumab, cabozantinib/nivolumab, or axitinib/avelumab) and VEGF-TT (sunitinib or pazopanib) from 2002-2021. The primary endpoint was overall survival (OS) and was calculated from time of initiation of first-line therapy to death or last follow up. Log-rank tests were conducted to compare favorable, intermediate, and poor risk OS outcomes within treatment groups. Overall response rates (ORR) and complete response (CR) rates were calculated based on physician assessment of best clinical response. Results: In total, 692 patients received IPI-NIVO, 244 received IOVE, and 7152 received VEGF-TT. Baseline characteristics for IPI-NIVO, IOVE, and VEGF-TT, respectively, were as follows: median age (interquartile range) 63 (56-69), 64 (57-70), and 63 (56-70); male 72%, 74%, and 72% (p=0.74); non-clear cell histology 15%, 10%, and 13% (p=0.15); sarcomatoid features 24%, 15%, and 13% (p&lt;0.0001); brain metastasis 8%, 4%, and 8% (p=0.04); liver metastasis 18%, 14%, and 18% (p=0.17); underwent nephrectomy 61%, 79% and 80% (p&lt;0.0001). OS and ORR are reported in the table. P-values (log rank) for OS between risk groups were significant for IPI-NIVO (p&lt;0.0001), IOVE (p=0.0005), and VEGF-TT (p&lt;0.0001). Conclusions: These findings provide real-world survival and response benchmarks for contemporary first-line mRCC treatments and could be helpful for patient counselling. In addition, these findings mirror the efficacy of combination therapies established in clinical trials against VEGF-TT monotherapy. IMDC criteria continue to risk stratify patients in these novel combination therapies.[Table: see text]

Management of metastatic renal cell carcinoma following prior vascular endothelial growth factor-targeted therapy: A real-world retrospective study from Taiwan.

There are limited real-world data to guide the sequencing of targeted therapies in patients with metastatic renal cell carcinoma (mRCC). The objective of this study was to characterize real-world treatment patterns (primarily second line [2L]) after prior vascular endothelial growth factor (VEGF) targeted therapy in an unselected mRCC population from Taiwan between 2013 and 2017. Treatment-related adverse events (TRAEs) and their management were also evaluated (NCT03633579). This retrospective cohort study included patients who had received prior VEGF-targeted therapy and were treated at the National Taiwan University Hospital or the Taipei Veterans General Hospital between June 2013 and December 2017. Outcomes were characterized using descriptive statistics. Overall, 27 patients were included: 22 (81.5%) male; mean standard deviation (SD) age, 63.1 (11.1) years; 18 (66.7%) initiated targeted therapy during the year immediately following mRCC diagnosis. All patients received sunitinib as their first-line (1L) targeted therapy, with a median (range) treatment duration of 10 (1.8-65.8) months. The most common reason for discontinuing 1L sunitinib was disease progression (88.9% of patients). Everolimus was the most common 2L targeted therapy, in 23 patients (85.2%); 4 patients (14.8%) received 2L axitinib. Median (range) duration of 2L therapy was 4.0 (0.1-30.5) months for everolimus and 4.2 (0.5-9.2) months for axitinib. Ten TRAEs were reported among seven patients receiving 2L everolimus: hypertension (n = 5), hand-foot syndrome (n = 2), hyperglycemia (n = 1), renal failure (n = 1), and interstitial pneumonitis (n = 1). The majority (80%) of TRAEs were managed in the outpatient setting. No TRAEs were reported in the axitinib group. Real-world management of patients with mRCC in Taiwan broadly aligned with clinical guidelines and national reimbursement policy at the time of the study. These findings may be a useful reference for assessing the implications of evolving mRCC management approaches in Taiwan.

Evolving landscape of first-line combination therapy in advanced renal cancer: a systematic review.

Background:Renal cell carcinoma (RCC) is a common malignancy with approximately 30% of cases diagnosed at the advanced or metastatic stage. While single-agent vascular endothelial growth factor-targeted therapy has been a mainstay of treatment, data from multiple phase III trials assessing first-line immune checkpoint inhibitor (ICI) combinations have demonstrated a significant survival benefit.Methods:A systematic search of the published and presented literature was performed to identify phase III trials assessing ICI combination regimens in RCC using search terms ‘immune checkpoint inhibitors’ AND ‘renal cell carcinoma,’ AND ‘advanced’.Results:Six phase III trials showed significant benefits for ICI combinations compared with sunitinib. Nivolumab plus ipilimumab significantly improved overall survival [OS; median, 47.0 versus 26.6 months, hazard ratio (HR) = 0.68, 95% confidence interval (CI) = 0.58–0.81, p < 0.0001) and progression-free survival (PFS; median 11.6 versus 8.3 months, HR = 0.73, 95% CI = 0.61–0.87, p = 0.0004) in International Metastatic renal cell carcinoma Database Consortium intermediate and poor-risk patients. OS was also significantly improved for ICI plus tyrosine kinase inhibitor combinations regardless of risk, including pembrolizumab plus either axitinib (HR = 0.73, 95% CI = 0.60–0.88, p < 0.001) or lenvatinib (HR = 0.66, 95% CI = 0.49–0.88, p = 0.005) and nivolumab plus cabozantinib (HR = 0.66, 95% CI = 0.50–0.87, p = 0.003). No new safety signals were identified.Conclusions:Phase III first-line trials of ICI combinations showed survival benefits compared with a control arm of sunitinib. Global access to these combinations should be made available to patients with advanced RCC.

Norcantharidin counteracts acquired everolimus resistance in renal cell carcinoma by dual inhibition of mammalian target of rapamycin complex 1 and complex 2 pathways in Vitro.

Everolimus, an oral mammalian target of rapamycin complex 1 (mTORC1) inhibitor, presents a therapeutic option in metastatic renal cell carcinoma (RCC) patients who were intolerant to, or previously failed, immune- and vascular endothelial growth factor-targeted therapies. However, the onset of drug resistance limits its clinical use. One possible mechanism underpinning the resistance is that inhibiting mTORC1 by everolimus results in mTORC2-dependent activation of v-Akt murine thymoma viral oncogene (AKT) and upregulation of hypoxia-inducible transcription factors (HIF). Norcantharidin (NCTD) is a demethylated derivative of cantharidin with antitumor properties which is an active ingredient of the traditional Chinese medicine Mylabris. In this study, everolimus-resistant RCC cells (786-O-R) obtained by chronic everolimus treatment revealed higher level of HIF2α and over-activated mTORC2 pathway and NCTD inhibits cell proliferation in both everolimus-resistant and -sensitive RCC cells by arresting cell cycle in G0/G1 phase and reducing cell cycle-related proteins of C-Myc and cyclin D. Furthermore, NCTD shows synergistic anticancer effects combined with everolimus in everolimus-resistant 786-O-R cells. Mechanically, NCTD repressed both mTORC1 and mTORC2 signaling pathways as well as downstream molecular signaling pathways, such as p-4EBP1, p-AKT, HIF1α and HIF2α. Our findings provide sound evidence that combination of NCTD and everolimus is a potential therapeutic strategy for treating RCC and overcoming everolimus resistance by dual inhibition of mTORC1 and mTORC2.

Effectiveness of first-line immune checkpoint inhibitors (ICI) in advanced non-clear cell renal cell carcinoma (ccRCC).

316 Background: Immune checkpoint inhibitors (ICI) have demonstrated impressive activity in metastatic clear-cell renal cell carcinoma (ccRCC) and have become standard treatment options in this setting. Data supporting the effectiveness of ICI based therapy in non-clear cell RCC (nccRCC) is more limited. Methods: We performed a retrospective analysis using the International Metastatic RCC Database Consortium (IMDC). Patients with nccRCC were classified into 3 groups based on first-line therapy: ICI based therapy (in monotherapy or in combination), vascular endothelial growth factor targeted therapy (VEGF-TT) monotherapy, or mammalian target of rapamycin (mTOR) inhibitor monotherapy. Primary outcome was overall survival (OS). Secondary outcomes were time to treatment failure (TTF) and objective response rate (ORR). We used Kaplan-Meier method to compare OS and TTF between treatment groups and Cox proportional hazards models to adjust for prognostic covariates. Results: We identified 1181 patients with nccRCC. In first-line, 78.2% received VEGF-TT, 15.8% mTOR inhibitors, and 5.5% ICI based therapy, of which 41.5% in monotherapy, 30.8% doublet-ICIs and 27.7% an ICI combined with VEGF-TT. Median OS in the ICI group was 28.6 months, compared to 19.2 and 12.6 in the VEGF-TT and mTOR groups, respectively. Median TTF was 6.9 months vs. 5.1 and 3.9 and ORR was 25% vs. 17.8% and 5.8% in the ICI, VEGF-TT and mTOR groups, respectively. After adjusting for IMDC risk group, histological subtype, and age, the hazard ratio (HR) for OS was 0.58 (95% CI 0.35-0.94, p=0.03) for ICI vs. VEGF-TT and 0.48 (95% CI 0.29-0.80, p=0.005) for ICI vs. mTOR. Conclusions: In advanced nccRCC, first-line ICI based treatment appears to be associated with improved OS compared to VEGF and mTOR targeted therapy. These results need to be confirmed in prospective randomized trials. [Table: see text]

Treatment sequencing strategies in metastatic renal cell carcinoma: A critical interpretation of available data

Therapeutic sequencing strategies for metastatic renal cell carcinoma have evolved significantly over time. For about 10 years, vascular endothelial growth factor receptor-targeted therapies and mammalian target of rapamycin inhibitors have been the standard of care. About 5 years ago an immunocheckpoint inhibitor, nivolumab, has opened new therapeutic perspectives. Recent clinical studies have confirmed the biological rationale of combining two immunocheckpoint inhibitors or vascular endothelial growth factor-targeted therapies plus immunocheckpoint inhibitors, demonstrating an improvement in clinical outcomes. We are still unable to recognize immunocheckpoint inhibitors responder patients from vascular endothelial growth factor-targeted therapies responder patients and, therefore, to quantify in a certain patient the benefits/harms ratio of upfront combination over sequence therapy in a certain patient. However, the metastatic renal cell carcinoma records of high-volume cancer centers could reveal the effectiveness and tolerability of combined treatments and indicate the potentially predictive factors and the management strategies in the real-world population.

A sequential targeting nanoplatform for anaplastic thyroid carcinoma theranostics

Effective accumulation of nanoparticles (NPs) in tumor regions is one of the major motivations in nanotechnology research and that the establishment of an efficient targeting nanoplatform for the treatment of malignant tumors is urgently needed for theranostic applications. In this study, we engineered multifunctional sequential targeting NPs for achieving synergistic antiangiogenic photothermal therapy (PTT) and multimodal imaging-guided diagnosis for anaplastic thyroid carcinoma (ATC) theranostics. Antibody bevacizumab with an affinity towards vascular endothelial growth factor (VEGF) on the tumor cell surface was conjugated onto the surface of polymer NPs for VEGF targeting and antiangiogenic therapy. Encapsulated IR825 was employed as a photothermal agent (PTA) with a mitochondrial targeting capability, which further cascades NPs into mitochondria to enhance hyperthermic efficiency in the ablation of tumor cells. Importantly, the combination of bevacizumab and IR825 in a single nanosystem achieved desirable accumulations of NPs and that sequential targeted PTT combined with antiangiogenesis significantly promoted the therapeutic efficiency in eradicating tumors by near-infrared (NIR) laser irradiation. Furthermore, these NPs are extraordinary contrast agents for photoacoustic, ultrasound and fluorescence imaging applications, providing multimodal imaging capabilities for therapeutic monitoring and a precise diagnosis. Therefore, this multifunctional nanoplatform provides a promising theranostic strategy for extremely malignant ATC. Statement of significanceAnaplastic thyroid carcinoma (ATC), with extremely aggressive behavior, lacks a satisfactory therapeutic method and a comprehensive early diagnostic strategy. Herein, we successfully synthesized a sequential targeting nanoplatform (IR825@Bev-PLGA-PFP NPs) with theranostic function, which specifically binds to VEGF on the tumor cell surface and further cascades into mitochondria to achieve effective accumulation of NPs in the tumor regions. As a result, it solves the urgent demand for ATC detection and therapy. By breaking the limitation of traditional target, such as low efficacy and frequent recurrence as the results of low accumulation, sequential targeting combined with synergistic antiangiogenic PTT completely eradicates tumors without any residual tissue and side effect. Therefore, this strategy paves a solid way for further investigation in the theranostic progressing of ATC.

Nrf2 gene mutation and single nucleotide polymorphism rs6721961 of the Nrf2 promoter region in renal cell cancer

BackgroundNuclear factor erythroid 2–related factor 2 (Nrf2) is involved in cell proliferation by promotion of metabolic activity. It is also the major regulator of antioxidants and has a pivotal role in tumor cell proliferation and resistance to chemotherapy. Accordingly, we investigated the role of Nrf2 in renal cell carcinoma (RCC).MethodsIn 50 patients who had metastatic RCC and received cytoreductive nephrectomy, we performed Nrf2 gene mutation analysis using targeted next-generation sequencing, as well as investigating a specific single nucleotide polymorphism (SNP; rs6721961) in the Nrf2 promoter region and Nrf2 protein expression.ResultsTargeted next-generation sequencing revealed that five tumors had SNPs of Nrf2 associated with amino acid sequence variation, while 11 tumors had SNPs of Kelch-like ECH-associated protein 1 gene, 35 had SNPs of von Hippel-Lindau gene, and none had SNPs of fumarate hydratase gene. The three genotypes of rs6721961 showed the following frequencies: 60% for C/C, 34% for C/A, and 6% for A/A. Nrf2 mutation and the C/A or A/A genotypes were significantly associated with increased Nrf2 protein expression (p = 0.0184 and p = 0.0005, respectively). When the primary tumor showed Nrf2 gene mutation, the C/A or A/A genotype, or elevated Nrf2 protein expression, the response of metastases to vascular endothelial growth factor-targeting therapy was significantly worse (p = 0.0142, p = 0.0018, and p < 0.0001, respectively), and overall survival was significantly reduced (p = 0.0343, p = 0.0421, and p < 0.0001, respectively). Elevated Nrf2 protein expression was also associated with shorter survival according to multivariate Cox proportional analysis.ConclusionThese findings suggest an associated between progression of RCC and Nrf2 signaling.

Re: Adjuvant Vascular Endothelial Growth Factor-Targeted Therapy in Renal Cell Carcinoma: A Systematic Review and Pooled Analysis.

Re: Adjuvant Vascular Endothelial Growth Factor-Targeted Therapy in Renal Cell Carcinoma: A Systematic Review and Pooled Analysis.

Radiological Response Heterogeneity Is of Prognostic Significance in Metastatic Renal Cell Carcinoma Treated with Vascular Endothelial Growth Factor-targeted Therapy

BackgroundResponse evaluation criteria in solid tumours (RECIST) is widely used to assess tumour response but is limited by not considering disease site or radiological heterogeneity (RH). ObjectiveTo determine whether RH or disease site has prognostic significance in patients with metastatic clear-cell renal cell carcinoma (ccRCC). Design, setting, and participantsA retrospective analysis was conducted of a second-line phase II study in patients with metastatic ccRCC (NCT00942877), evaluating 138 patients with 458 baseline lesions. InterventionThe phase II trial assessed vascular endothelial growth factor-targeted therapy±Src inhibition. Outcome measurements and statistical analysisRH at week 8 was assessed within individual patients with two or more lesions to predict overall survival (OS) using Kaplan-Meier method and Cox regression model. We defined a high heterogeneous response as occurring when one or more lesion underwent a ≥10% reduction and one or more lesion underwent a ≥10% increase in size. Disease progression was defined by RECIST 1.1 criteria. Results and limitationsIn patients with a complete/partial response or stable disease by RECIST 1.1 and two or more lesions at week 8, those with a high heterogeneous response had a shorter OS compared to those with a homogeneous response (hazard ratio [HR] 2.01; 95% confidence interval [CI]: 1.39–2.92; p<0.001). Response by disease site at week 8 did not affect OS. At disease progression, one or more new lesion was associated with worse survival compared with >20% increase in sum of target lesion diameters only (HR 2.12; 95% CI: 1.43–3.14; p<0.001). Limitations include retrospective study design. ConclusionsRH and the development of new lesions may predict survival in metastatic ccRCC. Further prospective studies are required. Patient summaryWe looked at individual metastases in patients with kidney cancer and showed that a variable response to treatment and the appearance of new metastases may be associated with worse survival. Further studies are required to confirm these findings.

Novel Agents and Drug Development Needs in Advanced Clear Cell Renal Cancer.

The treatment of metastatic clear cell renal cancer is changing rapidly, with the focus switching from vascular endothelial growth factor-targeted therapies to immune checkpoint inhibitors and novel combinations. Specifically, recent data with programmed death ligand inhibitors is revolutionizing the standard approach to metastatic renal cell carcinoma. However, there is speculation around a number of newer potentially therapeutic targets, such as indoleamine 2,3-dioxygenase, transforming growth factor-β, interleukin-10, and adenosine. In this article, we review novel treatments, promising combinations, and consideration in both trial design and clinical application of therapeutics that will influence practice in the future.

Carcinoma of Unknown Primary Site (CUP) With Metastatic Renal-Cell Carcinoma (mRCC) Histologic and Immunohistochemical Characteristics (CUP-mRCC): Results From Consecutive Patients Treated With Targeted Therapy and Review of Literature.

Carcinoma of unknown primary site (CUP) is a heterogenous group of metastatic cancer with no detectable primary tumor site. Diagnostic assessment occasionally presents CUP with metastatic renal-cell carcinoma (mRCC) histologic and immunohistochemical characteristics (CUP-mRCC). Efficacy and toxicity data for vascular endothelial growth factor inhibitor therapies in CUP-mRCC patients are few. We retrospectively reviewed consecutive patients with CUP-mRCC at a single institution between 2007 and 2018. Treatment outcomes were assessed from initiation of renal-cell carcinoma-specific therapy, including response rate, progression-free survival, and overall survival. Ten patients with CUP-mRCC were identified. Median age was 64 years. Histologies were clear-cell (30%), papillary type II (20%), and unclassified renal-cell (50%) carcinoma. International Metastatic Renal Cell Carcinoma Database Consortium risk group were favorable, intermediate, and poor in 0, 40%, and 60%, respectively. One patient received empiric first-line chemotherapy. Targeted treatments were pazopanib (n= 7), sunitinib (n= 2), and sorafenib (n= 1). Objective response rate was 40%, progression-free survival was 2.5 months (95% confidence interval, 1.2-3.8), and overall survival was 5.7 months (95% confidence interval, 0-24.0). Stratified for International Metastatic Renal Cell Carcinoma Database Consortium risk, overall survival in intermediate versus poor risk group were 18.6 months and 2.3 months, respectively. Second-line therapy did not result in disease control. No new or unexpected toxicities were observed. CUP-mRCC treated with vascular endothelial growth factor-targeted therapy is valid, feasible, and safe even though these patients had several negative prognostic factors. CUP-mRCC patients should be identified among CUP patients for specific renal-cell carcinoma therapy.

Reconciling the Role of Vascular Endothelial Growth Factor-Targeted Therapies in Adjuvant Renal Cell Carcinoma Treatment

Up to 40% of patients with high risk, localized RCC will relapse after nephrectomy and are at risk of eventually succumbing to the disease. Historically, phase 3 clinical trials failed to demonstrate meaningful benefit of adjuvant therapy in RCC, likely because these early trials used treatments that did not demonstrate meaningful clinical efficacy in mRCC. However, the clear clinical activity demonstrated by VEGF-TKIs in mRCC patients renewed the promise of adjuvant therapy. ASSURE, S-TRAC, and PROTECT are the first three trials to examine the clinical efficacy of 1 year of adjuvant VEGF-TKI therapy in patients with high-risk RCC following nephrectomy. In this review we reconcile the results of these studies and explore the future of adjuvant RCC therapy.

The neutrophil-to-lymphocyte ratio makes the Heng risk model improve better the prediction of overall survival in metastatic renal cell cancer patients.

The aim of this study was to predict the discriminating prognostic power of the neutrophil-to-lymphocyte ratio for overall survival in patients with metastatic renal cell carcinoma and to make a new model using the neutrophil-to-lymphocyte ratio. From 2007 to 2014, 190 patients with metastatic renal cell carcinoma treated with either systemic immunotherapy or/and vascular endothelial growth factor-targeted therapy were enroled. A multivariable proportional hazard model was developed to investigate the effects of the neutrophil-to-lymphocyte ratio as predictive prognostic factors for overall survival. This new model was incorporated into the current Heng risk model to validate a modified prognostic classification for overall survival. In multivariable analysis, a high neutrophil-to-lymphocyte ratio [hazard ratio (HR) = 1.65] was a significant independent predictor of shorter overall survival (P = 0.005). Additional neutrophil-to-lymphocyte ratio markers improved the discriminating power of the Heng risk classification, as compared to the existing classification model (C-statistic: 0.7198 vs. 0.6943, P = 0.008). The reclassification of patient prognostic categories using the new model showed a total overall net improvement of 61.4% (P < 0.001). The neutrophil-to-lymphocyte ratio was a significant prognostic factor of overall survival in metastatic renal cell carcinoma patients treated with systemic therapy. Adding the neutrophil-to-lymphocyte ratio to the Heng model significantly improved the discriminatory power of risk prediction in metastatic renal cell carcinoma.

Gut microbiome composition and response to sunitinib in metastatic renal cell carcinoma (mRCC).

657 Background: Recent evidence supports a link between stool microbiome composition and immunotherapy response. However, it is unclear how the microbiome may influence clinical outcome in mRCC where vascular endothelial growth factor-targeted therapies remains a standard of care. Methods: Five consecutive stool samples were collected at baseline and at weeks 2, 3, 4 and 12 of treatment with sunitinib in patients (pts) with mRCC. In responders (R: complete/partial response and stable disease) and non-responders (P: primary progression), gut microbiota composition was assessed through extraction of microbial DNA where 16s RNA gene tags (v4) were generated by PCR amplification and sequenced using MiSeq (Illumina). Sequence reads were processed by Mothur software, assembled in Operational Taxonomic Units (OTUs), taxonomically annotated to the genus level, and used to construct Bray-Curtis dissimilarity matrix. The similarity of samples was visualized by principle coordinate (PCo) analysis and further confirmed by k-means clustering and ANOSIM tests. Differentially abundant taxa were determined by METASTATS. Results: Stool bacteriomic profiling identified 25,304 OTUs attributable to 165 genera from 8 phyla in 4 of 6 pts evaluable for response. PCo analysis revealed clear separation of R and P (accounting for 28.9 % of dataset variation) where subsequent k-means clustering confirmed the difference of microbiota in 2 clusters that perfectly align with R and P groups. The significance of this separation was confirmed by ANOSIM analysis (p = 0.005). Analysis of microbiota composition in P and R groups revealed 14 differentially abundant taxonomic units at the genus level. Of those at ≥1% abundance, Bacteroides, Barnesiella and Phascolarctobacterium were elevated in R, while Bifidobacterium and Dorea were elevated in P (p &lt; 0.01 for all). Of those at &lt; 1% abundance, Lactococcus, Sporobacter, Acidaminococcus, Actinomyces, and Asaccharobacter were elevated in P (p &lt; 0.01 for all). Conclusions: Although limited by sample size, we report the first in-human study to suggest a link between microbiota and response to sunitinib as we identified a significant discrepancy in stool bacteriomic distribution between P and R.