First-line Treatment Of Advanced Renal Cell Carcinoma Research Articles

Comparative analysis of efficacy and safety of combined immunotherapy and immune targeted therapy in the first-line treatment of advanced renal cell carcinoma: a real-world study

Aim. To compare of efficacy and safety of combined immune therapy (dual immune-oncology – IO combination therapies, IO-IO) and immune targeted therapy (ITT) in the first line treatment of patients with advanced renal cell carcinoma (RCC) treated in real world clinical practice. Materials and methods. The ambispective study enrolled patients with metastatic RCC aged ≥18 years, with measurable neoplastic lesions, who were treated with first-line IO-IO therapy or ITT. The primary endpoint was progression-free survival (PFS). Results. The study included data from 126 patients treated with IO-IO [46 (36.5%) patients of the IMDC intermediate and poor prognostic groups] or ITT [80 (63.5%) patients of all IMDC prognostic groups]. In a median follow-up of all patients of 16.1 (0.1–44.9) months, the median PFS was 16.1 (10.9–21.3) months, the median overall survival (OS) was not reached; one-year OS was 83.0%; the objective response rate on the first line of therapy was 44.4% with a complete response rate of 3.2%. The rate of tumor control was 88.1%. In the overall population, ITT versus IO-IO provided a significant benefit in terms of ORR (51.2% vs 32.6%; p=0.032), PFS (median 22.9 months vs 8.0 months; p=0.004) and one-year OS (87.5% vs 65.2%; p=0.042). In the IPTW population, multivariate analysis confirmed the independent prognostic significance of the treatment regimen for PFS (hazard ratio, 2.3; 95% confidence interval, 1.1–4.8; p=0.037) and OS (hazard ratio, 2.3; 95% confidence interval 1.1–4.8; p=0.037). No difference in the safety profile of IO-IO and ITT was identified. Conclusion. The results support the hypothesis that ITT is more effective than IO-IO in the first-line treatment of advanced RCC in patients of IMDC intermediate and poor prognostic groups.

Reshaping Treatment Paradigms for Advanced Renal Cell Cancer Patients and Improving Patient Management : Optimal Management for Renal Cell Cancer Patients.

The treatment of renal cell carcinoma (RCC) is one of the great success stories in the field of oncology, which was revolutionized with the development of therapies aimed at disrupting crucial pathways. Tumor biology of RCC has provided insight into the disease through elucidation of the role of vascular endothelial growth-factor (VEGF) and the mammalian target of rapamycin (mTOR). Targeted agents against VEGF and mTOR, as well as agents targeting relevant immunomodulatory pathways, have shown clinical benefit for advanced disease. The targeted agents are highly effective in achieving a response and survival, particularly in high-risk patients. These include the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) axitinib and cabozantinib, and programmed cell death 1 protein (PD-1) immune checkpoint inhibitors (ICI) nivolumab and pembrolizumab. There is a wealth of evidence investigating different therapeutic options and combinations for first-line treatment of advanced RCC including the CheckMate 214 study, KEYNOTE-426, JAVELIN Renal 101, and CheckMate 9ER. Dual ICI and combination agents targeting the programmed cell death protein 1/programmed cell death protein ligand 1 (PD1/PDL1) and VEGF, began to demonstrate superiority over previously accepted standards in advanced clear-cell RCC. Data from a number of clinical studies are available to help physicians with evidence-based decisions for the sequence of second-line and future treatments for patients with progressive RCC. In this review, we focus on essentials for clinicians treating patients with clear-cell RCC.

Cost-Effectiveness Analysis of First-Line Nivolumab Plus Cabozantinib for Advanced Renal Cell Carcinoma in the United States.

Nivolumab plus cabozantinib improved progression-free survival and overall survival compared with sunitinib in the first-line treatment of advanced renal cell carcinoma (RCC) according to CheckMate 9ER study. A Markov model was developed to compare the costs and effectiveness of nivolumab plus cabozantinib with those of sunitinib in the first-line treatment of advanced RCC. Primary outcomes were costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Model uncertainty was assessed in univariable and probabilistic sensitivity analyses. The total cost per patient was $681,425 for nivolumab plus cabozantinib and $256,302 for sunitinib. The incremental QALYfornivolumab plus cabozantinib was0.49compared with sunitinib. The ICER for nivolumab plus cabozantinib was $863,720perQALY gainedversus sunitinib. The results remained robust in univariable and probabilistic sensitivity analyses. On the basis of a willingness-to-pay threshold of $150,000, nivolumab plus cabozantinib was not cost-effective under current drug pricing in the first-line treatment of advanced RCC from a US payer's perspective.

Abstract 161: Evaluating the clinical utility of RNA-seq-based PD-L1 expression and cellular deconvolution as alternatives to conventional immunohistochemistry in clear cell renal cell carcinoma

Abstract The emergence of immune checkpoint inhibitors (ICI) have revolutionized treatment of many cancer types, including renal cell carcinoma (RCC). Although there are currently three ICI combination regimens approved as standard of care for the first-line treatment of advanced RCC, the utility of PD-L1 detected by immunohistochemistry (IHC) as a predictive biomarker remains somewhat controversial. In this study, we sought to determine the ability to detect PD-L1 expression accurately and sensitively in comparison with IHC as well as whether RNA-seq-based cellular deconvolution potentially correlates with PD-L1 IHC for the development of a deconvolution-based biomarker. Tumors from 103 clear cell RCC (ccRCC) patients were collected to compare sensitivity and clinical utility of RNA-seq and IHC in PD-L1 detection. Additionally, we used gene expression signatures to comprehensively characterize the ccRCC tumor microenvironments (TMEs) from RNA-seq to examine PD-L1 expression levels across varied TMEs. This classification system revealed that the ccRCC samples clustered into an immune-enriched microenvironment with high lymphocyte infiltration and an immune desert microenvironment predominantly composed of malignant cells. For RNA-seq-based cellular deconvolution, a unique and robust machine learning algorithm, named Kassandra, was developed using over 8,000 RNA profiles of sorted cells that outperformed all current cellular deconvolution algorithms. The RNA-seq of ccRCC clinical tumors (n =89) were analyzed by Kassandra. Our RNA-seq analysis identified ccRCC tumors with high (maximum), intermediate and low (minimum) PD-L1 expression, which were then validated with IHC. Among these, 5/5, 10/10 and 87/88 ccRCC tumors with high, medium and low expression, respectively, detected via RNA-seq matched with the PD-L1 levels detected with IHC, suggesting a high degree of concordance (p < 0.01) between the two methods. Notably, the immune-enriched ccRCC clusters had a higher percentage of PD-L1-positive malignant and immune cells. PD1+ CD8 T cells, identified via RNAseq-based cellular deconvolution (Kassandra), most strongly correlated with PD-L1 IHC (p < 0.05). PD-L1 status was predicted with an 0.82 AUC performance score using a regression model. In conclusion, our results indicated that PD-L1 expression detected by RNA-seq as well as the presence of PD1+ CD8 T cells determined by applying Kassandra strongly correlated with the PD-L1 values obtained via IHC, potentially providing a less costly and more robust alternative to the conventional methods. In addition, an increased number of PD-L1-positive tumor and immune cells within the immune-enriched TME may suggest the significance of the TME composition as a predictive factor in response to ICIs. Citation Format: Natalia Miheecheva, Maria Sorokina, Akshaya Ramachandran, Yang Lyu, Danil Stupichev, Alexander Bagaev, Ekaterina Postovalova, Krystle Nomie, Felix Frenkel, Maria Tsiper, Nathan Fowler, Ravshan Ataullakhanov, James J. Hsieh. Evaluating the clinical utility of RNA-seq-based PD-L1 expression and cellular deconvolution as alternatives to conventional immunohistochemistry in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 161.

Lenvatinib (LEN) + pembrolizumab (PEMBRO) treatment in patients (pts) with metastatic clear cell renal cell carcinoma (RCC): Final results of a phase 1b/2 trial.

e16542 Background: Immune checkpoint inhibitors (ICIs) are commonly used as first-line treatment for pts with advanced RCC. In the recent phase 3 CLEAR trial, LEN + PEMBRO showed improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) vs sunitinib in first-line treatment of advanced RCC (Motzer R et al. NEJM. 2021). Additional treatment options are needed for pts with disease progression on ICIs. A phase 1b trial of LEN + PEMBRO was performed in multiple tumor types and included an expansion part into a phase 2 cohort of ICI-pretreated, treatment-naïve, or previously treated ICI-naïve pts with metastatic RCC (NCT02501096). We report the final results of the RCC cohort with an extended follow-up. Methods: Eligible pts were ≥18 years old and had measurable disease. Efficacy analyses were conducted by prior therapy grouping. The primary endpoint was ORR at week 24 (ORRwk24) per immune-related (ir) RECIST by investigator assessment. Secondary endpoints included ORR, duration of response (DOR), PFS, OS, and safety. Exploratory endpoints included tumor response assessed per RECIST v1.1 by independent review committee (IRC). Subgroup analyses of the ICI-pretreated group will be included in the poster. Results: The recommended doses determined in phase 1b were LEN 20 mg daily + PEMBRO 200 mg once every 3 weeks (Taylor M et al. JCO. 2020). The study enrolled 145 pts (efficacy analysis, n=143; safety analysis, n=145). At data cutoff (August 18, 2020), the median follow-up time was 19.8 months. The ORRwk24 was 55.8% (95% CI 45.7–65.5) for ICI-pretreated pts (n=104), 72.7% (95% CI 49.8–89.3) for treatment-naïve pts (n=22), and 41.2% (95% CI 18.4–67.1) for previously treated ICI-naïve pts (n=17). The median OS for the previously treated ICI-naïve pts was 30.3 months and was not reached in the other groups. Additional efficacy analyses are shown in the table. Treatment-related adverse events occurred in 99.3% of pts; the most common were fatigue (58.6%), diarrhea (55.2%), and hypertension (40.0%). Most pts (69%) maintained the LEN starting dose or were reduced to LEN 14 mg daily (dose level −1). Conclusions: LEN + PEMBRO demonstrated promising antitumor activity with a manageable safety profile in pts with metastatic RCC, including pts who were ICI-pretreated. Clinical trial information: NCT02501096. [Table: see text]

New approaches to first-line treatment of advanced renal cell carcinoma.

The treatment of patients with renal cell carcinoma (RCC) is evolving rapidly, with promising new regimens being developed and approved for patients with advanced disease, particularly the combination of tyrosine kinase inhibitors with immune checkpoint inhibitors. Within the last 6 months, favorable first-line setting results for patients with clear cell RCC have been reported for the combination of cabozantinib plus nivolumab in the phase III CheckMate 9ER study, leading to its regulatory approval, and lenvatinib plus pembrolizumab in the phase III CLEAR study. Additional systemic first-line treatments for clear cell RCC include axitinib plus pembrolizumab, pazopanib, and sunitinib for favorable-risk patients and ipilimumab plus nivolumab, axitinib plus pembrolizumab, axitinib plus avelumab, and cabozantinib for intermediate- or poor-risk patients. In this review of novel approaches for first-line treatment of advanced RCC, we present an overview of current treatment strategies, the basis behind emerging treatment approaches, a summary of key results from the pivotal studies using tyrosine kinase inhibitor and immune checkpoint inhibitor combination therapy, novel treatments and strategies under development, and efforts for identifying biomarkers to guide treatment decisions.

Cost-effectiveness of first-line therapy for advanced renal cell carcinoma in the immunotherapy era.

e19392 Background: The treatment landscape for advanced renal cell carcinoma (RCC) has transformed in the past two years. Both Nivolumab plus Ipilimumab and Pembrolizumab plus Axitinib are approved regimens for first-line treatment of intermediate to poor-risk patients with advanced RCC. The choice between these immunotherapy-based combinations for first-line therapy is highly debated; no prior study has evaluated the cost-effectiveness of both combinations compared to Sunitinib. Methods: We used a decision analytic Markov model informed by the recent Checkmate-214 and Keynote-426 phase 3 randomized controlled clinical trials to evaluate costs and effectiveness of Nivolumab plus Ipilimumab, Pembrolizumab plus Axitinib, and Sunitinib in the first-line treatment of advanced RCC from a US health payer perspective. We used the model to extrapolate survival beyond the closure of the trials and examined the robustness of our findings with sensitivity analyses. Main outcomes were life expectancy, quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios, all discounted at 3% annually. Results: Nivolumab plus Ipilimumab increased life expectancy by 0.58 years at cost of approximately $190,000 per QALY gained compared to Sunitinib. Pembrolizumab plus Axitinib increased life expectancy by 0.39 years at a cost of approximately $861,000 per QALY gained compared to Nivolumab plus Ipilimumab. The results were not sensitive to reasonable changes in drug costs and quality of life estimates. Both combinations cost more than the traditional willingness-to-pay threshold (WTP) of $150,000 per QALY gained. A 20% price reduction is required for Nivolumab and Ipilimumab to be cost-effective and a 48% price reduction is required for Pembrolizumab plus Axitinib to be cost-effective. Conclusions: Both Nivolumab plus Ipilumumab and Pembrolizumab plus Axitinib provide increased longevity and reduced morbidity relative to Sunitinib. However, the prolonged duration of treatment and doublet-drug pricing results in high-costs. Price reductions are required for both of the immunotherapy-based combinations to be cost-effective. [Table: see text]

A Cost-Effectiveness Analysis: First-Line Avelumab Plus Axitinib Versus Sunitinib for Advanced Renal-Cell Carcinoma

BackgroundCompared with the standard of care with sunitinib, avelumab plus axitinib can increase progression-free survival in the first-line of advanced renal cell carcinoma (RCC), but the economic effect of the treatment is unknown. The purpose of the research was to evaluate the cost-effectiveness of the avelumab plus axitinib versus sunitinib in first-line treatment for advanced RCC from the US payer perspective.MethodsA Markov model was developed to evaluate the economic and health outcomes of avelumab plus axitinib vs sunitinib in the first-line setting for advanced RCC. The clinical data were obtained from the JAVELIN Renal 101 Clinical Trials. Deterministic and probabilistic sensitivity analyses were performed to assess uncertainty in the model. Health outcomes were measured in quality-adjusted life-years (QALYs).ResultsThe incremental cost-effectiveness ratio (ICER) of avelumab plus axitinib compared with sunitinib was $565,232 per QALY, the costs were $884,626 and $669,838, QALYs were 3.67 and 3.29, respectively. Sensitivity analysis demonstrated that differences in utilities in PFS and after progression were the most influential factors within the model. When avelumab was at 30% of the full price or axitinib was at 40% of the full price, avelumab and axitinib were approved to be cost-effective if the WTP threshold was $150,000 per QALY. The subgroup analysis showed the ICER of avelumab plus axitinib compared with sunitinib for the patients with PD-L1–positive tumors was $588,105.ConclusionAvelumab plus axitinib in the first-line treatment was not cost-effective in comparison with sunitinib when the threshold of willingness to pay (WTP) was $150,000 per QALY.

958P - Combination therapy with checkpoint inhibitors for first-line treatment of advanced renal cell carcinoma: A systematic review and meta-analysis of randomized controlled trials

BackgroundManagement of advanced renal cell carcinoma (RCC) is an area in dire need of therapeutic innovation. In recent years, combining immunotherapy with chemotherapy has shown synergistic anticancer activities and multiple randomized clinical trials (RCT) have combined checkpoint inhibitors with chemotherapy as first-line treatment of advanced RCC. We undertook a combined analysis of phase III trials to evaluate the efficacy of first-line checkpoint inhibitors combination therapy in patients with advanced RCC. MethodsWe systematically conducted a comprehensive literature search using PUBMED, MEDLINE, EMBASE databases and meeting abstracts from inception through March 2019. RCTs utilizing first-line checkpoint inhibitors combination therapy in patients with advanced RCC were incorporated. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q -statistic. Random effects model was applied. ResultsFour phase III RCTs (CheckMate 214, IMmotion 151, Javelin Renal 101 and Keynote-426) including 3758 patients with advanced RCC were eligible. The study arm used nivolumab+ ipilimumab, pembrolizumab+ axitinib, avelumab+ axitinib or atezolizumab+ bevacizumab while control arm utilized sunitinib. The randomization ratio was 1:1 in all studies. The I2 statistic for heterogeneity was 24%, suggesting some heterogeneity among RCTs. The pooled HR for PFS was statistically significant at 0.79 (95% CI: 0.67-0.94; P=0.008) and the pooled HR for OS was 0.70 (95% CI: 0.58- 0.85; P=0.0002). In PD-L1 positive/ combined positive score of≥1% cohort, the pooled HR for PFS was noted at 0.62 (95% CI: 0.53- 0.73; P<0.00001). ConclusionsOur meta-analysis demonstrated that upfront checkpoint inhibitors combination regimen significantly improved progression-free survival and overall survival compared to standard sunitinib in patients with advanced renal cell carcinoma, favoring combination regimen. Legal entity responsible for the studyKyaw Zin Thein. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Cost-Effectiveness Analysis of Sunitinib versus Interferon-Alfa for First-Line Treatment of Advanced and/or Metastatic Renal Cell Carcinoma in Singapore.

This study was conducted to evaluate the cost-effectiveness of sunitinib versus interferon-alfa for the treatment of advanced and/or metastatic renal cell carcinoma (RCC) in Singapore. A partitioned survival model with three health states (progression-free, progressive disease, and death) was developed from a healthcare payer perspective over a 10-year time horizon. Survival curves from the pivotal trial of sunitinib versus interferon-alfa were extrapolated beyond the trial period to estimate the underlying progression-free survival and overall survival parametric distributions. Health state utilities were derived from the literature and direct costs were sourced from local public healthcare institutions. The sunitinib dose in the model reflected local prescribing practices whereby a combination of 50 mg (28 percent) and 37.5 mg (72 percent) strengths are used. The base-case analysis comparing sunitinib versus interferon-alfa resulted in an incremental cost effectiveness ratio (ICER) of SGD191,061 (USD139,757) per quality-adjusted life-year gained. Sensitivity analysis demonstrated that the ICER was most sensitive to variations in the utility value assumed for the progression-free health state and the price of sunitinib. In the absence of any price reduction, sunitinib had an exceedingly high ICER and was not considered a cost-effective use of healthcare resources in Singapore's context for the first-line treatment of advanced RCC. The findings from our evaluation will be useful to inform local healthcare decision making and resource allocations for tyrosine kinase inhibitors when appraised alongside comparative clinical effectiveness data and payer affordability considerations.

Cost-effectiveness of nivolumab plus ipilimumab as first-line therapy in advanced renal-cell carcinoma

BackgroundNivolumab plus ipilimumab improves overall survival and is associated with less toxicity compared with sunitinib in the first-line setting of advanced renal-cell carcinoma (RCC). The current study aimed to assess the cost-effectiveness of nivolumab plus ipilimumab for first-line treatment of advanced RCC from the payer perspectives high- and middle-income regions.MethodsA decision-analytic model was constructed to evaluate the health and economic outcomes of first-line sunitinib and nivolumab plus ipilimumab treatment associated with advanced RCC. The clinical and utility data were obtained from published reports. The cost data were acquired for the payer perspectives of the United States (US), United Kingdom (UK), and China. Sensitivity analyses were performed to test the uncertainties of the results. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were used.ResultsNivolumab plus ipilimumab gained 0.70–0.76 QALYs compared with sunitinib. Our analysis determined the following ICERs for nivolumab plus ipilimumab over sunitinib in first-line advanced RCC treatment: US $ 85,506 /QALY; UK $ 126,499/QALY; and China $ 4682/QALY. Sensitivity analyses found the model outputs to be most affected for body weight and for the prices of nivolumab, sunitinib and ipilimumab.ConclusionsNivolumab plus ipilimumab as first-line treatment could gain more health benefits for advanced RCC in comparison with standard sunitinib, which is considered to be cost-effective in the US and China but not in the UK.

Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use.

Oral cabozantinib tablets (Cabometyx®) are an important option for the treatment of advanced renal cell carcinoma (RCC). Cabozantinib is an anti-angiogenic agent and potently inhibits multiple tyrosine kinases, including those implicated in the development of RCC. The previously approved indication of cabozantinib tablets (i.e. treatment of advanced RCC following prior VEGF-targeted therapy) has been extended to include the first-line treatment of advanced RCC in treatment-naïve adults with intermediate or poor risk (EU) and all patients with advanced RCC (USA). These label extensions are based on the results of a randomized, open-label phase 2 trial, in which adults with metastatic RCC of poor or intermediate risk received targeted first-line treatment with cabozantinib or standard-of-care sunitinib. Relative to sunitinib, cabozantinib significantly prolonged median progression-free survival (primary endpoint; investigator and independent assessments), and increased the objective response rate (investigator assessment). The tolerability profile of cabozantinib is comparable to those of other tyrosine kinase inhibitors, with adverse events being manageable with medical intervention, dosage reductions, treatment interruption and/or permanent discontinuation.

A phase 3 trial to compare efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab versus sunitinib alone in first-line treatment of patients with metastatic renal cell carcinoma.

TPS706 Background: Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor 1–3, fibroblast growth factor receptor 1–4, platelet-derived growth factor receptor alpha, and RET and KIT. Based on a phase 2 study (Motzer et al. Lancet Oncol. 2015), LEN was approved in combination with everolimus (EVE) for the treatment of metastatic renal cell carcinoma (RCC) following 1 prior VEGF-targeted therapy. A phase 1b/2 study of LEN in combination with pembrolizumab (PEM) in patients (pts) with RCC LEN is also underway. We report the design of a multicenter, open-label, phase 3 trial of LEN plus EVE or PEM vs sunitinib (SUN; a standard therapy for RCC) as first-line treatment for advanced RCC. Methods: Pts aged ≥ 18 years with confirmed advanced RCC diagnosis, ≥ 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Karnofsky Performance Status ≥ 70, controlled blood pressure, and adequate blood coagulation, renal, hepatic, and bone marrow function are eligible. Pts will be randomized 1:1:1 to receive LEN 18 mg/d + EVE 5 mg/d, LEN 20 mg/d + PEM 200 mg every 3 wks, or SUN 50 mg/d (on a schedule of 4 wks on treatment followed by 2 wks off) until disease progression, unacceptable toxicity, withdrawal of consent, or study end. The primary endpoint is to show superiority of LEN+EVE or LEN+PEM over single-agent SUN as first-line treatment for advanced RCC in improving progression-free survival (PFS). Secondary endpoints include comparison of objective response rate, overall survival, PFS on next-line therapy, health-related quality of life, and safety and tolerability in pts receiving LEN+EVE or LEN+PEM vs SUN. Exploratory endpoints include PFS in the LEN+PEM arm using immune-related RECIST, comparison of duration of response, disease control rate, and clinical benefit rate in pts treated with LEN+EVE or LEN+PEM vs SUN, and analysis of the relationship between blood biomarkers and outcome. No interim analysis is planned for efficacy or futility. Enrollment of 735 pts is planned to achieve 90% power at 2-sided α = 0.05 to detect a difference in ≥ 1 of the primary comparisons. Clinical trial information: NCT02811861.

A phase III trial to compare efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab vs sunitinib alone in first-line treatment of patients (Pts) with metastatic renal cell carcinoma (RCC).

TPS4595 Background: Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor 1–3, fibroblast growth factor receptor 1–4, platelet-derived growth factor receptor alpha, and RET and KIT. Based on a phase 2 study (Motzer et al. Lancet Oncol 2015), LEN was approved in combination with everolimus (EVE) for treatment of metastatic RCC following 1 prior VEGF-targeted therapy. A phase 1b/2 study of LEN in combination with pembrolizumab (PEM) in pts with RCC LEN is also underway. We report the design of a multicenter, open-label, phase 3 trial of LEN plus EVE or PEM vs sunitinib (SUN; a standard therapy for RCC) as first-line treatment for advanced RCC. Methods: Pts aged ≥ 18 years with confirmed advanced RCC diagnosis, ≥ 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Karnofsky Performance Status ≥ 70, controlled blood pressure, and adequate blood coagulation, renal, hepatic, and bone marrow function are eligible. Pts will be randomized 1:1:1 to receive LEN 18 mg/day + EVE 5 mg/day, LEN 20 mg/day + PEM 200 mg every 3 weeks, or SUN 50 mg/day (on a schedule of 4 weeks on treatment followed by 2 weeks off) until disease progression, unacceptable toxicity, withdrawal of consent, or study end. The primary endpoint is to show superiority of LEN+EVE or LEN+PEM over single-agent SUN as first-line treatment for advanced RCC in improving progression-free survival (PFS). Secondary endpoints include comparison of objective response rate, overall survival, PFS on next-line therapy, health-related quality of life, and safety and tolerability in pts receiving LEN+EVE or LEN+PEM vs SUN. Exploratory endpoints include PFS in the LEN+PEM arm using immune-related RECIST, comparison of duration of response, disease control rate, and clinical benefit rate in pts treated with LEN+EVE or LEN+PEM vs SUN, and analysis of the relationship between blood biomarkers and outcome. No interim analysis is planned for efficacy or futility. Enrollment of 735 pts is planned to achieve 90% power at 2-sided α = 0.05 to detect a difference in ≥ 1 of the primary comparisons. Clinical trial information: NCT02811861.

Impact of adverse events, treatment modifications, and dose intensity on survival among patients with advanced renal cell carcinoma treated with first-line sunitinib: a medical chart review across ten centers in five European countries.

Angiogenesis inhibitors have become standard of care for advanced and/or metastatic renal cell carcinoma (RCC), but data on the impact of adverse events (AEs) and treatment modifications associated with these agents are limited. Medical records were abstracted at 10 tertiary oncology centers in Europe for 291 patients ≥18 years old treated with sunitinib as first-line treatment for advanced RCC (no prior systemic treatment for advanced disease). Logistic regression models were estimated to compare dose intensity among patients who did and did not experience AEs during the landmark periods (18, 24, and 30 weeks). Cox proportional hazard models were used to explore the possible relationship of low-dose intensity (defined using thresholds of 0.7, 0.8, and 0.9) and treatment modifications during the landmark periods to survival. 64.4% to 67.9% of patients treated with sunitinib reported at least one AE of any grade, and approximately 10% of patients experienced at least one severe (grade 3 or 4) AE. Patients reporting severe AEs were statistically significantly more likely to have dose intensities below either 0.8 or 0.9. Dose intensity below 0.7 and dose discontinuation during all landmark periods were statistically significantly associated with shorter survival time. This study of advanced RCC patients treated with sunitinib in Europe found a significant relationship between AEs and dose intensity. It also found correlations between dose intensity and shorter survival, and between dose discontinuation and shorter survival. These results confirm the importance of tolerable treatment and maintaining dose intensity.

1921 PROGNOSTIC IMPACT OF C-REACTIVE PROTEIN KINETICS FOR ADVANCED RENAL CELL CARCINOMA TREATED WITH SUNITINIB

You have accessJournal of UrologyKidney Cancer: Advanced (II)1 Apr 20131921 PROGNOSTIC IMPACT OF C-REACTIVE PROTEIN KINETICS FOR ADVANCED RENAL CELL CARCINOMA TREATED WITH SUNITINIB Tetsuo Fujita, Masatsugu Iwamura, Takahiro Hirayama, Daisuke Ishii, Ken-ichi Tabata, Kazumasa Matsumoto, and Kazunari Yoshida Tetsuo FujitaTetsuo Fujita Kanagawa, Japan More articles by this author , Masatsugu IwamuraMasatsugu Iwamura Kanagawa, Japan More articles by this author , Takahiro HirayamaTakahiro Hirayama Kanagawa, Japan More articles by this author , Daisuke IshiiDaisuke Ishii Kanagawa, Japan More articles by this author , Ken-ichi TabataKen-ichi Tabata Kanagawa, Japan More articles by this author , Kazumasa MatsumotoKazumasa Matsumoto Kanagawa, Japan More articles by this author , and Kazunari YoshidaKazunari Yoshida Kanagawa, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2340AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Since the introduction of sunitinib for patients with advanced renal cell carcinoma (RCC), significant objective responses have been reported. It is now widely approved for the first-line treatment of advanced RCC. A prognostic marker is required for selecting patients who will benefit most from sunitinib. We have previously revealed that pretreatment normal C-reactive protein (CRP) predicts better oncological outcomes of sunitinib. However, CRP kinetics of sunitinib have never been described. In the cytokine era, CRP kinetics have an impact on survival in patients with metastatic RCC. As such, in the present study, we evaluate CRP kinetics in advanced RCC patients treated with sunitinib. METHODS Between December 2008 and July 2012, 52 consecutive patients with advanced RCC who were treated with sunitinib, were enrolled. Patients divided into 3 groups according to the pretreatment CRP level and CRP kinetics: (i) normal CRP cohort; defined as pretreatment CRP levels ≤ 0.30 mg/dL, (ii) normalized CRP cohort; defined as pretreatment CRP > 0.30 mg/dL and normalized CRP within 2 cycles of treatment, (iii) non-normalized CRP cohort; defined as pretreatment CRP > 0.30 mg/dL and not normalized CRP after the initiation of sunitinib. Disease control rates, non-parametiric estimates of progression-free survival time and overall survival time were evaluated. RESULTS The normal CRP cohort comprised 16 patients (30.8%), the normalized CRP cohort comprised 8 patients (15.4%), and the non-normalized CRP cohort comprised 28 patients (53.8%). Disease control rates of the normal, normalized, and non-normalized CRP cohorts were 93.8%, 75.0%, and 32.1%, respectively. The normal and normalized CRP cohorts showed statistically significant better disease control rates than the non-normalized CRP cohort (P = 0.0003). The normal CRP cohort showed significantly longer progression-free survival time than the non-normalized CRP cohort (median 19.0 months vs 5.0 months, P = 0.0023). Also, the normal CRP cohort showed significantly longer overall survival time than the non-normalized CRP cohort (median 30.0 months vs 9.0 months, P = 0.0012). CONCLUSIONS CRP revealed prognostic significance in advanced RCC patients treated with sunitinib. Pretreatment CRP level could be a useful prognostic marker for sunitinib effectiveness. And a decrease of CRP level during sunitinib treatment predicts better response. CRP kinetics is a prognostic indicator as well as pretreatment CRP level for patients with advanced RCC treated with sunitinib. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e788 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tetsuo Fujita Kanagawa, Japan More articles by this author Masatsugu Iwamura Kanagawa, Japan More articles by this author Takahiro Hirayama Kanagawa, Japan More articles by this author Daisuke Ishii Kanagawa, Japan More articles by this author Ken-ichi Tabata Kanagawa, Japan More articles by this author Kazumasa Matsumoto Kanagawa, Japan More articles by this author Kazunari Yoshida Kanagawa, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Temsirolimus in Renal Cell Carcinoma

Patients with metastatic renal cell carcinoma (RCC) generally show a poor prognosis; treatment approaches have not significantly improved patient survival. Temsirolimus inhibits the mammalian target of rapamycin kinase. Clinical studies have shown positive results when the drug is administered to patients with this disease. The clinical benefit of temsirolimus for poor-risk, advanced RCC patients was demonstrated in a Phase III study comparing temsirolimus with interferon alpha (IFN-α) or combined temsirolimus plus IFN-α as first-line treatment of advanced RCC, showed that treatment with temsirolimus alone significantly increased median overall survival in poor-risk, advanced RCC patients (10.9 vs 7.3 vs 8.4 months). This was the first Phase III trial to demonstrate an overall improvement in survival using an agent as “targeted therapy” for patients with advanced RCC. By November 2007, 200 patients with advanced RCC had been treated with temsirolimus before its approval by the European Medicines Agency (EMEA) within a compassionate use program. The single-center treatment experiences using temsirolimus in patients for compassionate use are described herein. The treatment was generally well tolerated; side effects (mucositis, diabetes, and peripheral edema) were within the range expected from the pivotal trials and manageable with supportive care. Further development strategies for temsirolimus in patients with RCC include its evaluation with bevacizumab and also as second-line therapy in patients who have failed first-line therapy with sunitinib.