Renal cell carcinoma (RCC) is the most common type of kidney cancer. In 2019, 73,820 patients received a diagnosis of kidney cancer according to data from the American Cancer Society. Of those patients, roughly 30% to 35% present with de novo metastatic disease, and a subset of patients with localized disease subsequently develop metastatic disease.

 The multidisciplinary management of advanced RCC has undergone tremendous changes over the past several years. In 2005, the targeted therapy era was launched with the introduction of VEGF- and mTOR-targeted therapies. Most recently, immunotherapy (IO) has entered the treatment landscape, initially as single agents and now in combination with other IOs and also VEGF-targeted therapies. Additionally, the role of upfront cytoreductive nephrectomy (CN) has been evolving in advanced disease. In this review, we highlight multidisciplinary treatment for patients with advanced disease, integrating systemic therapy options with surgery and radiation therapy.

Risk Stratification for Patients With Advanced Disease

The most commonly used risk classification system is the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model, which was developed and validated in the era of tyrosine kinase inhibitors (TKI).

 Clinicians also use it for IO combinations, given the integration of these agents in today’s trials.

 This model includes scores for Karnofsky performance status, anemia hypercalcemia, thrombocytosis, neutrophilia, and less than 1 year from diagnosis to treatment. Patients with advanced RCC are stratified into 3 different groups based on the risk factors: favorable, intermediate, and poor. In addition, clinicians also use the Memorial Sloan Kettering Cancer Center (MSKCC) or Motzer’s criteria to stratify patients patients with metastatic RCC.

 This model was developed in the cytokine era and is less commonly applied now. Investigators have validated both models in numerous studies.

The role of CN in the setting of metastatic disease remains controversial. One of the first descriptions of CN in this setting was in a series of 33 patients in 1967 by Milton et al.

 From that time, the role of CN grew and was tested in the setting of cytokine therapy in 2 randomized controlled trials (RCTs).

 In both trials, patients were randomized to receive either interferon α (IFN-α) alone or CN followed by IFN-α. In a combined analysis of 331 patients from both trials, CN was associated with improved overall survival (OS; 13.6 vs 7.8 months, respectively; 

 < .01). However, the trials were criticized for their modest survival benefit and imbalance between treatment groups. Moreover, IFN-α was shown to have severe adverse effects (AEs) and was not widely used at that time.

More recently, 2 RCTs evaluated the role of CN in the context of targeted therapy use with sunitinib (Sutent). Although these trials have their limitations, their data have provided instruction regarding the utility of CN in advanced disease.

CARMENAInvestigators of the prospective phase 3 noninferiority CARMENA trial (NCT00930033) randomized patients to CN followed by sunitinib versus sunitinib alone if they had intermediate- or poor-risk disease. In this analysis, sunitinib alone was associated with noninferior OS for both intermediate- and poor-risk groups. This trial was criticized for its poor and slow accrual, patient selection, and risk stratification by the MSKCC risk model.

 Follow-up results presented at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium restratified patients using IMDC criteria. The results demonstrated a clear benefit for the sunitinib alone arm versus CN then sunitinib for patients with 2 IMDC risk factors (31.2 vs 17.6 months, respectively; 

 = .03). They also showed that in the sunitinib alone arm a subset of patients went on to receive CN, and those patients had a longer median OS compared with those receiving only sunitinib of 48.5 months (95% CI, 27.9-64.4) versus 15.7 months (95% CI, 13.3-20.5).

 Together, these results support the use of up-front systemic therapy and the hypothesis that some carefully selected patients may benefit from CN. 

In a second illustrative RCT, investigators of SURTIME (NCT01099423) evaluated immediate CN followed by sunitinib versus sunitinib followed by delayed CN. In the intention-to-treat population, OS was significantly higher in the deferred CN group compared with the immediate CN group (HR, 0.57; 95% CI, 0.34-0.95; 

 = .03). Similar to CARMENA, the study drew criticism for its slow and poor accrual. The gradual accrual led investigators to modify the primary end point to an intention-to-treat, 28-week progression-free rate (PFR) instead of progression-free survival (PFS). Nevertheless, both trials provide level 1 evidence indicating a need for systemic therapy and that the use of CN requires careful patient selection.

Additional studies hope to further clarify the answer regarding CN's role in the setting of metastatic RCC. NORDIC SUN (NCT03977571) is an RCT of intermediate- and poor-risk patients receiving checkpoint IO. After 3 months or a total of 4 doses of nivolumab (Opdivo) combined with ipilimumab (Yervoy), whichever comes first, patients will be evaluated for resectability at a multidisciplinary meeting. Those with at least 3 IMDC risk factors who are deemed suitable for CN will then undergo randomization.

At the forefront of trials in the development of CN's role, there are 2 additionally important studies. The PROBE trial (NCT04510597) will evaluate up-front IO therapy for patients with metastatic RCC, and those who have a complete response, partial response, or stable disease will be randomized to CN or continue systemic therapy alone.

 Investigators of the CYTOSHRINK trial (NCT04090710) will evaluate stereotactic body radiation therapy (SBRT) with or without nivolumab plus ipilimumab in patients with intermediate- and poor-risk disease. These more contemporary studies will evaluate the role of surgery or SBRT in the primary treatment of renal tumors in patients with advanced disease receiving modern therapy.

Until 2018, treatment with a single-agent TKI was the standard of care for patients with advanced RCC. In 2018, a significant transition in the treatment paradigm occurred in the front line setting for these patients. The CheckMate 214 trial (NCT02231749) compared sunitinib to nivolumab/ipilimumab and demonstrated improved 18-month OS (75% vs 60%), improved PFS (11.6 vs 8.4 months; 

 = .03), superior objective response rate (ORR; 42% vs 27; 

 < .01), and fewer grade 3 to 4 AEs (46% vs 63%).

 Updated results with a 42-month minimum follow-up demonstrated persistent improvement in OS (HR, 0.66; 95% CI, 0.55-0.9; 

 < .01). The median OS in the treatment group was 47 months versus 26.6 months in the sunitinib group, with a durable response observed in a subset of patients.

Furthermore, data have shown that IO combined with a VEGF-targeted TKI has been effective. The KEYNOTE-426 trial (NCT02853331) compared pembrolizumab (Keytruda) plus axitinib (Inlyta) to sunitinib in patients with advanced RCC. The initial analysis demonstrated that at a median follow-up of 12.8 months, median OS was higher in the pembrolizumab plus axitinib group (89.9%) compared with the sunitinib group (78.3%; HR, 0.53; 95% CI, 0.380.74; 

 < .01). The combination also showed superior PFS (HR, 0.69; 95% CI, 0.57-0.84; 

 < .01) compared with sunitinib. Lastly, pembrolizumab plus axitinib was shown to benefit all 3 risk groups irrespective of PD-L1 expression.

In an updated analysis of a 23-month minimum follow-up, the HR for OS in the favorable-risk group was 1.06 (95% CI, 0.60-1.86) and there was not much of a split between the groups. This is in contrast to intermediate- and poor-risk groups, where the HR for OS was 0.63 (95% CI, 0.50-0.81) and 0.69 (95% CI, 0.56-0.84) for PFS. Lastly, the ORR was 55.8% in the combination arm versus 35% in the sunitinib arm.

The JAVELIN Renal 101 trial (NCT02684006) compared avelumab (Bavencio) plus axitinib to sunitinib in patients with treatment-naïve, advanced clear cell RCC. The primary end points were PFS and OS. Data showed superior median PFS, at 13.8 months with avelumab plus axitinib versus 7.2 months with sunitinib, in patients with PD-L1 expression of at least 1% (HR, 0.61; 95% CI, 0.47-0.79; 

 < .01), as well as in the overall population (HR, 0.69; 95% CI, 0.56-0.84; 

 < .001). Patients treated with the combination therapy also had a greater ORR of 55.2% versus 25.5% with sunitinib.

 Lastly, median follow-up for OS was 11.6 months for the combination group and 10.7 months for the control arm (

 = .14). These studies designate a new frontline standard of care for patients with advanced RCC. For patients who have poor and intermediate disease, treatment will likely include an IO combination.

Data from the CheckMate 9ER (NCT03141177) were recently presented at the 2020 Europe-an Society for Medical Oncology Virtual Congress. In this trial, patients were randomized to receive cabozantinib (Cabometyx) plus nivolumab versus sunitinib. In the intention-to-treat arm, combination cabozantinib plus nivolumab demonstrated significantly improved PFS over sunitinib (16.6 vs 8.3 months, respectively; HR, 0.51; 95% CI, 0.41-0.64; 

 < .01), and a 40% decreased risk of death (median OS not reached; HR, 0.60; 95% CI, 0.40-0.89). Furthermore, the ORR was higher in patients who received cabozantinib plus nivolumab (55.7%; 95% CI, 50.1%-61.2%) compared with those receiving sunitinib (27.1%; 95% CI, 22.4%-32.3%; 

 < .01). Lastly, complete response rates were also higher among those receiving the combination (8.0% vs 4.6%).

It is important to caution against direct com-parison across these trials. They were all conducted at different time points and significant differences exist between them in terms of primary end points, patient populations, and pro-portion of patients with PD-L1 expression.

There are 3 ongoing studies that will further inform the treatment landscape for patients with advanced RCC (

). COSMIC-313 (NCT03937219) will evaluate the combination of nivolumab/ipilimumab/cabozantinib versus nivolumab/ipilimumab/placebo. This trial includes a control arm. CLEAR (NCT02811861) will evaluate pembrolizumab/lenvatinib (Lenvima) versus lenvatinib/everolimus (Afinitor) versus suntinib. The primary end point is PFS. Finally, the PDIGREE Study (NCT03793166) will examine therapy escalation for patients without complete response or progressive disease following treatment with nivolumab plus ipilimumab. These patients will be randomized to continued nivolumab versus nivolumab plus cabozantinib. The outcomes of these trials may further elucidate the optimal agents and sequencing for treatment.

Table. Select Ongoing Phase 3 Trials in Renal Cell Carcinoma

The role for single-agent TKIs in the frontline space is becoming more limited as IO combinations enter the treatment landscape. How-ever, they may still be considered in those patients with contraindications to IO or those with favorable-risk disease. The phase 2 CABO-SUN trial (NCT01835158) compared frontline cabozantinib versus sunitinib for patients with intermediate- or poor-risk disease per IMDC. The primary end point of this study was PFS. Among a total of 157 patients, the median PFS was 8.6 months (95% CI, 6.8-14.0) for cabozantinib versus 5.3 months (95% CI, 3.0-8.2) with sunitinib (HR, 0.48; 95% CI, 0.31-0.74; 2-sided 

 < .01). Additionally, the ORR was 20.0% (95% CI, 12.0%-30.8%) versus 9% (95% CI, 3.7%-17.6%), respectively.

 When stratified by MET tumor positivity, a subanalysis of PFS data showed that cabozantinib improved PFS independent of MET status. One of the notable drawbacks of this study was that patients deemed good risk were not included. Regardless, cabozantinib is included as a treatment option for patients with good-risk disease in the National Comprehensive Cancer Network guidelines.

Investigators have also evaluated single-agent IO for the treatment of patients with metastatic RCC; specifically, pembrolizumab in the KEYNOTE-427 trial (NCT02853344). The primary end point was ORR by RECIST 1.1 criteria. The confirmed ORR for the 107 patients included in the efficacy analysis was 33.6% (95% CI, 24.8%-43.4%). The median duration of response was not reached (NR; range 1.4 + to 8.2 + months), and the median PFS was 6.9 months (95% CI, 5.1-NR). OS rates at 3 and 6 months were 97.2% and 92.4%, respectively. According to investigators, 73.6% of patients experienced AEs, 18.2% of which were great-er than grade 3.

 Further investigation to test the additional benefit of ipilimumab to nivolumab in the frontline setting is ongoing in the CA209-8Y8 trial (NCT03873402). The trial has a primary end point of ORR and PFS and includes patients with intermediate- and poor-risk disease.

In comparing TKI therapy to IO therapy, it is important to consider the safety profile as well as contraindications to both. The combination of nivolumab plus ipilimumab has fewer grade 3 complications compared with sunitinib, and toxicity is generally limited to the induction of ipilimumab.

 Depending on the trial, approximately 11.1 % of patients required high-dose steroids to treat AEs.

 For IO-TKI therapy, patients generally experience more grade 3 complications, there is a higher toxicity profile, and the toxicity is likely to be more chronic due to the TKI component.

Several recent landmark studies have redefined our frontline treatment strategies for patients with advanced RCC. Multidisciplinary management is the future of RCC care and with combination therapy patients are living longer and better than before. However, many questions remain about optional choice in the front line and the sequencing of therapy.

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Articles

In this review, authors highlight multidisciplinary treatment for patients with advanced disease, and integrating systemic therapy options with surgery and radiation therapy. 

Ithaar Derweesh, MD

Articles

Frontline Therapeutic Planning for Metastatic Renal Cell Carcinoma