Reviewing Treatment Options For Advanced Renal Cell Carcinoma: Is There Still A Place For Tyrosine Kinase Inhibitor (TKI) Monotherapy

ABSTRACT

Renal cell carcinoma (RCC) comprises a highly heterogeneous group of kidney tumors built upon distinct genetic- and epigenetic-driven mechanisms and molecular pathways. Therefore, responsiveness to treatment is considerably variable across patients, adding an extra layer of complexity to the already challenging therapeutic decision process. The last decade brought an unprecedented shift in the medical approach to advanced or metastatic RCC; in fact, immunotherapy-based combinations have significantly transformed these patients' therapeutic arsenal and clinical outcomes. International guidelines committees quickly adopted these strategies as the new standards of care. However, this enhanced efficacy comes at the expense of tolerability, with a predictable negative impact on patients’ quality of life. Moreover, subgroup and post hoc analyses of the major clinical trials have shown that not all patients benefit equally from these innovative approaches. In this context, a group of experts on kidney cancer met and discussed the state of the art in the field, with a particular emphasis on the appropriateness of using monotherapy with an anti-angiogenesis tyrosine kinase inhibitor (TKI) to treat specific subgroups of patients with RCC. This article reviews the main topics that were considered to be pertinent for that discussion and establishes the profile of patients for whom TKI monotherapy remains a sensible frontline option by avoiding overtreatment and unnecessary exposure to treatment-related toxicity.

Keywords

Advanced or metastatic renal cell carcinoma (mRCC); Immune checkpoint inhibitor (ICI); Monotherapy; Tyrosine kinase inhibitor (TKI).

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INTRODUCTION

Renal cell carcinoma (RCC) is a heterogeneous group of malignancies that account for 2% of global cancer diagnoses and deaths [1]. Associated with several risk factors that are characteristic of so-called modern societies, RCC incidence has been rapidly increasing in the developed world, being now the seventh most common neoplasm in these regions [1, 2]. Of note, RCC has the highest fatality rate among urological neoplasms; whereastheoverall5-yearsurvivalrateis76%, this value drops dramatically to 12% in patients with stage IV disease [1]. Also, approximately 30% of patients newly diagnosed with RCC have metastatic disease, while 20–50% of patients treated for localized disease will eventually relapse and progress to the metastatic stage [1, 3]. Importantly, adjuvant therapeutic alternatives are yet to be approved for this setting in Europe.

RCC incidence and mortality rates vary widely according to its subtype; in fact, RCC comprises a group of independent histological entities, which are characterized by distinctive genetic and epigenetic alterations and molecular pathways, and as such, they respond to systemic therapy [4, 5]. The most common RCC subtype is clear cell, which accounts for 70–75% of all cases. From a genetic standpoint, this subtype is characterized by the loss of the short arm of chromosome 3, which encodes the tumor suppression gene VHL (von Hippel–Lindau) [4, 6, 7]. The other RCC forms are generally grouped under an umbrella term: the non-clear cell subtypes. Among these, the papillary variant has the highest incidence, comprising 15% of all kidney cancers [4, 6, 8]. Chromophobe RCC, which occurs in 5–10% of all cases, has a typically indolent course, although it is particularly hard to treat once it has metastasized [4, 6, 7]. Collecting duct carcinoma and renal medullary carcinoma account for less than 5% of all RCC cases. These rare subtypes are often aggressive, being generally resistant to most systemic therapy options available to date [6, 7]. Finally, about 5% of all RCC cases have sarcomatoid features; sarcomatoid RCC is usually symptomatic and highly aggressive, and its outcomes tend to be worse than those of non-sarcomatoid cases [9, 10].

Even among the clear cell subtype, advanced or metastatic RCC (mRCC) is known to be highly heterogeneous in terms of clinical progression and treatment outcomes. For that reason, a few prognostic risk models have been developed, of which the two most commonly used are the Memorial Sloan Kettering Cancer Center model (MSKCC) and the International mRCC Database Consortium model (IMDC). The MSKCC model was based on the retrospective analysis of 463 patients with mRCC treated with interferon-a, in whom the authors were able to identify five risk factors: low Karnofsky performance status (less than 80%), high serum lactate dehydrogenase (above 1.5 times the upper limit of normal), low hemoglobin (below the lower limit of normal), high corrected serum calcium (above 10 mg/dL) and a short period between the initial diagnosis and systemic therapy onset (less than 1 year) [11]. Patients were then stratified into three categories according to the number of risk factors present: those without risk factors were classified as a favorable risk; those with one or two risk factors were classified as an intermediate risk; and those with three or more risk factors were classified as a poor risk. Accordingly, the median overall survival (OS) was 30, 14, and 5 months in each of these groups, respectively [11]. IMDC was developed a few years later, being based on a retrospective analysis of 645 patients with mRCC treated with tumor vasculature-targeted therapy. The IMDC authors retained four MSKCC risk factors—low Karnofsky performance status (less than 80%), high corrected serum calcium (above the upper limit of normal), low hemoglobin (below the lower limit of normal), and a short period between initial diagnosis and systemic therapy onset (less than 1 year)—and added high neutrophil and platelet counts (above the upper limit of normal) [12]. After 2 years, 75% of the favorable-risk patients were still alive, as were 53% of the intermediate-risk patients and 7% of the poor-risk patients [12]. Afterward, several adjustments were made to these models, either to validate them in a salvage setting [13, 14] or to include other significant factors, such as metastasis location [15]. Still, despite several acknowledged limitations, the classical version of these prognostic models remains commonly used both in clinical trials and during routine clinical practice.

The management of advanced or mRCC has changed dramatically over the past 30 years. Initially based on a non-specific immune approach (high-dose interleukin-2 [IL-2] and interferon-a), this strategy evolved to target the tumor vasculature, intracellular oncogenic pathways, and the immune system signaling cascade. The new agents added to the mRCC therapeutic armamentarium include vascular endothelial growth factor (VEGF)-targeted molecules, inhibitors of the mechanistic target of rapamycin (mTOR), and novel immune checkpoint inhibitors (ICIs) [3, 6]. Recently, international guidelines have suggested a combination of two of these agents (ICI/ICI or ICI/ VEGF-targeted agent) as the best strategy to manage clear cell mRCC [16–18]. However, despite the undeniable benefits of these combination strategies—which were demonstrated in several clinical trials—they also represent enhanced toxicity when compared with monotherapy, with a predictable negative impact on patient’s quality of life (QoL), and likely limit the choice of subsequent therapeutic lines. Although this may be a result of the specific anti-VEGF tyrosine kinase inhibitor (TKI) used (e.g. pazopanib or sunitinib), the possible high grade of toxicity in a metastatic setting should be taken into careful consideration. However, whether combination treatment is always the most sensible option to treat mRCC is a question yet to be answered. Whereas the efficacy of any treatment is a key factor in the therapeutic decision-making process, avoiding overtreatment and unnecessary toxicity should also be carefully considered. In this context, a group of Portuguese experts participated in a series of virtual meetings held between February and April 2021, which were aimed at reviewing the clinical evidence concerning the frontline treatment of mRCC, as well as the profile of patients for whom TKI monotherapy is still the best available therapy. The topics considered to be relevant to this discussion are reviewed hereafter, as are the main conclusions reached by this panel of experts. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

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THE THERAPEUTIC LANDSCAPE OF MRCC

The first agents to be approved for mRCC treatment were interferon-a and high-dose IL-2. However, despite inducing highly durable responses in a limited number of patients, the efficacy of these drugs was considerably low (the reported response rates were 12% for interferon and 15% for IL-2), and their toxicity was rather high (particularly that of IL-2) [5, 6, 19]. As such, they were later replaced by targeted approaches directed at either the endothelium of the tumor vasculature (anti-VEGF drugs) or at the tumor’s oncogenic pathways (mTOR inhibitors). Anti-VEGF drugs include orally available TKIs targeting circulating VEGF itself or its receptors (axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, sunitinib, and tivozanib), as well as an intravenously administered anti-VEGF antibody (bevacizumab combined with interferon alfa-2a), whereas mTOR inhibitors include temsirolimus and everolimus [6, 19]. All of these agents have shown a progression-free survival (PFS) benefit over existing alternatives and have been extensively reviewed elsewhere [20–22].

Lately, there has been a resurgence of interest in immunotherapy to treat patients with mRCC; contrary to the initial non-specific approach, the most recent immunotherapy-based strategies successfully target certain immune checkpoints involved in peripheral tolerance. Nivolumab, an anti-programmed cell death 1 (PD-1) antibody that selectively blocks the interaction between PD-1 and its ligand (PD-L1), was the first ICI approved in this setting. When compared with everolimus in previously treated patients, nivolumab was shown to significantly extend OS (25.0 vs 19.6 months; hazard ratio [HR] 0.73; 98.5% confidence interval (CI) 0.57–0.93; p = 0.002) and to elicit a higher objective response rate (ORR 25% vs 5%; odds ratio [OR] 5.98; 95% CI 3.68–9.72; p ＜0.001) [23].

Finally, a major paradigm shift took place in the mRCC therapeutic armamentarium as dual agent combinations were introduced and, in many cases, replaced the TKI monotherapy strategy as the standard of care (SOC). One of these combinations involves the concerted action of two ICIs: nivolumab? ipilimumab (an anti-CTL4 [cytotoxic T-lymphocyte-associated protein 4] antibody) [24–26]. Still, the majority of these double treatments consist of the combination of an ICI with a VEGF-targeted drug: avelumab. axitinib [27], atezolizumab? bevacizumab [28], pembrolizumab? lenvatinib [29], pembrolizumab? axitinib [30, 31] and nivolumab? cabozantinib [32]. The rationale behind this strategy is the simultaneous attack of two pivotal features of the RCC tumor: angiogenesis and immunogenic regulation. Indeed, by activating the immune system and suppressing vasculature signaling in the tumor microenvironment, these combination strategies should, in theory, overcome the limitations of each drug individually, leading to a durable immunotherapy-induced response sustained by an effective modulation of the tumor microenvironment [33, 34].

1. International Guideline Recommended Treatment Strategies

Facing this rapidly evolving therapeutic landscape, international guidelines were adapted to consider the new treatment combinations. Some of these combinations are promising, but are not yet recommended as they have failed to demonstrate a significant OS signal (e.g. avelumab ? axitinib and axitinib ? atezolizumab). However, other combinations have been already considered as the new SOC in mRCC. In fact, in an update published in September 2021, the European Society for Medical Oncology (ESMO) recommends the use of pembrolizumab. lenvatinib, pembrolizumab? axitinib or cabozantinib? nivolumab as the first-line treatment for all patients with clear cell mRCC, irrespective of their IMDC risk group (all recommendations, level I, A; ESMO-MCBS v1.1, score 4) [16]. In patients with an IMDC favorable-risk prognosis, sunitinib or pazopanib are potential alternatives to PD-1 inhibitor-based combination treatment because of a lack of clear superiority of PD-1 inhibitor-based combinations over sunitinib in these patients, and the similar effectiveness of sunitinib and pazopanib in the COMPARZ study [35] (level I, B) [16].

The combinations of pembrolizumab? axitinib, cabozantinib? nivolumab and pembrolizumab? lenvatinib is also recommended as a preferred first-line approach for all patients with RCC according to the latest update of the National Comprehensive Cancer Network guidelines (with category 1 as the evidence level) [18]. Additionally, nivolumab? ipilimumab is also considered to be a preferential choice to treat poor- or intermediate-risk patients with clear cell mRCC. However, cabozantinib monotherapy is also acknowledged as preferential treatment for poor-/intermediate-risk patients according to this organization, with a 2A evidence level [18].

Finally, the 2021 update of the European Association of Urology (EAU) guidelines also gives immune-based combinations a central role in the clear cell mRCC treatment, recommending pembrolizumab. axitinib, nivolumab ? cabozantinib or pembrolizumab ? lenvatinib as the SOC for all patients with clear cell mRCC, and the nivolumab? ipilimumab combination in the poor-/intermediate-risk patients (all with a 1b evidence level) [17]. As in the ESMO guidelines, TKI monotherapy is relegated to an alternative option for patients who cannot receive or tolerate ICIs.

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2. Currently Recommended Combination Treatments: Efficacy and Safety Profile

In this section, we review the main evidence available to date concerning the use of combinations to treat clear cell mRCC. We focus on nivolumab. ipilimumab, pembrolizumab ? axitinib, nivolumab ? cabozantinib and pembrolizumab? lenvatinib, which are recommended by the three organizations cited earlier [16–18], and are the ones with the greatest amount of accumulated evidence.

The pivotal study that led to the approval and subsequent recommendation of nivolumab? ipilimumab was CheckMate-214 [24–26]. The authors of this phase 3 clinical trial analyzed the outcomes and safety profile of 1096 patients with previously untreated clear cell mRCC, who were randomized to receive nivolumab 3 mg/kg. ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off) [24–26]. The primary endpoints of this trial were OS, ORR, and PFS in the IMDCdefined intermediate-/poor-risk patients, which comprised approximately 77% of the intention-to-treat (ITT) population. The latest data release corresponds to a median follow-up of 55 months and demonstrates the superiority of nivolumab. ipilimumab over sunitinib in the intermediate-/poor-risk population: in fact, the risk of death for patients in the experimental arm was 35% lower than that of patients in the control arm (HR 0.65; 95% CI 0.54–0.78) [26]. Moreover, despite showing a delayed benefit, PFS was also significantly longer in nivolumab. ipilimumab-treated patients, with 4-year probabilities of 32.7% vs 12.3% (HR 0.74; 95% CI 0.62–0.88). Finally, the ORR was higher among patients in the experimental arm (41.9% vs 26.8%, p ＜0.0001), as was the proportion of patients achieving a complete response (10.4% vs 1.4%), and the duration of response (HR 0.45; 95% CI 0.31–0.65) [26].

The pembrolizumab? axitinib combination was addressed in the KEYNOTE-426 trial, which included 861 treatment-naı¨ve patients with clear cell mRCC [30, 31]. These patients were randomized to receive pembrolizumab 200 mg once every 3 weeks. axitinib 5 mg twice daily or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off) [30, 31]. OS and PFS were the primary endpoints, and the outcomes of both supported the superiority of the combination treatment compared with sunitinib. With a median follow-up of 30.6 months, the HR for OS was 0.68 (95% CI 0.55–0.85; p = 0.0003), while the HR for PFS was 0.71 (95% CI 0.60–0.84; p \ 0.0001) [31]. The ORR in pembrolizumab? axitinib-treated patients were significantly higher than that in sunitinib-treated patients (60% vs 40%; p \0.0001), as was the percentage of patients with complete response (9% vs 3%) and the median duration of response (23.5 vs 15.9 months) [31].

CheckMate-9ER was the phase 3 clinical trial that addressed the efficacy and toxicity of nivolumab. cabozantinib combination [32]. Briefly, 651 patients with previously untreated clear cell mRCC were randomized to receive nivolumab 240 mg every 2 weeks. cabozantinib 40 mg once daily or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off) [32]. After a median follow-up of 18.1 months, the primary endpoint (PFS) was met, with a median PFS of 16.6 months among patients in the experimental arm versus 8.3 months in the control arm (HR 0.51; 95% CI 0.41–0.64; p \0.001). There was also a significant difference in OS: the risk of death in nivolumab? cabozantinib-treated patients were 40% lower than that of sunitinib-treated patients (HR 0.60; 98.89% CI, 0.40–0.89; p = 0.001). Accordingly, the ORR reported for patients in the experimental arm was higher than that of patients in the control arm (55.7% vs 27.1%; p \ 0.001), as was the complete response rate (8.0% vs 4.6%) and the median duration of response (20.2 vs 11.5 months) [32].

The pembrolizumab? lapatinib combination was evaluated in the CLEAR trial of 1069 patients with previously untreated clear cell mRCC [29]. Patients were randomized to receive lenvatinib 20 mg once daily. pembrolizumab 200 mg every 3 weeks, lenvatinib 18 mg once daily? everolimus 5 mg once daily, or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off) [29]. After a median follow-up of 26.6 months, the median PFS (primary endpoint) was longer with pembrolizumab. lenvatinib versus sunitinib (23.9 vs 9.2 months; HR 0.39; 95% CI 0.32–0.49; p \0.001). Pembrolizumab? lapatinib-treated patients had improved OS versus sunitinib-treated patients, with the risk of death being 34% lower with pembrolizumab. lenvatinib (HR 0.66; 95% CI 0.49–0.88; p = 0.005). Compared with sunitinib, pembrolizumab? lapatinib was associated with a higher ORR (71.0% vs 36.1%), complete response rate (16.1% vs 4.2%), and median duration of response (25.8 vs 14.6 months) [29].

Although treatment combinations brought an undeniable benefit to many patients with clear cell mRCC, they did so at the cost of increased toxicity compared with single-agent therapy. Even though a greater proportion of the sunitinib-treated CheckMate-214 patients suffered grade 3 or 4 treatment-related adverse events (TRAEs) (64.1% vs 47.9% of the patients treated with nivolumab ? ipilimumab), the percentage of TRAEs leading to discontinuation was higher in the experimental arm (22.7% vs 13.1% in the control arm) [26]. As for the KEYNOTE-426 trial, the incidence of serious TRAEs was higher among patients treated with the combination (28% vs 16%) [31]. Moreover, 21%, 20%, and 7% of patients in the experimental arm discontinued pembrolizumab, axitinib, and both drugs, respectively, because of the presence of TRAEs, whereas this percentage was 12% among sunitinib-treated patients [31]. In CheckMate-9ER, grade 3 or higher TRAEs occurred in 60.6% of the nivolumab. cabozantinib-treated patients and 50.9% of the sunitinib-treated patients [32]. Additionally, the percentage of patients who discontinued the treatment because of AEs was 19.7% in the experimental arm (6.6% of patients discontinued nivolumab only, 7.5% discontinued cabozantinib only and 5.6% discontinued both), and 16.9% in the control arm [32]. Lastly, in CLEAR, the incidence of grade 3 or higher TRAEs was 71.6% with pembrolizumab. lenvatinib and 58.8% with sunitinib, and AEs led to treatment discontinuation in 37.2% and 14.4% of patients, respectively [29].

Two meta-analyses were carried out to address the toxicity of the combination treatments from a global perspective. One of them, by Quhal et al., included six phase 3 trials and 5121 patients, and considered the following combinations: nivolumab? ipilimumab, avelumab ? axitinib, pembrolizumab? axitinib, atezolizumab? bevacizumab, nivolumab? cabozantinib and pembrolizumab? lenvatinib [36]. When compared with sunitinib-treated patients, those treated with nivolumab? ipilimumab had a significantly higher likelihood of discontinuing treatment because of TRAEs, and of having hyperthyroidism, adrenal insufficiency, pneumonitis, colitis, and elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels. Likewise, pembrolizumab? axitinib treated patients had a significantly higher likelihood of having hyperthyroidism, adrenal insufficiency, pneumonitis, colitis, diarrhea, hand–foot syndrome, and elevated ALT and AST levels. Nivolumab? cabozantinib-treated patients had a significantly higher likelihood of discontinuing treatment because of TRAEs. Similarly, pembrolizumab? lapatinib-treated patients had a significantly higher likelihood of treatment discontinuation due to TRAEs, and of having hyperthyroidism, adrenal insufficiency, pneumonitis, diarrhea, and elevated AST levels. Of note, when compared with sunitinib, all combinations were associated with significantly lower rates of hematological adverse events (AEs) (namely neutropenia, anemia, and thrombocytopenia) [36].

The second meta-analysis, by Rizzo et al., focused on the incidence of gastrointestinal AEs and considered 3059 patients from four phase 3 trials, treated with either sunitinib or one of the following combinations: pembrolizumab. axitinib, nivolumab ? cabozantinib, avelumab ? axitinib and pembrolizumab? lenvatinib [37]. When compared with sunitinib-treated patients, those treated with pembrolizumab? axitinib or pembrolizumab? lenvatinib had a significantly higher likelihood of experiencing all-grade diarrhea, grades 3–4 diarrhea, and grades 3–4 decreased appetite. Moreover, the likelihood of experiencing all-grade diarrhea was also significantly higher in nivolumab. cabozantinib-treated patients. The likelihood of grades 3–4 nausea and all grade decreased appetite was higher with pembrolizumab. lenvatinib; however, the likelihood of all-grade nausea was lower with pembrolizumab. axitinib [37].

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3. Risk Stratification and its Clinical Implications: Patients with a Favourable Prognosis

Except for nivolumab? ipilimumab, the recommendations made by the international guidelines concerning the utilization of treatment combinations are independent of the patients’ prognostic risk. This is because the primary efficacy population of CheckMate-214 was limited to poor-/intermediate-risk patients, while the primary efficacy population of both KEYNOTE-426 and CheckMate-9ER included patients classified in all IMDC risk categories. However, the benefit demonstrated by favorable-risk patients when treated with combination treatments seems to be smaller than that shown by those in the intermediate- or poor-risk categories, sometimes lacking significance in its comparison with sunitinib-treated patients. This trend is consistent across all recommended combinations, as shown by a post hoc pooled analysis [38] and as briefly outlined below for each study.

In CheckMate-214, 23% of the patients allocated to each arm were of favorable risk (as defined by the IMDC prognostic model) [24, 25]. Although excluded from the primary efficacy analysis, these patients were nevertheless included in the ITT population and their outcomes were analyzed. Subgroup analyses revealed an almost overlapping pattern of the OS and PFS survival curves of both treatment arms among favorable-risk patients: at 48 months, 65.1% of patients were alive in the nivolumab. ipilimumab arm versus 68.9% in the sunitinib arm (HR 0.93; 95% CI 0.62–1.40), and 25.4% versus 31.6%, respectively, had not progressed (HR 1.84; 95% CI 1.29–2.62) [26]. The OS and PFS outcomes of favorable-risk patients treated with sunitinib were numerically superior to those treated with nivolumab. ipilimumab combination. Moreover, the ORR at 4 years was significantly higher in sunitinib-treated patients (51.6% vs 29.6% in the experimental arm, p = 0.0005), although the rates of complete response and duration of response favored nivolumab. ipilimumab [26]. Additionally, a post hoc analysis of the CheckMate-214 population stratified by IMDC risk factors showed that the ORR among patients with no risk factors was lower with nivolumab. ipilimumab than with sunitinib (39% vs 50%) [39]. Furthermore, while the ORR in sunitinib-treated patients decreases progressively as the number of risk factors increases, the ORR with nivolumab? ipilimumab is approximately the same for all patient risk categories, being slightly lower for patients in the favorable-risk category (39% vs 40–44% for patients with 1–6 risk factors) [39].

The KEYNOTE-426 population included approximately 31% of patients with a favorable-risk prognosis, as defined by the IMDC criteria [30, 31]. As in CheckMate-214, the OS curves of these patients have an overlapping pattern: at 2 years, 85.3% of the patients treated with the combination were still alive, which was slightly lower than the 87.7% observed among sunitinib-treated patients (HR 1.06; 95% CI 0.60–1.86; p = 0.58) [31]. In the prespecified subgroup analysis by IMDC risk category, the OS benefit was only evident in the intermediate-/poor-risk group (HR 0.63; 95% CI 0.50–0.81; p \0.001) [31]. In the PFS analysis by IMDC risk category, PFS benefits with pembrolizumab? axitinib was generally consistent across the risk categories, although the results in the favorable-risk category did not reach statistical significance (HR 0.79; 95% CI 0.57–1.09; p = 0.078). However, a post hoc subgroup analysis showed that the ORR benefit with pembrolizumab? axitinib was consistent across all IMDC risk categories [31].

Approximately 22% of the 651 patients included in the CheckMate-9ER had an IMDCdefined favorable prognosis [32]. In the prespecified subgroup analysis by IMDC risk category, patients in the favorable-risk category had a borderline significant PFS benefit with nivolumab. cabozantinib (HR 0.62; 95% CI 0.38–1.01), although the associated HR was higher than that of the intermediate-risk (HR 0.54; 95% CI 0.40–0.72) and poor-risk (HR 0.37; 95% CI 0.23–0.58) categories. For OS, there was no significant benefit from nivolumab. cabozantinib in the favorable risk (HR 0.84; 95% CI 0.35–1.97) or intermediate-risk (HR 0.70; 95% CI 0.46–1.07) categories, but a significant OS benefit was observed among patients in the poor-risk category (HR 0.37; 95% CI 0.21–0.66). Of note, and as reported in KEYNOTE-426, is the likelihood of having a higher ORR with nivolumab? cabozantinib versus sunitinib was observed consistently in patients in the favorable-risk (OR 25.9; 95% CI 9.8–40.2), intermediate-risk (OR 28.2; 95% CI 18.3–37.3), and poor-risk (OR 30.5; 95% CI 16.0–43.9) categories [32].

In the CLEAR study, approximately 33% of patients were in the favorable IMDC prognostic risk group [29]. In the prespecified subgroup analysis by IMDC risk category, the PFS benefit with pembrolizumab? lenvatinib was observed across all risk categories, although the HR was slightly higher in the favorable-risk subgroup (HR 0.41; 95% CI 0.28–0.62) than in the intermediate-risk (HR 0.39; 95% CI 0.29–0.52) or poor-risk (HR 0.28; 95% CI 0.13–0.60) subgroups. Similar to the CheckMate-9ER, significant OS benefit was observed in the poor-risk subgroup (HR 0.30; 95% CI 0.14–0.64), but not in the favorable-risk (HR 1.15; 95% CI 0.55–2.40) or intermediate-risk (HR 0.72; 95% CI 0.50–1.05) subgroups [29].

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4. Non-Clear Cell RCC

The medical management of patients with nonclear cell RCC remains a particularly challenging issue. As these subtypes are seldom included in phase 3 trials, the treatment strategies employed are often an extrapolation of what has been evaluated and approved in the setting of clear cell histology. However, the outcomes of patients with non-clear cell RCC treated with the currently approved systemic therapies are limited and usually are significantly inferior to those of patients with clear cell RCC. Acknowledging this fact, both the National Comprehensive Cancer Network (NCCN) and the EAU guidelines recommend the inclusion of patients with non-clear cell RCC in clinical trials whenever appropriate [17, 18]. However, both of these organizations also recommend the use of sunitinib, based on data from three phase 2 trials that reported a tendency for the superiority of this anti-VEGF TKI compared with everolimus (the ESPN [40], ASPEN [41] and RECORD-3 [42] trials). The NCCN guidelines also recommend cabozantinib [18].

The ESMO guidelines are more detailed regarding the management of the non-clear cell RCC subtype [43]. While they maintain the recommendation of including these patients in appropriate clinical trials, cabozantinib is the preferred first-line treatment option for patients with papillary mRCC without additional molecular testing (level II, B) [43]. The SWOG PAPMET trial demonstrated a PFS benefit for cabozantinib over sunitinib (9.0 vs 5.6 months; HR 0.60; 95% CI 0.37–0.97; p = 0.02) and higher ORR (23% vs 4%) [44]. Alternative options include sunitinib (level II, B) and pembrolizumab (level III, B; based on KeyNote-426 [30, 31]) without further molecular testing, and savolitinib in MET-driven tumors, where available (level III, C; based on SAVOIR trial [45]) [43]. In fact, in the era of precision oncology, results point to a SOC in non-clear cell RCC that will, in the future, be tailored to the specific histology within this broad group of tumors. For example, in patients with papillary type RCC, as stated above, the SWOG PAPMET Trial suggested a PFS benefit with cabozantinib over sunitinib [44], while savolitinib showed promising efficacy compared with sunitinib in the SAVOIR study [45], crizotinib showed sustained disease control in CREATE [46] and foretinib demonstrated antitumor activity in a phase 2 study [47]. These data suggest that treatment preferences for this specific subtype of tumor may change in the future.

Concerning combination therapy in patients with non-clear cell RCC, data are still scarce. The only trial specifically focused on non-clear cell RCC was reported by Gupta et al. [48]. In this study, nivolumab? ipilimumab was used to treat a small population of 18 patients with varying histological subtypes (papillary, chromophobe, unclassified, renal adenocarcinoma, translocation, and medullary). The results were positive overall, with an ORR of 33.3%, a median duration of response of 4.3 months, a median PFS of 7.1 months, and a 12-month OS of 64.2% [48]. However, these values are numerically similar to those obtained using anti-VEGF TKIs. Moreover, the efficacy of this combination may vary with the specific subtype of non-clear cell RCC. Tachibana et al. recently highlighted this aspect by showing the effect of nivolumab. ipilimumab in papillary RCC was inferior to that demonstrated in patients with clear cell RCC, with a lower ORR (14.2% vs 52.1%, p = 0.06) and a shorter median PFS (2.4 vs 28.1 months, p = 0.014) [49]. Additionally, Tykodi et al. recently presented the outcomes with nivolumab. ipilimumab treatment in a population of patients with previously untreated non-clear cell mRCC [50]. Although based on a small sample (n = 52), these results were rather promising, showing a median PFS of 3.7 months and a median OS of 21.2 months [50].

For all the other combinations, the scarcity of data prevents recommendations in the nonclear cell RCC setting. Therefore, as it currently stands, considering an approach with antiVEGF TKI monotherapy may provide non-inferior benefits with less toxicity than an ICI-based combination.

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Ma´rio Fontes-Sousa . Helena Magalha˜es . Alicia Oliveira . Filipa Carneiro . Filipa Palma dos Reis . Pedro Silvestre Madeira . Sara Meireles