An interdisciplinary consensus on the management of brain metastases in patients with renal cell carcinoma.

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489.

Advances in non-clear cell renal cell carcinoma management: From heterogeneous biology to treatment options.

Non-clear cell renal cell carcinoma (nccRCC) makes up nearly one quarter of all RCC subtypes, commonly impacts younger patients, and is often metastatic at presentation. Compared to clear-cell RCC (ccRCC), nccRCC typically has a worse prognosis in the metastatic setting, with overall survival durations that are ~10 months shorter. The nccRCC consists of a wide range of different histological subtypes, the majority of which are composed of papillary, chromophobe, renal medullary carcinoma, translocation RCC, collecting duct carcinoma and unclassified RCC. Most clinical trials have either excluded or only included small numbers of patients with nccRCC; owing to the lack of prospective studies focusing on this population, data on response rates and survival outcomes are lacking. NccRCC treatment is a nascent field with various therapeutic modalities and combinations under investigation, often based on data extrapolated from therapeutic studies in ccRCC. We herein review the use and outcomes of cytotoxic chemotherapy, various combination modalities of tyrosine kinase inhibitors and immune checkpoint inhibitors, and targeted agents. We discuss active ongoing clinical trials for patients with nccRCC and future directions in the treatment of this rare disease. Historically, treatment for nccRCC has been adopted from the standard of care for patients with ccRCC, although these treatments are less effective in the nccRCC population. As we begin to understand the underlying biology of these tumors, clinical trials have been able to slowly accrue and include more patients with various subtypes of nccRCC. There remains much room for improvement in this area of need, but there is hope on the horizon.

Special populations in metastatic renal cell carcinoma.

PURPOSE OF REVIEW: This review focuses on special populations poorly represented in current evidence-based practice for metastatic renal cell carcinoma (mRCC). This includes the elderly and frail, patients on immunosuppression or with autoimmune diseases, patients with brain, liver, and/or bone metastases, and RCC with sarcomatoid features. RECENT FINDINGS: Certain populations are poorly represented in current trials for mRCC. Patients with central nervous system (CNS) metastases are often excluded from first-line therapy trials. Modern doublet systemic therapy appears to benefit patients with bone or liver metastases, but data supporting this conclusion is not robust. Post-hoc analyses on patients with sarcomatoid differentiation have shown improved response to modern doublet therapy over historical treatments. The elderly are underrepresented in current clinical trials, and most trials exclude all but high-performing (nonfrail) patients, though true frailty is likely poorly captured using the current widely adopted indices. It is difficult to make conclusions about the efficacy of modern therapy in these populations from subgroup analyses. Data from trials on other malignancies in patients with autoimmune diseases or solid organ transplant recipients on immunosuppression suggest that immune checkpoint inhibitors (ICIs) may still have benefit, though at the risk of disease flare or organ rejection. The efficacy of ICIs has not been demonstrated specifically for RCC in this group of patients. SUMMARY: The elderly, frail, and immunosuppressed, those with tumors having aggressive histologic features, and patients with brain, bone, and/or liver metastases represent the populations least understood in the modern era of RCC treatment.

Tissue and imaging biomarkers of response to neoadjuvant nivolumab or nivolumab plus ipilimumab in patients with resectable hepatocellular carcinoma.

INTRODUCTION: Perioperative immunotherapy has shown promise in some patients with early-stage hepatocellular carcinoma (HCC). This study examined tissue and imaging biomarkers associated with pathologic response in a phase II clinical trial in patients with resectable HCC. METHODS: Analysis included 18 patients with biopsy-proven resectable HCC treated with neoadjuvant nivolumab plus ipilimumab or nivolumab alone in a phase II clinical trial at MD Anderson Cancer Center (NCT03222076). Liver MRE (to measure tissue fibrosis) and biopsies (to evaluate immune activation markers) were obtained serially pretreatment and after completing neoadjuvant immunotherapy. A major pathologic response (MPR) was defined as tumor necrosis of more than 70%. Data comparing patients with MPR versus those without was summarized using descriptive statistics and compared using the Wilcoxon rank sum test. RESULTS: Patients with MPR after neoadjuvant immunotherapy tended to have larger tumors (mean 9.52 vs. 4.99 centimeters; p = 0.050). They had a significant reduction in tumor size post-treatment (14.67% reduction vs. 9.15% increase in size; p = 0.042) and a non-significant decrease in serum AFP (-24.20% vs -14.00%; p = 0.085). Further, patients with MPR had a greater increase in intratumoral expression levels of CD8 (26.92% vs -0.04%; p = 0.026), Granzyme B (15.56% vs -2.24%; p = 0.011), and PD-1 (20.17% vs 0.40%; p = 0.048) but not PD-L1 (7.69% vs 0.57%; p = 0.26). Tumor and liver fibrosis were comparable before and after neoadjuvant therapy in patients with MPR versus non-responders. CONCLUSION: Changes in tumor size and immune cell infiltration and activation are candidate predictive markers of pathologic response to neoadjuvant immunotherapy in patients with resectable HCC.

Immune Checkpoint Therapy Combinations in Adult Advanced MiT Family Translocation Renal Cell Carcinomas.

BACKGROUND: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC). METHODS: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods. RESULTS: There were 29 patients identified with median age of 38 (21-70) years, and F:M ratio 0.9:1. FISH revealed TFE3 and TFEB translocations in 22 and 7 patients, respectively. Dual ICT and ICT + VEGF TT were used in 18 and 11 patients, respectively. Seventeen (59%) patients received ICT combinations as first-line therapy. ORR was 1/18 (5.5%) for dual ICT and 4/11 (36%) for ICT + VEGF TT. At a median follow-up of 12.9 months, median PFS was 2.8 and 5.4 months in the dual ICT and ICT + VEGF TT groups, respectively. Median OS from metastatic disease was 17.8 and 30.7 months in the dual ICT and ICT + VEGF TT groups, respectively. CONCLUSION: In this retrospective study of advanced tRCC, limited response and survival were seen after frontline dual ICT combination therapy, while ICT + VEGF TT therapy offered some efficacy. Due to the heterogeneity of tRCC, insights into the biological underpinnings are necessary to develop more effective therapies.

Efficacy of Cabozantinib in Metastatic MiT Family Translocation Renal Cell Carcinomas.

BACKGROUND: MiT family translocation renal cell carcinoma (TRCC) is a rare and aggressive subgroup of renal cell carcinoma harboring high expression of c-MET. While TRCC response rates to VEGF receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a VEGFR, MET, and AXL inhibitor) in this subgroup is unclear. METHODS: We performed a multicenter, retrospective, international cohort study of patients with TRCC treated with cabozantinib. The main objectives were to estimate response rate according to RECIST 1.1 and to analyze progression-free survival (PFS) and overall survival (OS). RESULTS: Fifty-two patients with metastatic TRCC treated in the participating centers and evaluable for response were included. Median age at metastatic diagnosis was 40 years (IQR 28.5-53). Patients' IMDC risk groups at diagnosis were favorable (9/52), intermediate (35/52), and poor (8/52). Eleven (21.2%) patients received cabozantinib as frontline therapy, 15 (28.8%) at second line, and 26 (50%) at third line and beyond. The proportion of patients who achieved an objective response was 17.3%, including 2 complete responses and 7 partial responses. For 26 (50%) patients, stable disease was the best response. With a median follow-up of 25.1 months (IQR 12.6-39), median PFS was 6.8 months (95%CI 4.6-16.3) and median OS was 18.3 months (95%CI 17.0-30.6). No difference of response was identified according to fusion transcript features. CONCLUSION: This real-world study provides evidence of the activity of cabozantinib in TRCC, with more durable responses than those observed historically with other VEGFR-TKIs or ICIs.

Outcomes of patients with intermediate-risk or poor-risk metastatic renal cell carcinoma who received their first cycle of nivolumab and ipilimumab in the hospital because of symptomatic disease: The MD Anderson Cancer Center experience.

Nivolumab plus ipilimumab (nivo/ipi) is an approved therapy for patients with intermediate-risk or poor-risk metastatic renal cell carcinoma (mRCC). Clinical factors that guide the selection of this regimen for patients with mRCC are urgently needed. We retrospectively analyzed medical records of patients with mRCC who were hospitalized at MD Anderson Cancer Center because of cancer-related symptoms and received their first cycle of nivo/ipi in the inpatient setting. Clinical parameters, including demographics, histology, clinical history, response, and survival, were collected. The 4-month survival probability, progression-free survival (PFS), and overall survival (OS) were calculated using Kaplan-Meier methods. Between November 2017 and 21 June 2020 patients were identified that fit the search: 19 patients (91%) had poor-risk disease based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score; 17 patients (81%) had ≥4 risk factors; and 9 patients (43%) had sarcomatoid features on histology. Shortness of breath (28%) and abdominal pain (19%) were the two most common reasons for hospitalization. Partial response was achieved in 14% (3/21) of patients. Median PFS for all patients was 1.7 months (95% CI 0-3.9); median OS for all patients was 1.7 months (95% CI 0-4.2); and the 4-month survival probability was 36% (95% CI 25%-47%). In this retrospective study, patients with intermediate-risk or poor-risk mRCC who are hospitalized at a large tertiary referral center for cancer-related symptoms derive limited clinical benefit from nivo/ipi when started in the inpatient setting. Alternative, more effective systemic therapies should be considered for these patients.

Management of Brain Metastases in Metastatic Renal Cell Carcinoma.

The development of brain metastases is a poor prognostic indicator in renal cell carcinoma. Regular imaging and clinical examinations are necessary to monitor the brain before or during systemic therapy. Central nervous system-targeted radiation therapy, including stereotactic radiosurgery, whole-brain radiation therapy, and surgical resection, is a standard treatment option. Clinical trials are currently investigating the role of targeted therapy and immune checkpoint inhibitor combinations in treating brain metastases and decreasing intracranial disease progression.

SETD2 Loss and ATR Inhibition Synergize to Promote cGAS Signaling and Immunotherapy Response in Renal Cell Carcinoma.

PURPOSE: Immune checkpoint blockade (ICB) demonstrates durable clinical benefits in a minority of patients with renal cell carcinoma (RCC). We aimed to identify the molecular features that determine the response and develop approaches to enhance it. EXPERIMENTAL DESIGN: We investigated the effects of SET domain-containing protein 2 (SETD2) loss on the DNA damage response pathway, the cytosolic DNA-sensing pathway, the tumor immune microenvironment, and the response to ataxia telangiectasia and rad3-related (ATR) and checkpoint inhibition in RCC. RESULTS: ATR inhibition activated the cyclic GMP-AMP synthase (cGAS)-interferon regulatory factor 3 (IRF3)-dependent cytosolic DNA-sensing pathway, resulting in the concurrent expression of inflammatory cytokines and immune checkpoints. Among the common RCC genotypes, SETD2 loss is associated with preferential ATR activation and sensitizes cells to ATR inhibition. SETD2 knockdown promoted the cytosolic DNA-sensing pathway in response to ATR inhibition. Treatment with the ATR inhibitor VE822 concurrently upregulated immune cell infiltration and immune checkpoint expression in Setd2 knockdown Renca tumors, providing a rationale for ATR inhibition plus ICB combination therapy. Setd2-deficient Renca tumors demonstrated greater vulnerability to ICB monotherapy or combination therapy with VE822 than Setd2-proficient tumors. Moreover, SETD2 mutations were associated with a higher response rate and prolonged overall survival in patients with ICB-treated RCC but not in patients with non-ICB-treated RCC. CONCLUSIONS: SETD2 loss and ATR inhibition synergize to promote cGAS signaling and enhance immune cell infiltration, providing a mechanistic rationale for the combination of ATR and checkpoint inhibition in patients with RCC with SETD2 mutations.

Current Systemic Treatments for the Hereditary Cancer Syndromes: Drug Development in Light of Genomic Defects.

Advances in the genetic basis of different tumors have led to identification of tumor vulnerabilities that can be turn into targeted therapies. In this regard, PARP inhibitors cause synthetic lethality with tumors harboring BRCA1 or BRCA2 genetic alterations. On the other hand, tumors with microsatellite instability, either due to germline or sporadic alterations, are candidates for immune checkpoint inhibitors. Finally, patients with von Hippel-Lindau disease who carry a germline alteration in the VHL gene may benefit form belzutifan, a hypoxia-inducible factor 2 alpha inhibitor. Overall, research on the underlying pathological mechanisms of these tumors has provided new therapeutic opportunities that might be expanded to other sporadic tumors with similar biology.

Serum IGF-1 Scores and Clinical Outcomes in the Phase III IMbrave150 Study of Atezolizumab Plus Bevacizumab versus Sorafenib in Patients with Unresectable Hepatocellular Carcinoma.

Purpose: Child-Turcotte-Pugh class A (CTP-A) in unresectable hepatocellular carcinoma (HCC) is the standard criterion for active therapy and clinical trial enrollment. We hypothesized that insulin-like growth factor-1 (IGF-1) derived scores may provide improved survival prediction over CTP classification. This study aimed to evaluate the potential prognostic and predictive effects of IGF-1 derived scores in the phase III IMbrave150 study. Patients and Methods: Baseline and on-treatment serum IGF-1 levels from 371 patients were subjected to central analysis. Patients' IGF-1 score (1/2/3) and IGF-CTP score (A/B/C) were determined based on pre-specified cutoffs. Outcomes were analyzed by baseline and by on-treatment changes of the IGF-1 and IGF-CTP scores within and between the two treatment arms. The interaction between these scores and outcomes was assessed using univariate and multivariate analyses. Results: Baseline IGF-CTP score (A vs B/C) showed prognostic significance for OS in both the atezolizumab-bevacizumab (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.20-0.56; P<0.001) and sorafenib (HR, 0.32; 95% CI, 0.16-0.65; P=0.002) arms. Baseline IGF-1 score (1 vs 2/3) also showed prognostic significance for OS in both the atezolizumab-bevacizumab (HR, 0.33; 95% CI, 0.20-0.55; P<0.001) and sorafenib (HR, 0.48; 95% CI, 0.26-0.89; P=0.02) arms. HRs for PFS were consistent with those for OS. No significant predictive effects were observed for either score between the two arms. Kinetic analysis revealed that patients with increased IGF-1 score (1-> 2/3) at 3 weeks post treatment had shorter OS than patients with stable IGF-1 score of 1 in both the atezolizumab-bevacizumab (HR, 3.70; 95% CI, 1.56-8.77; P=0.003) and sorafenib (HR, 5.83; 95% CI, 1.88-18.12; P=0.0023) arms. Conclusion: Baseline and kinetic change of IGF-CTP and IGF-1 scores are independent prognostic factors for patients with unresectable HCC treated with atezolizumab-bevacizumab or sorafenib. These novel scores may provide improved patient stratification in future HCC clinical trials. IMbrave150 ClincialTrials.gov number, NCT03434379.

Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial.

BACKGROUND: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. METHODS: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. FINDINGS: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3-4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47-not estimable [NE]) with nivolumab and 19·53 months (2·33-NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31-2·54); median time to progression was 9·4 months (95% CI 1·47-NE) in the nivolumab group and 19·53 months (2·33-NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31-2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. INTERPRETATION: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. FUNDING: Bristol Myers Squibb and the US National Institutes of Health.

MK-6482 as a potential treatment for von Hippel-Lindau disease-associated clear cell renal cell carcinoma.

INTRODUCTION: Von Hippel-Lindau (VHL) disease is an inherited autosomal dominant syndrome caused by a germline mutation and/or deletion of the VHL gene. Inappropriate hypoxia-inducible factor (HIF)-mediated transcription of proangiogenic and metabolic genes leads to the development of tumors and cysts in multiple organs. Surgery is a standard treatment for localized tumors with a risk of metastasis or organ dysfunction. Repeated surgeries cause substantial morbidity and have a major impact on quality of life. There is an urgent need to develop effective and safe systemic treatments for VHL disease manifestations. The small-molecule HIF 2 alpha inhibitor MK-6482 (belzutifan) has demonstrated significant efficacy in VHL disease related renal cell carcinomas, hemangioblastomas, and pancreatic neuroendocrine tumors while demonstrating an acceptable safety profile. AREAS COVERED: This paper reviews the development of the HIF-2 alpha inhibitor, MK-6482, and discusses preliminary results of ongoing phase I/II studies in renal cell carcinoma (RCC) and VHL disease. An examination of ongoing clinical development of MK-6482 and perspectives on potential future developments and challenges are offered. EXPERT OPINION: Because of its favorable safety profile, its clear efficacy in VHL disease, promising findings in sporadic, advanced RCC, and convenient oral formulation, MK-6482 is expected to become a leading treatment for VHL disease. Among other currently available oral agents, we believe that MK-6482 will be a preferred treatment for VHL-associated RCC.

Outcomes of changing systemic therapy in patients with relapsed breast cancer and 1 to 3 brain metastases.

The development of brain metastases (BMs) in breast cancer (BC) patients remains a challenging complication. Current clinical practice guidelines recommend local treatment of BMs without changing systemic therapy (CST) in patients with stable extracranial disease. We retrospectively investigated the impact of CST (when applicable as per treating physician's discretion) following the diagnosis and management of oligometastatic (1-3) BMs in patients without extracranial metastases on the progression-free survival time (PFS), and overall survival (OS). Hazard ratios (HRs) were calculated using the Cox proportional hazard model. Among the 2645 patients with BC and BMs treated between 2002 and 2015, 74 were included for analysis. 40.5% of patients had HER2 + disease. Median time from diagnosis of BC to BMs was 17.6 months. 54%, 8%, and 38% of BMs were managed by radiation, craniotomy, or combination, respectively. Following the primary management of BMs, we observed that CST occurred in 26 (35.5%) patients, consisting of initiation of therapy in 13.5% and switching of ongoing adjuvant therapy in 22%. Median PFS was 6.6 months among patients who had CST compared to 7.1 months in those who did not (HR = 0.88 [0.52-1.47], p = 0.62). Median OS was 20.1 months among patients who had CST compared to 15.1 months in those who did not (HR = 0.68 [0.40-1.16], p = 0.16). Upon the successful local management of oligometastatic BMs in patients without extracranial disease, we did not find a significant difference in survival between patients who experienced a change in systemic therapy as compared to those who did not.

Current Landscape and Future Directions of Biomarkers for Immunotherapy in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common liver cancer and one of the leading causes of cancer-related deaths in the world. Multiple immunotherapeutic approaches have been investigated to date, and immunotherapy has become the new standard of care therapy in HCC. However, the current role of immunotherapy in HCC remains non-curative. Given this context, a high priority for oncology is understanding the biomarkers that predict clinical response to immunotherapy, have the potential to improve patient selection to maximize the clinical benefit, and spare unnecessary toxicity. In this review, we summarize the key predictive and prognostic biomarkers investigated in immunotherapy clinical trials in HCC and the emerging biomarkers to serve as a roadmap for future clinical trials. Biomarkers from tumoral tissues including PDL-1 expression, tissue infiltrating lymphocytes, tumor mutational burden (TMB) and specific immune signatures, and from peripheral blood including neutrophil-to-lymphocytes ratio, platelet-to-lymphocytes ratio, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and specific cytokines, along with gut microbiota are among the studied biomarkers to date in the HCC era. More integrative approaches, including mathematical biomarkers to predict immunotherapy outcomes, are yet to be studied in HCC.

The Immunotherapy Revolution in Kidney Cancer Treatment: Scientific Rationale and First-Generation Results.

The recent discovery of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, including the treatment for renal cell carcinoma (RCC). Following the eras of cytokines and molecularly targeted therapies including vascular endothelial growth factor-directed agents and mammalian target of rapamycin (mTOR) inhibitors, ICIs have become the latest addition to the RCC armamentarium. To understand the scientific rationale behind this revolution in RCC treatment, we have reviewed the fundamental discoveries underlying the transition from old (cytokines) to new (ICIs) immunotherapies. We summarize the pivotal trials (CheckMate 025, CheckMate 214, KEYNOTE-426, JAVELIN Renal 101, IMmotion151) of checkpoint inhibitors for clear cell RCC in various treatment settings. With the availability of many different combination therapies and many more currently under investigation, clear cell RCC treatment is becoming more complex. Patient preferences, disease volumes, and adverse event profiles are essential in determining which option is the best for an individual patient. In the future, biomarkers currently under development could guide these treatment decisions.