Advanced Metastatic Renal Cell Carcinoma Research Articles

Administering immunotherapy after anti-vascular targeted therapy improves overall survival of patients with metastatic clear cell renal cell carcinoma.

The Food and Drug Administration of the United States has approved several drugs for treating advanced metastatic renal cell carcinoma, including anti-vascular tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). Options for first-line therapy include monotherapy or combination therapy. However, selecting a suitable first-line and second-line treatments to improve overall survival remains an unresolved issue. To evaluate the overall survival (OS) and progression-free survival (PFS) of patients with metastatic clear cell renal cell carcinoma (mRCC). Patients were divided into several grouped according to the treatment sequence of TKI and anti PD-1 administration. The overall survival benefit was evaluated based on the order of administration of anti PD-1 and TKI. In this retrospective propensity-matched cohort study, we identified 135 patients with mRCC treated at the Affiliated Cancer Hospital of Shandong First Medical University from January 1, 2017, to December 31, 2022. These patients had received anti PD-1 treatment as part of their first or second line of therapy. Statistical analysis was performed from June 1, 2023, to August 1, 2023. The primary outcome measure was OS, from the date of diagnosis to death or the last follow-up. PFS was monitored during treatment. Survival analyses were conducted using Cox proportional hazards regression and Kaplan-Meier estimates. By comparing the complete treatment course of patients, the survival of patients in different groups was compared according to the number of immunotherapy lines. The final cohort comprised 135 patients, of whom 84 received first-line therapy with anti PD-1 (include 6 patients treated with anti PD-1 (tislelizumab, carrelizumab, toripalimab or sintilizumab) alone and 78 patients treated with anti PD-1 combined with anti-vascular TKI (axitinib, sunitinib, solfanitinib or pazopanib)). The remaining 51 patients were treated with anti PD-1 as second-line therapy following an initial regime of TKIs. Patients were initially categorized based on whether anti PD-1 were used in the first-line treatment. It was observed that the OS of patients receiving first-line targeted therapy was higher than those receiving first-line immunotherapy, with a median OS of 33 months versus 15 months. To investigate this outcome further, we refined the patient groups based on the administration sequence of anti PD-1 and TKIs in the treatment regimen. We found that the median PFS of patients with first-line treatments of TKI combined with anti PD-1 was 3.5 months, compared to 14.5 months when TKI combined with anti PD-1 followed first-line TKI (p=0.0092). The median PFS for second-line treatments was 6.5 months versus 15 months (p=0.0014). Similarly, the median OS was 16.66 months and 31.88 months, respectively (p=0.008). This study indicates that administering immunotherapy following anti-vascular therapy significantly enhances both OS and PFS compared to other sequences of therapies. This finding provides valuable insights and robust data support for clinical decision-making regarding treatment sequencing.

Hemoglobin and neutrophil levels stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk predict the effectiveness of ipilimumab plus nivolumab in patients with advanced metastatic renal cell carcinoma.

To identify biomarkers associated with the effectiveness of ipilimumab plus nivolumab against advanced metastatic renal cell carcinoma. We retrospectively analyzed the data of 75 patients treated with ipilimumab plus nivolumab at seven hospitals between August 2018 and April 2021. Prognostic biomarkers were assessed prior to initiating treatment with ipilimumab plus nivolumab. Median overall survival and progression-free survival were examined using the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify predictors of disease progression. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors most important for predicting disease progression were determined using classification and regression tree analysis. Median overall survival and progression-free survival were longer in the intermediate IMDC risk group than in the poor IMDC risk group (overall: not reached vs. 18.3 months; progression-free: not reached vs. 13.5 months). The multivariate analysis identified poor IMDC risk as a risk factor for disease progression (hazard ratio 2.61, 95% confidence interval: 1.05-6.51). Based on the results of the classification and regression tree analysis, the cohort was divided into non-anemia, anemia + neutro-Low, and anemia + neutro-High groups. Median overall survival and progression-free survival were longer in the non-anemia and anemia + neutro-Low groups than in the anemia + neutro-High group (overall: not reached vs. 29.3 months vs. 4.3 months: progression-free: not reached vs. 29.0 months vs. 3.9 months). Hemoglobin and neutrophil levels may represent crucial biomarkers for predicting the effectiveness of ipilimumab plus nivolumab therapy in patients with renal cell carcinoma.

The role of blood cholesterol quality in patients with advanced cancer receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) became the standard of care for several solid tumors. A limited fraction of patients (pts) achieves a long-term benefit. Plasmatic and intracellular cholesterol levels have emerged as promising biomarkers. The aim of the present study was to determine whether cholesterol efflux capacity (CEC), mediated by serum transporters (ABCA1 and ABCG1) and passive diffusion (PD), impacts on clinical outcome of advanced non-small cell lung cancer (NSCLC) and metastatic renal cell carcinoma (mRCC) pts treated with ICIs. We retrospectively enrolled advanced NSCLC and mRCC pts consecutively treated with ICIs between October 2013 and October 2018. CEC and cholesterol loading capacity (CLC) were assessed by well-established specific cell models. As primary endpoint, CEC, PD and CLC were correlated with overall survival (OS) while the effects of these parameters on progression-free survival (PFS) and clinical benefit (CB), defined as complete/partial response or stable disease, represented secondary endpoints. NSCLC accounted for 94.2% of 70 enrolled cases, and serum sample suitable for CEC and PD determination was available in 68. Blood cholesterol and serum ABCA1, ABCG1, PD and CLC were associated with outcomes (OS, PFS and CB) at univariate analysis. At the multivariate analysis, only PD confirmed its positive prognostic value in terms of OS, PFS and CB. The favorable impact of cholesterol PD on clinical outcome might reflect its main conformation in mature HDL particles which potentially shape an inflamed context, ultimately promoting ICI efficacy. Further prospective studies are needed to support our findings and uncover targetable pathways.

Artificial intelligence-based prediction of overall survival in metastatic renal cell carcinoma.

Investigations of the prognosis are vital for better patient management and decision-making in patients with advanced metastatic renal cell carcinoma (mRCC). The purpose of this study is to evaluate the capacity of emerging Artificial Intelligence (AI) technologies to predict three- and five-year overall survival (OS) for mRCC patients starting their first-line of systemic treatment. The retrospective study included 322 Italian patients with mRCC who underwent systemic treatment between 2004 and 2019. Statistical analysis included the univariate and multivariate Cox proportional-hazard model and the Kaplan-Meier analysis for the prognostic factors' investigation. The patients were split into a training cohort to establish the predictive models and a hold-out cohort to validate the results. The models were evaluated by the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. We assessed the clinical benefit of the models using decision curve analysis (DCA). Then, the proposed AI models were compared with well-known pre-existing prognostic systems. The median age of patients in the study was 56.7 years at RCC diagnosis and 78% of participants were male. The median survival time from the start of systemic treatment was 29.2 months; 95% of the patients died during the follow-up that finished by the end of 2019. The proposed predictive model, which was constructed as an ensemble of three individual predictive models, outperformed all well-known prognostic models to which it was compared. It also demonstrated better usability in supporting clinical decisions for 3- and 5-year OS. The model achieved (0.786 and 0.771) AUC and (0.675 and 0.558) specificity at sensitivity 0.90 for 3 and 5 years, respectively. We also applied explainability methods to identify the important clinical features that were found to be partially matched with the prognostic factors identified in the Kaplan-Meier and Cox analyses. Our AI models provide best predictive accuracy and clinical net benefits over well-known prognostic models. As a result, they can potentially be used in clinical practice for providing better management for mRCC patients starting their first-line of systemic treatment. Larger studies would be needed to validate the developed model.

The Role of Cytoreductive Nephrectomy in Renal Cell Carcinoma with Sarcomatoid Histology: A Case Series and Review of the Literature

Background: Renal cell carcinoma with sarcomatoid dedifferentiation represents a rare histological entity characterized by aggressive behavior, limited efficacy of tyrosine kinase inhibitors or mTOR inhibitors, and poor outcome. The immune checkpoint inhibitor therapy regimen combining ipilimumab with nivolumab represents a new standard of care for this patient population due to a hitherto unprecedented response rate and overall survival. On the other hand, the role of cytoreductive nephrectomy in metastatic renal cell carcinoma, in particular, with sarcomatoid histology, remains controversial. Patient and Methods: In the present case series, we report six patients with locally advanced or synchronous metastatic sarcomatoid renal cell carcinoma and intermediate or poor International Metastatic RCC Database Consortium (IMDC) risk score, five of whom were successfully subjected to cytoreductive nephrectomy. Results: All six patients received the combination regimen of ipilimumab with nivolumab. Five of these patients underwent upfront cytoreductive nephrectomy followed by systemic treatment without any significant delay, with a durable treatment outcome. Notably, two patients with poor prognostic features achieved a long-term major partial response to therapy. We also performed a review of the literature on optimal treatment strategies for patients with sarcomatoid renal cell carcinoma. Conclusion: Herein, we highlight the feasibility of performing cytoreductive nephrectomy in patients with intermediate/poor prognosis metastatic renal cell carcinoma with sarcomatoid dedifferentiation followed by immunotherapy with ipilimumab and nivolumab. To enhance the chances of immunotherapy success, cytoreductive nephrectomy should also be considered for patients presenting with a disease with adverse prognostic parameters.

Activity of Systemic Treatments After Cabozantinib Failure in Advanced Metastatic Renal Cell Carcinoma.

Cabozantinib, a potent multityrosine kinases inhibitor (TKI), has demonstrated overall survival (OS) benefit over everolimus in patients previously treated with VEGFR TKI for metastatic Renal Cell Carcinoma (mRCC). The efficacy of systemic treatments after cabozantinib failure has not been investigated. We conducted a retrospective study on patients receiving systemic treatment after cabozantinib failure in heavily pretreated patient with mRCC. We assessed Time to Treatment Failure (TTF), OS and objective response rate (ORR). Among 150 patients treated with cabozantinib in our institution, 56 (37.3%) received subsequent systemic therapy and were eligible for the analysis. IMDC prognostic group was good, intermediate and poor in 11 (19.6%), 24 (42.9%) and 11 (19.6%) patients, respectively. Cabozantinib was administered mainly as a second (41.1%), or third (33.9%) line treatment. axitinib or immune-checkpoint inhibitors were the subsequent treatment in 18 (34.8%) patients for each everolimus (n:16, 28.6%), other angiogenesis inhibitors (n:4, 7.1%) TTF and OS from subsequent systemic therapy after cabozantinib failure were 2.8 months (95%CI 1.9-3.7) and 7.7 months (95%CI 4.4-10.8), respectively. ORR was 8.7% and 2 patients with axitinib and 2 patients treated with Immune checkpoint inhibitors achieved a partial response. Overall, activity of systemic therapies after cabozantinib was limited.

Prognostic Value of Thyroid Hormone Ratio in Patients With Advanced Metastatic Renal Cell Carcinoma: Results From the Threefour Study (Meet-URO 14).

BackgroundThyroid hormone impairment, represented as an alteration in levels of thyroid hormones and a lower fT3/fT4 ratio, has been correlated with a worse prognosis for both cancer and non-cancer patients. The role of baseline thyroid function in patients with metastatic renal cell carcinoma (mRCC) however, has not been studied yet.Materials and MethodsWe recorded clinical data, baseline biochemical results, and oncological outcomes from 10 Oncology Units in Italy. We stratified patients into three groups according to the fT3/fT4 ratio value and subsequently analyzed differences in progression-free survival (PFS) and overall survival (OS) in the three groups. We also performed univariate and multivariate analyses to find prognostic factors for PFS and OS.ResultsWe analyzed 134 patients treated with systemic treatment for mRCC. Median PFS in the low, intermediate, and high fT3/fT4 ratio group were 7.5, 12.1, and 21.7 months respectively (p<0.001); median OS in the three groups were 36.5, 48.6, and 70.5 months respectively (p =0.006). The low fT3/fT4 ratio maintained its prognostic role at the multivariate analysis independently from IMDC and other well-established prognostic factors. The development of iatrogenic hypothyroidism was not associated with a better outcome.ConclusionWe found that baseline thyroid hormone impairment, represented by a low fT3/fT4 ratio, is a strong prognostic factor in patients treated for mRCC in first line setting and is independent of other parameters currently used in clinical practice.

Next Steps: Sequencing Therapies in Metastatic Kidney Cancer in the Contemporary Era.

Systemic therapy for first-line metastatic renal cell carcinoma has evolved toward immune checkpoint blockade combinations incorporating a PD-1/L1 inhibitor along with CTLA-4 inhibition or VEGF-targeted therapy. The new treatment paradigm that integrates immunotherapy for treatment-naïve advanced metastatic renal cell carcinoma creates a new therapeutic challenge for clinicians including the optimal way to integrate multidisciplinary care involving surgery, radiotherapy, and application of contemporaneous systemic treatment in subsequent lines of therapy following discontinuation of combination therapy. We outline the available data for the multidisciplinary management of metastatic renal cell carcinoma, systemic therapy options in the post-immune checkpoint blockade setting, and novel therapies in development for advanced renal cell carcinoma. We provide practical considerations to assist clinicians in treatment choice and map future directions for progress.

Anlotinib: A Novel Targeted Drug for Bone and Soft Tissue Sarcoma.

Bone and soft tissue sarcomas account for approximately 15% of pediatric solid malignant tumors and 1% of adult solid malignant tumors. There are over 50 subtypes of sarcomas, each of which is notably heterogeneous and manifested by remarkable phenotypic and morphological variability. Anlotinib is a novel oral tyrosine kinase inhibitor (TKI) targeting c-kit, platelet-derived growth factor receptors, fibroblast growth factor receptor, and vascular endothelial growth factor receptor. In comparison with the placebo, anlotinib was associated with better overall survival and progression-free survival (PFS) in a phase III trial of patients with advanced non-small cell lung cancer (NSCLC), albeit with cancer progression after two previous lines of treatment. Recently, the National Medical Products Administration approved anlotinib monotherapy as a third-line treatment for patients with advanced NSCLC. Additionally, a phase IIB randomized trial substantiated that anlotinib is associated with a significant longer median PFS in patients with advanced soft tissue sarcoma. Moreover, anlotinib is also effective in patients with advanced medullary thyroid carcinoma and metastatic renal cell carcinoma. Anlotinib has similar tolerability to other TKIs targeting vascular endothelial growth factor receptors and other tyrosine kinase-mediated pathways. However, anlotinib has a notably lower rate of side effects ≥grade 3 relative to sunitinib. This review discussed the remarkable characteristics and major dilemmas of anlotinib as a targeted therapy for sarcomas.

Value of cabozantinib in the treatment of advanced metastatic clear cell renal cell carcinoma (ccRCC): Real-world data from a single Korean institution.

e16578 Background: Cabozantinib is a multitarget tyrosine kinase inhibitor and getting attention in these days through its combination with immune checkpoint inhibitors. In this article, we analyze the efficacy of cabozantinib in patients with metastatic ccRCC in Korean who had progression after 1 or more VEGFR TKI therapies. Methods: Seventy-five patients from Jan.2019 to Dec. 2021 at Yonsei Cancer Center who had received cabozantinib treatment in second to fourth line of therapy were retrospectively reviewed. The primary endpoint was PFS. The secondary outcomes were the response rate, disease control rate (DCR), and OS. The evaluable subjects for efficacy were those who had at least one response evaluation. Results: Among 75 patients, 57 (76.0%) were male and median age was 59 years (range 33-81). Median follow up time was 12.1 months. There were 22 (29.3%) patients of second line, 38 (50.7%) of third line and 15 (20.0%) of fourth line of treatment. Median PFS was 5.6 months (95% CI, 4.6-6.6). Median OS was 13.6 months (95% CI, 5.0-22.2). The PFS based on the line of treatment was 4.7 months for second line, 5.6 months for third line and 12.0 months for 4th line. Proportion of patients who were previously treated with ICI was different between treatment line groups and showed increasing trend toward later line; 13.6% of second line, 31.6% of third line, and 66.7% of fourth line, respectively. The objective response rate was 8.0% with 6 patients of partial response. The DCR was 69.3%. The major toxicities were similar with the western population and most of them were less than CTCAE grade 3. Most common grade 3 or 4 AEs were anemia, hand-foot syndrome, fatigue, and stomatitis. There were no grade 5 AEs. Conclusions: Our results demonstrate that cabozantinib is an effective treatment option after first line TKI in Korean ccRCC patients with manageable toxicities. Notably, its tolerability in the advanced line of treatment and synergy with ICIs are suggested in this study despite heterogeneous patients of real world setting. This is the first real world data with cabozantinib in Asian patients.

Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction.

Simple SummaryRenal cell carcinoma (RCC) is the eighth leading malignancy in the world, accounting for 4% of all cancers with poor outcome when metastatic. Protein kinases are highly druggable proteins, which are often aberrantly activated in cancers. The aim of our study was to identify candidate targets for metastatic clear cell renal cell carcinoma therapy, using chemo-genomic-based high-throughput screening. We found that the combined inhibition of the CK2 and ATM kinases in renal tumor cells and patient-derived tumor samples induces synthetic lethality. Mechanistic investigations unveil that this drug combination triggers apoptosis through HIF-2α-(Hypoxic inducible factor HIF-2α) dependent reactive oxygen species (ROS) overproduction, giving a new option for patient care in metastatic RCC.Kinase-targeted agents demonstrate antitumor activity in advanced metastatic clear cell renal cell carcinoma (ccRCC), which remains largely incurable. Integration of genomic approaches through small-molecules and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. The 786-O cell line represents a model for most ccRCC that have a loss of functional pVHL (von Hippel-Lindau). A multiplexed assay was used to study the cellular fitness of a panel of engineered ccRCC isogenic 786-O VHL− cell lines in response to a collection of targeted cancer therapeutics including kinase inhibitors, allowing the interrogation of over 2880 drug–gene pairs. Among diverse patterns of drug sensitivities, investigation of the mechanistic effect of one selected drug combination on tumor spheroids and ex vivo renal tumor slice cultures showed that VHL-defective ccRCC cells were more vulnerable to the combined inhibition of the CK2 and ATM kinases than wild-type VHL cells. Importantly, we found that HIF-2α acts as a key mediator that potentiates the response to combined CK2/ATM inhibition by triggering ROS-dependent apoptosis. Importantly, our findings reveal a selective killing of VHL-deficient renal carcinoma cells and provide a rationale for a mechanism-based use of combined CK2/ATM inhibitors for improved patient care in metastatic VHL-ccRCC.

Interdisciplinary recommendations for the treatment of advanced metastatic renal cell carcinoma

Due to novel therapies, the prognosis of patients with metastatic renal cell carcinoma (mRCC) has improved. A median overall survival of more than two years is a realistic goal. Immunotherapy combinations with checkpoint inhibitors or checkpoint inhibitors and the tyrosine kinase inhibitor axitinib are new first-line options.Sunitinib, pazopanib, tivozanib and the combination of bevacizumab + interferon alpha are approved for first-line therapy regardless of the progression risk score. The use of both the combination of nivolumab + ipilimumab and cabozantinib is restricted to intermediate and high-risk patients. In this subgroup, the immunotherapy combination was more effective in terms of overall survival compared with sunitinib. Temsirolimus is only approved for high-risk patients.Sunitinib and pazopanib can also be applied as second-line options - for pazopanib the use is restricted to the event of cytokine failure. Nivolumab and cabozantinib demonstrated superior overall survival compared with everolimus. Furthermore, the combination of lenvatinib + everolimus and axitinib are approved treatment options in the second-line and further settings. Everolimus has been replaced in the second-line setting by these new options.The question regarding the optimal sequence is still unanswered.The purpose of an interdisciplinary expert meeting was to debate which criteria should influence treatment. The members discussed several aspects of treating patients with advanced or metastatic RCC. As in previous years, the experts intended to provide recommendations for clinical practice. The results are presented in this publication.

Neutrophil-to-lymphocyte ratio as a predictor of oncologic outcomes in locally advanced non-metastatic clear cell renal carcinoma.

661 Background: An elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with worse oncologic outcomes in several malignancies, its prognostic role in kidney cancer, specifically in the non metastatic setting is controversial. We aimed to evaluate if an elevated NLR in patients with locally advanced non metastatic clear cell renal cell carcinoma (CCRCC) is associated with a worse survival and/or a higher cancer recurrence rate. Methods: We retrospectively identified 880 nephrectomies performed between 01/2009 to 12/2016 in a single center, reviewed data from 478 consecutive radical nephrectomies (RN) for kidney tumors and identified 187 patients with locally advanced non-metastatic CCRCC patients (pT3-T4 N0M0). The cut-off point of NLR = 2.5 was obtained using the receiver operating curve analysis (ROC). NLR was obtained preoperatively and calculated by dividing absolute neutrophil count by absolute lymphocyte count. Overall survival (OS) and recurrence-free survival (RFS) were evaluated using the Kaplan-Meier method. Cox regression models were utilized to evaluate predictors of recurrence and survival. Results: Median follow up was 48.7 months. The 3 year OS was significantly lower for patients with NLR ≥ 2.5 than those with NLR &lt; 2.5 (70% vs 85%, p = 0.049). In patients with a Fuhrman nuclear grade of differentiation of 3-4, the median time to recurrence was significantly shorter for patients with NLR ≥ compared to those with NLR &lt; 4 (24 vs 55 months p 0.045). On multivariable analysis adjusted for NLR ≥ 2.5, microvascular invasion, sarcomatoid differentiation, tumor size and body mass index, only nuclear grade of differentiation was found to be an independent predictor for recurrence (hazard ratio= 2.18; 95% confidence interval [CI]: 1.07 – 4.92, p = 0.03). Conclusions: Patients with non-metastatic CCRCC with higher nuclear grade of differentiation and a high preoperative NLR have shorter RFS and worse OS compared to patients with lower NLR.

Sertraline/ICG-loaded liposome for dual-modality imaging and effective chemo-photothermal combination therapy against metastatic clear cell renal cell carcinoma.

A large number of chemotherapeutic drugs, utilized in the treatment of advanced metastatic clear cell renal cell carcinoma, are typically prone to poor biocompatibility, lack of targeting specificity, and high toxicity, which mostly leads to unsatisfactory clinical outcomes. As a new drug delivery pathway, nanoliposomes have the advantages of simplifying metabolism, reducing drug side-effects, and providing specific targeting, which can potentially improve the therapeutic effect toward tumor therapy. In this study, a clinically integrated nanoliposome containing Sertraline Hydrochloride and indocyanine green (ICG), here named as Ser/ICG@Lip, was successfully synthesized by film-dispersion and hydration-sonication methods. The photoacoustic imaging and near-infrared fluorescence imaging capabilities of this novel nanoliposome were validated in vitro. The high encapsulation rate of Sertraline Hydrochloride and ICG ensured the safety and therapeutic efficacy of the particle. Moreover, our results suggest that chemo-photothermal combination therapy can be more effective than single photothermal or chemotherapy treatments against malignant tumor cells. This is the first study introducing Sertraline Hydrochloride as a liposome-encapsulated chemotherapeutic agent, containing photothermal capabilities, for the treatment of metastatic renal clear cell cancer cells. This novel drug system has potential to evolve into an alternate treatment method for metastatic clear cell renal cell carcinoma.

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.

A new strategy for the treatment of sorafenib-refractory metastatic renal cell carcinoma in China: combination with intermittent chemotherapy.

This study assesses the clinical safety and efficacy of Gemcitabine and S-1 combination chemotherapy in sorafenib-refractory metastatic renal cell carcinoma (RCC) patients. The baseline characteristics and survival outcomes of 19 patients suffering from metastatic and progressive sorafenib-refractory RCC were retrospectively collected and analyzed from January 2010 to April 2014. Patients were treated by combining Gemcitabine (1,000 mg/m2, day 1 and day 8 of every cycle of 21 days) and S-1 (40 mg/m2, twice a day for 14 days, followed by the rest period of 7 days), with a continual treatment of sorafenib 400 mg twice a day in a cycle of 28 days. After combination chemotherapy, the disease control rate was 68.4%. Among them, 6 patients (31.6%) had progressive disease (PD), 5 patients (26.3%) had stable disease (SD) and 8 patients (42.1%) had partial response (PR). The median time to progression (TTP) was 6.3 months (range, 2.0-32.7 months), and the median overall survival (OS) was 19.7 months (range, 5.7-45.0 months). In the survival analysis, comparing PD group, disease control (PR + SD) group showed an obviously longer TTP (median TTP: 9.5 vs. 2.0 months, 95% CI, 7.7-11.3 months, P<0.001) and OS (median OS: 21.0 vs. 8.3 months, 95% CI, 14.5-24.9 months, P<0.001). In univariate and multivariate analysis, TTP and OS were significantly associated with disease control condition. Side-effects were found in all patients at different degree, but only 3 patients suffered grade 3/4 toxicities (15.8%). No death related to treatment was observed. The combination chemotherapy could be a promising treatment option for advanced metastatic RCC (mRCC) patients after sorafenib refractory.

The impact of gastric acid suppressive agents on pazopanib exposure.

e16076 Background: Pazopanib has been registered for advanced soft tissue sarcoma (STS) and metastatic renal cell carcinoma (mRCC). The uptake of pazopanib is 40% reduced when a proton pump inhibitor is concomitantly used. Nevertheless, still a large group of cancer patients need a form of gastric acid suppressive agents (GAS, e.g. proton pump inhibitors or H2-anagonists) due to gastrointestinal adverse events. Recently, it was demonstrated that the use of pazopanib with GAS resulted in shorter overall survival and progression free survival in patients with STS. In order to limit the effect of GAS on pazopanib absorption, the advice is to take the GAS 1 hour after pazopanib. In that way the pazopanib is dosed at the lowest gastric pH value. However, the effect of this most optimal controlled intake on pazopanib absorption is unknown. Therefore, we investigated whether this controlled intake algorithm affects pazopanib exposure. Methods: In the DIET study, pazopanib trough concentrations (Ctrough) were measured at predefined moments. In this study a total of 80 patients with mRCC and STS were included. The concomitant use of GAS was recorded and taken according the intake algorithm. Patients were subdivided into two groups (with GAS or without GAS). Results: Of the 80 patients, 22 patients were treated with pazopanib in combination with GAS. In patients treated with pazopanib without GAS the geometric mean(GM) pazopanib Ctrough level was 29.1 mg/L (95% CI 26.4 -31.8) compared to 22.4 mg/L (95% CI 18.0-27.8) (p = 0.01) in those treated with GAS. Conclusions: Patient who use pazopanib with controlled intake of GAS had a 23% lower pazopanib exposure. Therefore, we advice that in patients, who are unable to quit their GAS agent, pazopanib trough concentrations should be monitored in order to prevent shorter treatment benefit. Clinical trial information: NCT02138526.

A reduced pazopanib dose with food: Is it more patient-friendly and does it reduce drug costs?

4564 Background: Pazopanib has been licensed for advanced soft tissue sarcoma and metastatic renal cell carcinoma in a fixed oral daily dose of 800mg taken fasted. We hypothesized that ingesting pazopanib with food may improve patients’ comfort and reduce gastro-intestinal adverse events. Moreover, a food intervention, resulting in a better absorption, can lead to a lower dose, which could significantly reduce treatment costs. Methods: Part 1 of the study was performed to determine whether 600mg pazopanib taken with a continental breakfast was bioequivalent to 800mg pazopanib taken fasted. In part 2, differences in GI-toxicity and patient satisfaction were assessed by the cancer-therapy-satisfaction-questionnaire after both intake regimens. Finally, patient’s preference for either intake regimen was asked. Results: 16 patients were included in the bioequivalence study. The geometric mean ratio (fed/fasted) of the area under the plasma concentration time curve was 1.10 (90% CI 1.00-1.19), maximum peak concentration was 1.12 (90% CI 1.02-1.22) and pazopanib trough concentration was 1.10 (90% CI 1.02-1.18). In part 2, 60 patients were included. No differences were seen in the occurrence of GI-toxicities under both intake regimens. Patients seem to be more positive about their feelings about side effects (72.3(95% CI 68.1-76.5) vs 68·2 (62.7-73.6); p=.092) and satisfaction with therapy scores were higher (84.7(95% CI 81.4-87.9) vs 81.9 (78.7-85.2); p= .059) when pazopanib was taken with food. 41 (68%) of the patients preferred the intake with continental breakfast. Conclusions: Intake of 600mg pazopanib with food results in bioequivalent exposure and was preferred over a standard pazopanib dose without food. Moreover, with this simple food intervention a large cost reduction can be realized in patients treated with pazopanib. Clinical trial information: NCT02138526.

Preliminary experience in guiding individualized targeted therapy of advanced metastatic renal cell carcinoma with gene detection technology

Objective To explore the efficacy and tolerance of adverse reactions of gene detection technique in guiding individualized targeted therapy for advanced metastatic renal cell carcinoma. Methods Retrospective analysis was performed on the clinical data of 62 patients with advanced metastatic renal cell carcinoma before and after receiving targeted drug treatment in our department from October 2015 to October 2017. Among the 62 patients, there were 36 males and 26 females, with an average age of (54±13)years old.16 patients were treated with sunitinib, 20 patients were treated with sorafenib and 26 patients were treated with pazopanib. A total of 28 patients (individualized group) were selected to receive targeted drug according to the results of gene detection, and 34 patients were treated with targeted drug empirically (empirical group). In individualized group, there were 17 males and 11 females with the average age of(51.3±15.6) years old. 20 patients accepted the operation. The distant metastasis included bone metastasis in 21 cases, lung metastasis in 7 cases, liver metastasis in 16 cases, epidermal metastasis in 4 cases and lymphatic metastasis in 14 cases. According to risk of MSKCC, the case number of low risk, moderate risk and high risk were 15, 7, 6, respectively. 7 patients were treated with sunitinib, 8 patients were treated with sorafenib and 13 patients were treated with pazopanib. In empirical group, there were 19 males and 15 females with the average age of (56.3±10.1) years old. 22 patients accepted the operation. The distant metastasis included bone metastasis in 20 cases, lung metastasis in 5 cases, liver metastasis in 13 cases, epidermal metastasis in 3 cases and lymphatic metastasis in 15 cases. According to risk of MSKCC, the case number of low risk, moderate risk and high risk were 20, 8, 6, respectively. 9 patients were treated with sunitinib, 12 patients were treated with sorafenib and 13 patients were treated with pazopanib.The baseline characteristics of the two groups of patients, including gender, age, whether operation was performed, site of metastasis, and risk of MSKCC, didn’t show significant difference. Patients in both groups received the standard treatment regimen and the follow-up duration was 4-26 months to observe the efficacy, progression-free survival and tolerance to adverse reactions of the targeted therapy. Results After 12 months of treatment, 13 patients in the individualized group was recorded objective remission. 7 patients in the empirical group was recorded objective remission, as well. The tumor control efficacy of the individualized group was significantly better than that of the empirical group (46.4% vs. 20.6%, P=0.03). Meanwhile, the median progression-free survival time (13.2 months, 3.7-24.2 months) in the individualized group was significantly longer than that in the empirical group (12.1 months, 2.8-22.1 months) (P=0.009). Compared with the empirical group, the higher incidence of targeted treatment-related adverse reactions occurred in the individualized group, including thrombocytopenia(46.4% vs.17.6% P=0.014), leukopenia(46.4% vs.17.6% P=0.005), hypertension(71.4% vs.44.1%, P=0.031) and hypothyroidism(60.7% vs.29.4%, P=0.013). Conclusions Compared with the patients with empirical drugs, the application of gene detection technique to select individualized targeted drugs for the treatment of advanced metastatic renal cancer is obvious curatively effective, and to a certain extent extends the progression-free survival time of patients. Key words: Advanced metastatic renal cell carcinoma; Molecular targeted therapy; Gene detection; Individualized

Surgical Management of Advanced Kidney Cancer: The Role of Cytoreductive Nephrectomy and Lymphadenectomy.

Despite the evolution of systemic therapy from the immunotherapy to targeted therapy eras, surgical management remains a mainstay of treatment of patients with locally advanced, lymph node-positive, and distant metastatic renal cell carcinoma. Balancing patient and disease characteristics with the potential morbidity of surgery has gained increasing attention to better define the role of cytoreductive nephrectomy and lymphadenectomy. In this review, we critically evaluate the literature for the potential therapeutic role of cytoreductive nephrectomy and lymphadenectomy in advanced kidney cancer, highlighting current evidence, limitations, and best-management practices. Although retrospective data supported a similar survival benefit for cytoreductive nephrectomy in the targeted therapy era as it did for the initial immunotherapy era (1992 to 2006), level 1 evidence from the randomized Clinical Trial to Assess the Importance of Nephrectomy (CARMENA) demonstrated no benefit for intermediate- and poor-risk patients in the setting of sunitinib therapy. Level 1 evidence among a favorable-risk subset is still awaited from the trial Targeted Therapy With or Without Nephrectomy in Metastatic Renal Cell Carcinoma: Liquid Biopsy for Biomarkers Discovery (TARIBO). Another trial, Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer (SURTIME), has compared upfront cytoreductive nephrectomy prior to targeted therapy with the initial initiation of targeted therapy followed by deferred cytoreductive nephrectomy. Lymphadenectomy is yet another controversial but less well-defined management option for patients with kidney cancer. The role of lymphadenectomy has been studied in both the localized and advanced settings over the past few decades, with a strong suggestion of no therapeutic benefit for patients with cT1-2N0M0 and cM1 disease, and with uncertain benefit in patients with high-risk disease (ie, locally advanced or cN1M0), leading to weak statements among clinical guidelines.