Axitinib is an oral TKI that has been approved as a monotherapy and, more recently, as a combination therapy in advanced RCC (15, 16). Axitinib was first evaluated in the neoadjuvant setting by Karam et al. In 24 patients with biopsy-confirmed, nonmetastatic cT2-T3b clear cell renal cell carcinoma (ccRCC), Axitinib was administered neoadjuvantly, followed by surgical resection. The median reduction in the primary renal tumor diameter was 28.3%, with 11 patients (45.8%) showing partial response and 13 patients having stable disease according to RECIST criteria. No disease progression was observed while on Axitinib. Postoperatively, there were thirteen grade 2 and two grade 3 complications, with no grade 4 or 5 complications. It was concluded that, in patients with locally advanced non-metastatic ccRCC, Axitinib demonstrated clinical effectiveness and was generally well-tolerated when used in the neoadjuvant setting (17).

Lebacle et al. also evaluated Axitinib’s use in the neoadjuvant setting. The aim was different as it was used to downstage cT2aN0-NxM0 ccRCC patients who were ineligible for partial nephrectomy. 18 patients were enrolled. After receiving 2-6 months of neoadjuvant therapy 12 patients achieved the primary outcome, tumor size <7 cm in size, and 16 patients’ tumors decreased in diameter, and they became eligible for PN. Grade 3 adverse events were observed in 5 patients, and another 5 patients faced Clavien III-V complications after their surgeries. At the 2-year follow-up, 6 patients exhibited metastatic progression, while two experienced a recurrence. The study authors concluded that Axitinib was an appropriate neoadjuvant strategy in selected patients. Specifically, in those with cT2 ccRCC tumors, Axitinib may decrease the size of the tumor and make PN possible (18).

Like Axitinib, Pazopanib is an oral VEGFR TKI but with an expanded mechanistic range. In addition to its VEGFR inhibitive properties, Pazopanib also inhibits platelet-derived growth factor (19). Pazopanib has been approved in the metastatic setting based on its demonstrated efficacy and tolerability (20). Neoadjuvant Pazopanib was evaluated in a phase II trial. The trial evaluated the ability of neoadjuvant Pazopanib to allow for PN in localized ccRCC, similar to Lebacle et al.’s Axitinib study. Patients accepted to the trial had to meet at least one preoperative criteria: either their PN or RN was likely to yield a glomerular filtration rate of less than 30 ml/minute/1.73 m2, or their planned PN was deemed high risk due to high complexity (21), which is a R.E.N.A.L. nephrometry score of 10-12 and/or tumor proximity to the renal hilar vessels (22). The primary endpoint was tumor size reduction to allow for PN. 25 patients were enrolled in the study, and 13 were ineligible for PN based on pre-therapy assessment. After treatment, the objective tumor response rate was reached in 33% of patients, and 6 of these 13 (46%) patients became eligible for PN with the tumor diameter reduction. In addition, these patients demonstrated improved preservation of functional renal parenchyma. Notably, most patients (64%) developed grade 3 adverse events. The study noted that neoadjuvant Pazopanib reduced the size of localized ccRCC, preserving more renal tissue and making PN possible for some patients who would otherwise need a radical nephrectomy (21).

Sorafenib is an oral, multi-targeting VEGFR, platelet-derived growth factor receptor, fibroblast growth factor receptor-1, and Ras/Raf/MEK pathway inhibitor (23). After approval for treatment of RCC in the metastatic setting, Sorafenib was evaluated in the adjuvant and neoadjuvant setting. In the neoadjuvant trial, patients were randomized in a 3:1 fashion to Sorafenib or placebo (24). The primary outcomes were a reduction in tumor volume and evaluation of R.E.N.A.L scores. Ultimately, while no significant change in tumor volume was seen in the placebo arm, in the Sorafenib arm tumor volume reduction was 29%. There was no statistically significant change in R.E.N.A.L scores in the placebo, whereas it decreased in four out of nine cases within the sorafenib group.

More recent data also suggests neoadjuvant treatment with cabozantinib contributed to tumor reduction with no disease (25). Bilen et al. demonstrated cabozantinib was clinically active and safe in the neoadjuvant setting in patients with locally advanced nonmetastatic ccRCC. 16 patients with biopsy-proven ccRCC were treated with neoadjuvant cabozantinib at a starting dose of 60 mg once per day for 12 weeks. The primary outcome of this study was an objective response rate at 12 weeks per RECIST v1.1, including complete and partial responses. Results from this analysis demonstrated that all patients had tumor reduction. 5 patients (29.4%) had a partial response (overall response rate = 0.29; 95% CI, 0.1-0.56) and 11 patients had stable disease. Progression of the disease was not observed in the patients treated with cabozantinib (25). The selected prospective studies of neoadjuvant/preoperative targeted therapy are summarized in Table 1 .

The adjuvant treatment strategies have been evolving with a particular focus on novel IO therapies. The standard of care for patients with localized and locoregional diseases involves definitive surgical strategies, with 5-year overall survival rates of 93% and 71% for these groups. However, the approval of Pembrolizumab in selected high-risk patients has led to a shift in treatment strategies and sparked the investigation of alternative options within this context (37).

For patients with localized or locoregional disease who have undergone surgical resection, the question of which patients would benefit from adjuvant therapy is key. Most trials evaluated and stratified patients’ risk according to tumor-node-metastasis (TNM) staging. The risk of recurrence can also be calculated using either the University of California, Los Angeles (UCLA) Integrated Staging System (UISS) or the Mayo Clinic Leibovich prognostic model (38, 39). Those patients with a higher estimated risk of recurrence at five years (≥30 percent) were also likely to benefit from adjuvant therapy. However, clinically and practically, most clinicians still use TNM staging to determine those at the highest risk of recurrence and, thus, most likely to benefit from adjuvant therapy.

Historical trials now provide important insight into agents that are not beneficial and, in some cases, may be detrimental. Interferon-alpha (IFN- α) and interleukin-2 (IL-2) were both studied in the 2000s as adjuvant agents. A study of high-dose IL-2 given after surgical resection in individuals with completely resected, locally advanced (T3b-4 or N1-3) or metastatic (M1) disease was found to be ineffective (40). DFS for the IL-2 and placebo groups were the same so the study was terminated early. IFN- α was also evaluated as a possible therapeutic agent. Those patients with T3-4a and/or N, M0 disease after complete surgical resection were tested with IFN- α against standard-of- care observation (29). Median OS was 7.4 years in the observation arm and 5.1 years in the treatment arm, indicating a lack of clinical benefit. POLAR-01 evaluated the combination of IFN α and low-dose IL-2 therapies in completely resected pT2-3bM0 and pN0-3M0 disease. The results were similar to those of IL-2 and IFN- α as monotherapy. Relapse-free survival (RFS) and OS were similar for the treatment and observation arms (41). Based on this data, it is clear that there is no clinical benefit to using IFN-α or IL-2, either as monotherapy or in combination in the adjuvant setting.

Sunitinib is currently approved by the Food and Drug Administration (FDA) for adjuvant therapy based on improved DFS in patients with high-risk diseases. However, it did not demonstrate a benefit in OS in any subgroup and is associated with significant toxicity. As a result, it is not a treatment that is widely used in clinical practice (42). In the S- TRAC trial, patients with locoregional, non-metastatic RCC (T3/4 and N0/x or any T stage with local node involvement and clear cell histology) were randomized in a 1:1 ratio to receive Sunitinib or placebo for 1 year. The primary endpoint of DFS was 6.8 years in the Sunitinib arm and 5.6 years in the placebo arm. Based on these data the FDA approved Sunitinib for use in the adjuvant setting for RCC patients with high-risk disease. At the conclusion of the study, OS data were immature and the number of deaths among treatment arms was equal. Upon closer analysis, it became evident that the administration came at a substantial cost. Only 56% were able to complete the full 1-year treatment, indicating that the discontinuation rate was unacceptably high. Later analyses evaluating the OS rate for Sunitinib failed to demonstrate meaningful benefit. The hazard ratio (HR) for Sunitinib vs placebo was 0.92 (95% CI 0.66 – 1.28, p = 0.6). While it technically remains approved, it is not the preferred choice in clinical practice.

Another study, the ASSURE trial, evaluated Sunitinib and Sorafenib, another VEGFR TKI, against placebo in a 1:1:1 ratio comparison (43). A total of 1943 patients with completely resected intermediate-, high-, or very high-risk RCC were randomly assigned to receive Sunitinib, Sorafenib, or placebo for up to one year. The median follow-up time was 5.8 years. Similar DFS was observed for the treatment arms: sunitinib versus placebo, with a median of 5.8 years versus 6.6 years (HR 1.02, 97.5% CI 0.85-1.23); sorafenib versus placebo, median 6.1 versus 6.6 years (HR 0.97, 97.5% CI 0.8-1.17). OS was also calculated and was similar between groups: sunitinib versus placebo (HR 1.17, 97.5% CI 0.9-1.52); sorafenib versus placebo (HR 0.98, 97.5% CI 0.75-1.28). Interestingly, in a post-hoc subgroup analysis, older women also experienced increased mortality. The treatment was also associated with substantial toxicity. Both VEGF TKIs were associated with hypertension, hand-foot syndrome, rash, and fatigue at significant rates (sunitinib and sorafenib vs placebo - hypertension 17% and 16% versus 4%, hand-foot syndrome 15% and 33% versus 1%, rash 2% and 15% versus <1%, and fatigue 18% and 7% versus 3% (44).

Pazopanib, another VEGFR TKI, was evaluated in the PROTECT trial, a study that compared adjuvant Pazopanib to placebo (45). Similar to other trials, and the general theme of VEGFR TKI vs placebo, DFS was similar between pazopanib and placebo (HR 0.86, 95% CI 0.70–1.06, p = 0.165). Interestingly, the study underwent a change from the initial protocol with a dose reduction amendment from 800mg to 600mg. A later analysis did not demonstrate an OS benefit (HR 1.0, 95% CI 0.80–1.26, p > 0.9). Notably, DFS was improved for those assigned to the higher daily dosing of 800mg/day (66% versus 56%, HR 0.66, 95% CI 0.49-0.9). The discontinuation rate was significantly higher in the Pazopanib group at 36% (46).

The ATLAS trial compared Axitinib against placebo in 724 patients who had undergone nephrectomy for a minimum of 1 year, up to 3 years. Axitinib failed to demonstrate a DFS benefit. As a result, in a pre-planned interim analysis, the trial was stopped early due to futility (HR 0.870, 95% CI 0.660–1.147, p = 0.3211). Axitinib was also associated with a higher rate of grade 3 toxicities (61% vs 30%) (47).

In another phase III trial, SORCE, adjuvant Sorafenib was evaluated in 1711 patients who had completely resected RCC and were at intermediate or high risk of disease recurrence. The trial had three arms: patients were randomized to either 3 years of placebo, 1 year of Sorafenib followed by 2 years of placebo, or 3 years of Sorafenib. Sorafenib did not improve DFS (HR 1.01, 95% CI 0.82 to 1.23, p = 0.946) or OS and was associated with higher rates of toxicity compared to placebo (48).

The ARISER trial studied 864 patients and was a randomized, double-blind, placebo- controlled phase 3 clinical trial that evaluated the safety and efficacy of adjuvant Girentuximab (an antibody targeting carbonic anhydrase IX) on DFS and OS (49). Girentuximab did not show statistically significant benefits in DFS (HR 0.97, 95% CI, 0.79-1.18) or OS (HR 0.99, 95% CI, 0.74-1.32). Everolimus (an mTOR inhibitor) was evaluated in the phase III EVEREST trial with resected non-metastatic RCC. The very high-risk population was defined by tumor stage 3a with grade 3 or 4; tumor stage 3b, 3c, or 4 with any grade; or nodal metastases with any tumor stage and any grade.

Everolimus failed to improve recurrence-free survival (RFS) or OS compared with placebo. It was also associated with high rates of treatment discontinuation due to its toxicity profile. Notably, RFS was improved in a subset of the study population. Those with a very high risk of disease recurrence had improved RFS (HR 0·79, 95% CI 0·65- 0·97; p=0·022), suggesting possible efficacy in this particular patient population. This finding was not replicated in the intermediate-high-risk group (HR 0·99, 95% CI 0·73- 1·35; p=0·96) (50).

Finally, several surveillance protocols have been proposed for the patients who were observed after definitive treatment and did not undergo adjuvant therapy. The American Urologic Association (AUA) and the National Comprehensive Cancer Network (NCCN) both have distinct but similar protocols (51, 52). Both of these surveillance protocols utilize a risk-stratified approach for monitoring patients and are equally effective in detecting both locoregional and distant metastases, serving as a useful tool for patient management. Ultimately, both guidelines provide an estimate of the risk of recurrence based on the extent of the disease (51, 52).

IO has proven its effectiveness in the metastatic setting of RCC. The FDA has approved multiple IO combinations, including Pembrolizumab + Lenvatinib, Pembrolizumab + Axitinib, Nivolumab + Ipilimumab, and Avelumab + Axitinib, all of which were approved for use in the first line setting for metastatic RCC. Considering the established use of IO in metastatic RCC and its growing clinical significance in other genitourinary (GU) and non-GU cancers, it is reasonable to question its potential role in the perioperative RCC space.

Currently, only Pembrolizumab is FDA-approved as adjuvant therapy for RCC patients at high risk of recurrence after nephrectomy. In the Keynote-564 study, which was a double-blind, placebo-controlled phase III trial, patients with histologically confirmed RCC treated with nephrectomy were randomized to receive either Pembrolizumab every three weeks for up to 1 year (17 cycles in total) or placebo. The risk for disease recurrence was defined as intermediate to high risk (pT2 tumors with grade 4 or sarcomatoid features N0, M0; or pT3, any grade, No, M0), high risk (pT4, any grade, N0, M0; or any pT, any grade, N1, M0), or M1 with no evidence of disease (resection of all oligometastatic sites (M1) with no evidence of disease (NED) within one year of nephrectomy). At the median follow-up duration of 24 months, Pembrolizumab improved DFS compared with placebo across all disease risk groups (24-months DFS 77.3% versus 68.1%, HR 0.68, 95% CI 0.53-0.87). This treatment also demonstrated an OS benefit across all disease risk groups (24-month OS 96.6% (%95 CI, 94.3-98) versus 93.5% (95% CI, 90.5-95.6)). However, OS data are not statistically significant yet and longer follow-up is required for the data maturation. Notably, the PD-L1 combined positive score (CPS) was greater than or equal to 1 for 73.6% of patients on Pembrolizumab and 76.9% on placebo. The discontinuation rate was significantly higher in the treatment arm at 20.7% compared to 2.0% in the placebo arm. Based on these data, the FDA and the European Medicines Agency (EMA) approved Pembrolizumab for adjuvant treatment of RCC patients at high risk of recurrence following nephrectomy. Interestingly, the study also included 58 patients with oligometastatic disease that was resected with NED within one year of nephrectomy (M1, NED). In this group of patients, adjuvant Pembrolizumab also increased DFS compared to placebo (median not reached versus 12 months, HR 0.28, 95% CI 0.12-0.66). Based on this data, the FDA also granted approval for Pembrolizumab’s use following nephrectomy and resection of metastatic lesions (53).

Some trials have also evaluated the use of IO therapy in the neoadjuvant setting. The Neoavax, a phase II study, assessed neoadjuvant Avelumab and Axitinib before nephrectomy in 40 patients with cT1b–4cN0–1M0, grades 3–4 RCC. None of the patients on trial had tumor progression while 30% (12 patients) had a partial response to the treatment (54). Neoadjuvant nivolumab was also evaluated in an early phase small study of 17 patients with nonmetastatic high-risk RCC. In this study, all 17 patients had stable disease according to the RECIST criteria, and the drug was found to be safe and well tolerated. 2 patients (11.8%) experienced grade 3 events. 10 patients (58.8%) experienced adverse events of any grade potentially attributable to nivolumab (all were grade 1-2), and there were no grade 4-5 adverse events (55). The mechanism of action of ICIs for RCC is shown in Figure 1 and the targated neoadjuvant therapies for RCC is schematized in Figure 2 .

There are a number of trials ongoing at the time of this publication and several others that have recently reported evaluating the efficacy and safety of adjuvant therapy in RCC. PROSPER RCC study evaluated the patients with clinical stage T2Nx, N+ any T, or M1 patients with planned resection. All patients in the study were planned to be definitively treated so that they would effectively be considered M1 NED. The patients with high-risk RCC were randomly assigned in an open-label design to undergo surgery alone, or an approach of priming the immune system with nivolumab prior to full or partial removal of the kidney followed by additional nivolumab. In the intervention arm, patients received one dose of nivolumab prior to surgery followed by adjuvant nivolumab every 4 weeks for up to 9 cycles. Notably, this approach was strongly supported by the patient advocates. However, this trial was stopped early because, at a planned interim analysis, it showed no difference (HR 0.97, 95% CI 0.74 – 1.28; p 1-sided = 0.43) in RFS between the arms in a patient population that included both clear cell and non–clear cell disease subtypes (58).

RAMPART is an ongoing multi-arm multi-stage (MAMS) platform trial in those patients with resected locally advanced RCC (both clear cell and non-clear cell histological subtypes are included in the study), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3-11). The trial is assessing if Durvalumab monotherapy or the combination of Durvalumab and Tremelimumab (an inhibitory agent against cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]) can improve DFS or OS compared to the active monitoring. Participants are randomly assigned (3:2:2) to Arm A - active monitoring (no placebo) for one year; Arm B - Durvalumab for one year; or Arm C - combination therapy with Durvalumab for 1 year plus two doses of Tremelimumab for the first two cycles. The primary outcomes will be measured as DFS and OS, and secondary outcomes will be measured for safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences (59, 60).

Checkmate-914 study enrolled patients with localized ccRCC who were at high risk of relapse after radical or partial nephrectomy between 4–12 weeks before random assignment (61, 62). In part A of the study, the patients were randomized to receive nivolumab plus ipilimumab or placebo, and the results were reported in early 2023.

Adjuvant therapy with Nivolumab plus Ipilimumab 5-year DFS Kaplan-Meier estimates 109.3 months (95% CI 83.9-134.6 months). Part B of the study, which is currently underway, evaluates the combination mentioned above versus single agent nivolumab for 1 year. DFS is the primary endpoint with safety serving as the secondary endpoint (61).

IMmotion010 was a randomized, double-blinded, multicenter, phase 3 trial that evaluated Atezolizumab in the adjuvant setting. After nephrectomy with or without metastasectomy, patients were randomly assigned in a 1:1 ratio to receive Atezolizumab or placebo once every 3 weeks for 16 cycles or 1 year. The primary endpoint was DFS. The results were reported in late 2022, revealing a median investigator-assessed disease-free survival of 57.2 months (95% CI 44.6 to not evaluable) with Atezolizumab and 49.5 months (47.4 to not evaluable) with placebo (HR 0.93, 95% CI 0.75-1.15, p=0.50). The study investigators found Atezolizumab as adjuvant therapy increased the risk of recurrence and showed no evidence of improved clinical outcomes compared to placebo. As a result, the study sponsor decided to terminate the study before the protocol-defined end-of-study (63).

LITESPARK-022 is a recently opened study that is currently ongoing, actively recruiting patients. It evaluates the combination of oral Belzutifan (a HIF-2 alpha inhibitor) plus Pembrolizumab, compared to placebo plus Pembrolizumab in the adjuvant treatment of RCC patients after nephrectomy. Patients with intermediate-high risk (pT2, Grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0), high risk (pT4, any Grade N0, M0; pT any stage, any grade, N1, M0), or M1 NED are actively being recruited. Patients must have undergone nephrectomy and/or metastasectomy ≤12 weeks before randomization and be tumor free, confirmed by imaging. Patients will be randomly assigned in a 1:1 ratio to receive either Belzutifan orally once daily plus Pembrolizumab every 6 weeks or oral placebo plus Pembrolizumab. Pembrolizumab treatment will be administered for up to 9 doses (ã1 year); Belzutifan and placebo may be continued for a maximum of 54 weeks. The primary endpoint of the study is DFS, and secondary outcomes include OS and safety (64).

Selected prospective studies of adjuvant/perioperative therapy are summarized in Table 2 . Additionally, other relevant ongoing neoadjuvant/perioperative trials are shown in Table 3 .

Furthermore, there have been some phase III clinical trials that included metastatic patients without prior nephrectomy. An exploratory post hoc analysis from the phase III CheckMate 214 trial showed the effectiveness of Nivolumab plus Ipilimumab (NIVO+IPI) compared to Sunitinib in 108 patients with advanced RCC who haven’t had nephrectomy, a group often overlooked in clinical studies. After a minimum of four years of follow-up, results showed a significant advantage for NIVO+IPI in terms of PFS, ORR, and OS compared to Sunitinib. The respective figures were 8.1 months, 34%, and 26.1 months for NIVO+IPI, versus 11.9 months, 15%, and 14.3 months for the Sunitinib arm. Notably, 35% of NIVO+IPI patients saw a 30% reduction in their renal tumor size versus 20% of patients with Sunitinib, with safety profiles aligning with the larger study cohort. These findings suggest that NIVO+IPI can offer significant survival and tumor reduction benefits for advanced RCC patients without previous nephrectomy, highlighting its potential in a population where such treatment outcomes are largely unknown (73).

A JAVELIN Renal 101 phase III trial, compared the effect of Avelumab plus Axitinib (A+Ax) with Sunitinib therapy for advanced RCC patients. For patients without a history of nephrectomy, ORR was better in the A+Ax arm, 34.4 months versus 16.9 months (15). In addition, 34.5%of patients in A+Ax compared to 9.7% in Sunitinib experienced at least a 30% reduction in the size of renal target lesions from baseline. The median time to achieve at least a 30% reduction was 4.4 months for A+Ax and 7.1 months for Sunitinib (74).

The phase III CLEAR study demonstrated that Lenvatinib plus Pembrolizumab (L+P) significantly improved efficacy versus Sunitinib as the first-line treatment for patients with advanced RCC (75). When the patients without prior nephrectomy were analyzed, the median OS was not reached for the L+P group, and it was 30.7 months for the Sunitinib group. Additionally, the median PFS was 22.1 months for L+P, versus 7.5 months for Sunitinib, and ORRs were 71.8% and 27.0%, respectively (76). Additionally, 76.8% of patients in the L+P compared to 25.6% in the Sunitinib experienced at least a 25% reduction in the size of renal target lesions from baseline, and 21.4% of patients in the L+P group achieved a 50% or greater reduction, outperforming the 7% in the Sunitinib group (77).

The CheckMate 9ER phase III trial compared Nivolumab plus Cabozantinib (N+C) with Sunitinib for the treatment of previously untreated patients with advanced RCC. In a subgroup analysis of patients without prior nephrectomy, PFS, ORR, and OS were superior in the N+C arm, with respective values of 11.3 months, 42%, and 31.11 months, compared to 7.06 months, 23%, and 27.07 months in the Sunitinib arm. Furthermore, 45% of patients treated with N+C, compared to 30% with Sunitinib, achieved a reduction of at least 30% in the size of renal target lesions from baseline. Moreover, those receiving N+C reported an improvement in health-related quality of life compared to those on Sunitinib (78, 79).

The phase III clinical trials that included metastatic RCC patients without prior nephrectomy are reported in Table 4 .

While definitive surgical resection has been extensively studied in localized and locally advanced settings, its role in the metastatic setting is still debated. Surgical resection of the primary tumor can be performed for palliative purposes to manage conditions such as gross hematuria, relieve abdominal pain, or address paraneoplastic syndromes. However, the therapeutic efficacy of nephrectomy in this context is a subject of ongoing debate. In recent years, the landscape of systemic treatment for metastatic RCC has changed considerably, yet our understanding of the role of cytoreductive nephrectomy (CN) has not advanced at the same oage. Historically, CN was considered the standard of care, offering a survival benefit when performed prior to treatment with IFN- α (81). However, the adoption and standardization of targeted therapies questioned the role of CN.

CARMENA and SURTIME were two pivotal phase III trials that questioned the use of CN in the era of targeted therapy. SURTIME examined whether a period of Sunitinib therapy before CN improved outcomes compared with immediate CN followed by Sunitinib (82). Although the trial did not meet its primary endpoint for PFS with deferred CN, It did reveal a modest survival benefit for this approach. Conversely, CARMENA, a randomized control phase III noninferiority trial, evaluated the efficacy of CN followed by Sunitinib against Sunitinib monotherapy in patients with metastatic RCC. The findings indicated that Sunitinib alone was not inferior to combination of nephrectomy followed by sunitinib in patients with metastatic RCC with intermediate or poor-risk disease (8).

The use of IO combinations and the increased number of systemic therapy options has further questioned the use of CN. Keynote-426, Checkmate 9ER, and Checkmate 214 are three pivotal trials that led to the approval of IO combinations and which reflect the current standard of care. Importantly, few patients with an intact primary tumor were included in these studies (17-30%) (16, 83, 84). Recent post hoc analysis from the pivotal CLEAR trial demonstrated an improvement in OS, PFS, and ORR for patients with an intact primary tumor who received Lenvantinib with Pembrolizumab when compared to Sunitinib (76). While these results do not provide definitive evidence of the lack of utility of CN, they do suggest that the primary tumor may respond similarly to systemic therapies as metastatic sites do.

To better understand the role of CN in the current landscape of IO therapy, multiple prospective clinical trials have been ongoing. NORDIC-SUN and PROBE are two phase III clinical trials evaluating the clinical impact of CN in the metastatic setting. NORDIC-SUN (NCT03977571) will compare the efficacy of Nivolumab plus Ipilimumab with or without CN. In contrast, PROBE (NCT04510597) will evaluate standard of care immunotherapy-based drug combinations with surgery versus the same drug combinations without surgery. Both of these trials have OS as their primary endpoint.

Cyto-KIK (NCT04322955), an open-label phase II, multicenter clinical trial, is evaluating a combination of Nivolumab and Cabozantinib prior to CN in patients with metastatic disease, focusing on complete response as its primary endpoint. Secondary endpoints include median size reduction of the primary tumor, ORR, PFS, OS, and surgical outcomes using the Clavien-Dindo classification system.

Consideration should also be given to the inherent risks associated with surgical intervention. Recently reported data from a large retrospective analysis concluded that postoperative complications after RN were approximately 22% for any complication and 4% for major complications (85). Additionally, as systemic therapies continue to provide durable responses and patients are becoming long-term survivors of metastatic disease, issues with nephrectomy leading to chronic kidney disease (CKD) are becoming more evident. Recent data estimated postoperative stage ≥3b CKD can range from 21% to as high as 69% depending on the patient’s age, diabetes status, and preoperative kidney function (86). While CN previously had a clearer role in the metastatic setting, its current use in the landscape of front-line IO-based systemic therapy needs through evaluation in prospective trials.