First-line Vascular Endothelial Growth Factor Research Articles

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

BackgroundThis 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.Materials and methodsIn 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.ResultsThe 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.ConclusionA 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.

Does red blood cell distribution width predict prognosis in metastatic renal cell carcinoma patients using first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy?

It is red cell distribution width (RDW) that has been reported to show an inflammatory response which has been studied recently. The aim of this study is to investigate whether the pre-treatment RDW in patients using first-line vascular endothelial growth factor tyrosine kinase inhibitor (VEGFR TKI) with the diagnosis of metastatic renal cell carcinoma (mRCC) predicts treatment response and is a prognostic factor or not. About 92 patients diagnosed with mRCC who were being treated with sunitinib or pazopanib in the first line between January 2015 and June 2021 were included in the study. The patients were divided into 2 groups, as being ≤15.3 and >15.3, according to the RDW cut-off value calculated by ROC analysis. The mOS of patients with a RDW of ≤15.3% was 45.0 (30.0-59.9) months, and of 21.3 (10.4-32.2) in those with a RDW of >15.3%. This difference was statistically significant (p < 0.001). In the group of patients with a RDW of ≤15.3, median progression free survival (mPFS) (38.04 [16.3-59.7] months) was found to be significantly higher than those with a RDW of >15.3 (17.1 [11.8-22.5] months) (p = 0.04). In multivariate analysis, RDW level (≤15.3, >15.3), was determined to be prognostic markers (p = 0.022). In mRCC patients, the RDW value measured before first-line VEGFR TKI therapy is an independent prognostic marker.

Mucinous Histology Is Associated with Resistance to Anti-EGFR Therapy in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer.

BackgroundLimited studies have suggested that mucinous histology is associated an attenuated response to anti-epidermal growth factor receptor (EGFR) therapy.MethodsWe conducted a single-institution, retrospective study to review the anti-EGFR response and the molecular profile of patients with left-sided microsatellite stable RAS/BRAF wild-type mucinous metastatic colorectal cancer.ResultsIn comparison to nonmucinous population (n = 98), mucinous histology (n = 20) was associated with a younger age (48 vs 54, P = .02), wild-type APC (80% vs 15.3%, P < .0001), and wild-type TP53 (40% vs 8.2%, P = .001). Guanine nucleotide binding protein, alpha stimulating (GNAS) mutations were exclusively found in mucinous tumors (20% vs 0, P < .0001). Genomic alterations associated with resistance to anti-EGFR therapy, such as ERBB2 amplification, PIK3CA mutation, MAP2K1 mutation, and KRAS amplification, were identified in patients with left-sided RAS/BRAF wild-type mucinous metastatic colorectal cancer. Mucinous histology was not associated with a worse outcome than non-mucinous histology (34.3 vs 42.2 months, P = .85). However, patients with left-sided RAS/BARF wild-type mucinous colorectal cancer treated with first-line anti-EGFR therapy had significantly worse progression-free survival (4 vs 6.5 months, hazard ratio [HR] = 5.3, 95% confidence interval [CI] 1.3-21.7, P = .01) than patients treated with the first-line vascular endothelial growth factor A antibody, bevacizumab. Anti-EGFR therapy was associated with limited responses and a short PFS across all lines of therapy in 12 patients with left-sided RAS/BRAF wild-type mucinous colorectal cancer.ConclusionsMucinous histology is associated with diminished benefits from anti-EGFR therapy in patients with left-sided RAS/BRAF wild-type colorectal cancer. These patients should be considered for bevacizumab-based therapy in the first- and second-line settings.

Molecular underpinnings of glandular tropism in metastatic clear cell renal cell carcinoma: therapeutic implications

Background Glandular metastases (GM) have been associated with improved survival in metastatic clear cell renal cell carcinoma (m-ccRCC). We aimed to molecularly characterize m-ccRCC with GM. Material and methods We performed a retrospective cohort study on all m-ccRCC patients with available tissue at our institution, diagnosed with metastatic disease from 2000 to 2019. We determined previously described angiogenesis- and immune-related gene expression signatures (GES) and ccrcc molecular subtypes through whole transcriptome RNA sequencing of primary tumors and metastases. We tested differences in GES and molecular subtypes across groups and studied overall (OS) and progression-free survival (PFS) using Kaplan–Meier survival analysis and Cox regression models. Results Primary tumors of patients who developed GM (n = 55) had higher IMmotion Angio (p < 0.001) and JAVELIN Angio (p = 0.003) GES as well as a higher proportion of angiogenic ccrcc2 molecular subtypes (p = 0.008) than primary tumors of patients with non-GM (n = 128). Metastatic lesions in glandular organs (n = 32) also had higher IMmotion Angio (p = 0.008) and JAVELIN Angio (p = 0.02) GES and were more frequently of the ccrcc2 molecular subtype (p = 0.03), compared to metastatic lesions in non-glandular organs in patients who did not develop any GM (n = 231), but not compared to metastatic lesions in non-glandular organs in patients who also developed GM (n = 18). Patients with GM had better OS (HR 0.49, p < 0.001) and PFS on first-line vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (HR 0.64, p = 0.045) than patients with non-GM. PFS on first- or any-line immuno-oncology (IO) was not different. IMmotion Angio, JAVELIN Angio GES, and ccrcc2 molecular subtype were associated with better OS and PFS on first-line VEGFR-TKIs, but not PFS on first or any-line IO. Conclusions Patients with m-ccRCC who develop GM are molecularly characterized by heightened angiogenesis, translating into better prognosis and better outcomes on VEGFR-TKIs, but not IO. Based on these findings, VEGFR-TKIs should be included in the first-line treatment of m-ccRCC patients with GM.

The impact of vitrectomy on outcomes achieved with 0.19 mg fluocinolone acetonide implant in patients with diabetic macular edema.

There is a lack of consensus on the use of intravitreal corticosteroid therapies in patients with diabetic macular edema (DME) and prior vitrectomized eyes in clinical practice. Retro-IDEAL was a 3-year retrospective, multicenter study in patients with chronic DME (i.e. DME that persists or recurs despite treatment) treated with ILUVIEN® (0.2 µg daily fluocinolone acetonide intravitreal implant), who had suboptimal outcomes with first-line vascular endothelial growth-factor inhibitors and other DME therapies. A total of 81 eyes (63 patients) were included of which 39 eyes had undergone prior vitrectomy (PV group) while 42 eyes had not undergone prior vitrectomy (NPV). Baseline characteristics were balanced; however, more patients had proliferative diabetic retinopathy in the PV group vs. the NPV group (21.62% vs 9.38%, respectively). Over 36 months, mean visual acuity (VA) increased in both groups with a tendency for more ETDRS letters being gained in the NPV group (+5.33) vs. the PV group (+2.42). By month 36, central retinal thickness was reduced to ⩽300 µm in two-thirds of the eyes in both groups and the mean change from baseline in intraocular pressure was similar in both groups (+0.50 mmHg -0.75 mmHg; NPV and PV group). These long-term data suggest that the 0.2 μg/day FAc implant is effective in both vitrectomized and non-vitrectomized patients, with a manageable safety profile, and improved VA and reduced supplemental therapies for patients with a suboptimal response to first-line DME therapies. Clinicians may consider utilizing the FAc implant earlier in the DME disease process.

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.

Abstract A053: Significance of Transglutaminase 2 expression on clinical outcome in metastatic renal cell carcinoma

Abstract Background: A few recent studies have demonstrated a possible role of transglutaminase 2 (TG2) in tumorigenesis or progression of renal cell carcinoma (RCC). The aim of this study was to examine TG2 expression and its clinical significance in patients with metastatic clear cell RCCs (ccRCCs). Methods: We analyzed 206 metastatic ccRCC patients who received the first-line vascular endothelial growth factor (VEGF) targeted therapy including sunitinib (n = 33), pazopanib (n = 120), and sorafenib (n = 53) between 2006 and 2016. The expression of TG2 was determined by immunohistochemistry and categorized into four groups, according to membranous staining intensity: negative (0), mild (1+), moderate (2+), and strong (3+). Results: TG2 staining intensity was negative in 20.9% of ccRCC (n = 43), 1+ in 46.6% (n = 96), 2+ in 9.71% (n = 20), and 3+ in 22.8% (n = 47). The survival analysis showed a significant association between stronger TG2 expression (≥ 2+) and worse progression-free survival (PFS) (P = 0.032) in the 1st line VEGF-targeted therapy. On multivariate analysis including previous nephrectomy, number of metastatic organs, and International Metastatic RCC Database Consortium Risk Score, stronger TG2 expression was a significant independent predictive indicator for poor PFS (P = 0.004). Conclusions: Our study is the first to demonstrate the significance of TG2 expression on clinical outcome in metastatic ccRCCs. TG2 expression was a significant negative predictive marker for PFS in 1st line VEGF-targeted therapy and targeting TG2 may be a new therapeutic approach to metastatic ccRCC. Citation Format: Seung-Hoon Beom, Sejung Park, Woo Sun Kwon, Sang Joon Shin, Soo-Youl Kim, Nam Hoon Cho, Sun Young Rha. Significance of Transglutaminase 2 expression on clinical outcome in metastatic renal cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A053. doi:10.1158/1535-7163.TARG-19-A053

Response of Primary Renal Cell Carcinoma to Systemic Therapy

BackgroundUpfront cytoreductive nephrectomy (CRN) in renal cell carcinoma (RCC) has come into question in recent prospective clinical trials. ObjectiveWe investigated the effect of systemic therapies on primary tumor response in patients with metastatic RCC. Design, setting, and participantsA pooled analysis of 12 phase II/III clinical trials of metastatic RCC patients treated with systemic therapy between 2003 and 2013 was performed. Patients with one target lesion in the kidney and no prior nephrectomy were identified as having their primary tumor in place. Outcome measurements and statistical analysisThe objective response rate (ORR) of the primary tumor was defined as per the Response Evaluation Criteria in Solid Tumors (RECIST). ORR was assessed in the overall population and patient subsets based on prior treatment and International Metastatic RCC Database Consortium (IMDC) risk group. Cox’s models adjusting for baseline characteristics, treatment, line of therapy, and site of metastases were used for survival analyses. Results and limitationsIn total, 4736 patients were identified, of whom 565 had their primary tumor in place: 461 (82%) were treatment naïve, 283 (50%) received first-line vascular endothelial growth factor (VEGF)-targeted therapy, and 222 (39%) were IMDC poor risk. The ORRs of the primary tumor were 19% (95% confidence interval 16–23) in patients treated with first-line therapy (any type), 28% (22–33) in those treated with first-line VEGF-targeted therapy, and 23% (19–28) in those treated with VEGF-targeted therapy (any line). The ORRs were 9% (5–13) and 20% (15–27) in IMDC poor- and intermediate-risk patients, respectively. ConclusionsSystemic therapy reduces primary tumor size in patients with metastatic RCC. Responses in primary tumors treated with VEGF-targeted therapy were observed in upward of 28% of patients. Selection of patients for immediate CRN requires careful consideration of patient and disease characteristics. Patient summaryAntiangiogenic therapy meaningfully decreases the size of primary kidney tumor. Hence, for patients with metastatic disease who are not undergoing upfront cytoreductive nephrectomy, systemic therapy can palliate both primary tumor and metastases.

Liver metastasis and Heng risk are prognostic factors in patients with non-nephrectomized synchronous metastatic renal cell carcinoma treated with systemic therapy.

ObjectiveThis study aimed to determine the prognostic factors of progression-free survival (PFS) and overall survival (OS) in non-nephrectomized patients with synchronous metastatic renal cell carcinoma (mRCC) receiving first-line vascular endothelial growth factor (VEGF)-targeted therapy or immunotherapy.MethodsOf 70 patients, 57 (81.4%) were treated with targeted therapy, including 5 (7.1%) with previous immunotherapy and 13 (18.6%) with immunotherapy only. The medical records of patients were retrospectively reviewed and analyzed to determine factors of PFS and OS using the Cox proportional hazards model with a statistical significance p-value <0.05.ResultsThe median treatment and follow-up periods were 3.9 and 30.9 months, respectively. Disease progression was reported in 90.0% of patients, with an objective response rate and clinical benefit rate of 26.1% and 76.8%, respectively. The lung (77.1%) was the most common site of metastasis. Multivariable analysis showed that poor Heng risk (hazard ratio [HR]: 2.37) and liver metastasis (HR: 2.34) were significant prognostic factors for PFS, and female sex (HR: 2.13), poor Heng risk (HR: 3.14), and liver metastasis (HR: 2.78) were significant prognostic factors for OS (p < 0.05). A subset analysis of risk factors among patients without previous history of immunotherapy also showed poor Heng risk (HR 2.92 and HR 4.24 for PFS) and liver metastasis (HR 2.87 and HR 4.81 for OS) as significant factors for both PFS and OS (p<0.05).ConclusionPoor Heng risk, sex, and liver metastasis were associated with survival outcomes after first-line systemic therapy in patients with non-nephrectomized synchronous mRCC.

Final Results of a Non-Interventional Study Evaluating the Quality of Life in Second-line Treatment of Metastatic Renal Cell Carcinoma With Everolimus: The EVERPRO Study

Background: This study assessed the quality of life (QoL) and the implication of time effort of everolimus treatment in patients with metastatic renal cell carcinoma (mRCC). Methods: Adult patients with mRCC were eligible for everolimus treatment after first-line vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors or bevacizumab therapy. The primary end-point, QoL, was assessed by means of the NCCN-FACT FKSI-19 questionnaire. Results: In total, 202 patients (24% of female patients; median age, 71 years) were evaluable for QoL analyses. The median treatment duration was 4.4 months (95% CI, 3.8-5.3) and the median time to progression was 6 months (95% CI, 5.4-7.5). The median FKSI-19 total score remained stable during treatment (52.0 at therapy start, 55.0 at observation end). The median time effort spent on total therapy was 20 hours per patient. Most of the patients stated to have “no limitations,” “a little” or “moderate” limitations in their daily, social, and professional lives. Two months after the start of treatment, 65 patients reported none or a little time burden due to therapy. Conclusions: QoL was maintained during the everolimus therapy and limitations as well as time effort were acceptable for most of the patients. The study supports previous findings on switching mode of action after anti-VEGFR-targeted therapy to a mammalian target of rapamycin inhibitor.

Cabozantinib for the treatment of patients with metastatic non-clear cell renal cell carcinoma: A retrospective analysis

BackgroundCabozantinib prolongs overall survival (OS) and progression-free survival (PFS) in patients with metastatic clear cell renal cell carcinoma (RCC) that progressed on first-line vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFR-TKI). The role of cabozantinib has not been established in non-clear cell renal cell carcinoma (nccRCC). MethodsThis is a retrospective study of 30 patients with nccRCC who received cabozantinib from January 2013 to January 2017. Information collected included baseline characteristics, toxicity, dose reductions, PFS and OS. A fellowship trained abdominal radiologist, blinded to patient history and clinical data, assessed radiographic response using RECIST, v1.1. ResultsWith a median follow-up of 20.6 months (95% confidence interval [CI]: 11.4–28.8), median PFS was 8.6 months (95% CI: 6.1–14.7), and median OS was 25.4 months (95% CI: 15.5–35.4). Of the 28 patients with measurable disease, 4 had partial responses (2 papillary, 1 chromophobe and 1 unclassified RCC), 18 had stable disease (64.2%) and 6 had progressive disease (21.4%), resulting in a 14.3% objective response rate and a 78.6% disease control rate. Two patients with papillary RCC who had experienced disease progression on savolitinib achieved durable partial response and stable disease, respectively, following treatment with cabozantinib. Of the 21 patients who started cabozantinib at 60 mg/d, 12 (57.1%) required dose reduction due to toxicity. ConclusionIn this retrospective study, cabozantinib produced a clinically meaningful benefit in patients with metastatic nccRCC, the majority of whom had disease progression on prior VEGFR-TKIs. Prospective trials of cabozantinib in nccRCC are warranted.

Treatment outcomes of metastatic nonclear cell renal cell carcinoma: A single institution retrospective analysis.

Introduction:Nonclear cell (NCC) metastatic renal cell carcinoma (mRCC) is a biologically heterogeneous entity. We report the outcomes of NCC mRCC treated with first-line vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin (mTOR) inhibitors at our institute. This is first such report from India.Methods:This is a retrospective analysis of the 40 consecutive patients of NCC mRCC treated between January 2013 and June 2015 in routine clinical practice at our institute. The primary endpoint analyzed was overall survival (OS) with respect to the type of first-line treatment and tumor histology.Results:The most common histological subtype was papillary in 25 patients (62.5%) followed by sarcomatoid in six (15%), chromophobe in 5 (12.5%), translocation-associated in one patient, and other nonspecified in three patients. First-line treatment was sorafenib in 14 (35%), sunitinib in 9 (22.5%), pazopanib in 8 (20%), everolimus in seven (17.5%), and best-supportive care (BSC) in two (5%) patients. Partial response, stable disease, and progression was observed in six (15%), 13 (32.5%), and nine (22.5%) cases, respectively, as the best response to first-line treatment. The median OS was 11.7 months and median event-free survival was 6.1 months in the whole cohort. The median OS in months for different first-line treatments were as follows: sorafenib (16.2), sunitinib (11.7), pazopanib (not reached, mean-23.9 ± 6.0), everolimus (4.1) and BSC (0.6) and for different histological subtypes were as follows: papillary (9.8), chromophobe (not reached, mean-30.3 ± 8.4), sarcomatoid (4.1), and others (7.9).Conclusions:Chromophobe histology has a better outcome compared to other histological subtypes, and anti-VEGF tyrosine kinase inhibitors are preferable first-line agents compared to mTOR inhibitors.

Targeting Bacteroides in Stool Microbiome and Response to Treatment With First-Line VEGF Tyrosine Kinase Inhibitors in Metastatic Renal-Cell Carcinoma.

Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) are a mainstay of treatment for metastatic renal-cell carcinoma. Stool microbiome composition is predictive of response to immunotherapy and cytotoxic chemotherapy. We sought to investigate whether antibiotics targeting Bacteroides species affect progression-free survival (PFS) while receiving first-line VEGF-TKI therapy. Using a retrospective cohort of intermediate- and poor-risk metastatic renal-cell carcinoma patients from the University of Utah, we categorized patients receiving first-line VEGF-TKIs by receipt of antibiotics (Bacteroides spp., non-Bacteroides spp., or none) and assessed PFS by Kaplan-Meier and Cox proportional hazard models. Of 145 patients, 17 received antibiotics with Bacteroides spp. coverage and 32 patients received antibiotics without Bacteroides spp. coverage. When compared to patients not receiving antibiotics, improved PFS was seen with each additional day antibiotics were prescribed with Bacteroides spp. coverage (hazard ratio= 0.92; 95% confidence interval, 0.83-0.99; P= .04). Targeting stool Bacteroides spp. with antibiotics improves PFS in patients receiving first-line VEGF-TKIs in a duration-dependent manner.

MP66-16 CLINICAL OUTCOMES OF AXITINIB VERSUS SUNITINIB AS A FIRST-LINE THERAPY FOR METASTATIC RENAL CELL CARCINOMA IN JAPANESE PATIENTS

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) II1 Apr 2018MP66-16 CLINICAL OUTCOMES OF AXITINIB VERSUS SUNITINIB AS A FIRST-LINE THERAPY FOR METASTATIC RENAL CELL CARCINOMA IN JAPANESE PATIENTS Yusuke Kiso, Takamitsu Inoue, Taketoshi Nara, Sohei Kanda, Kazuyuki Numakura, Hiroshi Tsuruta, Mitsuru Saito, Shintaro Narita, Shigeru Satoh, and Tomonori Habuchi Yusuke KisoYusuke Kiso More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Taketoshi NaraTaketoshi Nara More articles by this author , Sohei KandaSohei Kanda More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Hiroshi TsurutaHiroshi Tsuruta More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Shigeru SatohShigeru Satoh More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1888AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The optimal sequence of vascular endothelial growth factor (VEGF)-targeted therapies in patients with metastatic renal cell carcinoma (mRCC) has not been fully understood. We retrospectively compared the clinical outcomes between patients who underwent axitinib or sunitinib as a first-line therapy in patients with mRCC. METHODS From April 2008 to July 2016, 134 patients with mRCC underwent VEGF-targeted sequence therapies in a single institute. The patients with clear cell carcinoma including 49 and 48 patients who underwent sunitinib and axitinib as a first-line therapy were evaluated, respectively. No difference was observed in patient′s backgrounds including MSKCC risk classification at the initiation of the first-line VEGF therapies. RESULTS Patients treated with sunitinib had a higher incidence of drug discontinuation due to ≥ grade 3 adverse events (14.6% vs. 32.6%, p = 0.036) and ≥ grade 3 fatigue (4.1% vs. 18.3%, p = 0.027) as compared with those treated with axitinib. Objective response rate of axitinib was significantly better than that of sunitinib (41.6% vs. 20.4%, p = 0.023). The median progression free survival was significantly longer in patients underwent axitinib therapy as a first-line therapy than that in patients with sunitinib (13.6 months vs. 4.7 months, p = 0.014), and the median time to first-line treatment failure was also significantly longer in the axitinib group than in sunitinib group (11.8 months vs. 3.7 months, p = 0.007). However, no difference was observed in median overall survival between patients underwent axitinib and sunitinib as first-line therapies (22.3 months vs. 20.1 months, p = 0.087). CONCLUSIONS The axitinib as a first-line VEGF-targeted therapy for mRCC had a longer progression free survival and time to treatment failure with less toxic profile than sunitinib but did not extend the overall survival in Japanese retrospective study. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e874 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Yusuke Kiso More articles by this author Takamitsu Inoue More articles by this author Taketoshi Nara More articles by this author Sohei Kanda More articles by this author Kazuyuki Numakura More articles by this author Hiroshi Tsuruta More articles by this author Mitsuru Saito More articles by this author Shintaro Narita More articles by this author Shigeru Satoh More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Prognostic Value of Baseline Serum C-Reactive Protein Level in Intermediate-Risk Group Patients With Metastatic Renal-Cell Carcinoma Treated by First-Line Vascular Endothelial Growth Factor-Targeted Therapy.

Almost half of patients with metastatic renal-cell carcinoma (mRCC) are classified as intermediate risk by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model. The aim of this study was to evaluate whether baseline C-reactive protein (CRP) levels predict overall survival (OS) in intermediate-risk group mRCC patients. Data from 107 intermediate-risk group mRCC patients receiving first-line targeted therapy were retrospectively reviewed. We evaluated the correlation between baseline CRP levels as well as other indices and OS. Of the 107 patients with intermediate-risk disease, 46 patients (43%) were classified as having elevated CRP levels. The elevation of pretreatment serum CRP levels was the independent prognostic factor of OS in patients with intermediate risk (hazard ratio, 4.609; P= .001). The 1- and 3-year survival rates of patients with intermediate-nonelevated CRP were 90.0% and 64.7% compared to the favorable-risk group, at 92.1% and 68.5%, respectively. In contrast, the 1- and 3-year survival rates of patients with intermediate-elevated CRP were 80.5% and 37.4% compared to the poor-risk group, at 65.2% and 24.2%, respectively. Baseline CRP levels could divide mRCC patients in the intermediate-risk group into 2 prognostic subgroups.

Second-Line Therapy for Advanced Colorectal Cancer: EGFR vs. Continuation of VEGF Inhibition

We review second-line biological therapies for metastatic colorectal cancer (mCRC), including their mechanisms of action, adverse events, survival outcomes, optimal chemotherapy combinations, and sequencing of agents. The advent of biological therapeutics targeting vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways has enhanced the benefits afforded by the plethora of chemotherapeutic agents for patients with mCRC over the past 10 years, nearly tripling the median OS. Individual biomarkers predicting prognosis and response to VEGF vs. EGFR therapy have been identified. For patients who progress on first-line VEGF therapy, evidence suggests that continued VEGF inhibition may be as efficacious as changing to EGFR therapy with less adverse effects. However, for patients who progress after first-line EGFR therapy, early studies suggest changing to agents targeting the VEGF pathway. Biological options for patients with mCRC who progressed on first-line concomitant chemotherapy and biologic therapy depend on individual tumor characteristics and choice of first-line therapy. Future research should focus on prognostic and predictive biomarkers to better inform choice of first-line and sequential therapy beyond progression.

Evolution of Circulating Tumor DNA Profile from First-line to Subsequent Therapy in Metastatic Renal Cell Carcinoma

BackgroundTreatment of metastatic renal cell carcinoma (mRCC) typically entails mechanistically distinct agents across the first- and second-line setting. Activity of these agents may be predicated on selective pressure that modulates RCC biology. Circulating tumor DNA (ctDNA) is a platform to noninvasively ascertain temporal changes in genomic profile. ObjectiveTo assess the ctDNA profile in a large cohort of mRCC patients, and to assess changes across patients receiving first-line and later lines of therapy. Design, setting, and participantsWe obtained the ctDNA profile in mRCC patients who received ctDNA profiling as part of routine clinical care at progression using a 73-gene Clinical Laboratory Improvement Amendments-certified ctDNA platform. Outcome measurements and statistical analysisGenomic alterations (GAs) were pooled for the entire cohort. A comparison of first- and postfirst-line was performed with grouping based on conventional practice patterns (first-line regimens included sunitinib, pazopanib, and bevacizumab, and postfirst-line regimens included everolimus, axitinib, cabozantinib, and nivolumab). Results and limitationsctDNA clinical results from a nationwide cohort of 220 consecutive patients with mRCC were assessed (145 men, 75 women; median age: 63 yr, interquartile range: 57–70). GAs were detected in 78.6% of patients. The most frequent GAs in the overall cohort included TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). Thirty-eight and 64 patients were coded as receiving first-line and later line agents, respectively. The highest disparity in GA frequencies in postfirst-line versus first-line were in TP53 (49% vs 24%), VHL (29% vs 18%), NF1 (20% vs 3%), EGFR (15% vs 8%), and PIK3CA (17% vs 8%) while ARID1A was equivalent (13% vs 11%). Restricting the analysis to later lines versus first-line vascular endothelial growth factor inhibitors, these differences were even more prominent, particularly for TP53 (64% vs 31%) and NF1 (29% vs 4%). ConclusionsIn the largest assessment of ctDNA-detected GAs prevalence in mRCC to date, the majority of patients demonstrated clinically and biologically relevant GAs. Increasing p53 and mechanistic target of rapamycin pathway (eg, NF1, PIK3CA) alterations in postfirst-line patients with first-line vascular endothelial growth factor-directed therapy may underlie mechanisms of resistance. Routine ctDNA assessment during the clinical course of mRCC patients may have therapeutic implications. Patient summaryCollection of circulating tumor DNA is feasible in patients with metastatic renal cell carcinoma, and analysis of a large cohort demonstrates significant changes in circulating tumor DNA profile across patients’ clinical course which may have therapeutic implications.

T-cell receptor (TCR) repertoire in metastatic renal cell carcinoma (RCC) patients treated with first-line vascular endothelial growth factor receptor blockade.

501 Background: Reports have demonstrated an inverse relationship between suppression of immune surveillance mechanisms and activation of the vascular endothelial growth factor receptor (VEGFR) pathway suggesting that T cell repertoires may impact response to VEGFR blockade. We evaluated the association between clinical outcomes and T cell repertoire in metastatic RCC patients receiving a front-line anti-VEGFR, pazopanib. Methods: Pre-treatment RCC tumors were analyzed from VEG105192, a phase III study of mRCC patients randomized (2:1) to pazopanib (paz) 800 mg daily vs placebo (pbo) for TCR gamma (TCRG) and TCR beta (TCRB) CDR3 regions. Using the Adaptive Biotechnologies immunoSEQ Assay, we assessed TCR clonality, a measure of total repertoire represented by expanded clones, and entropy, a measure of evenness and diversity. PD-L1 was evaluated by immunohistochemistry (IHC) H-Scores. The goal of the study was to determine if the repertoire of T cell clones was associated with progression-free survival as a clinical endpoint. Results: In the cohort with available tissue, the median PFS was 10.8 and 5.5 months (mos) for paz and pbo, respectively. TCRB (n = 114) and TCRG (n = 43 pbo, 109 paz) clonality ranged from 0-0.31 and 0-0.98, and entropy from 1-12.1 and 0-10.37, respectively. TCRB and TCRG entropy were highly correlated (Spearman’s R = 0.92, n = 114). Samples from the pbo-treated group with higher TCRG entropy, defined as the top 25th percentile, were associated with an improved median PFS (12.8 months) when compared to the lower 75th percentile (3.1 months, P = 0.023); similar trends were seen for TCRB entropy. Neither entropy nor clonality was associated with maximal reduction in tumor volume in the paz-treated group. PD-L1 H-scores were not associated with entropy or clonality (P &gt; 0.05). Conclusions: Our data suggests that RCC samples with higher entropy are associated with a favorable prognosis. Identification of tumors with restricted TCRB/G chain usage and less diverse repertoire, as represented by lower entropy and higher clonality, may impact responses to VEGFR blockade and requires further study. Clinical trial information: NCT00334282.

Clinical experience with everolimus in the second-line treatment of advanced renal cell carcinoma.

Everolimus is an oral inhibitor of mammalian target of rapamycin (mTOR-I) and is currently approved for the treatment of metastatic renal cell carcinoma (mRCC) after failure of first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI). In this narrative review, we aim to report the available evidence about the use of everolimus as second-line therapy for mRCC. A literature search was performed using PubMed/MEDLINE and abstracts from major conferences on clinical oncology as sources. We report data from prospective as well as retrospective and real world data studies and we analyze the safety and efficacy profile of everolimus as second-line therapy for mRCC. Although different drugs are currently available for the second-line treatment of mRCC, everolimus represents a feasible and safe option in this setting, especially for patients who have experienced high-grade toxicity or are still carrying TKI-related toxicities from first-line treatment.

Long-term response in metastatic renal cell carcinoma patients receiving first-line therapy with VEGF TKIs.

436 Background: A subset of metatstatic renal cell carcincoma (mRCC) patients (pts) on first-line (1st) vascular endothelial growth factor inhibitors (VEGF TKIs) will have a long-term response (LTR) defined as a progression free survival (PFS) of &gt;18 months (mos) on continuous therapy, and may be candidates for intermittent VEGF TKI therapy. Methods: From our institutional dataset of mRCC pts, we identified pts receiving 1st VEGF TKIs and who achieved a LTR. Data on clinical characteristics and survival outcomes were compared between those with LTRs and rest of the patients (control). Continuous and categorical variables were assessed by Wilcoxon rank sum and chi-square, respectively; and survival outcomes were compared by log-rank tests. Results: Of 89 pts, 24 (33%) had LTRs, of whom 5 pts have discontinued treatment (range 1-5 years) without subsequent disease progression, and 4 pts took treatment breaks for 3-9 mos. Baseline pts or disease characteristics were not predictive of LTRs (Table). Conclusions: A subset of mRCC pts receiving 1st VEGF TKIs achieve a LTR, and are not currently identifiable by baseline clinical characteristics including prognostic risk categorization. Identification of biomarkers predictive of LTR may allow intermittent or even deferred therapy with VEGF TKIs minimizing toxicity and cost. [Table: see text]