Adjuvant therapy in renal cell carcinoma (RCC): progress, at last

Introduction

In the United States, renal cell carcinoma (RCC) is the sixth most common cancer in men and the ninth most common in women, with an estimated 14,890 people dying from kidney cancer in 2023 (1). The incidence has grown over time, doubling since 1975 and affecting males disproportionately in a 1.5–2:1 ratio (1,2). Treatment options have also dramatically improved in recent decades, bringing the 5-year survival rate in the U.S. from 50% in 1970s to 77% as of 2018 (1). RCC has traditionally been divided into histological subtypes with differing prevalence, with the most common being clear cell (75%), papillary (10%), and chromophobe (5%) (3). Of these three major subtypes, clear cell is the most aggressive and is by far the most highly represented subtype in most therapeutic clinical trials of RCC (3).

Advances in the field of RCC treatment include improved surgical technique for removal of primary tumors and metastases, improved radiation treatment modalities, as well as new systemic therapies for advanced disease. Researchers have worked in recent decades to expand these therapies to the localized setting in order to prolong survival and improve cure rates in RCC. This review will address the role and rationale of adjuvant therapy in patients at high risk of recurrence, provide a historical overview of adjuvant therapies in RCC, and summarize current guidelines and clinical practice, highlighting trials to anticipate in the years to come.

Treatment approaches

RCC, like other cancers, is treated by a variety of modalities depending on clinical criteria (grading, staging, histology, etc.) as well as a patient’s prognosis and personal decision-making process. While the mainstay of treatment in metastatic disease is systemic therapy (4,5), the first-line and often curative treatment for localized RCC [i.e., tumor node metastasis (TNM) stages I–III] is removal of the primary tumor (6). Patients with tumor spread to the ipsilateral adrenal gland are also considered to have localized disease for treatment purposes (7). Depending on factors including tumor size, tumor location, and involvement of veins or lymph nodes, patients may be eligible to receive a partial nephrectomy rather than a radical nephrectomy (8). Multiple meta-analyses showing comparable survival and better post-operative outcomes in partial nephrectomies have spurred a movement towards this approach in recent decades (9-11). It is worth noting that surgery with curative intent is not only an option in stages I–III but is increasingly being used in patients with advanced disease, including those with 1 to 3 resectable metastases. Although no randomized clinical trials have been performed of surgical metastasectomy (SM) in RCC, a systematic review showed SM to be associated with lower all-cause mortality while its morbidity is comparable to primary tumor surgery (12).

Adjuvant therapy in localized RCC: rationale and risk stratification

For many patients with localized RCC, surgery is definitive and curative; however, a significant portion will develop recurrence. The percentage cited in the literature depends on the source, although historically it is thought that approximately 25–50% of patients who undergo surgery for localized RCC will eventually develop metastatic RCC (13). A more recent analysis of European patients with localized clear cell RCC (ccRCC) in the RECUR database showed that recurrence rates can differ dramatically depending on risk factors, with those deemed intermediate-risk having a 5-year recurrence rate of 23.2% compared to 61.6% in the high-risk group (14). The question of how best to determine a patient’s risk for recurrence is an evolving area of research, however the models used clinically today rely on a variety of factors, including TNM staging, histology, and/or a patient’s symptoms and functional status.

The main such systems used in the clinic today are the UCLA Integrated Staging System (UISS), the Leibovich systems, the Stage, Size, Grade, and Necrosis (SSIGN) system, and the Karakiewicz nomogram (15-20). Since each model has unique variables, many of which are subjective, there is some heterogeneity in risk calculations depending on the system used. However, all have been validated to provide valuable information to patients and clinicians in predicting overall survival (OS) or progression to metastatic disease (see Table 1). These systems are routinely used as part of the inclusion criteria for clinical trials in the field of adjuvant therapy for RCC.

Although traditional risk-stratification strategies have proven useful to the field of localized RCC treatment, some newer models now incorporate molecular characteristics and genetic data from patients. Armed with this data, clinicians hope to more accurately risk-stratify patients and, in some cases, find actionable features of the disease which can be targeted with precision therapies. Studies have looked at chromosomal copy number variants or the presence of certain immune cell populations in tumor tissue as predictors of disease course (21,22). Other research has found numerous genetic biomarkers whose mutations, differential transcriptions, or differential protein expressions are associated with clinical outcomes (23). For patients with localized ccRCC, for example, one study found that tumor mutations in SETD2, BAP1, and PBRM1 were significantly associated with a higher risk of metastatic disease after nephrectomy (24). Other research groups have successfully developed multigene signatures of tumor transcription or translation that can predict recurrence, cancer-specific mortality, or overall mortality (23). Most published studies of these signatures, and indeed most other exploratory research on genomic and molecular biomarkers, have included only patients with ccRCC. Such signatures include ClearCode34 (25), the 16-gene recurrence score (26), and the epithelial-mesenchymal transition (EMT) score (27,28); the cell-cycle progression (CCP) score been validated in ccRCC and non-ccRCC patients as well (29). While molecular and genetic approaches to risk-stratification remain an exciting prospect, these have not yet been consistently applied to clinical practice or incorporated in official guidelines (30).

Adjuvant therapy after metastasectomy

Surgical intervention to remove metastatic lesions has been used with favorable long-term outcomes in a subset of patients, particularly in those with fully resectable oligometastatic disease with good performance status (31,32). After surgery, these patients are known in the literature as M1 with no evidence of disease (NED), and some have been included in trials of adjuvant therapy for localized RCC (33). In discussing these trials, this review will note when M1 NED patients have been included.

Historical overview of adjuvant therapy for localized RCC

Historically, RCC (localized or metastatic) was not responsive to traditional cytotoxic or hormonal treatments (34). Since the approval of interleukin 2 (IL-2) in 1992 by the Food and Drug Administration (FDA) as the first drug for metastatic RCC, we have made significant strides in therapeutics for patients with RCC (35). Despite these advances, relatively few options exist to prevent recurrence for localized RCC patients post-operatively. In the majority of adjuvant therapy trials time, drugs shown to work in the metastatic setting were trialed as adjuvant therapy and did not show an OS benefit for patients (see Figure 1) (34).

Figure 1 Historical timeline of adjuvant RCC trials, sorted by mechanism of action. RCC, renal cell carcinoma.

Trials of cytokine therapies in the adjuvant setting

The first systemic agents shown to improve outcomes in advanced RCC, albeit with low response rates and numerous side effects, were the cytokines IL-2 and interferon alpha (34). Subsequent randomized clinical trials published in the early- to mid-2000s put these agents to the test in the adjuvant setting; however, they uniformly demonstrated no benefit for patients.

A study conducted by Pizzocaro et al. [2001] of 247 patients in Italy with Stage II and Stage III RCC (any histology) compared adjuvant recombinant interferon alfa-2b to observation. The two groups did not differ in 5-year OS probability (0.665 for observation and 0.660 for treated, P=0.861) and 5-year event free survival (0.671 for observation and 0.567 for treated, P=0.107). Of note, sub-analysis showed a protective effect for pN2 and pN3 patients and a harmful effect for pN0 patients. Several years later in 2003, Messing et al. published a trial of interferon alfa-NL as adjuvant therapy for 283 patients with recent radical nephrectomy and/or lymphadenectomy for pT3–4a and/or node-positive disease. There was also no significant difference in OS and recurrence-free survival (RFS) between those who received interferon alfa-NL (median OS 5.1 years and median RFS 2.2 years) or observation (median OS 7.4 years and median RFS 3.0 years). Two-sided P values were 0.09 and 0.33 for OS and RFS, respectively.

In a trial published by Clark et al. in 2003 (36), 69 patients with completely resected RCC (locally advanced with pT3b-4 or N1–3; or M1) were randomized to receive either one course of high dose IL-2 or observation. The trial was terminated early due to lack of signal on interim analysis of the locally advanced subset of patients, for which the study was powered to detect a 30% absolute difference in disease-free survival (DFS). The authors concluded that the study was underpowered in the setting of an overly ambitious expected treatment benefit.

Other randomized trials tested combinations of cytokine drugs rather than individual agents. Atzpodien et al. [2005] used a two-arm design to compare groups who received either (A) 8 weeks of IL-2, interferon alpha-2a, and 5-fluorouracil or (B) observation (37). The trial included 203 RCC patients at high risk of relapse after surgery (pT3b-pT4 and/or nodal involvement; or with resected tumor relapse or solitary metastasis). The treatment group actually had worse OS compared to the observation group, with 2-, 5-, and 8-year survival rates of 81%, 58%, and 58% while the observation group had 2-, 5-, and 8-year survival rates of 91%, 76%, and 66% (log rank P=0.0278). The two groups did not differ significantly with regards to relapse-free survival. Another study looking at combination cytokines was performed by the Italian Oncology Group for Clinical Research (2014). This trial tested low doses of IL-2 and interferon alpha given over a 5-year period after partial or radical nephrectomy in 303 patients with RCC (pT2–3b pN0–3 M0, any histology) (38). Patients were randomized to receive cytokine treatment or observation, however, there was no significant difference in relapse-free survival [hazard ratio (HR) 0.84, 95% confidence interval (CI): 0.54–1.31, P=0.44].

Trials of autologous tumor cell vaccines in the adjuvant setting

Spurred by initial success in phase III trials of adjuvant therapy for colon cancer (39), researchers in 1990s started investigating autologous tumor cell vaccines as adjuvant therapy for RCC in attempts to increase patients’ immune responses to their own tumor cells. The first study was published in 1996 by Galligioni et al. in a cohort of 120 patients who were randomized to receive either injections of irradiated autologous tumor cells with Bacillus Calmette-Guèrin (BCG) or observation (40). Patients were stages I–III with fully resected tumor and Eastern Cooperative Oncology Group (ECOG) 0–1. Although the treatment group showed a significant delayed cutaneous hypersensitivity reaction to tumor cells compared to normal renal cells (indicating immunization to tumor antigen), the study failed to show a significant difference in DFS or OS between groups. The rate of 5-year DFS was 63% in the immunized group and 72% for the control group (P=0.21). The probability of 5-year OS in the immunized group and control group were 69% and 78%, respectively (P=0.28).

One study published by Jocham et al. in 2004 did show a DFS benefit from an adjuvant autologous renal tumor cell vaccine (41). Researchers randomly assigned 379 RCC patients after radical nephrectomy (pT2–3b pN0–N3 M0, any histology) to receive either an autologous renal tumor cell vaccine or observation. After 5 years of follow-up, analysis showed a hazard ratio of 1.58 (95% CI: 1.05–2.37, P=0.0204) in favor of the vaccine group. The authors concluded that autologous tumor cell therapy could be considered as adjuvant therapy for high-risk patients after radical nephrectomy. The excitement caused by this study was tempered by fundamental critiques of the trial, including unblinded design and concerns over differences in attrition rates between groups (42).

Finally in 2008, Wood et al. compared an autologous tumor-derived heat-shock protein complex to observation alone for 818 patients at high-risk of recurrence after nephrectomy (pT1b–T4 N0 M0 or pT_any N1–2 M0) (43). Results showed no significant difference in RFS between groups (HR 0.923, 95% CI: 0.729–1.169, P=0.506). A sub-analysis showed some signal of improvement for patients with stage I or II cancer, however this did not reach statistical significance (HR 0.576, 95% CI: 0.324–1.023, P=0.056).

Trial of a carbonic anhydrase inhibitor in the adjuvant setting

Carbonic anhydrase IX (CAIX) is a cell surface glycoprotein that is expressed in ccRCC but not normal renal tissue, and as such showed promise as a drug target (44). Girentuximab, a monoclonal antibody that binds CAIX, had been routinely used in PET CT imaging of RCC (45) and certain phase II studies in metastatic RCC suggested that it could slow disease progression (some in combination with cytokine therapy interferon alpha) (46-48). In this context, the ARISER trial published in 2017 investigated girentuximab as an adjuvant therapy versus placebo in 864 patients with high risk ccRCC (defined as pT3/pT4Nx/N0M0 or pT_anyN+M0 or pT1b/pT2Nx/N0M0 with nuclear grade 3 or greater) (49). The trial did not show any significant difference between groups in either of the primary endpoints of DFS (HR 0.97, 95% CI: 0.79–1.18) or OS (HR 0.99, 95% CI: 0.74–1.32).

Trials of VEGF receptor tyrosine kinase inhibitors (TKIs) in the adjuvant setting

After cytokine therapies, the next innovation in the field of RCC treatment came with the advent of drugs targeting angiogenesis, which is implicated in the pathogenesis of ccRCC via the von Hippel-Lindau (VHL) gene (50). Motzer et al. first published a trial in 2007 showing sunitinib, a receptor tyrosine kinase (RTK) inhibitor of the vascular endothelial growth factor (VEGF) pathway, to be superior to interferon alpha in metastatic RCC with a clear cell component (51). Sunitinib as well as other vascular endothelial growth factor receptor (VEGFR) TKIs pazopanib, axitinib, and sorafenib were all assayed in the adjuvant setting in trials published from 2016–2020. Of these trials, the only one to show a significant difference in a primary endpoint was the S-TRAC trial of sunitinib. Negative placebo-controlled trials of VEGFR TKIs in the adjuvant setting were ASSURE (2016) with sunitinib and sorafenib (52), PROTECT (2017) with pazopanib (53), ATLAS (2018) with axitinib (54), and SORCE (2020) with sorafenib (55). Each is explored in more detail in this section.

The S-TRAC trial enrolled 615 patients with recently resected ccRCC (≥pT3 and/or regional nodal involvement, ECOG ≤2, M=0) (56). Patients were randomly assigned 1:1 to receive either 50 mg of sunitinib or placebo for 1 year in a 4 weeks on, 2 weeks off schedule. Results published in 2016 showed that sunitinib was associated with a median DFS (determined by central review) of 6.8 years compared to 5.6 years in the placebo group (HR 0.76, 95% CI: 0.59–0.98). This improvement in the treatment group came at a cost of greater toxic events, with 63.4% and 21.7% of patients experiencing an adverse event of grade 3 or higher in the sunitinib and placebo groups, respectively. The rate of adverse events labeled as serious, however, was similar between the two groups (21.9% for sunitinib versus 17.1% for placebo). The most common adverse events in the sunitinib group included diarrhea, palmar-plantar erythrodysesthesia, and hypertension. Patients in the treatment group also reported significantly lower health-related quality of life on many items via questionnaire, with diarrhea and loss of appetite considered clinically meaningful by the investigators. The follow-up analysis continued to show increased DFS in the sunitinib group compared to placebo, 6.8 vs. 5.6 years respectively (HR 0.76, 95% CI: 0.76–0.98) (57). The HR for OS comparing sunitinib to placebo was 0.92 (95% CI: 0.66–1.28, P=0.6).

ASSURE (adjuvant sunitinib or sorafenib vs. placebo in resected unfavorable renal cell carcinoma), was a multicenter North American study that enrolled 1,943 patients in a 1:1:1 three-arm design to compare sunitinib, sorafenib, and placebo (52). Inclusion criteria were different from the S-TRAC trial with participants having T1b or greater high grade RCC and inclusion of patients with non-ccRCC (21% of total). Patients in the active drug groups suffered high toxicities, with rates of discontinuation in the sunitinib and sorafenib groups 44% and 45%, respectively. In response to this, the dosing scheme was revised after the trial began, however toxicity remained a serious issue. The most commonly reported adverse events were hypertension, hand-foot syndrome, rash, and fatigue. The results published in 2016 showed no difference between groups in the primary end point of DFS (by investigator review), with 5.8 years for sunitinib (HR 1.02, 97.5% CI: 0.85–1.23, P=0.8038), 6.1 years for sorafenib (HR 0.97, 97.5% CI: 0.80–1.17, P=0.7184), and 6.6 years for placebo. Secondary analysis of a high-risk subset of patients (node-positive or pT3 or greater), showed no effect on 5-year DFS and no effect of dosing on outcome (58).

PROTECT (Pazopanib As Adjuvant Therapy in Localized/Locally Advanced RCC After Nephrectomy) was a trial that enrolled 1,538 patients with ccRCC and M=0 after partial or radical nephrectomy (pT2G3–4N0, pT3–T4 G_anyN0, or pT_anyG_anyN1) to compare pazopanib versus placebo (59). In response to a higher than anticipated discontinuation rate due to toxicity, the starting dose was amended from 800 to 600 mg and the primary endpoint became DFS in the 600 mg group (n=571) versus placebo (n=564). Elevations in AST and ALT were the most common adverse events for patients. Initial results published in 2017 showed improved but not significant DFS in the 600 mg pazopanib group (HR 0.86, 95% CI: 0.70–1.06, P=0.165). Final follow-up analysis in 2021 showed no significant difference in OS between groups (HR 1.0, 95% CI: 0.80–1.26, P>0.9) (53). Subgroup analysis of the PROTECT trial showed that treatment with sunitinib was actually associated with significantly lower OS in older women (60).

The ATLAS (Adjuvant Axitinib Therapy of Renal Cell Cancer in High Risk Patients) trial enrolled 724 patients in centers across Asia, Europe, and the U.S. with recently diagnosed RCC (>50% clear cell component) and ≥pT2 and/or nodal involvement with any grade and ECOG 0–1 (54). Patients were assigned 1:1 to receive either 5 mg axitinib twice per day or placebo for between 1 and 3 years. About 56% of the study sample was considered “highest risk” with pT3 and grade ≥3, pT4, or nodal involvement. The study was stopped early due to futility, failing to show a difference in the primary end point of DFS (determined by central committee) with a hazard ratio of 0.870 (95% CI: 0.660–1.147, P=0.3211). Axitinib was associated with greater grade 3 or 4 adverse events (61% versus 30% in placebo).

Lastly, the SORCE trial assigned patients into three groups (in a 2:3:3 ratio): the first group received 3 years of placebo, the second group received 1 year of sorafenib followed by 2 years of placebo, and the third group received 3 years of sorafenib (55). 1,711 patients were enrolled with completely resected RCC of any histology, M=0, and an intermediate or high risk of relapse according to the 2003 Leibovich risk model. Similar to other trials of VEGFR inhibitors, the protocol was amended in response to high discontinuation rates, with the dose of sorafenib reduced from 400 mg twice per day to 400 mg once per day. Despite this change, 58.6% of patients receiving sorafenib for 1 year and 63.9% of patients receiving sorafenib for 3 years reported an adverse reaction of grade 3 or higher, compared to 29.2% in the placebo group. The primary outcome analysis published in 2020 showed no difference in survival between the group who received sorafenib for 3 years versus placebo for three years (HR 1.01, 95% CI: 0.83–1.23, P=0.95).

Based on the positive signal in the S-TRAC trial, the FDA approved sunitinib in 2017 for treatment of RCC after surgery for resection, the first therapy approved for this indication (61). This move was widely criticized by providers who were not convinced that the treatment toxicities were outweighed by the potential benefits, which had not been replicated in other trials of VEGFR TKIs (62). Indeed, meta-analysis by Riaz et al. [2021] showed with high certainty that there was no benefit in OS (HR 1.01, 95% CI: 0.91–1.12) or DFS (HR 0.92, 95% CI: 0.86–1.00), including across subgroups and in the highest-risk patients (63). Because of this conflicting data and the drug’s significant toxicity, sunitinib was not widely adopted by clinicians despite being the first RCC drug formally approved in the adjuvant setting.

Trial of a mammalian target of rapamycin (mTOR)R pathway inhibitor in the adjuvant setting

The mTOR pathway has been another target of investigation given that this pathway is often inappropriately upregulated in RCC (64). mTOR inhibitor temsirolimus was approved by the FDA as first line therapy for metastatic RCC in 2007 after a phase III trial showed superiority in OS for patients taking temsirolimus plus interferon alpha compared to those taking interferon-alpha alone (65). Another mTOR inhibitor, everolimus, was approved by the FDA in 2009 for patients with metastatic RCC who had failed therapy with a VEGFR TKI (66). Despite mTOR inhibitors’ success in treating metastatic disease, the only published phase III trial to date of an mTOR inhibitor as adjuvant therapy has not shown improvement in outcomes for patients with resected RCC. The EVEREST trial [2023] looked at 1,545 RCC patients (any histology) who were deemed to have intermediate-high or very high risk of recurrence per a modified UISS, comparing daily everolimus for one year to placebo (67). The everolimus group did have longer RFS than the placebo group, with 5-year RFS of 67% and 63%, respectively (log rank P=0.05). However, this did not meet the study’s pre-specified threshold of significance of P=0.044. Sub-analysis showed that only the very-high risk group had longer RFS with everolimus compared with placebo (HR 0.79, 95% CI: 0.65–0.97, P=0.022). The everolimus group also had significantly more grade 3 or higher adverse events compared to placebo (46% vs. 11%). The authors concluded that the results do not support the use of everolimus for RCC in the adjuvant setting.

Trials of immune checkpoint inhibitors (ICIs) in the adjuvant setting

Therapies harnessing the human immune system to fight cancer, in particular the ICIs of programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4), have shown great promise in treating a wide variety of cancers over the last decade. Nivolumab was the first such therapy approved in 2015 for patients with metastatic RCC previously treated with anti-angiogenic therapy, based on data from a phase III trial showing an OS benefit when compared to everolimus (68,69). Since then, several phase III trials of ICIs have been performed in the adjuvant setting (see Table 2), with only one (KEYNOTE-564) meeting its primary endpoints and demonstrating a survival benefit.

The KEYNOTE-564 trial randomly assigned 994 patients to either receive placebo or 200 mg of PD-1 inhibitor pembrolizumab every 3 weeks for up to a year (70). Patients exclusively had ccRCC and included those at stage II with nuclear grade 4 or sarcomatoid differentiation, stage III or higher, regional lymph node-metastasis, and/or M1 with NED. Initial analysis showed significantly longer DFS in the pembrolizumab group compared to the placebo group, with 24-month DFS rates of 77.3% and 68.1%, respectively (HR for recurrence or death 0.68, 95% CI: 0.53–0.87, P=0.002). OS was higher in the treatment group (HR for death 0.54, 95% CI: 0.30–0.96), however the data were immature, preventing definitive interpretation. Toxicities due to treatment were as expected based on prior experience with pembrolizumab, with 32.4% of patients experiencing a grade 3 or higher adverse reaction compared to 17.7% in placebo, the most common including hypertension and increased alanine aminotransferase levels. In response to this trial, the FDA approved pembrolizumab in 2021 as adjuvant therapy for patients at intermediate-high or high risk of recurrence following nephrectomy with or without metastasectomy (71). Follow-up analysis published in 2022 showed that the pembrolizumab group continued to demonstrate superior DFS (HR 0.63, 95% CI: 0.5–0.8) (72) and recent data from the third prespecified interim analysis showed a clinically meaningful and statistically significant increase in the secondary endpoint of OS in the pembrolizumab group compared to placebo, with no new safety signals observed (73).

The PROSPER study was an open-label trial comparing PD-1 inhibitor nivolumab versus observation in the perioperative setting for 819 patients with ≥pT2, pT_anyN+, or M1 with NED after partial or total nephrectomy for RCC of any histology (74). This study was unique compared to other adjuvant ICI trials in that it included a pre-operative dose of nivolumab in addition to 9 post-operative doses (480 mg every 4 weeks). The study was stopped early due to futility after interim analysis showed similar RFS between arms (HR 0.97, 95% CI: 0.74–1.28, P1-sided=0.43). OS was not mature at the time the study was stopped but this was also similar between groups (HR 1.48, 95% CI: 0.89–2.48, P1-sided=0.93).

Published in 2022, IMmotion010 randomly assigned patients to receive either PD-L1 inhibitor atezolizumab or placebo (75). Its sample included 778 patients with RCC (with a clear cell or sarcomatoid histological component) and pT2 with grade 4, pT3a with grade 3–4, pT3b through pT4 with any grade, nodal involvement, and/or M1 with NED after nephrectomy and/or metastasectomy. DFS as assessed by investigator did not differ significantly between groups (HR 0.93, 95% CI: 0.75–1.15, P=0.50). 18% of patients on nivolumab and 12% of patients on placebo had a serious adverse event.

The most recent trial to be published of an ICI in the adjuvant setting for RCC, CheckMate-914, was a 2-part trial comparing the combination of nivolumab plus ipilimumab and nivolumab monotherapy to placebo (76). The Part A (ipi+nivo vs. placebo) treatment group received 240 mg of nivolumab every 2 weeks for 12 doses with 1 mg/kg of ipilimumab every 6 weeks for four doses. The study’s patient sample included 816 patients at high risk of recurrence [staging pT2a(grade III–IV)N0M0, pT2b(any grade)N0M0, pT3(any grade)N0M0, pT4(any grade)N0M0, or pT_any(any grade) N1M0]. Notably, those who were at stage M1 with NED were excluded. Primary analysis showed no significant difference between the treatment and placebo group with regards to DFS (HR 0.92, 95% CI: 0.71–1.19, P=0.53). OS data were not mature at the time of data cutoff. Those receiving nivolumab and ipilimumab experienced considerably more toxicity than the placebo group, with rates of adverse events leading to discontinuation of 32% and 2% for treatment and placebo, respectively. Part B (ipi+nivo vs. nivo vs. placebo) presented at the 2024 ASCO Genitourinary Cancers Symposium showed no DFS benefit from adjuvant nivolumab monotherapy.

A meta-analysis of the four trials with data available showed considerable heterogeneity across studies due to inclusion criteria and statistical methods (I²=64%) as well as no significant improvement in DFS in the pooled dataset (HR 0.85, 95% CI: 0.69–1.04, P=0.11) (77). Differential DFS was seen, however, when patients were stratified by PD-L1 expression (positive versus negative, HR 0.72, 95% CI: 0.55–0.94, P=0.02) and presence of sarcomatoid features (HR 0.59, 95% CI: 0.38–0.91, P=0.02). Stratification by nephrectomy type (partial vs. radical) or risk category (intermediate-high, high, M1 NED) did not show a differential effect of ICIs.

Differences in patient inclusion criteria, dosing, treatment discontinuation and treatment duration across studies have been posited as explanations for disparate results (76). Patients who were M1 with NED were able to enroll in IMmotion010, PROSPER, and KEYNOTE-564 but not CheckMate-914. PROSPER and IMmotion010 allowed patients with non-clear cell histology to enroll but KEYNOTE-564 and CheckMate-914 did not. Whereas patients in KEYNOTE-564 and IMmotion010 were protocoled to receive treatment for 1 year, those in PROSPER and CheckMate-914 were planned for 9 months and 6 months, respectively. Given these factors, it is tough to put each individual trial’s results in the context of the others when determining whether these agents have a potential role for RCC patients in the adjuvant setting.

Current standard of care: guidelines and clinical practice

Recent developments in the field of ICIs, and the resulting FDA approval of pembrolizumab as adjuvant therapy in 2021, have given patients and clinicians more options for post-surgical treatment of RCC. However, many clinical societies have yet to incorporate trials from the last several years into official guidelines, including the National Comprehensive Cancer Network (NCCN) and American Urological Association (AUA) (8,78). The European Association of Urology (EAU) issued a guideline update in 2022 with a “weak” recommendation for pembrolizumab but advised caution given the negative trials published of other ICI drugs (6).

The only other drug approved for adjuvant therapy in RCC, sunitinib, has not been routinely used in clinical practice in the United States despite its FDA approval, with many citing concerns about negative trials and toxicities for patients (62). NCCN and AUA guidelines recommend that patients with stage III Category 3 ccRCC at high risk of recurrence receive counseling on systemic treatment with sunitinib and consider enrolling in a clinical trial of adjuvant therapy (preferred) or active surveillance (8,78). Sunitinib never achieved regulatory approval in Europe, and up until its 2022 update incorporating the KEYNOTE-564 trial, EAU’s guidelines recommended systemic adjuvant therapy only in the context of a clinical trial (79,80).

Within the existing NCCN framework for counseling patients on options after nephrectomy, many clinicians are offering adjuvant pembrolizumab to those patients at high risk of recurrence. Patients who received benefit per the KEYNOTE-564 included those with “intermediate-high” risk (pT2N0M0 with grade 4 or sarcomatoid features or pT3N0M0 with any grade), “high risk” (pT4N0M0 any grade or any pT, any grade, N+, M0), and M1 NED (81). Those who were M1 NED received the highest DFS benefit from pembrolizumab in subgroup analysis of the trial (72). Patients had good functional status, with ECOG 0 or 1, and received the therapy within 12 weeks of surgery (81). For patients at high risk of recurrence as defined by these criteria or by other commonly used risk stratifiers (UISS, Leibovich, etc.), enrolling in a clinical trial or active surveillance remain valid treatment strategies, especially for those concerned about efficacy of ICIs and side effects of systemic therapy. Ultimately, clinicians must engage in conversation with patients so that they can make their own informed decision of how to proceed with care after a nephrectomy and/or metastasectomy, as summarized in Figure 2.

Figure 2 Algorithm for decision-making after surgery for RCC. RCC, renal cell carcinoma; UISS, UCLA Integrated Staging System.

Future directions

Adjuvant therapy in patients with high risk localized ccRCC is a rapidly evolving field. The most exciting and consequential recent development is the data from KEYNOTE-564 showing that adjuvant pembrolizumab increases OS in a high-risk population, representing a new standard of care for ccRCC patients after surgery. Trials that are ongoing are summarized in Table 3 below. In particular, two phase III trials are in the pipeline with primary results expected in coming years. The first, RAMPART, is a study based in the United Kingdom that uses a three-arm design to compare PD-1 inhibitor durvalumab +/− CTLA-4 inhibitor tremelimumab versus placebo. It has a goal recruitment of 1750 RCC patients of any histology with Leibovich scores from 3–11. It is estimated to reach its primary completion date in July 2024. The other phase III study, LITESPARK-022, aims to test the efficacy of an PD-1 inhibitor pembrolizumab in combination with hypoxia-inducible factor 2 alpha inhibitor belzutifan as adjuvant RCC therapy. It is a two-arm, placebo-controlled study organized by Merck Sharp & Dohme LLC. Patients will have ccRCC that is intermediate-high risk (pT2, grade 4 or sarcomatoid, N0M0; pT2, any grade, N0M0), high risk (pT4, any grade, N0M0; pT_any stage, any grade, N+, M0), or M1 with NED. The recruitment goal is 1600 patients with an expected primary completion date in October 2027.

Besides these phase III trials, there are several phase II trials to follow in the pipeline as well. IUNU-RC is a phase II study developed by Nanjing University in China looking at the efficacy and safety of toripalimab (PD-1 inhibitor) plus VEGF inhibitor axitinib, specifically in patients with non-ccRCC at high risk for recurrence. This represents one of the few adjuvant studies performed specifically for patients with non-ccRCC. MRD GATE RCC is a trial at the University of Alabama at Birmingham evaluating pembrolizumab after surgery for localized RCC only for patients with molecular residual disease (MRD) as evidenced by presence of circulating tumor DNA (ctDNA). Patients without MRD in this study will receive surveillance only. Lastly, PE-PE is an Italian phase II study looking at pembrolizumab as adjuvant treatment after local therapy with surgery or radiation for up to 3 metastases. The treatment group will receive pembrolizumab in addition to local therapy while the control group will receive local therapy alone.

Conclusions

In conclusion, we have reached a pivotal moment for adjuvant treatment of patients with high risk localized ccRCC after surgery. The data from KEYNOTE-564 trial data showing not only an improved progression-free survival but also an OS benefit is transformative and this represents a new standard of care. We are optimistic about new trials such as RAMPART and LITESPARK-022 which may provide additional treatment options in the adjuvant setting. Further, genomic and clinical biomarkers may help to objectively risk stratify patients so that we may identify those who would derive the most benefit from adjuvant therapy. Overall, the future looks far brighter now than it did even several years ago: after a long streak of unsuccessful trials, progress is here at last.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-2247/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-2247/coif). M.N.S. reports receiving grants or contracts from Janssen Oncology, Advaxis, Bristol-Myers Squibb, Lilly, Seattle Genetics, Xencor, Tmunity, Exelixis, Bellicum Pharmaceuticals, Regeneron, Bicycle Therapeutics and AstraZeneca, all of which have provided payment to his institution; and also receiving consulting fees from Exelixis, Xencor, Janssen, Vaccitech, Merck, and Bristol-Myers Squibb/Medarex. K.R. reports receiving funding from the 2023 Robert A. Winn Diversity in Clinical Trials Career Development Award, and a payment for serving as a steering committee for a phase III trial for Janseen. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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