Adjuvant Sunitinib Research Articles

Association between age and sex and mortality after adjuvant therapy for renal cancer.

In phase 3 trials of patients with resected high-risk renal cell carcinoma, adjuvant sunitinib has demonstrated no overall survival (OS) benefit, an uncertain disease-free survival (DFS) benefit, and increased toxicity versus placebo. To identify patients who may derive benefit or harm from adjuvant therapy, the authors assessed the effects of age and sex on treatment outcomes in the phase 3 Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Cancer (ASSURE) trial. The authors conducted a post hoc subgroup analysis of age and sex among patients in the ASSURE trial. Adjusted hazard ratios (HRs) for OS and DFS were evaluated with sunitinib or sorafenib versus placebo in 4 patient subgroups defined by sex and median age at the time of the study. Sunitinib treatment was associated with decreased OS (HR, 2.21; 95% confidence interval, 1.29-3.80) among women aged >56 years, but not in women aged ≤56 years or men of any age. Similar associations with age and sex were observed for DFS, but these were not statistically significant (women aged >56 years: HR, 1.41 [95% confidence interval, 0.94-2.10]). No such association was found for sorafenib. The interaction by age and sex on mortality was found to be statistically significant for sunitinib (P=.01), but not sorafenib (P=.10). Adjuvant sunitinib may increase mortality among older women with renal cell carcinoma. Given the recent approval of adjuvant sunitinib for patients with high-risk resected renal cell carcinoma, additional studies are needed to confirm these findings.

High-Risk Locoregional Renal Cell Cancer: S-TRAC Criteria for the Selection of Adjuvant Treatment Candidates

Introduction and objective: Clear-cell renal-cell carcinoma (RCCcc) is the genitourinary neoplasm with the highest mortality rate despite primary surgical treatment, which highlights the necessity for adjuvant treatment. To date, only the use of sunitinib in the S-TRAC study (Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy) has shown improvement of disease-free survival (DFS). The aim of the present study is to identify, using a single-center sample of patients with locally advanced RCC, potential candidates for adjuvant treatment by the application of the S-TRAC criteria.

High-Risk Locoregional Renal Cell Cancer: S-TRAC Criteria for the Selection of Adjuvant Treatment Candidates

Introduction and objective: Clear-cell renal-cell carcinoma (RCCcc) is the genitourinary neoplasm with the highest mortality rate despite primary surgical treatment, which highlights the necessity for adjuvant treatment. To date, only the use of sunitinib in the S-TRAC study (Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy) has shown improvement of disease-free survival (DFS). The aim of the present study is to identify, using a single-center sample of patients with locally advanced RCC, potential candidates for adjuvant treatment by the application of the S-TRAC criteria.

Adjuvant sunitinib in patients with high-risk renal cell carcinoma: A closer look.

Adjuvant sunitinib in patients with high-risk renal cell carcinoma: A closer look.

A systematic review and combined analysis of phase III trials to evaluate the safety of adjuvant sunitinib in patients with high risk renal cell carcinoma after nephrectomy.

214 Background: Sunitinib, an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, has been approved in adjuvant treatment of high risk renal cell carcinoma (RCC) after nephrectomy despite distinct results among studies, along with notable safety concerns. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of grade 3 and 4 adverse events in patients treated with adjuvant sunitinib. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through June 2018 were queried. Phase 3 RCTs which utilized adjuvant sunitinib in high risk RCC after nephrectomy were included. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: Two phase III RCTs with a total of 1866 patients were eligible. Studies utilized sunitinib versus placebo. The randomization ratio was 1:1 in both ASSURE and S-TRAC studies. The RR of high-grade adverse effects were as follows: hypertension, 4.26 (95% CI: 2.89 – 6.26, p < 0.001); fatigue, 5.40 (95% CI: 3.49 – 8.34; p < 0.001); rash/desquamation, 5.00 (95% CI: 1.59 – 15.68; p = 0.006); hand foot syndrome, 18.68 (95% CI: 5.98 – 58.28, p < 0.001); asthenia, 6.57 (95% CI: 1.005 – 43.04; p = 0.049); diarrhea, 18.08 (95% CI: 6.63 – 49.32; p < 0.001); dyspepsia, 12.68 (95% CI: 2.40 – 66.80, p = 0.003); stomatitis, 29.15 (95% CI: 5.73 – 148.18; p < 0.001); nausea, 19.63 (95% CI: 3.81 – 100.97; p < 0.001); and vomiting, 8.21 (95% CI: 2.21 – 30.51; p = 0.002). Conclusions: The rate of high-grade hypertension, fatigue, asthenia, dermatological toxicities, including hand foot syndrome, and gastrointestinal toxicities were extremely high in patients treated with adjuvant sunitinib, compared to placebo arm. Fatigue, hand foot syndrome and gastrointestinal toxicities significantly contribute to patients’ quality of life and providing good supportive care is warranted.

Discontinuation of adjuvant sunitinib due to adverse events in patients with high-risk renal cell carcinoma after nephrectomy: A combined analysis of phase III trials.

215 Background: Dysregulation in the vascular endothelial growth factor (VEGF) pathway has been implicated in the pathogenesis of renal cell carcinoma (RCC). Sunitinib is an oral VEGF receptor tyrosine kinase inhibitor and has been approved in the adjuvant treatment of high-risk RCC. However, there are significant adverse events, impacting patients’ quality of life, and leading to treatment discontinuation. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of high-grade toxicities and the rate of treatment discontinuation due to adverse events. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2018. Phase III RCTs which utilized adjuvant sunitinib in high risk RCC after nephrectomy and mentioned treatment interruption or discontinuation or dose reduction due to adverse events were included. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Fixed effects model was applied. Results: Two phase III RCTs with a total of 1866 patients were eligible. Studies utilized sunitinib versus placebo. The randomization ratio was 1:1 in both ASSURE and S-TRAC studies. The incidence of high-grade adverse events was 568 (60.5%) in sunitinib group versus 183 (19.6%) in placebo arm, with the relative risk of 3.10 (95% CI: 2.69 – 15.93, P < 0.001). The reduction in dose was reported in 541 (57.9%) in study arm versus 86 (9.2%) in placebo group. The pooled RR for dose reduction was statistically significant at 6.28 (95% CI: 5.10 – 7.74, P < 0.001). The treatment discontinuation rate was 27.9% higher with sunitinib than with placebo (RR - 4.14; 95% CI: 3.31 – 5.16, P < 0.001). Conclusions: Our meta-analysis demonstrated that the rate of dose reduction, treatment discontinuation and the risk of grade 3 and 4 adverse events were notably high in sunitinib group. Timely recognition and proper supportive care are entailed in minimizing those adverse events which may ultimately improve patients’ quality of life and overall compliance.

Pre- and post-operative anti-PD-L1 plus anti-angiogenic therapies in mouse breast or renal cancer models of micro- or macro-metastatic disease

BackgroundThere are phase 3 clinical trials underway evaluating anti-PD-L1 antibodies as adjuvant (postoperative) monotherapies for resectable renal cell carcinoma (RCC) and triple-negative breast cancer (TNBC); in combination with antiangiogenic VEGF/VEGFR2 inhibitors (e.g., bevacizumab and sunitinib) for metastatic RCC; and in combination with chemotherapeutics as neoadjuvant (preoperative) therapies for resectable TNBC.MethodsThis study investigated these and similar clinically relevant drug combinations in highly translational preclinical models of micro- and macro-metastatic disease that spontaneously develop after surgical resection of primary kidney or breast tumours derived from orthotopic implantation of murine cancer cell lines (RENCAluc or EMT-6/CDDP, respectively).ResultsIn the RENCAluc model, adjuvant sunitinib plus anti-PD-L1 improved overall survival compared to either drug alone, while the same combination was ineffective as early therapy for unresected primary tumours or late-stage therapy for advanced metastatic disease. In the EMT-6/CDDP model, anti-PD-L1 was highly effective as an adjuvant monotherapy, while its combination with paclitaxel chemotherapy (with or without anti-VEGF) was most effective as a neoadjuvant therapy.ConclusionsOur preclinical data suggest that anti-PD-L1 plus sunitinib may warrant further investigation as an adjuvant therapy for RCC, while anti-PD-L1 may be improved by combining with chemotherapy in the neoadjuvant but not the adjuvant setting of treating breast cancer.

Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial

BackgroundAdjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59–0.98; two-sided P=0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial. Patients and methodsPatients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1 : 1) to receive sunitinib (50mg/day) or placebo. Single dose reductions to 37.5mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients’ health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). ResultsPatients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ∼1month (median) after start of treatment and resolved within ∼3.5weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases. ConclusionsIn S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects. Clinical trial registrationClinicalTrials.gov, NCT00375674.

Is there a role for adjuvant therapy after surgery in "high risk for recurrence" kidney cancer? An update on current concepts.

Although surgical resection remains the standard of care for localized kidney cancers, a significant proportion of patients experience systemic recurrence after surgery and hence might benefit from effective adjuvant therapy. So far, several treatment options have been evaluated in adjuvant clinical trials, but only a few have provided promising results. Nevertheless, with the recent development of targeted therapy and immunomodulatory therapy, a series of clinical trials are in progress to evaluate the potential of those novel agents in the adjuvant setting. In this paper, we provide a narrative review of the progress in this field, and we summarize the results from recent adjuvant trials that have been completed. A literature search was conducted. The primary search strategy at the medline, Cochrane reviews, and http://ClinicalTrials.gov/databases included the keywords "adjuvant therapy," "renal cell carcinoma," and "targeted therapy or/and immunotherapy." Data from the s-trac study indicated that, in the "highest risk for recurrence" patient population, disease-free survival was increased with the use of adjuvant sunitinib compared with placebo. The assure trial showed no benefit for adjuvant sunitinib or sorafenib in the "intermediate- to high-risk" patient population. The ariser (adjuvant girentuximab) and protect (adjuvant pazopanib) trials indicated no survival benefit, but subgroup analyses in both trials recommended further investigation. The inconsistency in some of the current results can be attributed to a variety of factors pertaining to the lack of standardization across the trials. Nevertheless, patients in the "high risk of recurrence" category after surgery for their disease would benefit from a discussion about the potential benefits of adjuvant treatment and enrolment in ongoing adjuvant trials.

Developments in urologic oncology “OncoForum”: The best of 2017

ObjectiveTo put forth new findings of urologic oncology with an impact on clinical practice presented during 2017 in the main annual meetings. MethodsThis document reviews abstracts on prostate, kidney and bladder cancer presented at the congresses of 2016 (EAU, AUA, ASCO, ESMO and ASTRO) and publications with the highest impact in this period valued with the highest scores by the OncoForum committee. ResultsAmong patients at high risk of recurrent renal cell carcinoma after nephrectomy, adjuvant sunitinib compared to placebo showed a benefit in patients at higher risk of recurrence. In cisplatin-ineligible advanced urothelial cancer, pembrolizumab elicits clinically meaningful, durable responses. Among patients with localized prostate cancer, treatment for disease progression was less frequent (absolute difference, 26.2 percentage points) and adverse events were more frequent with surgery than with observation. Among patients with locally advanced or merastatic prostate cancer, androgen-deprivation therapy plus abiraterone and prednisolone resulted in fewer deaths and fewer treatment-failure events (P<0.001). Among patients with metastatic castration-resistant prostate cancer previously treated with abiraterone acetate, enzalutamide median radiographic progression-free survival was 8.1 months and enzalutamide median overall survival was not reached. ConclusionsAmong patients at high risk of recurrent renal cell carcinoma after nephrectomy, adjuvant sunitinib showed a benefit across subgroups including patients at higher risk of recurrence. Among patients with localized prostate cancer, surgery was not associated with significantly lower all-cause or prostate-cancer mortality than observation. Among patients with locally advanced or merastatic prostate cancer, androgen-deprivation therapy plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than androgen-deprivation therapy alone. In patients with metastatic castration-resistant prostate cancer previously treated with abiraterone enzalutamide remained active.

Perspectives on Adjuvant Therapy in Renal Cell Carcinoma

Perspectives on Adjuvant Therapy in Renal Cell Carcinoma

Avances en uro-oncología «OncoForum»: lo mejor del 2017

ObjectiveTo put forth new findings of urologic oncology with impact on clinical practice presented during 2017 in the main annual meetings. MethodsThis document reviews abstracts on prostate, kidney and bladder cancer presented at the congresses of 2016 (EAU, AUA, ASCO, ESMO and ASTRO) and publications with the highest impact in this period valued with the highest scores by the OncoForum committee. ResultsAmong patients at high risk of recurrent renal cell carcinoma after nephrectomy, adjuvant sunitinib compared to placebo showed a benefit in patients at higher risk of recurrence. In cisplatin-ineligible advanced urothelial cancer, pembrolizumab elicits clinically meaningful, durable responses. Among patients with localized prostate cancer, treatment for disease progression was less frequent (absolute difference, 26.2 percentage pontis) and adverse events was more frequent with surgery than with observation. Among patients with locally advanced or merastatic prostate cancer, androgen-deprivation therapy plus abiraterone and prednisolone resulted in fewer deaths and fewer treatment-failure events (P<.001). Among patients with metastatic castration-resistant prostate cancer previously treated with abiraterone acetate, enzalutamide median radiographic progression free survival was 8,1 months and enzalutamide median overall survival was not reached. ConclusionsAmong patients at high risk of recurrent renal cell carcinoma after nephrectomy, adjuvant sunitinib showed a benefit across subgroups including patients at higher risk of recurrence. Among patients with localized prostate cancer, surgery was not associated with significantly lower all-cause or porstate-cancer mortality than observation. Among patients with locally advanced or merastatic prostate cancer, androgen-deprivation therapy plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than androgen-deprivation therapy alone. In patients with metastatic castration-resistant prostate cancer previously treated with abiraterone enzalutamide remained active.

An Attempt to Quantitate "Value" In Medical Oncologic Therapy.

ObjectiveWe wanted to examine the incremental cost-effective ratio (ICER) for a variety of Food and Drug Administration (FDA) approved oncology drugs in the adjuvant or curative setting to determine the value provided.DesignWe examined the annualized incremental drug costs of a variety of FDA approved chemotherapeutic drugs used in an adjuvant or curative setting based on National Comprehensive Cancer Network (NCCN) category 1 practice guidelines for melanoma, Her2/neu over-expressive breast cancer, renal cell carcinoma, stage IIIA non-small cell lung cancer, myeloma, B cell lymphoma, and Hodgkin lymphoma. The studies we examined were randomized clinical trials on which the NCCN guidelines are based; we solely examined the incremental cost-effectiveness of the trial drug as we assumed that the costs of the health care provided were equivalent between the two treatment arms. We used a formula to determine the incremental cost-effectiveness ratio (ICER). The ICER compares a new intervention (C new) with its alternate (C alt) divided by the quality-adjusted life-years (QALY) that results from the new intervention (QALY new) versus the alternate (QALY alt) and is expressed as ICER = (C new-C alt)/(QALY new-QALY alt). The QALY’s were derived from what was reported in the study and based on the incremental disease-free survival.ResultsDrugs such as rituximab provide high value in the curative therapy for lymphoma. Drugs such as adjuvant dabrafenib and trametinib provide intermediate value in the treatment of melanoma, and similarly with maintenance lenalidomide in myeloma and adjuvant trastuzumab in breast cancer. Oncologic drugs that provide low value include adjuvant ipilimumab in melanoma, adjuvant sunitinib in renal cell carcinoma, adjuvant neratinib in breast cancer, adjuvant durvalumab in lung cancer, and brentuximab in the curative therapy for Hodgkin’s lymphoma.ConclusionThe ICER needs to be evaluated for newly approved FDA oncology chemotherapeutic drugs before incorporating them into routine clinical practice.

Updates to the Management of Kidney Cancer.

Several updates were made to the 2018 NCCN Guidelines for Kidney Cancer. Adjuvant sunitinib is the first adjuvant therapy to be endorsed by the panel for patients with stage II and III clear cell histology renal cell carcinoma (RCC; category 2B). A promising new treatment-ipilimumab plus nivolumab for patients at intermediate and poor risk in the frontline setting-was added to the guidelines as well. Cabozantinib was added as a first-line option for poor- and intermediate-risk patients with advanced RCC.

Highlights of This Issue

Preclinical experiments demonstrate that interleukin-15 (IL-15) can control homeostasis and stimulate natural killer (NK) and antigen-specific CD8+ T cell activity without causing activation induced cell death or promoting T regulatory (Treg) cell function. Miller and colleagues conducted the first-in-human outpatient phase I dose escalation of subcutaneous (SC) rhIL-15 in refractory solid tumor cancer patients. SC rhIL-15 treatment was well tolerated and resulted in substantial increases in circulating NK and CD8+ T cells. These results will allow the export of IL-15 immunotherapy to an outpatient setting and testing of combinatorial strategies to improve cancer treatment.Treatment of cancer by targeting VEGF-A with bevacizumab has been extensively validated in the clinic; however, not all tumors respond to VEGF-A blockade. Angiopoietin-2 (Ang-2) and VEGF-A have complementary roles in regulating tumor angiogenesis and metastasis, suggesting that dual pathway inhibition is necessary to improve treatment outcomes. Vanucizumab is an investigational, first-in-class, bi-specific IgG1-like monoclonal antibody that simultaneously blocks VEGF-A and Ang-2 from interacting with their receptors. Hidalgo and colleagues conducted a first-in-human study that demonstrated an acceptable safety and tolerability profile for vanucizumab in patients with advanced solid tumors. Vanucizumab also demonstrated consistent pharmacokinetic and pharmacodynamic effects, and showed encouraging signs of antitumor activity that support further evaluation of vanucizumab in clinical trials.Adjuvant sunitinib prolonged disease-free survival over placebo in patients with locoregional renal cell carcinoma at high risk of recurrence postnephrectomy in the randomized phase III STRAC trial. In a prospectively designed exploratory analysis of tissue samples from a subset of patients in this trial, George and colleagues identify predictive biomarkers that could facilitate future patient selection for adjuvant sunitinib and mechanisms of interaction that might explain the durable treatment effect, potentially leading to future combination approaches. Tumor tissue expression levels of CD4, CD8, CD68, and PD-L1 were compared with efficacy outcomes. The observed association between higher CD8+ T-cell density in tumor tissue with longer disease-free survival with sunitinib, but not placebo, suggested predictive potential of CD8+ T-cell density, which warrants further independent cohort validation studies. The prognostic value of PD-L1 expression in primary tumors in this setting also should be further explored.The thymocyte differentiation antigen-1 (Thy1) is differentially expressed on the neovasculature of human PDAC compared to chronic pancreatitis and normal pancreas. To engineer a human Thy1-binding single-chain-antibody-ligand (Thy1-scFv) conjugated to microbubbles (MBThy1-scFv), Abou-Elkacem and colleagues designed and validated a clinically translatable Thy1-scFv for contrast-enhanced ultrasound molecular imaging of PDAC. The MBThy1-scFv was highly specific to murine/human Thy1, and in vivo ultrasound molecular imaging of PDAC-bearing mice demonstrated specific binding to Thy1. Ongoing translational studies are targeted at developing clinical-grade MBThy1-scFv which may improve visualization of PDAC and enable diagnosing at earlier disease state to ultimately improve survival of PDAC patients.

Adjuvant Sunitinib for Renal Cell Carcinoma: Still at the Beginning of the Road

Adjuvant Sunitinib for Renal Cell Carcinoma: Still at the Beginning of the Road

The merit of tyrosine kinase inhibitors in the adjuvant setting of high-risk renal cell carcinoma: a meta-analysis.

As no meta-analyses have evaluated tyrosine kinase inhibitors in the adjuvant setting of high-risk renal cell carcinoma (RCC), the aim was to evaluate the benefit of sunitinib and pazopanib in the adjuvant setting. This meta-analysis included all Phase III randomized controlled trials evaluating adjuvant sunitinib and pazopanib in high-risk RCC. Primary outcome was the comparison of disease-free survival (DFS) between tyrosine kinase inhibitors and placebo. There was a tendency for significant overall effect of both sunitinib and pazopanib on DFS (hazard ratio: 0.85; 95% confidence interval: 0.72-1.01; p = 0.06). There was no significant difference between the effect of sunitinib and pazopanib on DFS (p = 0.51; I2 = 0%). Pazopanib and sunitinib could prolong DFS in the adjuvant treatment of high-risk RCC and seem equally effective in this setting.

The US Food and Drug Administration’s Approval of Adjuvant Sunitinib for Renal Cell Cancer

The US Food and Drug Administration’s Approval of Adjuvant Sunitinib for Renal Cell Cancer

Kidney Cancer Research Network of Canada consensus statement on the role of adjuvant therapy after nephrectomy for high-risk, non-metastatic renal cell carcinoma: A comprehensive analysis of the literature and meta-analysis of randomized controlled trials.

The Kidney Cancer Research Network of Canada (KCRNC) collaborated to prepare this consensus statement about the use of target agents as adjuvant therapy in patients with non-metastatic renal cell carcinoma (nmRCC) after nephrectomy. We reviewed the published data and performed a meta-analysis of studies that focused on vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). A systematic literature search identified seven trials on adjuvant target therapy in nmRCC. Three trials, the ASSURE, S-TRAC, and PROTECT, focused on VEGFR TKIs and represented the focus of the study, including a meta-analysis combining their data on disease-free survival (DFS) and overall survival (OS). The ASSURE trial showed no DFS or OS benefit of TKIs over placebo after one year of adjuvant sorafenib or sunitinib. In contrast, the S-TRAC trial showed improved DFS after one year of adjuvant sunitinib using central review process, but not using investigator review process. No OS benefit was recorded in either study. Recently, the PROTECT trial also showed no DFS or OS benefit when one year of adjuvant pazopanib was compared to placebo. Meta-analyses of the pooled DFS and OS estimates from all three trials resulted in DFS and OS hazard ratios of 0.87 (95% confidence interval [CI] 0.73-1.04) and 1.04 (95% CI 0.89-1.22), respectively. Data from three available clinical trials of adjuvant VEGFR TKIs vs. placebo do not currently support the use of adjuvant TKI therapy as standard of care after nephrectomy for nmRCC. At this time, adjuvant TKI-based adjuvant therapy is not recommended for routine use after nephrectomy for high-risk nmRCC, but highly motivated patients may benefit from a discussion with their oncologist regarding the risks and benefits of adjuvant TKI.

Association of age and sex with mortality following adjuvant therapy for renal cell cancer (RCC): Subgroup analysis of the ASSURE (E2805) trial.

575 Background: The benefit of vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) as adjuvant therapy for RCC remains a subject of controversy. Given the uncertain risk-benefit ratio, identifying subgroups expected to derive benefit or harm from therapy could lead to a more precise approach to therapy. Because of known sex-differences in the pharmacokinetics and tissue distribution of VEGF-TKIs, we assessed the interaction of age and sex on treatment outcomes among patients in the phase III ASSURE trial (Adjuvant Sorafenib or Sunitinib for Unfavorable RCC). Methods: ASSURE included 1,943 patients with ≥ pT1b resected RCC. There was no OS or DFS benefit with adjuvant sunitinib or sorafenib relative to placebo. In this post-hoc subgroup analysis of age and sex based on the median age of 56 years, Cox regression computed hazard ratios (HR) and 95% confidence intervals (CIs) for OS and DFS with sunitinib or sorafenib compared to placebo across age- and sex-specific strata (males ≤ 56 years [n = 689], males &gt; 56 years [n = 620], females ≤ 56 years [n = 317], and females &gt; 56 years [n = 317]). Models were adjusted for race, histology, and UISS risk group. A 3-way interaction term was calculated for sex, age, and treatment. Results: Treatment with sunitinib was associated with increased mortality among women &gt; 56 years (sunitinib vs placebo [HR OS 2.38; 95% CI, 1.39-4.07]), but not in women ≤ 56 years or in men of any age. Similarly, among women &gt; 56 years, the risk of disease recurrence was increased with sunitinib relative to placebo (HR DFS 1.53; 95% CI, 1.03-2.28). There were no statistically significant differences in OS or DFS associated with sorafenib (women &gt; 56 years: HR OS 1.50, 95% CI, 0.83-2.71; HR DFS 1.23, 95% CI, 0.81-1.89). The 3-way interaction between age, sex, and sunitinib treatment on mortality was statistically significant (p = 0.0166). Conclusions: Adjuvant sunitinib after nephrectomy was associated with increased mortality among older women, which may be explained by increased risk of RCC recurrence. These findings, if validated, highlight the importance of considering sex and age on VEGF-TKI treatment outcomes, future study designs, and RCC tumor biology. Clinical trial information: NCT00326898.