Impact of smoking status on clinical outcomes in patients with metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based regimens.

BACKGROUND: Current tobacco smoking is independently associated with decreased overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) treated with targeted monotherapy (VEGF-TKI). Herein, we assess the influence of smoking status on the outcomes of patients with mRCC treated with the current first-line standard of care of immune checkpoint inhibitor (ICI)-based regimens. MATERIALS AND METHODS: Real-world data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were collected retrospectively. Patients with mRCC who received either dual ICI therapy or ICI with VEGF-TKI in the first-line setting were included and were categorized as current, former, or nonsmokers. The primary outcomes were OS, time to treatment failure (TTF), and objective response rate (ORR). OS and TTF were compared between groups using the log-rank test and multivariable Cox regression models. ORR was assessed between the 3 groups using a multivariable logistic regression model. RESULTS: A total of 989 eligible patients were included in the analysis, with 438 (44.3%) nonsmokers, 415 (42%) former, and 136 (13.7%) current smokers. Former smokers were older and included more males, while other baseline characteristics were comparable between groups. Median follow-up for OS was 21.2 months. In the univariate analysis, a significant difference between groups was observed for OS (P = .027) but not for TTF (P = .9), with current smokers having the worse 2-year OS rate (62.8% vs 70.8% and 73.1% in never and former smokers, respectively). After adjusting for potential confounders, no significant differences in OS or TTF were observed among the 3 groups. However, former smokers demonstrated a higher ORR compared to never smokers (OR 1.45, P = .02). CONCLUSION: Smoking status does not appear to independently influence the clinical outcomes to first-line ICI-based regimens in patients with mRCC. Nonetheless, patient counseling on tobacco cessation remains a crucial aspect of managing patients with mRCC, as it significantly reduces all-cause mortality.

How I Do It: Maintenance avelumab for advanced urothelial carcinoma

For more than four decades, platinum-based chemotherapy regimens have served as the established standard-of-care for advanced urothelial carcinoma (aUC). However, advancements in our understanding of cancer biology and tumor microenvironment have reshaped the therapeutic landscape and prognosis of this incurable disease. Immune checkpoint inhibitors (ICIs) that target programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are firmly established tools in aUC management, leading to enhanced life span and improved quality of life for patients. In patients who achieved stable disease or better following platinum-based chemotherapy, maintenance therapy with the PD-L1 antibody avelumab significantly enhanced overall survival (OS) by approximately 7 months compared to best supportive care in the phase 3 JAVELIN Bladder 100 trial. As a result, avelumab received FDA approval in June 2020 as a maintenance therapy for aUC patients treated with first-line platinum-based chemotherapy. Therefore, aUC care plans should incorporate maintenance avelumab into standard first-line treatment regimens for these patients. The objective of this brief article is to provide insight into the utilization of avelumab, identify patients who may benefit from this treatment, and review the methodology, advantages, potential side effects and their management.

Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma.

BACKGROUND: Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC. METHODS: mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan-Meier methods. RESULTS: Of the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion. CONCLUSIONS: Combination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.

Targeted genomic landscape of metastases compared to primary tumours in clear cell metastatic renal cell carcinoma.

BACKGROUND: The genomic landscape of primary clear cell renal cell carcinoma (ccRCC) has been well described. However, little is known about cohort genomic alterations (GA) landscape in ccRCC metastases, or how it compares to primary tumours in aggregate. The genomic landscape of metastases may have biological, clinical, and therapeutic implications. METHODS: We collected targeted next-generation sequencing mutation calls from two independent cohorts and described the metastases GA landscape and descriptively compared it to the GA landscape in primary tumours. RESULTS: The cohort 1 (n = 578) consisted of 349 primary tumours and 229 metastases. Overall, the most common mutations in the metastases were VHL (66.8%), PBRM1 (41.87%), and SETD2 (24.7%). TP53 was more frequently mutated in metastases compared to primary tumours (14.85% versus 8.9%; p = 0.031). No other gene had significant difference in the cohort frequency of mutations between the metastases and primary tumours. Mutation burden was not significantly different between the metastases and primary tumours or between metastatic sites. The second cohort (n = 257) consisted of 177 primary tumours and 80 metastases. No differences in frequency of mutations or mutational burden were observed between primaries and metastases. CONCLUSIONS: These data support the theory that ccRCC primary tumours and metastases encompass a uniform distribution of common genomic alterations tested by next-generation sequencing targeted panels. This study does not address variability between matched primary tumours and metastases or the change in genomic alterations over time and after sequential systemic therapies.

Apatorsen plus docetaxel versus docetaxel alone in platinum-resistant metastatic urothelial carcinoma (Borealis-2).

BACKGROUND: A randomised study to assess the addition of apatorsen, an antisense oligonucleotide that inhibits Hsp27 expression, to docetaxel in patients with metastatic urothelial carcinoma (mUC) relapsed after prior platinum-based chemotherapy. METHODS: Multicentre, phase II study with 1:1 randomisation to apatorsen (three loading doses at 600 mg intravenous followed by weekly doses) plus docetaxel (75 mg/m2 intravenous every 21 days) (A/D) or docetaxel alone. Overall survival (OS) was the primary end point with a P value <0.1 (one-sided) being positive. Progression-free survival (PFS), objective response rate (ORR), safety, and effect of Hsp27 levels on outcomes were secondary end points. RESULTS: Patients randomised to A/D (n = 99) had improved OS compared to docetaxel alone (n = 101): HR: 0.80, 80% CI: 0.65-0.98, P = 0.0784, median 6.4 vs 5.9 months. PFS and ORR were similar in both arms. A/D had more incidence of sepsis and urinary tract infections. Patients with baseline Hsp27 levels <5.7 ng/mL had improved OS compared to those with levels ≥5.7 ng/mL. Patients with a decline or ≤20.5% increase in Hsp27 from baseline benefited more from A/D than those with >20.5% increase. CONCLUSIONS: A/D met its predefined OS end point in patients with platinum-refractory mUC in this phase II trial. This trial is hypothesis generating requiring further study before informing practice.

Adjuvant immunotherapy in high-risk muscle invasive urothelial carcinoma: A systematic review and meta-analysis of randomized clinical trials.

Despite surgical resection, many patients with muscle invasive urothelial carcinoma (MIUC) experience recurrence. Adjuvant immune checkpoint inhibition (ICI) following radical resection in patients with MIUC demonstrates disparate outcomes among phase III randomized controlled trials (RCTs). Our objective was to synthesize available data regarding the disease-free survival (DFS) benefit of adjuvant ICIs for patients with MIUC and evaluate the overall safety profile of ICIs in this setting. The protocol was registered with PROSPERO, CRD42022352587. We searched MEDLINE, Embase, CENTRAL, and relevant conference proceedings from inception up to January 29, 2024. Only phase III RCTs comparing adjuvant ICI versus placebo/observation were selected. Study screening and selection, along with data extraction was performed in duplicate according to a predefined registered protocol. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was used. Quality assessment was performed using the Cochrane risk-of-bias (RoB 2) tool for randomized trials. The primary and secondary endpoints were DFS and serious adverse events, respectively. All outcomes were analyzed using random-effects meta-analysis owing to inter-study heterogeneity. Sensitivity and subgroup analyses were performed to identify potential sources of heterogeneity. A priori defined subgroups of interest included positive program death-ligand 1 (PD-L1) expression, previous use of neoadjuvant chemotherapy (NAC), primary tumor origin, pathologic lymph node status, and baseline Eastern Cooperative Oncology Group performance status. Pooled results across the 3 RCTs (2,220 patients) demonstrated significantly improved DFS for patients treated with ICI in the intention-to-treat cohorts (HR 0.76, 95% CI 0.65-0.90). There was considerable clinical and statistical heterogeneity (I2 = 44%) due to differences in inclusion criteria and interventions. Overall, there was a low risk of bias among the RCTs. Regarding subgroup analyses, there was significant benefit among patients with negative PD-L1 expression (HR 0.76, 95% CI 0.64-0.90), those who received prior NAC (HR 0.69, 95% CI 0.52-0.91), and patients with lower tract (HR 0.71, 95% CI 0.55-0.92) but not upper tract disease (HR 1.21, 95% CI 0.87-1.68). This pooled analysis of DFS and safety provides support for ICI utilization in the setting of high-risk resected MIUC.

Characterization of Responses to Lenvatinib plus Pembrolizumab in Patients with Advanced Renal Cell Carcinoma at the Final Prespecified Survival Analysis of the Phase 3 CLEAR Study.

In the phase 3 CLEAR trial, lenvatinib plus pembrolizumab (L + P) showed superior efficacy versus sunitinib in treatment-naïve patients with advanced renal cell carcinoma (aRCC). The combination treatment was associated with a robust objective response rate of 71%. Here we report tumor responses for patients in the L + P arm in CLEAR, with median follow-up of ∼4 yr at the final prespecified overall survival (OS) analysis. Tumor responses were assessed by independent review using Response Evaluation Criteria in Solid Tumors v1.1. Patients with a complete response (CR; n = 65), partial response (PR) with maximum tumor shrinkage ≥75% (near-CR; n = 59), or PR with maximum tumor shrinkage <75% (other PR; n = 129), were characterized in terms of their baseline characteristics. The median duration of response was 43.7 mo (95% confidence interval [CI] 39.2-not estimable) for the CR group, 30.5 mo (95% CI 22.4-not estimable) for the near-CR group, and 17.2 mo (95% CI 12.5-21.4) for the other PR group. The 36-mo OS rates were consistently high in the CR (97%), near-CR (86%), and other PR (62%) groups. Robust objective response rates were observed across International Metastatic RCC Database Consortium favorable-risk (69%, 95% CI 60-78%), intermediate-risk (73%, 95% CI 67-79%), and poor-risk (70%, 95% CI 54-85%) subgroups. The robust response to L + P supports this combination as a standard-of-care first-line treatment for patients with aRCC. PATIENT SUMMARY: The CLEAR trial enrolled patients with advanced kidney cancer who had not previously received any treatment for their cancer. Here we report results for tumor shrinkage observed in the group that received lenvatinib plus pembrolizumab combination treatment during the trial. Shrinkage of target tumors with this combination was long-lasting and was observed in patients irrespective of their disease severity. This trial is registered on ClinicalTrials.gov as NCT02811861.

Impact of Timing of Immunotherapy and Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma: Real-World Data on Survival Outcomes from the CKCis Database.

Immunotherapy-based systemic treatment (ST) is the standard of care for most patients diagnosed with metastatic renal cell carcinoma (mRCC). Cytoreductive nephrectomy (CN) has historically shown benefit for select patients with mRCC, but its role and timing are not well understood in the era of immunotherapy. The primary objective of this study is to assess outcomes in patients who received ST only, CN followed by ST (CN-ST), and ST followed by CN (ST-CN). The Canadian Kidney Cancer information system (CKCis) database was queried to identify patients with de novo mRCC who received immunotherapy-based ST between January 2014 and June 2023. These patients were classified into three categories as described above. Cox proportional hazards models were used to assess the impact of the timing of ST and CN on overall survival (OS) and progression-free survival (PFS), after adjusting for the International Metastatic RCC Database Consortium (IMDC) risk group, age, and comorbidities. Best overall response and complications of ST and CN for these cohorts were collected. A total of 588 patients were included in this study: 331 patients received ST only, 215 patients received CN-ST, and 42 patients received ST-CN. Patient and disease characteristics including age, gender, performance status, IMDC risk category, comorbidity, histology, type of ST, and metastatic sites are reported. OS analysis favored patients who received ST-CN (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.13-0.68) and CN-ST (HR 0.68, CI 0.47-0.97) over patients who received ST only. PFS analysis showed a similar trend for ST-CN (HR 0.45, CI 0.26-0.77) and CN-ST (HR 0.9, CI 0.68-1.17). This study examined baseline features and outcomes associated with the use and timing of CN and ST using real-world data via a large Canadian real-world cohort. Patients selected to receive CN after ST demonstrated improved outcomes. There were no appreciable differences in perioperative complications across groups. Limitations include the small number of patients in the ST-CN group and residual confounding and selection biases that may influence the outcomes in patients undergoing CN.

Outcomes of Patients with Brain Metastases from Renal Cell Carcinoma Receiving First-line Therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Patients with brain metastases (BrM) from renal cell carcinoma and their outcomes are not well characterized owing to frequent exclusion of this population from clinical trials. We analyzed data for patients with or without BrM using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). A total of 389/4799 patients (8.1%) had BrM on initiation of systemic therapy. First-line immuno-oncology (IO)-based combination therapy was associated with longer median overall survival (OS; 32.7 mo, 95% confidence interval [CI] 22.3-not reached) versus tyrosine kinase inhibitor monotherapy (20.6 mo, 95% CI 15.7-24.5; p = 0.019), as were intensive focal therapies with stereotactic radiotherapy or neurosurgery (31.4 mo, 95% CI 22.3-37.5) versus whole-brain radiotherapy alone or no focal therapy (16.5 mo, 95% CI 10.2-21.1; p = 0.028). On multivariable analysis, IO-based regimens (HR 0.49, 95% CI 0.25-0.97; p = 0.040) and stereotactic radiotherapy or neurosurgery (HR 0.48, 95% CI 0.29-0.78; p = 0.003) were independently associated with longer OS, as was IMDC favorable or intermediate risk (HR 0.40, 95% CI 0.24-0.66; p < 0.001). Intensive systemic and focal therapies were associated with better prognosis in this population. Further studies should explore the clinical effectiveness of multimodal strategies. PATIENT SUMMARY: In a large group of patients with advanced kidney cancer, we found that 8.1% had brain metastases when starting systemic therapy. Patients with brain metastases had significantly poorer prognosis than those without brain metastases. Receipt of combination immunotherapy, stereotactic radiotherapy, or neurosurgery was associated with longer overall survival.

Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final prespecified overall survival (OS) analysis of the open-label, phase III CLEAR study in treatment-naïve patients with advanced renal cell carcinoma (aRCC). With an additional follow-up of 23 months from the primary analysis, we report results from the lenvatinib plus pembrolizumab versus sunitinib comparison of CLEAR. Treatment-naïve patients with aRCC were randomly assigned to receive lenvatinib (20 mg orally once daily in 21-day cycles) plus pembrolizumab (200 mg intravenously once every 3 weeks) or sunitinib (50 mg orally once daily [4 weeks on/2 weeks off]). At this data cutoff date (July 31, 2022), the OS hazard ratio (HR) was 0.79 (95% CI, 0.63 to 0.99). The median OS (95% CI) was 53.7 months (95% CI, 48.7 to not estimable [NE]) with lenvatinib plus pembrolizumab versus 54.3 months (95% CI, 40.9 to NE) with sunitinib; 36-month OS rates (95% CI) were 66.4% (95% CI, 61.1 to 71.2) and 60.2% (95% CI, 54.6 to 65.2), respectively. The median progression-free survival (95% CI) was 23.9 months (95% CI, 20.8 to 27.7) with lenvatinib plus pembrolizumab and 9.2 months (95% CI, 6.0 to 11.0) with sunitinib (HR, 0.47 [95% CI, 0.38 to 0.57]). Objective response rate also favored the combination over sunitinib (71.3% v 36.7%; relative risk 1.94 [95% CI, 1.67 to 2.26]). Treatment-emergent adverse events occurred in >90% of patients who received either treatment. In conclusion, lenvatinib plus pembrolizumab achieved consistent, durable benefit with a manageable safety profile in treatment-naïve patients with aRCC.

The emerging landscape of neo/adjuvant immunotherapy in renal cell carcinoma.

Adjuvant and neoadjuvant therapies that reduce the risk of renal cell carcinoma (RCC) recurrence remain an area of unmet need. Advances have been made in metastatic RCC recently by leveraging PD-1/PD-L1 immune checkpoint inhibitors (ICIs). These agents are currently being investigated in the adjuvant and neoadjuvant settings to determine if intervention early in the disease trajectory offers a clinically meaningful benefit. While a disease-free survival benefit has been demonstrated with pembrolizumab, results from other ICI studies have not been positive to date. More mature data from these studies are needed to determine whether there is a survival benefit to ICIs in the curative-intent setting. The success of ICIs has also ushered a new wave of studies combining ICIs with other agents such as targeted therapies and vaccines, which are in early stages of investigation. We review the current state of adjuvant/neoadjuvant therapy in RCC and highlight opportunities for ongoing study.

Evaluating the impact of early identification of asymptomatic brain metastases in metastatic renal cell carcinoma.

BACKGROUND: Brain metastases (BM) in metastatic renal cell carcinoma (mRCC) have been reported to be present in up to 25% of patients diagnosed with mRCC. There is limited published literature evaluating the role of routine intra-cranial imaging for the screening of asymptomatic BM in mRCC. AIMS: To evaluate the potential utility of routine intra-cranial imaging, a retrospective cohort study was conducted to characterize the outcomes of mRCC patients who presented with asymptomatic BM, as compared to symptomatic BM. METHODS AND RESULTS: The Canadian Kidney Cancer Information System (CKCis) database was used to identify mRCC patients diagnosed with BM. This cohort was divided into two groups based on the presence or absence of BM symptoms. Details regarding patient demographics, disease characteristics, systemic treatments, BM characteristics and survival outcomes were extracted. Statistical analysis was through chi-square tests, analysis of variance, and Kaplan-Meier method to characterize survival outcomes. A p-value of <0.05 was considered statistically significant for all analyses. A total of 267 mRCC patients with BM were identified of which 106 (40%) presented with asymptomatic disease. The majority of patients presented with multiple (i.e., >1) BM (75%) with no significant differences noted in number of BM or BM-directed therapy received in symptomatic, as compared to asymptomatic BM patients. Median [95% confidence interval (CI)] overall survival (OS) from mRCC diagnosis was 42 months (95% CI: 32-62) for patients with asymptomatic BM, and 39 months (95% CI: 29-48) with symptomatic BM (p = 0.10). OS from time of BM diagnosis was 28 months (95% CI: 18-42) for the asymptomatic BM group, as compared to 13 months (95% CI: 10-21) in the symptomatic BM group (p = 0.04). CONCLUSIONS: Given a substantial proportion of patients may present with asymptomatic BM, limiting intra-cranial imaging to patients with symptomatic BM, may be associated with a missed opportunity for timely diagnosis and treatment. The utility of routine intra-cranial imaging in patients with renal cell carcinoma, warrants further prospective evaluation.

Trends of Utilization of Systemic Therapies for Metastatic Renal Cell Carcinoma in the Canadian Health Care System.

PURPOSE: Standard-of-care therapies for metastatic renal cell carcinoma (mRCC) have greatly evolved. However, the availability of emerging options in global health care systems can vary. We sought to describe the integration and usage of systemic therapies for mRCC in Canada since 2011. METHODS: We included patients with mRCC enrolled in the Canadian Kidney Cancer Information System, a prospective cohort of patients from 14 Canadian academic centers, who received systemic therapy from January 1, 2011, to December 31, 2021. Patients were stratified by treatment era (cohort 1: 2011-2015, cohort 2: 2016-2021). Stacked bar charts were used to present treatment proportions; Sankey diagrams were used to show the evolution of treatment sequencing between the two cohorts. RESULTS: Four thousand one hundred seven patients were diagnosed with mRCC, of whom 2,752 (67%) received systemic therapy. Among these patients, mean age was 64 years, 74% were male, 75% had clear cell histology, and International Metastatic RCC Database Consortium risk classification was favorable, intermediate, and poor in 16%, 56%, and 28%, respectively. Utilization of immune checkpoint inhibition (ICI)-based treatments has increased in Canada and reflects global and local patterns of approval and adoption. The use of therapies after doublet ICI has mostly shifted toward vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs) that were previously used in first line with subsequent treatments reflecting approved and available agents after previous VEGF-TKI. Clinical trial participation among patients who received systemic therapy was 18% in first, 21% in second, and 24% in third line. CONCLUSION: In Canada's publicly funded health care system, availability of standard mRCC therapies broadly reflects access from government-funded clinical trials and compassionate access program sources. In an evolving therapeutic landscape, ongoing advocacy is required to continue to facilitate patient access to efficacious therapies.

Adjuvant therapy for renal cell carcinoma: 2023 Canadian Kidney Cancer Forum consensus statement.

INTRODUCTION: Several recent randomized trials evaluated the impact of adjuvant immune checkpoint inhibitor (ICI)-based therapy on post-surgical outcomes in renal cell carcinoma (RCC), with disparate results. The objective of this consensus statement is to provide data-driven guidance regarding the use of ICIs after complete resection of clear-cell RCC in a Canadian context. METHODS: An expert panel of genitourinary medical oncologists, urologic oncologists, and radiation oncologists with expertise in RCC management was convened in a dedicated session during the 2022 Canadian Kidney Cancer Forum in Toronto, Canada. Topic statements on the management of patients after surgery for RCC, including counselling, risk stratification, indications for medical oncology referral, appropriate followup, eligibility and management for adjuvant ICIs, as well as treatment options for patients with recurrence who received adjuvant immunotherapy, were discussed. Participants were asked to vote if they agreed or disagreed with each statement. Consensus was achieved if greater than 75% of participants agreed with the topic statement. RESULTS: A total of 22 RCC experts voted on 14 statements. Consensus was achieved on all topic statements. The panel felt patients with clear-cell RCC at increased risk of recurrence after surgery, as per the Keynote-564 group definitions, should be counselled about recurrence risk by a urologist, should be informed about the potential role of adjuvant ICI systemic therapy, and be offered referral to discuss risks and benefits with a medical oncologist. The panel felt that one year of pembrolizumab is currently the only regimen that should be considered if adjuvant therapy is selected. Panelists emphasized current opinions are based on disease-free survival given the available results. Significant uncertainty regarding the benefit and harms of adjuvant therapy remains, primarily due to a lack of consistent benefit observed across similar trials of adjuvant ICI-based therapies and immature overall survival (OS) data. CONCLUSIONS: This consensus document provides guidance from Canadian RCC experts regarding the potential role of ICI-based adjuvant systemic therapy after surgery. This rapidly evolving field requires frequent evidence-based re-evaluation.

Evolving landscape of first-line combination therapy in advanced renal cancer: a systematic review.

Background: Renal cell carcinoma (RCC) is a common malignancy with approximately 30% of cases diagnosed at the advanced or metastatic stage. While single-agent vascular endothelial growth factor-targeted therapy has been a mainstay of treatment, data from multiple phase III trials assessing first-line immune checkpoint inhibitor (ICI) combinations have demonstrated a significant survival benefit. Methods: A systematic search of the published and presented literature was performed to identify phase III trials assessing ICI combination regimens in RCC using search terms 'immune checkpoint inhibitors' AND 'renal cell carcinoma,' AND 'advanced'. Results: Six phase III trials showed significant benefits for ICI combinations compared with sunitinib. Nivolumab plus ipilimumab significantly improved overall survival [OS; median, 47.0 versus 26.6 months, hazard ratio (HR) = 0.68, 95% confidence interval (CI) = 0.58-0.81, p < 0.0001) and progression-free survival (PFS; median 11.6 versus 8.3 months, HR = 0.73, 95% CI = 0.61-0.87, p = 0.0004) in International Metastatic renal cell carcinoma Database Consortium intermediate and poor-risk patients. OS was also significantly improved for ICI plus tyrosine kinase inhibitor combinations regardless of risk, including pembrolizumab plus either axitinib (HR = 0.73, 95% CI = 0.60-0.88, p < 0.001) or lenvatinib (HR = 0.66, 95% CI = 0.49-0.88, p = 0.005) and nivolumab plus cabozantinib (HR = 0.66, 95% CI = 0.50-0.87, p = 0.003). No new safety signals were identified. Conclusions: Phase III first-line trials of ICI combinations showed survival benefits compared with a control arm of sunitinib. Global access to these combinations should be made available to patients with advanced RCC.

Next Wave of Targets in the Treatment of Advanced Renal Cell Carcinoma.

While surgical resection has remained the mainstay of treatment in early-stage renal cell carcinoma (RCC), therapeutic options in the advanced setting have remarkably expanded over the last 20 years. Tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor (VEGF-TKIs) and anti-programmed cell death 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) have become globally accepted options in the upfront metastatic setting, with different ICI-based combination strategies improving overall survival compared to single-agent Sunitinib. Although some patients benefit from long-term responses, most eventually develop disease progression. Ongoing efforts to better understand the biology of RCC and the different mechanisms of acquired resistance have led to the identification of promising therapeutic targets. Belzutifan, a novel agent targeting the angiogenic pathway involving hypoxia-inducible factors (HIFs), has already been approved for the treatment of early-stage tumors associated with VHL disease and represents a very promising therapy in advanced RCC. Other putative targets include epigenetic regulation enzymes, as well as several metabolites such as adenosine, glutaminase and tryptophan, which are critical players in cancer cell metabolism and in the tumor microenvironment. Different methods of immune regulation are also being investigated, including CAR-T cell therapy and modulation of the gut microbiome, in addition to novel agents targeting the interleukin-2 (IL-2) pathway. This review aims to highlight the emergent novel therapies for RCC and their respective completed and ongoing clinical trials.

Utilization and Safety of Ipilimumab Plus Nivolumab in a Real-World Cohort of Metastatic Renal Cell Carcinoma Patients.

INTRODUCTION: Ipilimumab plus nivolumab was associated with a survival benefit in a phase III clinical trial of first-line treatment for metastatic renal cell carcinoma (mRCC). In this study, mRCC patients from the Canadian Kidney Cancer Information System (CKCis) database who received first-line ipilimumab plus nivolumab were analyzed to determine the safety and outcomes in a real-world setting. PATIENTS AND METHODS: Patients who received ipilimumab plus nivolumab as first-line therapy for mRCC in CKCis, were identified, and the amount of treatment received, discontinuation rates, and reasons for discontinuing treatment were determined. Toxicity data, including type and grade, were collected. Efficacy outcomes of interest included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS: The cohort included 195 patients, the majority with clear cell histology (74%). All 4 cycles of ipilimumab plus nivolumab were administered in 124 patients (64%). Progressive disease (n = 87; 45%) and toxicity (n = 36; 18%) were the most common causes for discontinuing treatment. Several patients (n = 18) did not receive all 4 doses of ipilimumab but received single agent nivolumab. The estimated median OS was 54.5 months (95% CI, 17.7 - NE) and 12-month OS was 72.2% (95% CI, 65.0 - 79.3). Median PFS was 7.4 months (95% CI 5.3 - 10.2) and ORR was 42.5%. Patients who received all 4 cycles of ipilimumab plus nivolumab had better ORR (50% vs. 28%) and a longer PFS and OS than those who received less than 4 cycles (P < .0001). Ninety-five AEs were documented in 72 patients who required dose reduction/change, with colitis being the most frequent. CONCLUSION: In this real-world cohort of treatment-naïve mRCC patients, outcomes, and safety were comparable to previously reported clinical trial data.

Outcomes of Radiation Therapy Plus Immunotherapy in Metastatic Renal Cell Carcinoma: Results From the Canadian Kidney Cancer Information System.

Purpose: With the integration of immunotherapy (IO) agents in the management of metastatic renal cell carcinoma (mRCC), there has been interest in the combined use with radiation therapy (RT). However, real world data are limited. The purpose of this study was to evaluate outcomes in patients with mRCC receiving both RT and IO compared with IO alone. Methods and Materials: Data were collected from Canadian Kidney Cancer Information System from January 2011 to September 2019 across 14 academic centers. Patients with mRCC who received IO as first- or second-line therapy were included. RT was categorized as radical dose or palliative dose. Kaplan-Meier estimates were reported for overall survival (OS) and time to treatment failure. Cox proportional hazard models were used adjusted for age and International Metastatic RCC Database Consortium risk categories. Results: In total, 505 patients were included in the study: 179 received RT + IO and 326 received IO alone. Two-year OS for the RT + IO group was 55.0% compared with 66.4% in the IO alone cohort (adjusted hazard ratio [aHR], 1.38; P = .07). At 2 years, 12.2% of the RT + IO patients remained on therapy versus 30.9% in the IO alone group (aHR, 1.30; P = .02). For patients receiving first-line therapy, 2-year OS in the RT + IO group was 56.4% versus 78.4% in the IO alone arm, though this difference was not statistically significant (aHR, 1.23; P = .56). For patients receiving radical dose and palliative dose, 2-year OS was 57.0% and 53.9%, respectively (aHR, 0.86; P = .63). Conclusions: In this descriptive analysis, more than one-third of patients with mRCC received RT and demonstrated inferior outcomes compared with IO alone. Potential explanations include greater presence of adverse metastatic sites in those receiving RT. Prospective clinical trials evaluating potential benefits of RT in an IO era remain an important need.

Association of Neutrophil-to-Lymphocyte Ratio with Efficacy of First-Line Avelumab plus Axitinib vs. Sunitinib in Patients with Advanced Renal Cell Carcinoma Enrolled in the Phase 3 JAVELIN Renal 101 Trial.

PURPOSE: To evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and efficacy of avelumab plus axitinib or sunitinib. EXPERIMENTAL DESIGN: Adult patients with untreated advanced renal cell carcinoma (RCC) with a clear-cell component, ≥1 measurable lesions, Eastern Cooperative Oncology Group performance status of 0 or 1, fresh or archival tumor specimen, and adequate renal, cardiac, and hepatic function were included. Retrospective analyses of the association between baseline NLR and progression-free survival (PFS) and overall survival (OS) in the avelumab plus axitinib or sunitinib arms were performed using the first interim analysis of the phase 3 JAVELIN Renal 101 trial (NCT02684006). Multivariate Cox regression analyses of PFS and OS were conducted. Translational data were assessed to elucidate the underlying biology associated with differences in NLR. RESULTS: Patients with below-median NLR had longer observed PFS with avelumab plus axitinib [stratified HR, 0.85; 95% confidence interval (CI), 0.634-1.153] or sunitinib (HR, 0.56; 95% CI, 0.415-0.745). In the avelumab plus axitinib or sunitinib arms, respectively, median PFS was 13.8 and 11.2 months in patients with below-median NLR, and 13.3 and 5.6 months in patients with median-or-higher NLR. Below-median NLR was also associated with longer observed OS in the avelumab plus axitinib (HR, 0.51; 95% CI, 0.300-0.871) and sunitinib arms (HR, 0.30; 95% CI, 0.174-0.511). Tumor analyses showed an association between NLR and key biological characteristics, suggesting a role of NLR in underlying mechanisms influencing clinical outcome. CONCLUSIONS: Current data support NLR as a prognostic biomarker in patients with advanced RCC receiving avelumab plus axitinib or sunitinib.