Cytoreductive Nephrectomy in Patients with Synchronous Metastases from Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

Background

The benefit of cytoreductive nephrectomy (CN) for overall survival (OS) is unclear in patients with synchronous metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.

Objective

To determine OS benefit of CN compared with no CN in mRCC patients treated with targeted therapies.

Design, setting, and participants

Retrospective data from patients with synchronous mRCC (n = 1658) from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were used to compare 982 mRCC patients who had a CN with 676 mRCC patients who did not.

Outcome measurements and statistical analysis

OS was compared and hazard ratios (HRs) adjusted for IMDC poor prognostic criteria.

Results and limitations

Patients who had CN had better IMDC prognostic profiles versus those without (favorable, intermediate, or poor in 9%, 63%, and 28% vs 1%, 45%, and 54%, respectively). The median OS of patients with CN versus without CN was 20.6 versus 9.5 mo (p < 0.0001). When adjusted for IMDC criteria to correct for imbalances, the HR of death was 0.60 (95% confidence interval, 0.52–0.69; p < 0.0001). Patients estimated to survive <12 mo may receive marginal benefit from CN. Patients who have four or more of the IMDC prognostic criteria did not benefit from CN. Data were collected retrospectively.

Conclusions

CN is beneficial in synchronous mRCC patients treated with targeted therapy, even after adjusting for prognostic factors. Patients with estimated survival times <12 mo or four or more IMDC prognostic factors may not benefit from CN. This information may aid in patient selection as we await results from randomized controlled trials.

Patient summary

We looked at the survival outcomes of metastatic renal cell carcinoma patients who did or did not have the primary tumor removed. We found that most patients benefited from tumor removal, except for those with four or more IMDC risk factors.     

Current and Future Treatment Options for Metastatic Renal Cell Carcinoma

ContextMetastatic renal cell carcinoma (mRCC) is associated with poor survival, and until recently, treatment options have been very limited. However, the advent of targeted therapies has radically improved the outlook for patients with mRCC.ObjectiveThis review describes current treatment options for mRCC and summarizes the data on efficacy and safety of approved and newly emerging targeted therapies.Evidence acquisitionMedical literature was retrieved from PubMed during January 2009. Additional relevant articles were included from the bibliographies of retrieved literature.Evidence synthesisThere continues to be a role for surgery and immunotherapy in mRCC, but this role is limited to specific patient subgroups. Several pivotal, phase 3 trials have established the efficacy and tolerability of agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways in various clinical settings. The benefit of everolimus after failure of VEGF-targeted therapy in the phase 3 RECORD-1 trial has demonstrated the value of sequential treatment for patients with mRCC. Other sequential regimens as well as the combination of targeted agents with each other or with immunotherapy are all promising approaches warranting further investigation. There may also be a potential role for targeted agents in both the neoadjuvant and adjuvant settings.ConclusionsThe development of targeted therapies for mRCC has substantially improved the treatment options for patients. The results of further studies that will enable the optimal integration of targeted agents into treatment strategies for mRCC are awaited with interest.     

The Impact of Low Serum Sodium on Treatment Outcome of Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Cancer Database Consortium

BackgroundHyponatremia has been associated with poor survival in many solid tumors and more recently found to be of prognostic and predictive value in metastatic renal cell cancer (mRCC) patients treated with immunotherapy.ObjectiveTo investigate the influence of baseline hyponatremia in mRCC patients treated with targeted therapy in the International Metastatic Renal Cell Carcinoma Database Consortium.Design, setting, and participantsData on 1661 patients treated with first-line vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) targeted therapy for mRCC were available from 18 cancer centers to study the impact of hyponatremia (serum sodium level <135 mmol/l) on clinical outcomes.Outcome measurements and statistical analysisThe primary objective was overall survival (OS) and secondary end points included time to treatment failure (TTF) and the disease control rate (DCR). The chi-square test was used to compare the DCR in patients with and without hyponatremia. OS and TTF were estimated with the Kaplan-Meier method and differences between groups were examined by the log-rank test. Multivariable logistic regression (for DCR) and Cox regression (for OS and TTF) were undertaken adjusted for prognostic risk factors.Results and limitationsMedian OS after treatment initiation was 18.5 mo (95% confidence interval [CI], 17.5–19.8 mo), with 552 (33.2%) of patients remaining alive on a median follow-up of 22.1 mo. Median baseline serum sodium was 138 mmol/l (range: 122–159 mmol/l), and hyponatremia was found in 14.6% of patients. On univariate analysis, hyponatremia was associated with shorter OS (7.0 vs 20.9 mo), shorter TTF (2.9 vs 7.4 mo), and lower DCR rate (54.9% vs 78.8%) (p < 0.0001 for all comparisons). In multivariate analysis, these effects remain significant (hazard ratios: 1.51 [95% CI, 1.26–1.80] for OS, and 1.57 [95% CI, 1.34–1.83] for TTF; odds ratio: 0.50 [95% CI, 34–0.72] for DCR; adjusted p < 0.001). Results were similar if sodium was analyzed as a continuous variable (adjusted p < 0.0001 for OS, TTF, and DCR).ConclusionsThis is the largest multi-institutional report to show that hyponatremia is independently associated with a worse outcome in mRCC patients treated with VEGF- and mTOR-targeted agents.     

Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma

Context

The role of cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) in the targeted therapy (TT) era is controversial.

A multicenter study assessing survival in patients with metastatic renal cell carcinoma receiving immune checkpoint inhibitor therapy with and without cytoreductive nephrectomy

BackgroundCytoreductive nephrectomy (CN) for the treatment of metastatic renal cell carcinoma (mRCC) was called into question following the publication of the CARMENA trial. While previous retrospective studies have supported CN alongside targeted therapies, there is minimal research establishing its role in conjunction with immune checkpoint inhibitor (ICI) therapy.ObjectiveTo evaluate the association between CN and oncological outcomes in patients with mRCC treated with immunotherapy.Materials and methodsA multicenter retrospective cohort study of patients diagnosed with mRCC between 2000 and 2020 who were treated at the Seattle Cancer Care Alliance and The Ohio State University and who were treated with ICI systemic therapy (ST) at any point in their disease course. Overall survival (OS) was estimated using Kaplan Meier analyses. Multivariable Cox proportional hazards models evaluated associations with mortality.ResultsThe study cohort consisted of 367 patients (CN+ST n = 232, ST alone n = 135). Among patients undergoing CN, 30 were deferred. Median survivor follow-up was 28.4 months. ICI therapy was first-line in 28.1%, second-line in 17.4%, and third or subsequent line (3L+) in 54.5% of patients. Overall, patients who underwent CN+ST had longer median OS (56.3 months IQR 50.2–79.8) compared to the ST alone group (19.1 months IQR 12.8–23.8). Multivariable analyses demonstrated a 67% reduction in risk of all-cause mortality in patients who received CN+ST vs. ST alone (P < 0.0001). Similar results were noted when first-line ICI therapy recipients were examined as a subgroup. Upfront and deferred CN did not demonstrate significant differences in OS.ConclusionsCN was independently associated with longer OS in patients with mRCC treated with ICI in any line of therapy. Our data support consideration of CN in well selected patients with mRCC undergoing treatment with ICI.     

Improved survival after cytoreductive nephrectomy for metastatic renal cell carcinoma in the contemporary immunotherapy era: An analysis of the National Cancer Database

ObjectivesDespite immune checkpoint inhibitor (ICI) approval for metastatic renal cell carcinoma (mRCC) in 2015, cytoreductive nephrectomy (CN) is guided by extrapolation from earlier classes of therapy. We evaluated survival outcomes, timing, and safety of combining CN with modern immunotherapy (IO) for mRCC.MethodsFrom 96,329 renal cancer cases reported to the NCDB between 2015 and 2016, we analyzed 391 surgical candidates diagnosed with clear cell mRCC treated with IO ± CN and no other systemic therapies. Primary outcome was overall survival (OS) stratified by the performance of CN (CN + IO vs. IO alone). Secondary outcomes included OS stratified by the timing of CN, pathologic findings, and perioperative outcomes.ResultsOf 391 patients, 221 (56.5%) received CN + IO and 170 (43.5%) received IO only. Across a median follow-up of 14.7 months, patients who underwent CN + IO had superior OS (median NR vs. 11.6 months; hazard ratio 0.23, P < 0.001), which was upheld on multivariable analyses. IO before CN resulted in lower pT stage, grade, tumor size, and lymphovascular invasion rates compared to upfront CN. Two of 20 patients (10%) undergoing CN post-IO achieved complete pathologic response in the primary tumor (pT0). There were no positive surgical margins, 30-day readmissions, or prolonged length of stay in patients undergoing delayed CN.ConclusionUsing a large, national, registry-based cohort, we provide the first report of survival outcomes in mRCC patients treated with CN combined with modern IO. Our findings support an oncologic role for CN in the ICI era and provide preliminary evidence regarding the timing and safety of CN relative to IO administration.     

The Role of Cytokine Therapy in Metastatic Renal Cell Cancer

ObjectivesTreatment of metastatic renal cell cancer (mRCC) is rapidly evolving since evidence concerning efficacy of novel molecular targeted drugs recently became available. This paper provides a critical overview of the current and future role of cytokine-based immunotherapy in mRCC in light of these new developments.MethodsPublished data from phase 3 studies and meta-analyses were analyzed by means of a systematic literature search in PubMed and Medline databases.ResultsRandomized trials using interferon-α (IFN-α), interleukin-2 (IL-2), and combinations have produced overall response rates of 4–31%. For IFN-α, a modest but significant survival advantage of 2.5 mo over hormonal therapy has been demonstrated. No significant survival advantage was shown for IL-2. High-dose IL-2 may induce complete and durable regression of mRCC in up to 5% of patients, but is characterized by high toxicity. Placebo-controlled prospective studies with these cytokines have not been published. Results from cytokine combination trials are difficult to compare because of differences in administration, dosing, and schedules. No internationally recognized standard immunotherapy treatment protocol could be defined for mRCC. Tyrosine kinase inhibitors achieve objective response or disease stabilization in a higher proportion of patients, but neither cure nor significant survival advantage has been shown for these agents. Combined and sequential treatments with cytokines and targeted agents are being investigated.ConclusionsFor selected patients, first-line cytokine therapy may still be an option in the repertoire of therapies for mRCC. A better knowledge of molecular markers could allow rational use of different therapies in individual patients in the future.     

Metastatic Renal Cell Carcinoma: Pathogenesis and the Current Medical Landscape

ContextRenal cell carcinoma (RCC) represents a worldwide epidemiologic burden. Patients with metastatic disease usually have poor prognosis, and traditional treatments are often ineffective.ObjectiveThis review describes the epidemiology and pathogenesis of metastatic RCC (mRCC) and highlights the unmet clinical need for effective, targeted treatments.Evidence acquisitionMedical literature was retrieved from PubMed during January 2009. Additional relevant articles were included from the bibliographies of retrieved literature.Evidence synthesisThere were approximately 200 000 new kidney cancer cases worldwide in 2002, and the disease's incidence is increasing in the United States and parts of Europe. The occurrence of RCC can be either sporadic or familial, and risk factors include smoking, obesity, and hypertension. RCC can be asymptomatic, and 25–30% of patients will present with metastatic disease at the time of diagnosis. Patients with mRCC usually have a poor prognosis, and estimates for their 5-yr survival range between 0% and 20%. Traditional therapies—namely, cytokines or chemotherapy—have limited efficacy in the majority of patients. Recently, the emergence of novel targeted therapies has provided new treatment options with increased efficacy. Clinical trials with these agents have highlighted a need to accurately assess activity and efficacy end points such as progression-free survival, which may be a useful surrogate for overall survival.ConclusionsDespite substantial progress in our understanding and treatment of mRCC in recent years, its incidence is increasing, and the disease is still considered incurable. The increasing accuracy of diagnosis and prognosis and the development of novel targeted agents are vital for the effective management of mRCC.     

Molecular Pathways in Metastatic Renal Cell Carcinoma: The Evolving Role of Mammalian Target of Rapamycin Inhibitors

ContextMetastatic renal cell carcinoma (mRCC) is particularly resistant to conventional treatments. Improved understanding of the molecular pathways involved in mRCC has led to the development of novel targeted therapies for this disease.ObjectiveThis review describes key molecular pathways that have emerged as therapeutic targets for mRCC. Particular emphasis is placed on the mammalian target of rapamycin (mTOR) pathway and the newer class of targeted agents (ie, mTOR inhibitors).Evidence acquisitionMedical literature was retrieved from PubMed during January 2009. Additional relevant articles were included from the bibliographies of retrieved literature.Evidence synthesisThe von Hippel-Lindau (VHL) tumour suppressor gene was discovered in 1993 and has a vital role in renal cell carcinoma (RCC) pathogenesis. VHL mutations lead to accumulation of hypoxia-inducible factors (HIFs) that stimulate overexpression of the proangiogenic vascular endothelial growth factor (VEGF). The mTOR pathway was subsequently identified, which regulates cell growth, proliferation, and angiogenesis, and also has a pivotal role in RCC. An increase in HIF expression is a product of the mTOR pathway. Therefore, agents that suppress the mTOR pathway have become the focus of much research. Such mTOR inhibitors as everolimus and temsirolimus have shown robust clinical efficacy in treating mRCC. For example, everolimus has proved effective in patients whose disease has progressed after treatment with VEGF-targeted therapy.ConclusionsTargeted agents against components of the mTOR pathway are in clinical use and have improved outcomes for patients with advanced disease and poor prognosis or with advanced disease that has become refractory to sunitinib or sorafenib.     

Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Nivolumab plus Cabozantinib Joins Immune Checkpoint Inhibition Combination Therapies for Treatment-naïve Metastatic Clear-Cell Renal Cell Carcinoma

Longer follow-up and new trial data from phase 3 randomised controlled trials investigating immune checkpoint blockade (PD-1 or its ligand PD-L1) in advanced clear-cell renal cell carcinoma (RCC) have recently become available. The CheckMate 9ER trial demonstrated an improved progression-free survival (PFS) and overall survival (OS) benefit for the combination of cabozantinib plus nivolumab. A Keynote-426 update demonstrated an ongoing OS benefit for pembrolizumab plus axitinib in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups, while an update of CheckMate 214 confirmed the long-term benefit of ipilimumab plus nivolumab in IMDC intermediate and poor risk patients. The RCC Guidelines Panel continues to recommend these tyrosine kinase inhibitors + immunotherapy (IO) combination across IMDC risk groups in advanced first-line RCC and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate and poor risk.Patient summaryNew data from trials of immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit with the combination of cabozantinib plus nivolumab and pembrolizumab plus axitinib and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.     

Treatment Algorithms in Metastatic Renal Cell Carcinoma,Including the Potential Role of the Novel Oral Mammalian Target of Rapamycin Inhibitor Everolimus

ContextFew treatment options were available for metastatic renal cell carcinoma (mRCC) until the development of novel targeted agents directed against angiogenesis and tumour growth.ObjectiveThis review discusses current targeted therapies for mRCC and outlines the position of everolimus, a novel, orally administered inhibitor of the mammalian target of rapamycin (mTOR), in current treatment algorithms.Evidence acquisitionMedical literature was retrieved from PubMed during January 2009. Additional relevant articles were included from the bibliographies of retrieved literature.Evidence synthesisTargeted treatment for mRCC can be categorised for the following patient groups: previously untreated patients, those refractory to immunotherapy or chemotherapy, and those refractory to vascular endothelial growth factor (VEGF)–targeted therapy. Sunitinib and bevacizumab (combined with interferon alfa) are generally considered first-line treatment options in patients with favourable or intermediate prognosis. Temsirolimus is considered a first-line treatment option for poor-risk patients. Either sorafenib or sunitinib may be valid second-line treatments for patients who have failed prior cytokine-based therapies. For patients refractory to treatment with VEGF-targeted therapy, one recommendation is to switch to an agent with a different mechanism of action or molecular target, for example, an mTOR inhibitor. Everolimus (RAD001) has shown promising efficacy in the first phase 3 clinical trial in patients with mRCC with favourable, intermediate, and poor risk whose disease had progressed on VEGF-targeted therapy.ConclusionsIncreasing clinical evidence is clarifying appropriate first- and second-line treatment with targeted agents for patients with mRCC. Based on good results of published phase 3 clinical data, the potential use of everolimus in the second-line setting has been recognised in recent (2008 and 2009) guidelines, including those of the European Society of Medical Oncology, the European Association of Urology, the European Organisation for Research and Treatment of Cancer Genitourinary Group, the Spanish Oncology Genitourinary Group, the French Urology Association, the UK consensus guidelines, the National Comprehensive Cancer Network (United States), and Cancer Care Ontario (Canada).     

Sunitinib in Advanced Renal Cell Carcinoma: Clinical Evidence

ContextThe development of targeted agents has improved the outlook for patients with metastatic renal cell carcinoma (mRCC). Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activities. In mRCC, sunitinib has demonstrated efficacy for the treatment of cytokine-refractory and previously untreated mRCC.ObjectiveThis article reviews the available efficacy data from sunitinib clinical studies, including data that led to the approval of sunitinib for mRCC.Evidence acquisitionThe efficacy data from sunitinib phase 2 and 3 trials as well as the expanded-access study were examined.Evidence synthesisIn a pivotal phase 3 trial in treatment-naïve mRCC patients, sunitinib was found to provide significantly superior efficacy compared with interferon-α (IFN-α; assessed as progression-free survival [PFS] and objective response). The median PFS was 11.0 mo (95% confidence interval [CI]: 10.7–13.4) in patients treated with sunitinib and 5.1 mo in IFN-α–treated patients (95% CI: 3.9–5.6; p < 0.000001). Sunitinib also demonstrated antitumor activity in two phase 2 trials of patients with cytokine-refractory mRCC. The expanded-access study provided access to sunitinib for patients ineligible for participation in the registrational studies and provides a useful insight into the profile of sunitinib in a heterogeneous mRCC population, including subgroups such as older patients (≥65 yr), patients with brain metastases, patients with poor performance status (PS ≥2), and patients with non–clear-cell histology.ConclusionsSunitinib is considered a reference standard of care for the first-line treatment of patients with mRCC, which is reflected in the current treatment guidelines. Sunitinib is now approved multinationally for the first- and second-line treatment of advanced renal cell carcinoma and/or mRCC.     

Tumor Growth Rate Provides Useful Information to Evaluate Sorafenib and Everolimus Treatment in Metastatic Renal Cell Carcinoma Patients: An Integrated Analysis of the TARGET and RECORD Phase 3 Trial Data

BackgroundResponse Evaluation Criteria in Solid Tumors (RECIST) criteria may not be sufficient to evaluate the response of targeted therapies in metastatic renal cell carcinoma (mRCC). The tumor growth rate (TGR) incorporates the time between evaluations and may be adequate.ObjectiveTo determine how TGR is modified along the treatment sequence and is associated with outcome in mRCC patients.Design, setting, and participantsMedical records from all patients prospectively treated at Gustave Roussy (IGR) in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) (sorafenib vs placebo, n = 84) and the RECORD (everolimus vs placebo, n = 43) phase 3 trials were analyzed. TGR was computed across clinically relevant periods: BEFORE treatment introduction (wash-out), UNDER (first cycle), at PROGRESSION (last cycle) and AFTER treatment discontinuation (washout). The association between TGR and outcome (overall survival [OS] and progression-free survival [PFS]) was computed in the entire TARGET cohort (n = 903).InterventionSorafenib, everolimus, or placebo.Outcome measurements and statistical analysisTGR, RECIST, OS, and PFS rates.Results and limitationsAlthough nearly all the patients (IGR) were classified as stable disease (RECIST) after the first cycle, the great majority of the patients exhibited a decrease in TGR UNDER compared with BEFORE (sorafenib: p < 0.00001; everolimus: p < 0.00001). In sorafenib-treated but not in everolimus-treated patients (IGR), TGR at PROGRESSION (last cycle) was still lower than TGR BEFORE (washout) (p = 0.012), while TGR AFTER progression (washout) was higher than TGR at PROGRESSION (last cycle) (p = 0.0012). Higher TGR (first cycle) was associated with worse PFS (hazard ratio [HR]: 3.61; 95% confidence interval [CI], 2.45–5.34) and worse OS (HR: 4.69; 95% CI, 1.54–14.39), independently from the Motzer score and from the treatment arm in the entire TARGET cohort.ConclusionsComputing TGR in mRCC patients is simple and provides clinically useful information for mRCC patients: (1) TGR is independently associated with prognosis (PFS, OS), (2) TGR allows for a subtle and quantitative characterization of drug activity at the first evaluation, and (3) TGR reveals clear drug-specific profiles at progression.     

Retrospective Comparison of Triple-sequence Therapies in Metastatic Renal Cell Carcinoma

Background

The optimal sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been defined.

Objective

To describe the efficacy and toxicity of the most common sequences of targeted therapy, namely, receptor tyrosine kinase inhibitor (rTKI) and mammalian target of rapamycin inhibitor (mTORi), in different sequences after failure of vascular endothelial growth factor signaling inhibition (VEGFi) in first-line therapy.

Design, setting and participants

Retrospective study of 103 patients receiving VEGFi-rTKI-mTORi (n = 62) or VEGFi-mTORi-rTKI (n = 41) at two German academic centers.

Intervention

Sequence of systemic targeted treatment.

Outcome measurements and statistical analysis

Response was assessed using Response Evaluation Criteria in Solid Tumors 1.0 and toxicity was measured using the Common Terminology Criteria for Adverse Events 3.0. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Predictors of survival were analyzed using Cox regression.

Results and limitations

Sequence groups did not significantly differ by patient characteristics and response rate following first VEGFi failure. Median PFS for second-line therapy was 4.6 mo (95% confidence interval [CI], 3.8–5.4), 4.1 mo (95% CI, 3.4–4.9) for rTKI treatment, and 5.4 mo (95% CI, 2.7–8.1) for mTORi treatment (p = 0.400). No differences in PFS were observed among third-line therapy groups (3.6 mo for mTORi; 3.7 mo for rTKI). Treatment duration following first VEGFi failure (combined second- and third-line PFS) was 10.0 mo for VEGFi-rTKI-mTORi and 12.2 mo for VEGFi-mTORi-rTKI (p = 0.103). No significant differences in OS were observed among sequence groups (33.7 mo [95% CI, 30.4–37.1] for VEGFi-rTKI-mTORi; 38.7 mo [95% CI, 24.4–52.9] for VEGFi-mTORi-rTKI). Primary resistance on first-line therapy was an independent predictor of OS, but type of sequence was not. Limitations are the retrospective design and limited numbers of cases.

Conclusions

The sequence therapies VEGFi-mTORi-rTKI and VEGFi-rTKI-mTORi with the currently available agents appear to be equally efficacious in terms of PFS, OS, and response rate, with no apparent beneficial effect with an early use of mTORi.     

Progression-free Survival After Second Line of Therapy for Metastatic Clear Cell Renal Cell Carcinoma in Patients Treated with First-line Immunotherapy Combinations

Immunotherapy (IO)-based combinations used to treat metastatic clear cell renal cell carcinoma (ccRCC) include dual immune checkpoint inhibition with ipilimumab and nivolumab (IO/IO) and several combinations of vascular endothelial growth factor receptor–targeting tyrosine kinase inhibitors (TKIs) with an immune checkpoint inhibitor (TKI/IO). IO/IO and TKI/IO approaches have not been compared directly, and it is unknown whether patients who do not respond to first-line IO/IO can salvage long-term survival by receiving a second-line TKI. Progression-free survival after second-line therapy (PFS-2) evaluates the ability to be salvaged by second-line therapy. We retrospectively evaluated 173 patients treated with first-line IO/IO or TKI/IO for metastatic ccRCC at Memorial Sloan Kettering Cancer Center and report PFS-2, overall survival, and response to second line of therapy (ORR_2nd) for groups defined by first-line category. Although ORR_2nd was significantly higher with IO/IO than with TKI/IO (47% vs 13%, p < 0.001), there was no significant difference in median PFS-2 for TKI/IO versus IO/IO (44 vs 23 mo, log-rank p = 0.1) or restricted mean survival time (RMST) for PFS-2 when adjusted for propensity score (33 vs 30 mo; difference 2.6 mo [95% confidence interval {CI}: –2.6, 7.9]; p = 0.3). There was also no significant difference in RMST for overall survival when adjusted for propensity score (38 vs 37 mo; group difference 1.0 mo [95% CI: –3.4, 5.5]; p = 0.7). These findings do not support a change in current utilization practices for IO/IO and TKI/IO treatment strategies for ccRCC.Patient summaryIn cases of metastatic clear cell renal cell carcinoma, no significant difference was observed in progression-free survival after second line of therapy between patients receiving ipilimumab plus nivolumab and those receiving a combination of a tyrosine kinase inhibitor and an immune checkpoint inhibitor.     

Integrating Surgery with Targeted Therapies for Renal Cell Carcinoma: Current Evidence and Ongoing Trials

Context

Surgical intervention is the primary treatment for early-stage renal cell carcinoma (RCC), but alone it has limited benefit in patients with metastatic disease. The advent of targeted agents for RCC has improved the outcome in these patients, and there is increasing interest in exploring the efficacy and safety of these agents in combination with surgery in both early and advanced disease.

Objective

This article reviews approved and emerging targeted therapies for RCC and outlines the rationale and implications for combining these therapies with surgery.

Evidence acquisition

A search of the literature, trial registries, and meeting proceedings was performed, and reports on surgery, receptor tyrosine kinase inhibitors, vascular endothelial growth factor antibodies, mammalian target of rapamycin inhibitors, and cytokine adjuvant therapy relating to RCC were critically reviewed.

Evidence synthesis

Nephrectomy has been shown to improve overall survival in patients with metastatic RCC (mRCC) treated with interferon alpha. Combining targeted therapy with surgery has the potential to improve efficacy and tolerability relative to cytokine therapy and prospective studies are underway. In the localized setting, there is some evidence of tumor downsizing with neoadjuvant targeted therapy. The tolerability and safety of targeted agents used perioperatively must be considered, particularly in the adjuvant setting where chronic therapy is required to prevent recurrence or metastasis. Novel agents with greater specificity and improved safety profiles are under development and have the potential to enhance efficacy and minimize the risk of complications.

Conclusions

For patients with mRCC, randomized controlled trials are ongoing to define the role and sequence of nephrectomy in combination with targeted therapy. Until data are available, nephrectomy remains part of the mRCC treatment algorithm for patients with good performance status and a resectable tumor. Targeted therapy to downsize large primary tumors in nonmetastatic disease is investigational, but the rate of surgically relevant down-staging and tumor shrinkage seen with the current generation of agents is limited. In patients with high-risk nonmetastatic disease, adjuvant therapy must be administered only in the context of the ongoing clinical trials since there are no data showing efficacy in this setting.     

Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial

BackgroundThe use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively.ObjectiveTo evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC.Design, setting, and participantsIMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab.InterventionPatients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy.Outcome measurements and statistical analysisThe secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods.Results and limitationsFifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors.ConclusionsThe atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC.Patient summaryPatients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.     

Outcomes following cytoreductive nephrectomy without immediate postoperative systemic therapy for patients with synchronous metastatic renal cell carcinoma

BackgroundWhile the recent CARMENA trial evaluated upfront cytoreductive nephrectomy (CN) among patients treated with immediate subsequent systemic therapy for metastatic renal cell carcinoma (mRCC), the role of CN in patients not immediately requiring systemic therapy remains to be determined.ObjectiveTo describe the oncologic outcomes of patients with de-novo synchronous mRCC who underwent CN +/- metastasis-directed therapy (MDT) and subsequent surveillance without planned immediate post-CN systemic therapy.Design, Setting, ParticipantsAdults who underwent CN for unilateral, sporadic mRCC between 1996 and 2016 without immediate postoperative systemic therapy were identified using the prospectively-maintained Mayo Clinic Nephrectomy Registry. Co-primary outcomes were survival free of systemic therapy or death and overall-survival.ResultsOf 156 patients who met inclusion criteria for study, 37 (24%) patients were managed after CN with surveillance alone and 119 (76%) underwent MDT. Seventy-two patients ultimately initiated systemic therapy at a median of 0.7 years (IQR 0.3–1.7). Median follow-up among survivors was 6.2 years (IQR 4.4–9.5), during which time 133 patients died. At 1, 3, and 5 years, survival free of systemic therapy or death rates were 47%, 21% and 14% and overall-survival rates were 69%, 37%, and 28%.ConclusionAmong carefully selected patients managed with surveillance after CN +/- MDT, approximately half may avoid systemic therapy for 1 year, with a subset achieving long-term survival free of systemic therapy or death. Having a single metastatic site and disease amenable to complete metastasectomy are features of patients who might be well served with upfront CN +/- MDT.     

European Association of Urology Guidelines for Systemic Therapy in Metastatic Renal Cell Carcinoma: What is Recommended and Why?

Metastatic renal cell carcinoma (mRCC) is largely resistant to conventional chemotherapy, hormonal therapy, and cytokine therapy and is associated with a poor prognosis. The European Association of Urology (EAU) recently published updated guidelines, with specific recommendations for treating mRCC. The EAU recommendations were based on recent clinical study data, which demonstrated the superiority of newer targeted therapies over interferon-α (IFN-α). mRCC is a highly vascularised tumour, characterised in the majority of cases by over-production of angiogenic peptides such as vascular endothelial growth factor. The targeted therapies selectively inhibit proteins whose functions include the stimulation of angiogenesis; two of these therapies, sunitinib and sorafenib, are currently approved in the European Union for use in mRCC. Reflecting the improved options now available, the updated EAU guidelines recommend using sunitinib, an orally administered antiangiogenic drug that selectively targets several receptors whose ligands are up-regulated in RCC, as first-line therapy for mRCC in good- and intermediate-risk patients. This recommendation is based on compelling data from a phase 3 trial that demonstrated longer progression-free survival and greater objective response rates for untreated patients with mRCC receiving sunitinib than for those receiving IFN-α. Other recommendations include using sorafenib as second-line therapy for mRCC and considering temsirolimus as first-line therapy for poor-risk patients with mRCC. Clinical studies investigating these agents, both alone and in combination, are ongoing. We review the clinical studies that form the basis of the EAU guidelines to gain an insight into the rationale behind the updated recommendations.     

Efficacy of Second-line Targeted Therapy for Renal Cell Carcinoma According to Change from Baseline in International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Category

Background

We hypothesized that changes in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic category at start of second-line therapy (2L) for metastatic renal cell carcinoma (mRCC) might predict response.