Vascular Endothelial Growth Factor Receptor-tyrosine Kinase Inhibitor Therapy Research Articles

Development and validation of a tumor tissue based multivariate biomarker for predicting angiogenesis inhibitor clinical benefit in renal cell carcinoma (RCC).

467 Background: Angiogenesis inhibitors, including vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs), are standard of care therapy (alone and in combination) for several advanced cancers, including RCC. There is an unmet need for a biomarker to identify patients with RCC most likely to benefit from VEGFR TKIs to guide individualized treatment decision making. Hence, we sought to develop and validate a biomarker for predicting single-agent systemic VEGFR TKI benefit in patients with RCC. Methods: Candidate biomarkers were selected by co-expression patterns in VEGFR TKI sensitive/resistant tumor types from pan-solid tumor TCGA expression profiling data and the literature. The angiogenesis inhibitor treatment response score (Angio TRS) was developed as a multivariate expression-based algorithm from RNA-based quantitative transcriptional profiling (qTP) performed in parallel with clinical FFPE tumor based comprehensive genomic profiling, with the Angio TRS High/Low threshold set at the median of clear cell RCC samples. The locked Angio TRS (and High/Low status) was then validated in a cohort of adult RCC patients treated with a systemic line of single agent VEGFR TKI therapy within a prospective observational trial; group outcomes (by time to next therapy [TTNT]) were compared by univariate analysis, Cox proportional hazards modeling (adjusting for age, biologic sex, histology, nuclear grade [incorporating sarcomatoid features], therapy line, and TKI type), and unadjusted Kaplan Meier analysis. Laboratory information for IMDC risk group status was not available. Results: Across 3,721 solid tumor tissue samples, median Angio TRS was highest in known VEGFR TKI sensitive tumors (RCC, thyroid carcinoma, sarcoma). Angio TRS was then validated in a separate cohort of 86 patients with RCC treated with single agent systemic VEGFR TKI (median follow-up 29.2 months; 76% male, 77% clear cell, 14% with sarcomatoid features, 84% 1st line, and 71% treated with sunitinib, pazopanib or axitinib); 52% of patients were Angio TRS High. By univariate analysis, Angio TRS status (p=0.008) and nuclear grade 4 (with or without sarcomatoid features; p=0.06 & 0.07) were most significantly associated with VEGFR TKI TTNT; by multivariate analysis, only Angio TRS status was significantly associated with TTNT (High vs. Low median TTNT 15.8 vs. 5.6 months, adjusted hazard ratio 0.46, p=0.012). Conclusions: Angio TRS is a multivariate expression-based algorithm performed on FFPE tumor tissue, validated to be prognostic of clinical outcome for patients with RCC treated with single agent VEGFR TKI when controlling for clinical factors. Angio TRS may support individualized treatment decision making in patients with advanced RCC. Additional independent validation in a cohort of Kaiser Permanente patients will be presented. Clinical trial information: NCT03061305 .

Abstract CT257: First-in-human phase 1 studies of PTPN2/1 inhibitors ABBV-CLS-484 and ABBV-CLS-579 in locally advanced or metastatic tumors

Abstract Background: Protein tyrosine phosphatase non-receptor type 2 and type 1 (PTPN2/1) antagonists inhibit PTPN2/1-mediated negative regulation of immune response pathways. They may promote antitumor activity by increasing function of immune cells such as T cells and dendritic cells, inducing cytokine production, increasing antigen presentation, and amplifying interferon gamma-mediated tumor growth arrest. ABBV-CLS-484 and ABBV-CLS-579 are potent, orally bioavailable, first-in-class PTPN2/1 inhibitors that showed promising antitumor activity and were well tolerated in preclinical models. Preclinical data also indicated that PTPN2/1 inhibitors have improved efficacy when combined with PD-1-targeting agents (eg, pembrolizumab) or vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in multiple tumor models. Here, we describe 2 first-in-human trials of ABBV-CLS-484 or ABBV-CLS-579 as monotherapy and in combination with pembrolizumab or VEGFR TKI in patients with locally advanced/metastatic tumors. Methods: These phase 1, open-label, multicenter, non-randomized trials (ABBV-CLS-484: NCT04777994; ABBV-CLS-579: NCT04417465) comprise dose-escalation (ESC) and dose-expansion (EXP) phases. ESC is guided by a Bayesian optimal interval design based on dose-limiting toxicities. ESC data are used to inform evaluation of EXP cohorts in select tumor types including relapsed/refractory (R/R) head and neck squamous cell carcinoma, R/R non-small cell lung cancer, advanced renal cell carcinoma, and microsatellite instability-high tumors. In both ESC and EXP phases, the study drug (ABBV-CLS-484 or ABBV-CLS-579) is administered orally either alone or in combination with pembrolizumab (200 mg intravenously once every 3 weeks) and is slated to also be administered in combination with a VEGFR TKI. Eligible patients have locally advanced/metastatic tumors for which no effective standard therapy exists (or has failed), and Eastern Cooperative Oncology Group performance status ≤2. Patients (≥18 years) must have received ≥1 prior systemic anticancer therapy for the indication being considered, have relapsed or be refractory to ≥1 prior anti-PD-1/PD-L1 therapy (EXP monotherapy and pembrolizumab combination), or have relapsed after ≤1 (ABBV-CLS-484) or ≥1 (ABBV-CLS-579) prior VEGFR TKI therapy (EXP VEGFR TKI combination). Primary objectives are to assess safety, tolerability, pharmacokinetics, and to determine the recommended expansion dose and/or maximum tolerated dose of ABBV-CLS-484 or ABBV-CLS-579, both as monotherapy and in combination. Evaluation of objective response rate (RECIST v1.1) is a primary objective in EXP phase and a secondary objective in ESC phase. Both studies are active, and as of 30 Nov 2022, 30 (ABBV-CLS-484) and 45 (ABBV-CLS-579) patients had been enrolled in ESC phase. Citation Format: Patricia M. LoRusso, Emiliano Calvo Aller, Noboru Yamamoto, Chia-Chi Lin, Thaddeus Beck, David Sommerhalder, Do-Youn Oh, John D. Powderly, Talia Golan, Linu Sara Abraham, Joel S. Hayflick, Tamar Uziel, Priya Brunsdon, Wijith Munasinghe, Marcia Paddock, Cathleen Brdlik Hartman, Jonathan Powell, Bruno Medeiros, Martha R. Neagu, Benedito A. Carneiro. First-in-human phase 1 studies of PTPN2/1 inhibitors ABBV-CLS-484 and ABBV-CLS-579 in locally advanced or metastatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT257.

Final efficacy and safety results and biomarker analysis of a phase 2 study of cabozantinib in Japanese patients with advanced renal cell carcinoma

BackgroundCabozantinib was established as the standard of care for the treatment of patients with renal cell carcinoma (RCC) whose disease had progressed after vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy in the global randomized trial METEOR. A phase 2 study was conducted to bridge the findings in METEOR to Japanese patients. Here, we report a biomarker analysis and update the efficacy and safety results of cabozantinib treatment.MethodsJapanese patients with RCC who received at least one prior VEGFR-TKI were enrolled and received cabozantinib 60 mg orally once daily. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival, overall survival, and safety. Exploratory analyses included the relationship between plasma protein hepatocyte growth factor (HGF) levels and treatment responses.ResultsIn total, 35 patients were enrolled. The median treatment duration was 58.3 (range 5.1–131.4) weeks. The objective response rate was 25.7% (90% confidence interval [CI] 14.1–40.6). Kaplan–Meier estimate of median progression-free survival was 11.1 months (95% CI 7.4–18.4). The estimated progression-free survival proportion was 73.1% (95% CI 54.6–85.0) at 6 months. Median overall survival was not reached. Adverse events were consistent with those in METEOR and the safety profile was acceptable. Nonresponders to cabozantinib showed relatively higher HGF levels than responders at baseline.ConclusionsUpdated analyses demonstrate the long-term efficacy and safety of cabozantinib in Japanese patients with advanced RCC after at least one VEGFR-TKI therapy. Responders tended to show lower baseline HGF levels ClinicalTrials.gov Identifier: NCT03339219.

Thyroid dysfunction related to vascular endothelial growth factor receptor tyrosine kinase inhibitors: A real-world study based on FAERS.

The adverse events of thyroid dysfunction caused by the use of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) have not been confirmed in a real-world investigation. The aim of this study was to evaluate the relationship between thyroid dysfunction and treatment using Food and Drug Administration (FDA)-approved VEGFR-TKIs. Four data-mining algorithms were employed to detect thyroid dysfunction signals for VEGFR-TKIs, using data in the FDA Adverse Event Reporting System (FAERS) database from 68 quarters. MySQL Workbench and R were used to conduct statistical analysis. We identified 32679 reports of thyroid dysfunction, of which 1567 listed VEGFR-TKIs as the primary suspected drugs. All four algorithms showed that the strength of the signals for hypothyroidism were greater than those for hyperthyroidism, for all the VEGFR-TKIs. In most cases, the median appearance time was within 100days of initiation of VEGFR-TKIs therapy, except in the case of ponatinib. This indicated the need to actively identify and manage thyroid dysfunction during the early stages of VEGFR-TKIs treatment. This study systematically identified the pharmacovigilance signals of thyroid dysfunction associated with the use of VEGFR-TKIs, using the FAERS database.

Outcomes of Patients with Metastatic Renal Cell Carcinoma Treated with Targeted Therapy After Immuno-oncology Checkpoint Inhibitors

BackgroundImmuno-oncology (IO) therapies have changed the treatment standards of metastatic renal cell carcinoma (mRCC). However, the effectiveness of targeted therapy following discontinuation of IO therapy in real-world settings has not been well studied. ObjectiveTo describe treatment sequence and assess clinical effectiveness of targeted therapy for mRCC patients who received prior IO therapy. Design, setting, and participantsA retrospective, longitudinal cohort study using data from eight international cancer centers was conducted. Patients with mRCC were ≥18yr old, received IO therapy in any line, and initiated targeted therapy following IO therapy discontinuation. InterventionPatients were treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) or mammalian target of rapamycin inhibitors (mTORIs). Outcome measurements and statistical analysisOutcomes were time to treatment discontinuation (TTD), overall survival (OS), and objective response rate (ORR). Crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. Models were adjusted for age, sex, therapy line, and International Metastatic RCC Database Consortium risk group. Results and limitationsAmong 314 patients, 276 (87.9%) and 38 (12.1%) were treated with VEGFR-TKI and mTORI therapy, respectively. The most common tyrosine kinase inhibitor treatments were axitinib, cabozantinib, and sunitinib following IO therapy. In adjusted models, patients treated with VEGFR-TKI versus mTORI therapy had lower hazard of TTD after IO treatment (aHR=0.46; 95% CI: 0.30–0.71; p < 0.01). One-year OS probability (65% vs 47%, p < 0.01) and proportion of ORR (29.8% vs 3.6%, p < 0.01) were significantly greater for patients treated with VEGFR-TKIs versus those treated with mTORIs. ConclusionsTargeted therapy has clinical activity following IO treatment. Patients who received VEGFR-TKIs versus mTORIs following IO therapy had improved clinical outcomes. These findings may help inform treatment guidelines and clinical practice for patients post-IO therapy. Patient summaryPatients may continue to experience clinical benefits from targeted therapies after progression on immuno-oncology treatment.

Risk of hand-foot skin reaction associated with vascular endothelial growth factor–tyrosine kinase inhibitors: A meta-analysis of 57 randomized controlled trials involving 24,956 patients

Multiple randomized controlled trials have assessed hand-foot skin reaction (HFSR) caused by vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). We performed a meta-analysis to determine the incidence and the relative risk (RR) of HFSR associated with these agents. Databases were searched for relevant studies. Statistical analyses were conducted to calculate the summary incidences, RR, and 95% confidence intervals (CIs) by using random-effects or fixed-effects models according to the heterogeneity of the included studies. A total of 24,956 patients from 57 studies were included. The overall incidence of all-grade and high-grade HFSR associated with VEGFR-TKIs was 35.0% (95% CI, 28.6%-41.6%) and 9.7% (95% CI, 7.3%-12.3%), respectively. The use of VEGFR-TKIs significantly increased the risk of developing all-grade (RR, 5.09; 95% CI, 3.52-7.35; P<.001) and high-grade (RR, 9.42; 95% CI, 5.59-15.90; P<.001) HFSR. Subgroup analyses revealed that the risk of HFSR was significantly increased according to tumor type, VEGFR-TKI, trial phase, treatment regimen, and control therapy. No evidence of publication bias was observed. High heterogeneity in most studies. High risk of HFSR is prone to develop in cancer patients receiving VEGFR-TKIs.

Outcomes of patients (pts) with metastatic clear-cell renal cell carcinoma (mCCRCC) treated with second-line (2L) vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) after first-line (1L) immune checkpoint inhibitors (ICI).

682 Background: Little data exists on objective response rates (ORR), progression-free survival (PFS), and safety of 2L VEGFR-TKI after 1L ICI therapy in pts with mCCRCC. Methods: This is a retrospective study of pts with mCCRCC who received 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Tumor response was assessed by a blinded radiologist using RECIST 1.1. Descriptive statistics, the Fisher’s test, and Kaplan-Meier method were used. Results: We report on 43 pts who were treated at MDACC from 2015 till present. Median age at mCCRCC diagnosis was 59 years (range: 43-72). 33 pts had lung mets, 20 had LN mets, 14 had bone mets, and 3 had liver mets. As 1L therapy, 20 pts received nivolumab + ipilimumab, 14 received nivolumab + bevacizumab, and 9 received nivolumab. Median time on ICI therapy was 29.4 weeks. All pts had resolution of Grade 3/4 AEs from ICI and PD before initiation of VEGFR-TKI. One patient (2%) had CR, 17 pts (40%) had PR, and 25 pts (58%) had SD, leading to 100% disease control rate (DCR) as best response to 2L VEGFR-TKI. Median PFS was 10.0 months (95% CI: 7.4, NA). Estimated 1-yr overall survival (OS) was 87.5% (95% CI: 74.6 - 100). Seven pts (16%) discontinued VEGFR-TKI therapy because of AEs: Gr 3 transaminitis (3 on pazopanib), Gr 3 hand-foot skin reaction (1 on axitinib), impaired wound healing (1 on axitinib), and Gr 3 pancreatitis (1 on pazopanib, 1 on axitinib). Conclusions: In this retrospective study, we observed a 42% ORR, a 10-month median PFS, and a 100% DCR in pts with mCCRCC who received VEGFR-TKI after PD with ICI. These results inform the design of trials with 2L VEGFR-TKI after failure of ICI therapy. [Table: see text]

Relationship between treatment-related hypertension and therapeutic efficacy of vascular endothelial growth factor receptor tyrosine kinase inhibitors in metastatic renal cell carcinoma

Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) are widely used for the treatment of metastatic renal cell carcinoma (mRCC). The aim of this study was to investigate the association between treatment-related hypertension and the therapeutic efficacy of VEGFR-TKIs. Clinical data of 155 mRCC patients treated with VEGFR-TKIs at the Cancer Hospital of Chinese Academy of Medical Sciences from 2006 to 2014 were retrospectively analyzed. All patients received first-line TKI therapy. Among them, 69 patients were treated with sunitinib, 14 cases with pazopanib, and 51 cases with fazotinib. Kaplan-Meier curves were used to evaluate the survival of the patients. The median survival for the whole group (n=155) was 36.2 months. Among the 98 (63.2%) patients who developed hypertension, 9 patients (5.8%) were evaluated as grade Ⅰ, 54 (34.8%) as grade Ⅱ and 35 (22.6%) as grade Ⅲ, and there was no patient with grade Ⅳ hypertension. The occurrence of TKI-related hypertension was correlated with age and MSKCC score (P<0.05), while not significantly correlated with gender, nephrectomy, T stage, number of metastases, lung metastasis or sunitinib treatment (P>0.05 for all). For the whole group (n=155), the therapeutic efficacy rate was 43.2% (67/155), the median progression-free survival (PFS) was 12.0 months, and the median overall survival (OS) was 36.2 months. The response rate (RR) was 26.3% (15/57) in patients with normal blood pressure and 53.1% (52/98) in patients with hypertension (P=0.001). The median PFS was 7.1 months in the cases with normal blood pressure and 13.8 months in patients with hypertension (P=0.032). The response rates were 33.3% (3/9), 51.9% (28/54) and 60.0% (21/35) in patients with grade Ⅰ, Ⅱ and Ⅲ hypertension (P=0.006). The median PFS was 7.1, 9.7, and 12.0 and 19.5 months in patients with normal blood pressure, and patients with grade Ⅰ, Ⅱ and Ⅲ hypertension, respectively (P=0.039). Both univariant and multivariant analyses indicated that treatment-related hypertension is an important predictive factor for the efficacy of VEGFR-TKIs therapy. Hypertension might be an effective predictive factor for efficacy of VEGFR-TKIs therapy in mRCC patients. Large-sample studies are warranted to further prove these results.

Association between hand-foot skin reaction and effectiveness of vascular endothelial growth factor receptor tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma

Objective: To investigate the association between hand-foot skin reaction (HFSR) in the treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) and the effectiveness of VEGFR-TKIs. Methods: Clinical data of 155 patients with metastatic renal cell carcinoma (mRCC) treated with VEGFR-TKIs at the Cancer Hospital of Chinese Academy of Medical Sciences between January 2006 and January 2014 were retrospectively analyzed. All the patients received first-line VEGFR-TKI therapy. The treatment effectiveness and outcome between patients developing HFSR and those without HFSR were compared. Comparison of treatment response rate (RR) was performed with χ2 test, survival analysis was performed using Kaplan-Meier method, with a significance level of 0.05. Results: The median survival of all the 155 patients was 36.2 months. Among the 117 (75.5%) patients who developed HFSR, 19 patients (12.3%) had grade Ⅰ HFSR, 73 (47.1%) had grade Ⅱ, and 25 (16.1%) had grade Ⅲ; there were no grade Ⅳ events. The RR and median progression-free survival (mPFS) in patients who did not develop HFSR were 15.8% and 6.7 months, respectively; while the RR and mPFS in patients who developed HFSR were 52.1% and 13.8 months, respectively (P<0.001, P=0.002). The RR and mPFS in patients with grade Ⅰ HFSR were 42.1% and 9.5 months, respectively; those in patients with grade Ⅱ HFSR were 56.2% and 12.2 months, respectively, in patients with grade Ⅲ were 48.0% and 22.2 months, respectively, with statistically significant differences among the three grades of HFSR (P=0.001, 0.009). Conclusions: HFSR might be an effective predictor for effectiveness of VEGFR-TKIs in mRCC patients. Large-sample studies are warranted to further prove these results.

Long-term outcomes of tyrosine kinase inhibitor discontinuation in patients with metastatic renal cell carcinoma.

The purpose of the current study was to evaluate the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) who interrupted vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy. A retrospective analysis of medical records was performed on all patients with mRCC treated with VEGFR-TKIs between January 2008 and July 2014 (n=505). Patients who achieved stable disease (SD) or a better response under TKI and later discontinued TKI treatment for any reason with the exception of disease progression were included in the analysis. We identified 32 patients (sunitinib=20, sorafenib=7, and pazopanib=5). The responses to VEGFR-TKIs were complete response (CR, n=4), partial response (PR, n=11), SD (n=15), and controlled but nonmeasurable response (n=2). Median time to TKI discontinuation from the initiation of VEGFR-TKI therapy was 16.6months (95% CI 12.8-20.3), and the main cause of VEGFR-TKI discontinuation was toxicity (n=19, 59.4%). At the time of analysis, 16 patients had disease progression and one patient died. With a median follow-up duration of 51.7months (range 11.5-87.6), median progression-free survival (PFS) after TKI discontinuation was 20.2months (95% CI 6.4-34.0). In multivariate analysis, the duration of TKI therapy (<1year) before TKI discontinuation was an independent significant prognostic factor of poor PFS (p=0.045). Among 11 patients who were retreated with the same TKI, two patients (18.2%) achieved PR and nine achieved SD (81.8%). VEGFR-TKI could be interrupted at least temporarily when clinically warranted in patients with mRCC sufficiently controlled by TKIs.

Everolimus Versus Temsirolimus in Metastatic Renal Cell Carcinoma After Progression With Previous Systemic Therapies

BackgroundEverolimus is an approved agent for use after disease progression with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. With recently published trials showing efficacy of nivolumab and cabozantinib in the second-line therapy setting, the use of everolimus will likely move to the third- or fourth-line therapy setting. Temsirolimus has occasionally been used instead of everolimus for many reasons, including financial considerations, assurance of patient compliance given its intravenous administration, its toxicity profile, patient performance status, and patient or physician preference. However, efficacy of everolimus and temsirolimus in this setting have not been compared in a randomized trial. The results from retrospective studies have been inconsistent. Materials and MethodsWe identified patients treated with a first-line VEGFR-TKI for metastatic renal cell carcinoma and then treated with either everolimus or temsirolimus on progression from the databases of 2 large academic cancer centers. Progression-free survival (PFS) and overall survival (OS) were assessed from the initiation of second-line treatment using the Kaplan-Meier method. ResultsA total of 90 patients received either everolimus (n = 59; 66%) or temsirolimus (n = 31; 34%) after progression during first-line VEGFR-TKI therapy. The patient and disease characteristics were similar in both groups. The median PFS was not different, but OS was superior with everolimus compared with temsirolimus (24.2 months vs. 12.1 months; hazard ratio, 0.58; P = .047). ConclusionOur results bolster existing guidelines supporting everolimus over temsirolimus as salvage therapy after previous systemic therapies.

Cardiovascular toxicity after antiangiogenic therapy in persons older than 65 years with advanced renal cell carcinoma.

Sorafenib and sunitinib are oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) approved in 2005 and 2006, respectively, for the treatment of patients with renal cell carcinoma (RCC). A population-based, observational cohort study of the cardiovascular risk of VEGFR TKI therapy in elderly RCC patients was conducted. Using the Surveillance, Epidemiology, and End Results-Medicare database, this study analyzed patients who were 66 years old or older and were diagnosed with RCC from 2000 to 2009. The incidence of cardiovascular adverse events, including congestive heart failure and cardiomyopathy (CHF/CM), acute myocardial infarction (AMI), stroke, and cardiovascular deaths, was examined through December 2010. A Cox proportional hazards model was created to calculate the hazard ratio (HR), and adjustments were made for age, sex, comorbidity, and the use of other systemic therapy. A total of 171 of 670 patients who received sunitinib or sorafenib had cardiovascular events. The incidence rates for CHF/CM, AMI, and stroke were 0.87, 0.14, and 0.14 per 1000 person-days, respectively. Sunitinib or sorafenib use was associated with an increased risk of cardiovascular events (HR, 1.38; 95% confidence interval [CI], 1.02-1.87) and especially stroke (HR, 2.84; 95% CI, 1.52-5.31) in comparison with 788 patients diagnosed with advanced RCC from 2007 to 2009 who were eligible for Part D but did not receive either agent. In subgroup analyses, patients who were 66 to 74 years old at diagnosis had the highest increased risk of stroke associated with the use of either or both drugs. Sunitinib and sorafenib might be associated with an increased risk of cardiovascular events and particularly stroke.

Correlation of Degree of Hypothyroidism With Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma Receiving Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors

BackgroundHypothyroidism is a common adverse effect of vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy in patients with metastatic renal cell carcinoma (mRCC). Some studies have shown an association with improved survival. However, hypothyroidism severity has not been correlated with survival outcomes. We report the incidence and severity of VEGFR-TKI therapy-associated hypothyroidism in correlation with the survival outcomes of patients with mRCC. Patients and MethodsA retrospective analysis of patients with mRCC who received VEGFR-TKIs (2004 through 2013) was conducted from a single institutional database. Hypothyroidism, progression-free survival (PFS), and overall survival (OS) were assessed. Univariate and multivariate analyses were performed using the Kaplan-Meier method and Cox proportional hazard models. ResultsOf 125 patients with mRCC, 65 were eligible. Their median age was 59 years (range, 45-79 years), and 46 (70.8%) were male. Hypothyroidism occurred in 25 patients (38.5%), of whom 13 had a peak thyroid-stimulating hormone (TSH) level > 10 mIU/L during treatment. The median OS was significantly longer in patients with a peak TSH > 10 mIU/L than in patients with a peak TSH of ≤ 10 mIU/L (not reached vs. 21.4 months, P = .005). On multivariate analysis, risk criteria, number of previous therapies, and severe hypothyroidism (TSH > 10 mIU/L) during VEGFR-TKI therapy remained significant for improvements in PFS and OS. ConclusionThe severity of VEGFR-TKI therapy-associated hypothyroidism (TSH > 10 mIU/L) was associated with improved survival outcomes in patients with mRCC and should not necessitate a dose reduction or therapy discontinuation.

Efficacy and safety of everolimus in korean patients with metastatic renal cell carcinoma following treatment failure with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor.

PurposeThe purpose of this study is to assess the efficacy and safety of everolimus in Korean patients with metastatic renal cell carcinoma (mRCC) for whom initial treatment with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) has failed.Materials and MethodsEligible patients with mRCC (any histology) who had progressed on or were intolerant of VEGFr-TKI therapy received oral everolimus (10 mg dose once daily). Tumor response was reassessed according to Response Evaluation Criteria in Solid Tumors (RECIST).ResultsThis study included 100 patientswith a median follow-up duration of 10.2 months, a median progression-free survival (PFS) of 4.2 months (95% confidence interval [CI], 3.4 to 5.0 months), and an overall survival of 10.1 months (95% CI, 6.9 to 13.3 months). The most common grade 3 or greater adverse events (AEs) overall were anemia (13%), pneumonitis (9%), hyperglycemia (8%), and stomatitis (6%). While the incidence of pneumonitis was similar (26 cases, 26%) to the reported incidence in Western patients, the Korean presentations were more severe: 10 patients permanently discontinued everolimus due to pneumonitis, including two deaths on treatment. Statistically significant relationships were established between biologic toxicities, hyperglycemia and anemia, and PFS (hyperglycemia vs. non-hyperglycemia: hazard ratio [HR], 0.61; p=0.055 and anemia vs. non-anemia: HR, 0.51; p=0.021).ConclusionEverolimus was effective in Korean patients with mRCC who had failed initial VEGFr-TKI therapy. While everolimus was well tolerated in general and the AE incidence of this study was similar to those of previous reports, severe pneumonitis was common. Hyperglycemia and anemia showed significant correlation with PFS and thus may be potentially useful as prognostic indicators.

Effect of race on survival of metastatic renal cell carcinoma treated with VEGFR-TKI therapy.

e15507 Background: African Americans (AAs) with renal cell carcinoma (RCC) have a higher incidence of disease, younger age of onset, and at least in the cytokine era AA have had a shorter progression free survival (PFS) and overall survival (OS) relative to Caucasians (Cs). Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors (VEGFR-TKIs) were approved for advanced RCC based on trials with minimal AA participation. This study was undertaken to examine if VEGFR-TKIs are similarly effective in AA patients. Methods: This was a single institution retrospective cohort study. We examined the medical records from 2004 to 2012 of all C and AA patients with metastatic RCC started on first line VEGFR-TKI therapy with at least one follow up visit. This resulted in 34 C patients and 12 AA patients. We abstracted self- reported race, treatment type, MSKCC prognosis, date of progression as defined by the treating physician, and other demographic and clinical variables. The Social Security Death Index was used to establish date of death. OS and PFS were analyzed using Kaplan-Meier and Cox proportional hazards models. Gene expression data from TCGA was analyzed for biological differences between RCC occurring in AAs and Cs. Results: 54.6% of AAs were classified into the MSKCC poor prognosis group compared with 10.7% of Cs. AAs compared to Cs had a non-significant trend toward worse OS (HR 1.49, p = 0.36) and PFS (HR 1.59, p = 0.27). After adjustment for risk group we found no significant difference between AAs and Cs for OS (HR 1.00, p = 0.99) and PFS (HR 1.26, p = 0.66). Comparison of the RCC gene expression profiles demonstrated significant differences in gene expression with AA tumors showing enrichment for genes involved in ion transport and cell-cell junctions. Conclusions: This is a preliminary study that suggests first line VEGFR-TKI therapy is an effective choice for AA patients as metastatic RCC in AAs responds similarly as Cs to VEGFR-TKI treatment. In addition, there are distinct gene expression differences that distinguish AA and C tumors.

Safety and efficacy of everolimus in Chinese patients with metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy: an open-label phase 1b study

BackgroundIn China, there are currently no approved therapies for the treatment of metastatic renal cell carcinoma (mRCC) following progression with vascular endothelial growth factor (VEGF)-targeted agents. In the phase 3 RECORD-1 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus afforded clinical benefit with good tolerability in Western patients with mRCC whose disease had progressed despite VEGF receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. This phase 1b study was designed to further evaluate the safety and efficacy of everolimus in VEGFr-TKI-refractory Chinese patients with mRCC.MethodsAn open-label, multicenter phase 1b study enrolled Chinese patients with mRCC who were intolerant to, or progressed on, previous VEGFr-TKI therapy (N = 64). Patients received everolimus 10 mg daily until objective tumor progression (according to RECIST, version 1.0), unacceptable toxicity, death, or study discontinuation for any other reason. The final data analysis cut-off date was November 30, 2011.ResultsA total of 64 patients were included in the study. Median age was 52 years (range, 19–75 years) and 69% of patients were male. Median duration of everolimus therapy was 4.1 months (range, 0.0-16.1 months). Expected known class-effect toxicities related to mTOR inhibitor therapy were observed, including anemia (64%), hypertriglyceridemia (55%), mouth ulceration (53%), hyperglycemia (52%), hypercholesterolemia (50%), and pulmonary events (31%). Common grade 3/4 adverse events were anemia (20%), hyperglycemia (13%), increased gamma-glutamyltransferase (11%), hyponatremia (8%), dyspnea (8%), hypertriglyceridemia (6%), and lymphopenia (6%). Median PFS was 6.9 months (95% CI, 3.7-12.5 months) and the overall tumor response rate was 5% (95% CI, 1-13%). The majority of patients (61%) had stable disease as their best overall tumor response.ConclusionsSafety and efficacy results were comparable to those of the RECORD-1 trial. Everolimus is generally well tolerated and provides clinical benefit to Chinese patients with anti-VEGF-refractory mRCC.Trial registrationclinicaltrials.gov, NCT01152801

Everolimus in patients with metastatic renal cell carcinoma refractory to VEGF-targeted therapy: REACT subgroup analysis of prior therapy.

391 Background: Efficacy of everolimus (EVE) in metastatic renal cell carcinoma (mRCC) refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) therapy is well established. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with VEGFR-TKI-refractory mRCC access to EVE in advance of regulatory approval. Methods: REACT, an open-label, international, expanded-access clinical trial (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy. Long-term safety of EVE 10 mg/day in patients with mRCC, as determined by overall incidence of grade 3/4 and serious adverse events (AEs) was documented. RECIST-defined tumor response was also assessed by local investigator. Subgroup analyses evaluated effect of prior treatment on safety and efficacy of EVE. Results: Of 1367 patients enrolled, most (92.7%) had progressed on prior VEGFR-TKI therapy, and some (24.4%) were VEGFR-TKI intolerant. Across patient subgroups by prior VEGFR-TKI treatment, median EVE treatment duration was similar (Table). Best overall response rates were similar in the VEGFR-TKI-intolerant subgroup and overall populations: respectively, 1.8% and 1.7% had partial response (PR) while 53.5% and 51.6% had stable disease (SD). Incidence of grade 3/4 AEs across all prior treatment subgroups were similar to those of the overall population. (See table.) Conclusions: Patients enrolled in REACT derived benefit from EVE irrespective of prior VEGFR-TKI therapy, including VEGFR-TKI-intolerant patients. EVE is well tolerated and affords disease stabilization in the majority of patients with VEGFR-TKI-refractory mRCC, and is the standard of care in this patient population. [Table: see text]

Everolimus in metastatic renal cell carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study

IntroductionIn the phase III RECORD-1 trial (ClinicalTrials.gov: NCT00410124), patients with metastatic renal cell carcinoma (mRCC) who progressed on previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy were randomised 2:1 to everolimus 10mg once daily (n=277) or placebo (n=139). Median progression-free survival (PFS) was 4.9months with everolimus and 1.9months with placebo (hazard ratio [HR], 0.33; P<.001). This preplanned, prospective sub-analysis evaluated PFS benefit of everolimus versus placebo in patients who had previously received 1 or 2 VEGFr-TKIs. Patients and methodsMedian PFS was estimated using the Kaplan–Meier method, and Cox proportional hazards model was used to analyse differences in PFS. ResultsAll patients (100%) received ⩾1 previous VEGFr-TKI; 26% of patients received 2 previous VEGFr-TKIs. Among patients who received 1 previous VEGFr-TKI, median PFS was 5.4months with everolimus and 1.9months with placebo (HR, 0.32; 95%confidence interval [CI], 0.24–0.43; P<.001). Among patients who received 2 previous VEGFr-TKIs, median PFS was 4.0months with everolimus and 1.8months with placebo (HR, 0.32; 95%CI, 0.19–0.54; P<.001). The everolimus safety profile was similar for both groups. ConclusionsEverolimus was associated with prolonged PFS relative to placebo in patients who received 1 or 2 previous VEGFr-TKIs. Patients who received only 1 previous VEGFr-TKI had apparently longer PFS with everolimus in reference to those who received 2 previous VEGFr-TKIs. These results support the use of everolimus as the standard of care in patients who fail initial VEGFr-TKI therapy.

An international expanded-access programme of everolimus: Addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy

Background and objectivesThe RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to address an unmet medical need by providing everolimus prior to commercial availability, and also to further assess the safety and efficacy of everolimus in patients with VEGFr-TKI-refractory mRCC. Patients and methodsREACT (Clinicaltrials.gov: NCT00655252) was a global, open-label, expanded-access programme in patients with mRCC who were intolerant of, or who had progressed on or after stopping treatment with, any available VEGFr-TKI therapy. Patients received everolimus 10mg once daily, with dose and schedule modifications allowed for toxicity. Patients were closely monitored for the development of serious and grades 3/4 adverse events (AEs). Response was assessed by RECIST every 3months for the first year and every 6months thereafter. ResultsA total of 1367 patients were enroled. Safety findings and tumour responses were consistent with those observed in RECORD-1, with no new safety issues identified. The most commonly reported serious AEs were dyspnoea (5.0%), pneumonia (4.7%) and anaemia (4.1%), and the most commonly reported grades 3/4 AEs were anaemia (13.4%), fatigue (6.7%) and dyspnoea (6.5%). Best overall response was stable disease in 51.6% and partial response in 1.7% of patients. Median everolimus treatment duration was 14weeks. ConclusionEverolimus is well tolerated in patients with mRCC and demonstrates a favourable risk–benefit ratio.

Final results of the international, expanded-access program of everolimus in patients with advanced renal cell carcinoma who progress after prior vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFr-TKI) therapy.

4601 Background: The phase III RECORD-1 trial established everolimus as the only agent proven to benefit patients with metastatic renal cell carcinoma (mRCC) after failure of initial VEGFr-TKI therapy. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, more than doubled median progression-free survival compared with placebo, from 1.9 months to 4.9 months. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated in order to address an unmet medical need and provide everolimus in advance of regulatory approval and commercial availability to patients with mRCC after failure of initial VEGFr-TKI therapy. Methods: REACT was an open-label, international, expanded-access clinical trial (Clinicaltrials.gov: NCT00655252). Eligible patients had measurable or nonmeasurable mRCC of any histology, were intolerant of, or progressed while on, VEGFr-TKI therapy, had a Karnofsky performance score ≥70%, and had adequate bone marrow, hepatic, and renal function. Patients received everolimus 10 mg/day orally, with dose and schedule modifications allowed for toxicity. The primary objective of REACT was to evaluate the long-term safety of everolimus in patients with mRCC, as determined by the overall incidence of grade 3/4 and serious adverse events (AEs). Tumor response to everolimus was also assessed according to RECIST. Results: A total of 1367 patients from 34 countries were enrolled. Safety findings and tumor responses were consistent with those observed in RECORD-1. The most commonly reported grade 3/4 AEs were anemia (13.4%), fatigue (6.7%), and dyspnea (6.4%), and the most frequent serious AEs were dyspnea (5.0%), pneumonia (4.7%), and anemia (4.1%). Median dose intensity was 10.0 mg/day; relative dose intensity ranged from 0.90 to 1.10 in 68.9% of patients. Conclusions: REACT evaluated the safety and tolerability of everolimus in a broader patient population than the controlled trial RECORD-1. Everolimus was well tolerated, with no new safety issues identified and infrequent dose reductions/interruptions in the majority of patients.