Endothelial Growth Factor Tyrosine Kinase Research Articles

DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy

BackgroundLoss-of-function alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may determine benefit from immune-oncology (I/O) agents as shown in colon cancer. However, biologic significance and...

Trial in progress: A phase I study of AMG 199, a half-life extended bispecific T-cell engager (HLE BiTE) immune therapy, targeting MUC17 in patients with gastric and gastroesophageal junction (G/GEJ) cancer.

TPS4649 Background: Prognosis for advanced G/GEJ cancer is poor and new treatment modalities are urgently needed. MUC17 is a transmembrane protein overexpressed and differentially localized on the cell membrane of G/GEJ cancer cells; expression and localization in normal cells is much more limited. AMG 199 is an HLE BiTE immune therapy designed to engage CD3-positive T cells to MUC17-positive G/GEJ cancer cells, mediate redirected tumor cell lysis, and induce T cell activation and proliferation. A clinical trial is being conducted for this novel and targeted immune therapy agent in patients with MUC17-positive G/GEJ cancer. Methods: This is a first-in-human phase 1, open-label, dose escalating study (NCT04117958) evaluating AMG 199 in patients with MUC17-positive G/GEJ cancer. Key eligibility criteria include metastatic or locally advanced unresectable MUC17-positive (as determined by IHC using a central laboratory assay) gastric adenocarcinoma or gastroesophageal junction adenocarcinoma ineligible for curative surgery and relapsed or treatment-refractory following ≥2 lines including a platinum, a fluoropyrimidine, taxane or irinotecan, and an approved vascular endothelial growth factor receptor antibody or tyrosine kinase inhibitor. Patients eligible for human epidermal growth factor receptor 2 (HER2) directed therapy should have received an approved HER2 targeting antibody. Primary endpoints include: dose-limiting toxicities, treatment-emergent or -related adverse events, vital signs, electrocardiogram (ECG), and laboratory changes. Secondary endpoints include: pharmacokinetics of AMG 199, objective response, duration of response, time to progression, 6-month and 1-year progression-free survival, and 1-year and 2-year overall survival. The dose exploration (n = 30) will estimate the maximum tolerated dose and/or recommended phase 2 dose; this will be followed by a dose expansion (n = 40) and evaluation of the benefit/risk profile of AMG 199. The study began enrolling patients in January 2020 and is ongoing. This is the first clinical trial to investigate MUC17 as a potential anti-tumor target. For more information, please contact Amgen Medical Information: medinfo@amgen.com . Clinical trial information: NCT04117958 .

Randomized prospective trial assessing Bifidobacterium-containing probiotic supplementation in metastatic renal cell carcinoma (mRCC) patients receiving vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs).

5078 Background: Studies suggest a link between the gut microbiome and mRCC outcomes, including evidence that mRCC patients (pts) possess a lower abundance of Bifidobacterium spp compared to healthy adults (Pal et al Clin Cancer Res 2015). The aim of this study was to assess if Bifidobacterium-containing probiotics could modulate the gut microbiome and impact rates of clinical benefit (CB) from VEGF-TKIs. Methods: Pts initiating VEGF-TKI therapy for mRCC were randomized to probiotic supplemented (PSu) or probiotic restricted (PRe) treatment arms. Pts in the PSu arm consumed two 4 oz servings of Activia daily. Stool samples were collected prior to therapy and at wks 2, 3, 4 and 12. Gut microbiota composition was assessed using whole genome shotgun metagenomic sequencing (Zhu et al Microbiome 2018). The primary endpoint was change in Bifidobacterium spp with therapy. Microbiome composition was compared across pts with CB (complete/partial response or stable disease) versus no CB (NCB). Results: In total, 20 pts were enrolled. The most frequent VEGF-TKIs were cabozantinib (45%), sunitinib (25%) and lenvatinib (25%). Median progression-free survival (PFS) was 6.5 months (95%CI 0.3-12.9) and CB rate was 75%. Bifidobacterium animalis, the active ingredient of Activia, reached detectable levels in all pts in the PSu arm, but was only detectable in one pt in the PRe arm. CB rate was not significantly different in PSu vs PRe arms (70% vs 80%, p > 0.05), and there was no difference in PFS. LDA effect size (LEfSe) analysis of MetaPhIAn2 data captured 25 enriched species demonstrating an LDA score > 3 in either CB or NCB. Of those with high LDA scores, Barnesiella intesitinihominis and Akkermansia municiphila were the most significant members (p = 7.4 x 10−6 and p = 5.6 10−3, respectively). While 92% of B. intestinihominis positive pts obtained a CB, only 50% of B. intestinihominis negative pts obtained CB (p = 0.036). Conclusions: This is the first prospective randomized study demonstrating modulation of the gut microbiome with probiotics in mRCC. While microbiome modulation by probiotics did not increase CB rates as intended, consecutive stool specimens allowed us to identify an association between B. intesitinihominis, A. municiphila and CB with VEGF-TKIs. In addition to the previously documented association between A. municiphila and immunotherapy outcome (Routy et al. Science 2018), this species may predict activity with VEGF-TKIs. Clinical trial information: NCT02944617 .

Prophylactic low-molecular-weight heparin administration protected against severe acute pancreatitis partially by VEGF/Flt-1 signaling in a rat model.

The present study was aimed to explore the effects and the underlying mechanism of prophylactic low-molecular-weight heparin (LMWH) treatment on taurocholate-induced severe acute pancreatitis (SAP) in a rat model. Rat SAP model was induced by injection of 4% sodium taurocholate into the pancreatic duct. LMWH was applied half an hour before the induction of pancreatitis at the dose of 200 IU/kg subcutaneous injection. The rats were euthanized at 1 h, 6 h, and 12 h after taurocholate-induced SAP. The inflammatory and oxidative response markers were assessed. And the vascular endothelial growth factor (VEGF) and Fms-related tyrosine kinase 1 (Flt-1) expression were evaluated by immunohistochemistry (IHC) and western blot methods. The expression of inflammatory and oxidative response markers increased after induction of SAP. IHC and western blot results showed the VEGF and Flt-1 expression were increased in SAP group. Prophylactic LMWH administration reduced the inflammatory and oxidative response markers expression and decreased the expression of VEGF and Flt-1. This study suggested that prophylactic LMWH treatment mitigated the severity of pancreatitis in rat SAP model by anti-inflammation and oxidative response. The underlying mechanism may result from downregulating VEGF/Flt-1 signaling of LMWH in SAP rat model.

Treatment for Recurrent Differentiated Thyroid Cancer: A Canadian Population Based Experience.

Introduction: Management of recurrent differentiated thyroid cancer (DTC) may include surgery, radioactive iodine (RAI), and external beam radiotherapy (EBRT). Systemic therapy may also be offered for RAI-refractory DTC. The study objective was to review patterns of practice in British Columbia (BC) for treatment of recurrent DTC, assess rates of RAI-refractory disease, and evaluate outcomes.Methods: BC Cancer provides cancer care to a population of 4.6 million. A retrospective review of all patients with DTC stage I-IVB disease referred to BC Cancer from 2009 to 2013 was conducted. Patient and DTC characteristics, locoregional and distant recurrence, surgical management, RAI, EBRT, and systemic therapy details were retrospectively collected. Relapse-free survival (RFS), overall survival (OS), and disease-specific survival (DSS) were calculated using the Kaplan-Meier method.Results/Discussion: Some 1062 DTC patients were identified. Median follow-up was 4.1 years. Baseline characteristics: female 74%, median age 50, papillary/follicular/Hurthle cell 92%/6%/2%. Stage at presentation: I 60%, II 8%, III 22%, IVA/IVB 10%. Locoregional and/or distant recurrence occurred in 136 patients (13%). Locoregional recurrence (n=118) was treated with surgery +/- RAI or EBRT 48%, RAI +/- EBRT 40%, EBRT alone 1%, 11% were observed without treatment. Some 27 patients had a second cancer recurrence. Some 37 patients (3%) developed distant metastatic disease and common sites of distant metastases were: lung 76%, bone 30%, and liver 8%. Some 27 cases (2%) were deemed RAI-refractory. Some six patients (0.6%) received systemic therapy with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). Five-year RFS was calculated to be 82%, OS 95%, and DSS 98% for the study population.Conclusions: In our population-based study cohort, 87% of patients were rendered disease-free by primary disease management. Multi-modality treatment of locoregional recurrence facilitated disease-free status in the majority of patients (67%). RAI-refractory disease developed in 2% of patients and despite a significant number of metastatic recurrences, only a small number of patients received systemic therapy.

Adjuvant therapy in high-risk renal cell cancer: A systematic review and cumulative meta-analysis.

708 Background: Patients with high risk non-metastatic renal cell cancer (RCC) are at significant risk of recurrence following nephrectomy. Previously, we reported no benefit of adjuvant tyrosine kinase inhibitor (TKI) treatment in high-risk patients. Since our most recent publication, efficacy results from the multicenter double-blind SORCE trial have become available. We updated our meta-analysis to include these additional data and performed a cumulative meta-analysis. Methods: PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials were searched to identify relevant RCTs. A generic variance-weighted random effects model was used to derive estimates for efficacy. Heterogeneity was assessed using the Cochran Q statistic and was quantified using the I2 test. The primary outcome was disease-free survival (DFS), defined as the interval between randomization and the first recurrence, the occurrence of metastasis or a secondary cancer, or death due to any cause. Statistical analysis was performed using Comprehensive Meta-Analysis version 3 (Biostat). Results: Five phase 3 trials were identified, enrolling 6531 patients. Two trials compared sunitinib with placebo (S-TRAC and ECOG-ACRIN), two compared sorafenib with placebo (ECOG-ACRIN and SORCE) and one trial each compared pazopanib (PROTECT) and axitinib (ATLAS) vs placebo. Cumulative evidence suggests that adjuvant therapy with TKIs showed no significant improvement in (DFS) hazard ratio [HR] of 0.93 (95% CI, 0.85-1.02), compared to placebo. There was no significant heterogeneity among included trials ( I2= 52%, P= .41). Overall, the trials were at low risk of bias. Conclusions: Adjuvant vascular endothelial growth factor tyrosine kinase inhibitors in high-risk renal cell carcinoma did not improve DFS as compared to placebo. Improved patient selection using better prognostic biomarkers or scoring systems may identify subsets of patients who can benefit from adjuvant treatments. Toxicity estimates will be updated as data from SORCE trial publication becomes available.

Second-line VEGF TKI after IO combination therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

684 Background: Immuno-Oncology (IO) combinations are standard of care first-line treatment for metastatic renal cell carcinoma (mRCC). Data on therapy with vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI) post-progression on IO-combination therapy are limited. Methods: Using the IMDC, a retrospective analysis was done on mRCC patients treated with second-line VEGF TKIs after receiving IO combination therapy. Patients received first-line ipilimumab+nivolumab (IOIO) or anti-PD(L)1+anti-VEGF (IOVE). Baseline variables and second-line IMDC risk factors were collected. Overall response rates (ORR), time to treatment failure (TTF) and overall survival (OS) were determined. Multivariable Cox regression analysis was performed. Results: 142 patients were included. 75 patients received IOIO and 67 received IOVE pretreatment. The ORR of 2nd line therapy was 17/46 (37%) and 7/57 (12%) in the IOIO and IOVE pretreated groups, respectively (p<0.01). 2nd-line TTF was 5.4 months (95% CI 4.1-8.3) for the IOIO- and 4.6 months (95% CI 3.7-5.8) for the IOVE-pretreated group (p=0.37). 2nd-line median OS was 17.2 months (95% CI 10.8-35.1) and 11.8 months (95% CI 9.9-21.3) for the prior IOIO and IOVE groups, respectively (p=0.13). The hazard ratio adjusted by IMDC for IOVE vs IOIO pretreatment was 1.22 (95% CI 0.73-2.07, p=0.45) for 2nd line TTF and 1.43 (95% CI 0.74-2.8, p=0.29) for 2nd line OS. Conclusions: VEGF TKIs show activity after combination IO therapy. Response rates are higher in patients treated with VEGF TKIs after first-line IOIO compared to after IOVE. In patients with VEGF TKI after IOIO or IOVE, no difference in OS and TTF was observed.[Table: see text]

UNISON: Nivolumab then ipilimumab + nivolumab in advanced nonclear cell renal cell carcinoma (ANZUP 1602).

TPS768 Background: Renal cell carcinomas (RCC) are predominantly the clear cell (cc) subtype, with a unique biology, characterized by sensitivity to angiogenesis inhibition. However vascular endothelial growth factor-tyrosine kinase inhibitors elicit modest responses in people with rare variant non-clear cell (ncc) RCC. Immune checkpoint inhibitors (ICI) are active against many cancers, but people with rare variant nccRCC have been excluded from frontline trials despite experiencing a more aggressive disease course and poorer prognosis compared to those with ccRCC. UNISON (NCT03177239) aims to test 2 ideas; the activity of ICI in nccRCC, and the novel sequencing strategy of anti-programmed cell death protein (PD)1 immunotherapy, followed by the combination of anti-PD1 and anti-cytotoxic T-lymphocyte-associated protein (CTLA)4 blockade, in people failed by single agent treatment. Methods: This single-arm, two-part trial recruits people of good performance status suffering metastatic or locally advanced unresectable rare variant nccRCC, including but not limited to papillary (type 1/2), chromophobe, sarcomatoid, Xp11 translocation, collecting duct, and unclassified histological subtypes. Participants are offered fixed dose nivolumab at 240mg every two weeks in Part 1 of the trial. If they experience progressive disease, eligible participants may proceed to Part 2 consisting of nivolumab (3mg/kg) plus ipilimumab (1mg/kg) every 3 weeks for up to 4 doses. People experiencing disease control after single-agent or combined ICI are eligible to continue treatment for up to 1 year. UNISON is powered to distinguish a clinically non-relevant objective tumor response rate (OTRR) of 15% in people taking combination ICI whose cancers are refractory to single-agent PD1, versus a clinically-relevant OTRR of 30% at 5% level of significance with 80% power. 85 participants were recruited in Part 1, on the assumption that 55% of those entering Part 1 will be eligible for inclusion in Part 2. Enrolment commenced in November 2017 and was completed ahead of schedule in September 2019. Of the 48 participants projected to experience progression on anti-PD1 immunotherapy, 36 have so far commenced combination ICI in Part 2. Clinical trial information: NCT03177239.

Immune Checkpoint Inhibitor-Related Adverse Cardiovascular Events in Patients With Lung Cancer

ObjectivesThe purpose of this study was to evaluate whether immune checkpoint inhibitors (ICIs) are associated with an increased risk of major adverse cardiovascular events (MACE) compared with non-ICI therapies in patients with lung cancer. BackgroundICIs activate the host immune system to target cancer cells. Though uncommon, cardiovascular immune-related adverse events can be life-threatening. MethodsA retrospective single-institution cohort study of 252 patients with pathologically confirmed lung cancer who received ICI or non-ICI therapy was analyzed. The primary endpoint was MACE, defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure. ResultsDuring a median follow-up of 6 months, MACE occurred in 13.3% of ICI-treated patients, with a median time to event of 51 days, compared with 10.3% and 64 days in non-ICI patients. ICIs were not associated with MACE (hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 0.57 to 2.43; p = 0.66) in a univariable Fine-Gray regression analysis incorporating noncardiovascular death as a competing risk. Multivariable regression analyses determined that patients treated with ICIs with elevated serum troponin I >0.01 ng/ml (HR: 7.27; 95% CI: 2.72 to 19.43; p < 0.001) and B-type natriuretic peptide (BNP) >100 pg/ml (HR: 2.65; 95% CI: 1.01 to 6.92; p = 0.047) had an increased risk of MACE. Patients pre-treated or receiving combined immunotherapy with ICIs and vascular endothelial growth factor inhibitors (VEGFIs) or tyrosine kinase inhibitors (TKIs) had an increased risk of MACE (HR: 2.15; 95% CI: 1.05 to 4.37; p = 0.04). ConclusionsICIs were not independently associated with an increased risk of MACE in patients with lung cancer, although power is an important limitation in these analyses. ICI-associated cardiotoxicity was associated with elevations in serum troponin and BNP, and combined immunotherapy with VEGFIs or TKIs. Future studies are needed to further define the role of cardiac biomarkers as a monitoring strategy with ICI therapy.

Is there truly an increase in risk of cardiovascular and hematological adverse events with vascular endothelial growth factor receptor tyrosine kinase inhibitors?

ABSTRACTObjectives: Recent studies have shown an increase risk of cardiovascular and hematological adverse events associated with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs). The authors hypothesize that the original studies may have produced exaggerated results because of the small baseline risks involved.Methods: A meta-analysis that included 71 trials, 8 different VEGFR-TKIs, and 11 adverse events were re-analyzed. The outcome of interest was re-defined as the complementary outcome (i.e. remaining free of an adverse event). The inverse variance heterogeneity model was used to pool the effect size.Results: VEGFR-TKIs decreased the risk of remaining free of hypertension by 7% (RR 0.93; 95%CI:0.88–0.97). Specific VEGFR-TKIs; pazopanib, regorafenib, and nintedanib were associated with a decrease risk of remaining free of an arterial thrombotic event (RR 0.96; 95%CI:0.93–0.99), thrombocytopenia (RR 0.91; 95%CI:0.89–0.93), and bleeding (RR 0.96; 95%CI:0.93–0.99) respectively. VEGFR-TKIs were not associated with the thrombotic event, myocardial infarction, stroke, venous thrombotic event, pulmonary embolism, left ventricular dysfunction, or QTc interval prolongation.Conclusion: VEGFR-TKIs are associated with a small increase in the risk of patients developing hypertension, arterial thrombotic events, thrombocytopenia, and bleeding. Previous studies overestimated the actual risk associated with VEGFR-TKIs by analyzing the outcome with the lower baseline risk.

Increase in Blood Pressure Associated With Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor

ObjectivesThis study quantified the change in blood pressure (BP) during antivascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy, compared BPs between TKIs, and analyzed change in BP during antihypertensive therapy. BackgroundTKIs targeting VEGF are associated with hypertension. The absolute change in BP during anti-VEGF TKI treatment is not well characterized outside clinical trials. MethodsA retrospective single-center study included patients with metastatic renal cell carcinoma who received anti-VEGF TKIs between 2007 and 2018. Mixed models analyzed 3,088 BPs measured at oncology clinics. ResultsIn 228 patients (baseline systolic blood pressure [SBP] 130.2 ± 16.3 mm Hg, diastolic blood pressure [DBP] 76.8 ± 9.3 mm Hg), anti-VEGF TKIs were associated with mean increases in SBP of 8.5 mm Hg (p < 0.0001) and DBP of 6.7 mm Hg (p <0.0001). Of the anti-VEGF TKIs evaluated, axitinib was associated with the greatest BP increase, with an increase in SBP of 12.6 mm Hg (p < 0.0001) and in DBP of 10.3 mm Hg (p < 0.0001) relative to baseline. In pairwise comparisons between agents, axitinib was associated with greater SBPs than cabozantinib by 8.4 mm Hg (p = 0.004) and pazopanib by 5.1 mm Hg (p = 0.01). Subsequent anti-VEGF TKI courses were associated with small increases in DBP, but not SBP, relative to the first course. During anti-VEGF TKI therapy, calcium-channel blockers and potassium-sparing diuretic agents were associated with the largest BP reductions, with decreases in SBP of 5.6 mm Hg (p < 0.0001) and 9.9 mm Hg (p = 0.007), respectively. ConclusionsAnti-VEGF TKIs are associated with increased BP; greatest increases are observed with axitinib. Calcium-channel blockers and potassium-sparing diuretic agents were associated with the largest reductions in BP.

The Emerging Role of Combination Angiogenesis Inhibitors and Immune Checkpoint Inhibitors in the Treatment of Metastatic Renal Cell Cancer

The advent of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) a decade ago revolutionized the treatment paradigm in advanced metastatic clear cell renal cell carcinoma (RCC) with improved survival rates compared to the pre-TKI era. Monotherapy with VEGF TKIs has remained first-line. However, sequencing of different TKIs, mammalian target of rapamycin (mTOR) inhibitors, or immune checkpoint inhibitors (ICIs) has been the subject of controversy in the treatment landscape of metastatic RCC. First-line treatment further evolved with the approval of nivolumab plus ipilimumab in intermediate-and poor-risk patients based on an overall survival (OS) benefit demonstrated in the CheckMate214 trial as well as a progression-free survival (PFS) benefit of cabozantinib in the CABOSUN trial. Optimal sequencing, patient selection, and understanding resistance pathways continue to be prominent concerns. Efforts to bypass resistance mechanisms have led to the study of combination therapies. Given enhancement of immune checkpoint inhibitor (ICI) T-cell mediated effects by VEGF-mediated immunosuppression, the combination of VEGF inhibitors and ICIs in treatment-naïve locally advanced and metastatic RCC has shown promise. Available results of phase III trials utilizing these combinations are discussed herein.

Adjuvant Therapy in High-Risk Renal Cell Cancer: A Systematic Review and Meta-analysis

ObjectiveTo perform a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating risk-benefit for adjuvant postoperative treatments in high-risk renal cell carcinoma by assessing reported disease-free survival (DFS), overall survival (OS), toxicity, and quality of life. MethodsA literature search was performed in PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials to identify relevant RCTs (from database inception through May 15, 2018). The results of the ATLAS trial were published while writing this manuscript, and the manuscript was updated accordingly. A generic variance-weighted random effects model was used to derive estimates for efficacy and common adverse effects. Heterogeneity was assessed using the Cochran Q statistic and was quantified using the I2 test. ResultsAdjuvant therapy with tyrosine kinase inhibitors compared with placebo was observed to have a DFS hazard ratio [HR] of 0.92 (95% CI, 0.83-1.01) and an OS HR of 1.01 (95% CI, 0.89-1.15) (4 RCTs; 4417 patients). Analysis of DFS for sunitinib compared with placebo (n=1909) in the adjuvant setting detected an HR of 0.90 (95% CI, 0.67-1.19). Increased risk of grade 3 or 4 adverse events (relative risk [RR]=2.6; 95% CI, 2.28-2.97), diarrhea (RR=9.89; 95% CI, 4.22-23.14), fatigue (RR=3.11; 95% CI, 1.86-5.18), hypertension (RR=3.63; 95% CI, 2.99-4.41), and palmar/plantar dysesthesia (RR=2.70; 95% CI, 2.47-2.96) was observed. ConclusionAdjuvant vascular endothelial growth factor tyrosine kinase inhibitors in high-risk renal cell carcinoma did not improve OS or DFS, and there was a significant increased risk of toxicity in greater than half of the patients, leading to a decline in quality of life.

Random Allocated Study of Wrapping Oblate for Prevention of Everolimus-associated Stomatitis in Patients With Metastatic Renal Cell Carcinoma.

The study aim was to evaluate the efficacy of wrapping oblate for prevention of everolimus-associated stomatitis in metastatic renal cell carcinoma (mRCC). Patients with mRCC prescribed everolimus after failure of vascular endothelial growth factor-tyrosine kinase inhibitor were enrolled. Patients were consecutively assigned to take everolimus covered with or without oblate. The primary end-points were the incidence of and time to grade 2 or more stomatitis. Additionally, we assessed whether grade 2 or more stomatitis that occurred in the non-oblate group could be prevented with crossover application of oblate. This study included 79 patients [oblate group: 42(53%); non-oblate group: 37(47%)]. Thirty (38%) patients developed grade 2 or more stomatitis [incidence: oblate group, 31% (13/42); non-oblate group, 46% (17/37), p=0.245; median time to grade 2 or more stomatitis: oblate group, not reached; non-oblate group, 6.0 months, p=0.251]. Among 10 patients who developed grade 2 or more stomatitis in the non-oblate group and received oblate-covered everolimus, nine (90%) showed complete recovery or improved to grade 1, which persisted until discontinuation of everolimus. Oblate-covered everolimus improved the incidence of and time to grade 2 or more stomatitis, although it was not statistically significantly different compared to the non-oblate group. Oblate wrapping prevented recurrence of grade 2 or more stomatitis in patients who took uncovered everolimus and developed significant stomatitis.

Clinical significance of programmed death-1 and programmed death-ligand 1 expression in the tumor microenvironment of clear cell renal cell carcinoma.

Recently, immunotherapy based on blocking immune checkpoints with programmed death‐1 (PD‐1) or PD‐ligand 1 (PD‐L1) Abs has been introduced for the treatment of advanced clear cell renal cell carcinoma (ccRCC), especially tumors resistant to vascular endothelial growth factor‐tyrosine kinase inhibitors (VEGF‐TKIs), but the significance of their expression in the tumor microenvironment is unclear. We investigated these immune checkpoint markers in tumor cells and tumor‐infiltrating immune cells (TIIC) in the tumor microenvironment of 100 untreated and 25 VEGF‐TKI‐treated primary ccRCC tissues. Upregulated expression of PD‐1 and PD‐L1 by TIIC, and PD‐L1 by tumor cells was associated with the histological grade and unfavorable prognosis of RCC patients. High PD‐1 and PD‐L1 expression by TIIC was associated with a poorer response to VEGF‐TKI, whereas PD‐L1 expression by tumor cells did not affect the efficacy of the treatment. Furthermore, increased PD‐1‐positive TIIC and PD‐L1‐positive TIIC were observed in tumors treated with VEGF‐TKIs compared with those in untreated tumors. Our data suggest that PD‐1 and PD‐L1 expression by TIIC in the tumor microenvironment is involved in treatment resistance, and that sequential therapy with immune checkpoint inhibitors could be a promising therapeutic strategy for ccRCC resistant to VEGF‐TKI 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.

HSR19-108: A Meta-Analysis of Randomized Controlled Trials (RCTs) for Efficacy and Safety of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors (VEGF-TKIs) Adjuvant Therapy in High-Risk Renal Cell Cancer (RCC)

Background: Four large RCTs (ASSURE, S-TARC, PROTECT, ATLAS) tested adjuvant VEGF-TKI therapy in high risk RCC. The results were variable for efficacy and there were concerns for increased toxicity and decline in quality of life (QoL). We performed an updated meta-analysis including results of ATLAS trial to asses a risk-benefit for adjuvant post-operative treatments in high risk RCC patients by assessing reported disease-free survival (DFS), overall survival (OS), and toxicity endpoints. Methods: Literature search was done using Medline, CENTRAL, and Embase. The DerSimonian and Laird random effects model was used to pool estimates for DFS, OS, and common side effects across the 4 trials. A subgroup analysis was performed for sunitinib alone because of its FDA approval. Heterogeneity was assessed with Cochrane Q statistic and was quantified with I2 test. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: The 4 RCTs included 4,820 patients. Adjuvant therapy with TKIs yielded no significant improvement in DFS or OS as compared to placebo (DFS HR=0.916; 95% CI, 0.832–1.009 and OS HR=1.09; 95% CI, 0.886–1.150). Separate analysis of DFS in sunitinib vs placebo did not show any benefit (2 studies, N=1,909; HR=0.90; 95% CI, 0.67–1.19). Use of TKIs was associated with significantly increased risk of drug toxicity. Increased risk of grade 3 or 4 adverse events (RR=5.110; 95% CI, 3.765–6.935), diarrhea (RR=10.725; 95% CI, 4.672–24.622), fatigue (RR=3.310; 95% CI, 1.879–5.829), hypertension (RR=4.274; 95% CI, 3.452–5.292) and palmar/plantar dysesthesia (RR=20.53; 95% CI, 9.006–46.801) was observed. There was no statistically significant heterogeneity amongst included trials. QoL endpoints were inconsistently reported. Risk of bias was low. Conclusions: This pooled analysis provides further evidence that there is no OS or DFS benefit associated with adjuvant TKI treatment. There was a significantly increased risk of grade 3 or 4 toxicity in greater than half of the patient population leading to decline in QoL during TKI therapy. Carefully selected very high-risk patients who can tolerate these agents without dose modifications may benefit from adjuvant TKI approach.

Targeted Therapy and Immunotherapy: Effect of Body Mass Index on Clinical Outcomes in Patients Diagnosed with Metastatic Renal Cell Carcinoma

Background: Previous research has identified an association between high body mass index (BMI) and better overall survival (OS) in metastatic renal cell carcinoma (mRCC) patients treated with vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs). Objective: The current study sought to determine whether the effect of BMI on OS extends beyond VEGF-TKIs to mTOR inhibitors or immunotherapy (IO). Design, Setting and Participants: A retrospective study was conducted among patients diagnosed with mRCC treated at a single institution from 2009 to 2017. Demographic and clinical variables were collected. BMI was characterized as high (≥25 kg/m2) versus low (&lt;25 kg/m2). Outcomes Measurement and Statistical Analysis: The Kaplan-Meier method was used to estimate the difference in OS, with comparisons based on BMI and by treatment type. Results and Limitations: Among 353 patients (M = 64 years old, 73% male) 66% were overweight or obese (BMI≥25 kg/m2). Patients were treated with VEGF-TKI (65%), mTOR (23%), or IO (12%). Among patients treated with VEGF-TKI with low BMI, median OS was 24.0 months (95% CI, 20.7–27.2) versus 36.0 months (95% CI, 18.6–53.3) among patients with high BMI (P = 0.02). The median OS for patients with low BMI treated with mTOR was 18.0 months (95% CI, 2.8–33.1), versus 25.0 months (95% CI, 16.6–33.4) among patients with high BMI (P = 0.04). In contrast, patients with low BMI treated with IO had a median OS of 23.6 months (95% CI, 17.5–29.7) versus 19.9 months (95% CI, 10.6–29.2) among patients with high BMI (P = 0.26). The retrospective nature and the small sample size are the main limitations of this study. Conclusions: High-BMI was associated with improved OS in patients with mRCC treated with VEGF-TKI and mTOR, but the inverse trend was observed among patients receiving IO. Our data highlight the need to reassess this phenomenon in the context of IO-based regimens.

Perioperative Therapy in Renal Cell Carcinoma: What Do We Know, What Have We Learned, What's Next?

Recent adjuvant vascular endothelial growth factor tyrosine kinase inhibitor trials in resected high-risk renal cell carcinoma that compared sunitinib, sorafenib, pazopanib, and axitinib with placebo controls have demonstrated mixed impact on disease-free survival, no improvement in overall survival, and, thus, controversy. Here, we discuss the results and conduct of these trials to provide new insight into the goals and strategies of treating resected renal cell cancer that is at high risk for recurrence. The potential for leveraging what we have learned from these trials to conduct successful contemporary adjuvant and perioperative immune checkpoint inhibition trials and future adjuvant trial design is discussed.

A Phase Ib, Open-Label Study of Dalantercept, an Activin Receptor-Like Kinase 1 Ligand Trap, plus Sorafenib in Advanced Hepatocellular Carcinoma

Lessons Learned. Patients with hepatocellular carcinoma (HCC) often have limited therapeutic responses to the vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor sorafenib, which is standard of care in advanced HCC. Targeting the activin receptor‐like kinase 1 (ALK1) and VEGF pathways simultaneously by combining the ALK1 ligand trap dalantercept with sorafenib may result in more effective angiogenic blockade and delay tumor progression in patients with advanced HCC.Although the combination was generally well tolerated, there was no additive antitumor activity with the combination of dalantercept plus sorafenib in patients with advanced HCC. No complete or partial responses were observed, and overall survival ranged from 1.9 to 23.3 months.These results suggest that, in this patient population, further development of the possible limited benefits of combination therapy with dalantercept plus sorafenib is not warranted.Background.Targeting the activin receptor‐like kinase 1 (ALK1) and vascular endothelial growth factor (VEGF) pathways may result in more effective angiogenic blockade in patients with hepatocellular carcinoma (HCC).Methods.In this phase Ib study, patients with advanced HCC were enrolled to dose‐escalation cohorts, starting at 0.6 mg/kg dalantercept subcutaneously every 3 weeks plus 400 mg sorafenib orally once daily, or to a dose expansion cohort. The primary objective was to determine the safety and tolerability and the dalantercept maximum tolerated dose (MTD) level. Secondary objectives were to assess the preliminary activity and the association of pharmacodynamic biomarkers with tumor response.Results.A total of 21 patients were enrolled in the study. Five patients received 0.6 mg/kg dalantercept in the first dose escalation cohort. Based on the initial safety results, the dose level was de‐escalated to 0.4 mg/kg in the second cohort (n = 6). The MTD was identified as 0.4 mg/kg and used for the dose expansion cohort (n = 10). At this dose level, the combination was generally well tolerated. Overall survival ranged from 1.9 to 23.3 months, and the best overall response was stable disease.Conclusion.The addition of dalantercept to sorafenib did not improve antitumor activity in patients with HCC. The dalantercept program in this population was discontinued.