Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma

INTRODUCTION — Surgical resection of localized renal cell carcinoma (RCC) can be curative for localized disease, but many patients eventually recur. In addition, many RCCs are clinically silent for much of their course, and the initial diagnosis can be delayed until disease is either locally advanced and unresectable or metastatic. The natural history of disease for patients with advanced or metastatic RCC can vary widely from a few months to many years depending on the clinical, pathologic, laboratory, and radiographic features of disease, as well as the response to therapy.

Understanding the molecular pathogenesis of RCC has identified targets for therapeutic intervention (figure 1) and led to the development of multiple agents that have an important role in the management of patients with advanced RCC. Antiangiogenic and molecularly targeted agents and their application in patients with advanced RCC will be reviewed here, with the primary focus on the treatment of clear cell RCC because much of the data have been derived from clinical trials in these patients.

An overview of the treatment approach to RCC, prognostic factors in RCC, and the role of immunotherapy alone or in combination with antiangiogenic agents are discussed separately. (See "Overview of the treatment of renal cell carcinoma" and "Systemic therapy of advanced clear cell renal carcinoma".)

MOLECULAR PATHOGENESIS — Approximately 65 to 75 percent of renal epithelial tumors are clear cell carcinomas; other important subtypes include papillary (chromophilic), chromophobe, collecting duct, and medullary carcinomas, as well as oncocytomas. The different RCC subtypes are increasingly being characterized by unique genetic abnormalities and associated gene expression patterns [1,2]. The pathogenesis of clear cell carcinoma is the best understood. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Genomic alterations in clear cell carcinoma'.)

The initial insights into the molecular pathogenesis of clear cell RCC came from studies on Von Hippel-Lindau (VHL) disease. VHL is characterized by the development of cerebellar and spinal hemangioblastomas, retinal angiomas, pheochromocytomas, and renal cysts and tumors. Clear cell RCCs develop in 40 to 60 percent of patients with VHL disease; these tend to be multicentric and bilateral with an unusually early age of onset. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)

Genetic analyses of VHL-associated RCCs showed loss of heterozygosity at the VHL locus on chromosome 3p25, and the same abnormality is present in 75 to 80 percent of sporadic clear cell RCCs. These findings implicated the VHL gene in the pathogenesis of clear cell RCCs. This abnormality results in the overproduction of vascular endothelial growth factor (VEGF). (See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)

VEGF is probably the most important growth factor that is involved in tumor angiogenesis, and it plays a significant role in the growth and progression of many types of human cancer, including RCC. Elucidation of the downstream pathways from the VEGF receptor (VEGFR) has defined a number of targets for interruption of the signaling that results in angiogenesis (figure 1). (See 'Inhibitors of the VEGF pathway' below and "Overview of angiogenesis inhibitors", section on 'VEGF receptors'.)

An alternative pathway is mediated by the mechanistic target of rapamycin (mTOR), which is downstream of the phosphoinositide 3-kinase and Akt and is regulated by the phosphatase and tensin homolog (PTEN) tumor suppressor gene. Inhibition of this pathway leads to decreased protein translation and inhibition of both angiogenesis and tumor cell proliferation. (See 'Inhibitors of the mTOR pathway' below.)

OVERVIEW OF APPROACH TO TREATMENT — The integration of antiangiogenic and molecularly targeted therapy into the overall management of patients with advanced clear cell RCC is discussed here. The timing of these agents relative to checkpoint inhibitor immunotherapy and the efficacy of combined immunotherapy plus antiangiogenic therapy are discussed in detail separately. (See "Systemic therapy of advanced clear cell renal carcinoma".)

Multiple agents targeting the vascular endothelial growth factor (VEGF) pathway and drugs inhibiting the mechanistic target of rapamycin (mTOR) are active and approved for the management of advanced clear cell RCC. The integration and choice of initial systemic therapy in patients with advanced or metastatic RCC are outlined here (algorithm 1), and details of the specific targeted agents are provided below.

The choice of treatment for patients with advanced disease has been based on prognostic risk factors historically developed in the era of frontline VEGF tyrosine kinase inhibitors (TKIs). The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model integrates six adverse factors to stratify patients into favorable-, intermediate-, or poor-risk groups (table 1) [3].

The relevance of the IMDC prognostic criteria in the era of frontline combination immunotherapy remains to be established. In the absence of alternative immunotherapy-based prognostic criteria, these criteria continue to be used in clinical trials to risk-stratify patients and, to some extent, by providers and clinical guidelines to direct therapy. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Risk stratification'.)

INHIBITORS OF THE VEGF PATHWAY — Vascular endothelial growth factor (VEGF) pathway inhibitors, used principally in combination with checkpoint inhibitor immunotherapy, are important agents in the initial treatment of patients with advanced or metastatic RCC. Some agents also have an established role in the treatment of patients who are ineligible for immunotherapy-based combinations as well as those refractory to prior courses of immunotherapy and/or molecularly targeted therapy.

While a number of agents are available, there are only limited data comparing all these agents directly. Available options include the following:

●VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs), such as cabozantinib, pazopanib, sunitinib, axitinib, lenvatinib, sorafenib, and tivozanib (see 'Preferred VEGFR inhibitors' below and 'Other agents' below)

●Bevacizumab, a monoclonal antibody that targets circulating VEGF, in combination with interferon alfa (see 'Bevacizumab plus interferon alfa' below)

The mechanism of action of these agents is interruption of the VEGF signaling pathway, which leads to death of vascular endothelial cells causing hypoxic stress (necrosis) within tumor cells. This hypoxic stress ultimately leads to physiologic angiogenic escape as new vasculature forms under the influence of alternative pro-angiogenic factors induced by hypoxia. Since this resistance tends to be plastic (eg, tumor vasculature prefers to be supported by VEGF), some tumors can respond to retreatment with the same antiangiogenic agent after a drug holiday (eg, rechallenge with sunitinib [4] or cabozantinib [5]), or sequential therapy with different antiangiogenic agents [6-11]. (See 'Preferred VEGFR inhibitors' below.)

Preferred VEGFR inhibitors — Multiple VEGF receptor (VEGFR) TKIs are active against RCC. Although there are differences among these agents, some toxicities are common to this class. The toxicities observed with VEGFR TKIs are discussed separately. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

Pazopanib — Pazopanib is an oral agent that inhibits the TKIs associated with VEGFR, platelet-derived growth factor (PDGF) receptor, and Kit receptor.

The activity of pazopanib was initially demonstrated in a phase III trial that enrolled 435 patients who were randomly assigned to pazopanib or placebo, all of whom had good- or intermediate-risk disease [12]. Approximately one-half were treatment naïve and one-half had received prior cytokine therapy. Compared with placebo, pazopanib resulted in:

●A significant increase in progression-free survival (PFS; median, 9 versus 4 months, hazard ratio [HR] for recurrence 0.46, 95% CI 0.34-0.62).

●There was no improvement in OS (median, 23 versus 21 months, HR for mortality 0.91, 95% CI 0.71-1.16). However, the lack of benefit in OS was probably due to the high rate of crossover and to the use of other treatments after disease progression in patients on the placebo arm.

Sunitinib — Sunitinib is a TKI that inhibits VEGFR as well as other tyrosine kinases associated with the PDGF receptor and c-Kit oncogene.

Multiple schedules of sunitinib have been evaluated in clinical studies. Based upon the results of these trials, we generally initiate sunitinib at 50 mg daily using three-week cycles of two weeks on therapy followed by one week off therapy. In the phase III trial that established its efficacy in renal cell carcinoma, sunitinib was administered at an initial dose of 50 mg daily for four weeks followed by two weeks off [13-15]. However, subsequent phase II studies [16-20] have shown that a schedule of 50 mg daily for two weeks followed by one week off is better tolerated, with reduced side effects, fewer dose reductions, and similar efficacy. Additionally, a retrospective analysis of patients switched from the four-week-on/two-week-off schedule to a two-week-on/one-week-off schedule also supported this alternative approach [21].

The benefit of sunitinib was initially demonstrated in a phase III trial of 750 patients with largely good- or intermediate-prognosis metastatic clear cell RCC who had not received prior systemic therapy [13-15]. In this trial, patients were randomly assigned to sunitinib or interferon alfa-2a. Compared with interferon alfa-2a, sunitinib resulted in [14]:

●A significantly higher objective response rate (47 versus 12 percent, respectively)

●Significantly longer PFS (median, 11 versus 5 months, HR 0.54)

●Longer OS (median, 26.4 versus 21.8 months, HR 0.82, 95% CI 0.67-1.00)

Over one-half of all patients on both arms were treated with VEGF pathway inhibitors after completion of the trial. Multivariate analysis of survival based upon the pretreatment stratification parameters and treatment assignment found that initial treatment with sunitinib was a statistically significant predictor of prolonged survival.

Sunitinib is better tolerated with scheduled treatment breaks. The schedule of sunitinib used in the phase III trial above (ie, the four-week-on/two-week-off schedule) was compared with continuous daily treatment (37.5 mg/day) in a separate randomized trial that included 292 patients with advanced RCC [22]. The four-week-on/two-week-off schedule resulted in a significantly longer time to deterioration.

Although data are limited, sunitinib appears to be efficacious regardless of age. In a retrospective study that included over 1000 previously untreated patients, there were no significant differences in PFS (median, 11 versus 10 months) and OS (26 versus 24 months) among patients <70 and ≥70 years, respectively [23]. Similar results were reported among patients receiving sunitinib following progression on prior cytokine treatment. However, patients ≥70 years experienced significantly more treatment-related toxicity. Decisions on the administration of sunitinib among older patients should be based on considerations of the treatment-related risks and the goals and preferences of the individual patient.

The role of cytoreductive nephrectomy among patients treated with sunitinib is discussed separately. (See "Role of surgery in patients with metastatic renal cell carcinoma", section on 'Antiangiogenic therapy and immune checkpoint inhibitors'.)

Pazopanib versus sunitinib — Both pazopanib and sunitinib improve PFS (compared with placebo or interferon alfa-2a, respectively). Prospective data indicate that they result in similar survival outcomes, although pazopanib results in less toxicity, including fatigue.

Pazopanib and sunitinib have been compared in two randomized trials:

●In one, 1110 patients were randomly assigned to treatment with pazopanib or sunitinib [24,25]. Compared with sunitinib, pazopanib resulted in:

•No difference in PFS (median, 8.4 versus 9.5 months, HR 1.05, 95% CI 0.90-1.22).

•No difference in OS (median, 28.3 versus 29.1 months, HR 0.92, 95% CI 0.79-1.06).

•A significantly higher objective response rate (31 versus 25 percent).

•A similar rate of drug discontinuation due to toxicity (24 versus 20 percent), which was predominantly driven by abnormal liver function tests (6 versus 1 percent).

•Better health-related quality of life scores, including better mouth and throat symptoms, less fatigue, and less foot soreness.

●In the PISCES trial, the tolerances of these agents were compared to evaluate if differences in toxicity affected patient preferences [26]. All patients (n = 169) were randomly assigned to a 10-week course of pazopanib or sunitinib followed by a two-week washout period. Patients then crossed over to the alternative agent for an additional 10 weeks. Following this double-blind phase, patients were allowed to continue on whichever agent they preferred. The primary endpoint was patient preference for a specific treatment as assessed by questionnaire at the end of the two treatment periods. Other endpoints were clinician preference, safety, and health-related quality of life. The main results were as follows:

•Among the patients who completed the study questionnaires, received at least one dose of treatment during each study phase, and did not exhibit disease progression before crossover, significantly more patients preferred pazopanib over sunitinib (70 versus 22 percent).

•Clinicians also preferred pazopanib (61 percent) over sunitinib (22 percent).

•Overall, pazopanib resulted in a significantly better health-related quality of life, with less fatigue and less dysgeusia reported compared with sunitinib.

Cabozantinib — Cabozantinib is a small-molecule TKI that targets VEGFR. It also inhibits the MET and AXL genes, which are associated with a poor prognosis and the development of resistance to VEGF inhibition. Cabozantinib has been compared with everolimus in previously treated patients and with sunitinib in previously untreated patients.

The approved dose and formulation of cabozantinib (Cabometyx) for RCC is different from that used for metastatic medullary thyroid cancer (Cabometriq), and the two forms of cabozantinib should not be interchanged [27].

Cabozantinib versus everolimus — A phase I study in previously treated patients demonstrated activity and provided the rationale for phase III evaluation [28].

In the phase III METEOR trial, 658 previously treated patients were randomly assigned to cabozantinib (60 mg/day) or everolimus (10 mg/day) [29-31]. All patients had progressed after receiving prior VEGF TKI therapy; 69 percent of patients had received only one prior course of systemic therapy, while 31 percent had been treated with two or more prior regimens.

Efficacy — Key efficacy results from the phase III trial included the following [29,30,32-34]:

●PFS (defined by radiologic progression or by death from any cause) was the primary endpoint. PFS was significantly longer with cabozantinib compared with everolimus (median, 7.4 versus 3.9 months, HR 0.51, 95% CI 0.41-0.62).

●OS was significantly prolonged with cabozantinib compared with everolimus (median, 21.4 versus 17.1 months, HR 0.70, 95% CI 0.58-0.85). The improvement in OS was consistent across all preplanned subgroups.

●The objective response rate, based upon independent radiologic review, was significantly higher with cabozantinib (17 versus 3 percent).

●Cabozantinib may have particular value in patients with bone metastases, a subset that has a relatively poor prognosis in patients with advanced RCC [35]. In a secondary analysis of the 142 patients with bone metastases, cabozantinib improved both PFS survival (median 7.4 versus 2.7 months, HR 0.33, 95% CI, 0.21-0.51) and OS (median 20.1 versus 12.1 months, HR 0.54, 95% CI 0.34-0.84) compared with everolimus [33].

Toxicity — All-cause toxicity in patients on the cabozantinib arm was significant, with 68 percent of patients experiencing a grade 3 or 4 event [29]. Serious (grade ≥3) toxicities associated with cabozantinib included [27]:

●Hemorrhage (2.1 versus 1.6 percent with everolimus)

●Gastrointestinal perforation and/or fistula (1.2 versus 0.0 percent)

●Thrombotic events and pulmonary emboli (7.3 versus 2.5 and 3.9 versus 0.3 percent, respectively)

●Hypertension (15 versus 7.1 percent)

●Diarrhea (11 versus 2 percent)

●Palmer-plantar erythrodysesthesia syndrome (42 versus 6 percent)

●Reversible posterior leukoencephalopathy syndrome has also been reported with cabozantinib

Cabozantinib versus sunitinib — Cabozantinib was compared with sunitinib in previously untreated patients with intermediate- or high-risk metastatic RCC in the CABOSUN trial [36-38]. In this trial, 157 patients were randomly assigned to cabozantinib (60 mg/day) or sunitinib (50 mg/day for four weeks on each six-week cycle).

●PFS, the primary endpoint of the trial, was significantly prolonged with cabozantinib (median, 8.6 versus 5.3 months, HR 0.48, 95% CI 0.31-0.74). The objective response rate was significantly higher with cabozantinib (20 versus 9 percent).

●OS was increased with cabozantinib compared with sunitinib (median, 26.6 versus 21.2 months), but the difference was not statistically significant (HR 0.80, 95% CI 0.53-1.21).

●The safety profile was similar to that observed in the larger METEOR trial and similar to the intensity of side effects with sunitinib in this trial.

Axitinib — Axitinib is an orally available inhibitor of VEGFR1, VEGFR2, and VEGFR3. Axitinib had a higher response rate than sorafenib in randomized clinical trials. However, axitinib has not been directly compared with pazopanib or sunitinib as initial therapy, or with cabozantinib as subsequent therapy. (See 'Axitinib versus sorafenib' below.)

Hypertension on axitinib appears to be a promising biomarker of treatment response. Although titrating axitinib dosing to levels that produce hypertension may improve its efficacy both in treatment-naïve patients and in those with disease progression on immunotherapy, the benefits of this approach have not been clearly established.

In a randomized phase II trial, 213 treatment-naïve patients were treated with axitinib (5 mg twice daily) for four weeks and then randomly assigned to axitinib dose titration (stepwise from 5 to 7 mg to 10 mg twice a day based on tolerability) or axitinib with placebo dose titration [39,40]. Objective response rates were higher for those receiving axitinib titration versus placebo titration (54 versus 34 percent), but PFS was similar (median 14.5 versus 15.7 months, HR 0.85, 95% CI 0.54-1.35), suggesting that titrating axitinib until hypertension was observed did not influence outcomes in a majority of patients.

Among patients with disease progression on immunotherapy, the use of titrated axitinib dosing as subsequent therapy remains investigational, having been evaluated only in a single phase II study [41]. Titrated dosing of axitinib has also not been directly compared in this setting with standard dosing of axitinib or other VEGF inhibitors, either as single agents (eg, cabozantinib) or in combination with other agents (eg, lenvatinib plus everolimus). (See 'Overview of approach to treatment' above and 'Cabozantinib' above and 'Lenvatinib plus everolimus' below.)

Lenvatinib plus everolimus — Lenvatinib plus everolimus is one treatment option for patients with clear cell RCC who progress on prior antiangiogenic therapy, as this approach improved PFS over single-agent everolimus in a randomized trial [42]. When combined with everolimus, we initiate lenvatinib at 18 mg daily, which prolonged time to deterioration compared with a lower starting dose (14 mg daily) in a randomized trial [43].Patients should discontinue any prior tyrosine kinase inhibitor therapy and allow it to wash out (approximately three to five half-lives) before starting lenvatinib at 18 mg daily in combination with everolimus to avoid toxicity from overlapping antiangiogenic therapy.

In a phase II trial, 153 patients with metastatic or unresectable, locally advanced, clear cell RCC were randomly assigned to either lenvatinib (18 mg daily) plus everolimus (5 mg daily); lenvatinib (24 mg daily); or everolimus (10 mg daily) [42]. All patients had received prior antiangiogenic therapy and had an ECOG performance status 0 or 1. At median follow-up of 18 months, results were as follows:

●Compared with everolimus, lenvatinib plus everolimus improved PFS (median 14.6 versus 5.5 months, HR 0.40, 95% CI 0.24-0.68). OS was also higher with the combination versus everolimus but the difference was not statistically significant (median 25.5 versus 17.5 months, HR 0.55, 95% CI 0.30-1.01).

●Compared with single-agent lenvatinib, lenvatinib plus everolimus had a non-statistically significant trend towards higher PFS and OS (median PFS 14.6 versus 7.4 months, HR 0.66, 95% CI 0.39-1.10; median OS 25.5 versus 18.4 months, HR 0.74, 95% CI 0.40-1.36).

●Single-agent lenvatinib improved PFS but not OS compared with single-agent everolimus (median PFS 7.4 versus 5.5 months, HR 0.61, 95% CI 0.38-0.98; median OS 18.4 versus 17.5 months, HR 0.74, 95% CI 0.42-1.31).

Lenvatinib plus everolimus is approved by the US Food and Drug Administration (FDA) as treatment for adult patients with advanced renal cell carcinoma following one prior antiangiogenic therapy.

Studies evaluating lenvatinib plus everolimus as initial therapy for metastatic clear cell RCC are discussed separately. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Lenvatinib plus everolimus'.)

Tivozanib — Tivozanib, a selective VEGFR inhibitor, is active in patients who have progressed on two or more systemic therapies (including at least one prior VEGFR inhibitor). Tivozanib is one available option for patients who have progressed on both checkpoint inhibitor immunotherapy and a VEGFR inhibitor, either as single agents or in combination. In a phase III trial (TIVO-3), tivozanib improved PFS but not OS in patients with treatment-refractory RCC, including those who received prior VEGF inhibitor therapy either alone or in combination with immunotherapy [11,44].

Data for tivozanib are as follows:

●Treatment-naïve patients – In an open-label phase III trial (TIVO-1), 517 patients with metastatic RCC who were either treatment-naïve or had progressed on prior chemotherapy or immunotherapy (but not VEGFR or mTOR inhibitors) were randomly assigned to tivozanib or sorafenib [45]. Tivozanib improved PFS in the entire study population (median 12 versus 9 months, HR 0.80, 95% CI 0.64-0.99), including those with treatment-naïve disease (median 13 versus 9 months, HR 0.76, 95% CI 0.58-0.99), but not in those with disease progression on prior chemotherapy or immunotherapy (median 12 versus 9 months, HR 0.88 95% CI 0.59-1.31). Additionally, tivozanib did not improve OS; rather, a trend towards longer survival was demonstrated in those treated with sorafenib (median 29 months each, HR 1.25, 95% CI 0.95-1.62). The lack of OS advantage with tivozanib was attributed to the crossover design of the trial; a majority of patients who progressed on sorafenib were subsequently treated with tivozanib while many of the patients initially treated with tivozanib did not receive any subsequent therapy after disease progression.

●Treatment-refractory patients – In an open-label phase III trial (TIVO-3), 350 patients with metastatic RCC refractory to at least two previous therapies including at least one prior VEGFR inhibitor (eg, at least two VEGFR inhibitors, a VEGFR inhibitor plus immunotherapy, or VEGFR inhibitor plus other therapy) were randomly assigned to either tivozanib or sorafenib [11]. At a median follow-up of 19 months, relative to sorafenib, tivozanib improved PFS (median six versus four months, HR 0.73, 95% CI 0.56-0.94) but not OS (median 16 versus 19 months, HR 0.97, 95% CI 0.75-1.24) [44]. Tivozanib was also better tolerated with less toxicity than sorafenib [46].

Tivozanib is also active in patients who received prior therapy with axitinib. Among a subset of 172 patients in this study who received prior axitinib monotherapy either as second- or third-line therapy, subsequent therapy with tivozanib resulted in higher PFS (median six versus four months, HR 0.68) and objective response rates (13 versus 8 percent) compared with sorafenib [47].

Based on the results of the TIVO-3 study, the US FDA granted regulatory approval for tivozanib in patients with advanced RCC who have progressed on two or more prior systemic therapies [48]. Based on data from the TIVO-1 trial, tivozanib also has regulatory approval in Europe as initial therapy in patients with advanced RCC disease or as subsequent therapy in those who have progressed after one prior treatment with cytokine therapy, but are treatment-naïve to VEGF or mTOR pathway inhibitors.

Other agents

Sorafenib — Sorafenib is a potent small-molecule inhibitor of multiple TKIs, including VEGFR2, FLT3, PDGF receptor, and fibroblast growth factor receptor-1 (FGFR1) (figure 1). It also inhibits C-raf and both mutant- and wild-type B-raf. Raf kinase is an important mediator of the Ras/Raf/MEK pathway. Although activating mutations in B-raf (BRAF) have not been identified in RCC, constitutive activation in the BRAF pathway (Raf, MEK, and ERK) has been observed in approximately 50 percent of tumors [49].

Sorafenib is mainly limited to use as a subsequent-line molecularly targeted agent. Sorafenib does not have a clear role in the approach to previously untreated patients.

●Previously untreated patients – Sorafenib was compared with interferon alfa-2a in a phase II trial in previously untreated patients [50]. Although greater tumor shrinkage and better quality of life were observed with sorafenib, there was no increase in PFS.

●Previously treated patients – In the phase III TARGET trial, 903 patients with advanced RCC who had progressed despite cytokine therapy were randomly assigned to treatment with sorafenib (400 mg orally twice daily) or placebo [51-53].

The median PFS was significantly longer in those receiving sorafenib compared with placebo (5.5 versus 2.8 months, HR 0.44, 95% CI 0.35-0.55). OS was not significantly prolonged with sorafenib compared with placebo (median, 17.8 versus 15.2 months, HR 0.88, 95% CI 0.74-1.04). However, the patients originally assigned to placebo could cross over to sorafenib. In a separate analysis from this trial, sorafenib appeared to be effective in carefully selected older patients (≥70 years), as evidenced by a significant improvement in PFS (26 versus 14 weeks with placebo) [53].

Axitinib versus sorafenib — Axitinib is generally preferred over sorafenib as a VEGFR-targeted agent, based on the results of two randomized trials, which showed improvement (either a trend or significant) in PFS and response rate.

●Treatment-naïve patients – The role of axitinib in previously untreated patients with metastatic RCC was evaluated in a multicenter randomized trial in which 288 patients were randomly assigned to treatment with axitinib (5 mg twice a day) or sorafenib (400 mg twice a day) [54].

Treatment with axitinib resulted in a trend toward improved PFS (10 versus 6.5 months, HR 0.77, 95% CI 0.56-1.05) and a higher objective response rate (32 versus 15 percent). However, with further follow-up, there was no difference in OS between axitinib and sorafenib (median, 21.7 versus 23.3 months, HR 0.995, 95% CI 0.31-1.36) [55].

Axitinib therapy was associated with higher rates of toxicity, including diarrhea (50 versus 40 percent), hypertension (49 versus 29 percent), weight loss (37 versus 24 percent), fatigue (33 versus 26 percent), and anorexia (29 versus 19 percent).

●Previously treated patients – In the AXIS phase III trial, in which 723 patients with previously treated RCC were randomly assigned to axitinib or sorafenib [56,57], all patients had prior treatment with a cytokine (35 percent) or other anti-VEGF or molecularly targeted treatment. Quality of life (with a time to deterioration endpoint) was prospectively assessed using standardized questionnaires.

Treatment with axitinib resulted in a significant improvement in PFS compared with sorafenib (median, 8 versus 6 months, HR 0.66, 95% CI 0.55-0.78). The benefit was higher in patients previously treated with either cytokines (12 versus 8 months, HR 0.51, 95% CI 0.37-0.68) or sunitinib (6.5 versus 4.4 months, HR 0.72, 95% CI 0.57-0.90). There was a significant increase in objective response rate with axitinib (23 versus 12 percent), but there was no significant difference in OS (median, 20 versus 19 months, HR 0.96, 95% CI 0.80-1.17).

In addition, there were no differences seen in patient-reported outcomes between the treatment groups. Among patients treated with axitinib, the major serious (grade 3/4) adverse events were hypertension (17 percent), diarrhea (11 percent), and fatigue (10 percent). The major adverse events in those treated with sorafenib were hand-foot syndrome (17 percent), hypertension (12 percent), and diarrhea (8 percent).

Bevacizumab plus interferon alfa — Bevacizumab is a monoclonal antibody that binds circulating VEGF and prevents its interaction with VEGFR. Two phase III trials demonstrated improved PFS with the addition of bevacizumab to interferon alfa (either interferon alfa-2a or interferon alfa-2b). However, there are no trials comparing bevacizumab plus interferon alfa with bevacizumab alone.

●In the AVOREN trial, 649 previously untreated patients were randomly assigned to interferon alfa-2a plus either bevacizumab or placebo [6,58-60]. Interferon alfa-2a plus bevacizumab improved PFS compared with interferon alfa-2a plus placebo (median, 10.2 versus 5.5 months, HR 0.63, 95% CI 0.45-0.72), and there was a trend toward improved OS (median survival, 23.3 versus 21.3 months, HR 0.86, 95% CI 0.72-1.04).

●In the CALGB 90206 trial, 732 previously untreated patients with metastatic RCC were randomly assigned to either interferon alfa-2b plus bevacizumab or interferon alfa-2b plus placebo [7,61]. Treatment with bevacizumab plus interferon alfa-2b resulted in improvement in PFS (median, 8.5 versus 5.2 months, HR 0.71, 0.61-0.83) and a trend toward improved OS (median, 18.3 versus 17.4 months). Of note, interferon alfa-2b has limited availability, as the manufacturer has discontinued production.

●In the BEST trial (E2804), 331 patients with no prior antiangiogenic therapy were randomly assigned to bevacizumab monotherapy, bevacizumab plus temsirolimus, bevacizumab plus sorafenib, or sorafenib plus temsirolimus [62]. The activity of bevacizumab (as assessed by PFS) was not improved upon by the addition of either sorafenib or temsirolimus nor by the use of sorafenib plus temsirolimus. The rates of severe (grade 3 or higher) toxicity were significantly lower with bevacizumab monotherapy compared with the three combination regimens (44 versus 77 to 84 percent).

Toxicities of VEGF inhibition (hypertension) — Hypertension has been consistently associated with all of the vascular endothelial growth factor (VEGF) inhibitors. Guidelines for pretreatment assessment, monitoring, and management of elevated blood pressure in patients receiving bevacizumab are available (table 2A-B). (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Hypertension'.)

In addition to its effects on blood pressure, preclinical studies suggest that angiotensin II can stimulate angiogenesis and tumor growth. Two retrospective analyses have found that treatment of hypertension with angiotensin system inhibitors (ASIs; including angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor blockers [ARBs]) may have antitumor activity in patients with metastatic RCC [63,64]. Both studies found that ASIs significantly increased both PFS and OS, and that this effect was present in both those with pre-existing hypertension and treatment with ASIs and in those who developed hypertension during VEGF pathway inhibition and were subsequently treated with ASIs. Although there are no data from prospective trials, our approach is to use an ACEI or ARB as a component of antihypertensive treatment in patients with advanced RCC, pending additional prospective and mechanistic studies.

Other side effects associated with inhibitors of VEGF are discussed separately. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

INHIBITORS OF THE mTOR PATHWAY — The mechanistic target of rapamycin (mTOR) pathway is downstream of the phosphoinositide 3-kinase and AKT pathway that is regulated by the phosphatase and tensin homolog (PTEN) tumor suppressor gene (figure 2). Although mTOR inhibitors have some activity, temsirolimus (table 3) and everolimus have limited, if any, role in advanced RCC except for patients whose disease is refractory to initial treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) or who have mutations in the PI3K pathway.

Temsirolimus — Randomized trials have shown that temsirolimus (table 3) has activity in advanced or metastatic RCC, but other options are preferred for both initial and subsequent-line therapy (algorithm 1).

●In a phase III trial, 626 previously untreated patients were randomly assigned to temsirolimus, temsirolimus plus interferon alfa-2a, or interferon alfa-2a monotherapy [65]. Temsirolimus significantly prolonged the median overall survival (OS) compared with interferon alfa-2a as a single agent (10.9 versus 7.3 months, hazard ratio [HR] for mortality 0.73, 95% CI 0.58-0.92). There was no additional benefit from combining temsirolimus with interferon alfa-2a.

●In the INTORSECT trial of 512 patients who had progressed on sunitinib, temsirolimus was less active than sorafenib [66]. OS was shorter (median, 12.3 versus 16.6 months, HR 1.31, 95% CI 1.05-1.63).

●In the BEST trial (E2804) of 361 patients who had not received prior targeted therapy, patients were randomly assigned to bevacizumab as a single agent, bevacizumab plus temsirolimus, bevacizumab plus sorafenib, or sorafenib plus temsirolimus [62]. None of the combination regimens improved progression-free survival (PFS) compared with bevacizumab monotherapy; the two combinations incorporating temsirolimus had a worse therapeutic index compared with bevacizumab monotherapy.

Everolimus — Everolimus is an orally administered mTOR inhibitor. Although everolimus has activity in patients with advanced RCC [67,68], randomized trials using active rather than placebo comparators have not established a role as either initial therapy or second-line therapy.

●In the phase II RECORD-3 trial, 471 previously untreated patients were randomly assigned to either everolimus or sunitinib [69,70]. PFS, the primary endpoint, was worse with everolimus (7.9 versus 10.7 months, HR 1.4, 95% CI 1.2-1.8). Overall PFS after crossover to sunitinib following everolimus was inferior to sunitinib followed by everolimus (21.1 versus 25.8 months).

●In previously treated patients, several randomized trials have demonstrated that everolimus is less effective than cabozantinib, nivolumab, and lenvatinib [29,42,71]. (See 'Cabozantinib' above and "Systemic therapy of advanced clear cell renal carcinoma", section on 'Nivolumab'.)

Toxicity — The mTOR inhibitors are associated with multiple side effects, although serious (grade 3 or 4) toxicities are not common.

●Hypersensitivity reactions have been reported with temsirolimus and may be severe or life-threatening [72]. Premedication with diphenhydramine (25 to 50 mg intravenous [IV] prior to each dose of temsirolimus) is recommended. (See "Infusion reactions to systemic chemotherapy", section on 'Temsirolimus'.)

●Temsirolimus and everolimus were associated with pneumonitis in 0.5 to 5 percent of patients in clinical studies, which in some cases included severe toxicity and fatalities. Baseline radiographic assessment (chest radiograph or computed tomography [CT]) is advised for all patients when an mTOR inhibitor is being considered. Periodic follow-up imaging should be performed even in the absence of clinical symptoms. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Temsirolimus'.)

●Cases of opportunistic infection with Pneumocystis jirovecii pneumoniae, including fatalities, have been reported in patients treated with temsirolimus [73]. Thus, close follow-up for respiratory symptoms is strongly recommended. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)

●Other frequent toxicities include asthenia, rash, anemia, nausea, anorexia, and hyperglycemia.

OTHER ISSUES

Role of VEGF inhibitors for brain metastases — The approach to sequencing initial systemic therapies (including VEGF inhibitors) and intracranial therapies in patients with brain metastases due to RCC is discussed separately. (See "Overview of the treatment of renal cell carcinoma", section on 'Brain metastases, treatment naïve'.)

Combinations of targeted agents — The understanding of the molecular pathogenesis of RCC might make it possible to further improve the efficacy of treatment by blocking multiple steps in the same pathway ("vertical blockade") or by simultaneously inhibiting more than one pathway ("horizontal blockade"). However, even with the data from the lenvatinib plus everolimus combination, there remains limited evidence that combinations are superior to sequential use of targeted agents with different mechanisms.

Adjuvant targeted therapy — The role of vascular endothelial growth factor receptor (VEGFR)-targeted systemic adjuvant therapy after complete surgical resection is limited and discussed separately. (See "Overview of the treatment of renal cell carcinoma", section on 'Adjuvant therapy for locoregional disease'.)

Cytoreductive nephrectomy — The role of cytoreductive nephrectomy among select patients treated with antiangiogenic agents is discussed separately. (See "Role of surgery in patients with metastatic renal cell carcinoma", section on 'Antiangiogenic therapy and immune checkpoint inhibitors'.)

Biomarkers — The role of various biomarkers in predicting responsiveness to molecularly targeted agents remains unknown. The use of tumor tissue and circulating biomarkers to help select therapies is not part of standard clinical practice and should be confined to prospectively designed clinical trials.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cancer of the kidney and ureters".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (See "Patient education: Renal cell carcinoma (kidney cancer) (Beyond the Basics)".)

SUMMARY AND RECOMMENDATIONS

●Initial treatment – For most patients with advanced or metastatic, unresectable clear cell renal cell carcinoma (RCC), systemic therapy is typically initiated promptly with immunotherapy and/or vascular endothelial growth factor receptor (VEGFR) inhibitors. The decision to start systemic therapy and the selection of agent(s) depend on disease-related symptoms, patient comorbidities, and tumor risk stratification (table 1 and algorithm 1). Clinical trials are encouraged, if available. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Selection of initial therapy'.)

•Favorable-risk disease with limited disease burden – For patients with treatment-naïve, favorable-risk disease and limited disease burden (table 1), we offer close active surveillance. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Active surveillance'.)

For those who desire a more aggressive management approach, options include a single-agent VEGFR inhibitor (typically sunitinib or pazopanib) or single-agent immunotherapy (either pembrolizumab or nivolumab). (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Limited disease burden' and 'Sunitinib' above and 'Pazopanib' above.)

•Favorable-risk disease, substantial disease burden – For patients with favorable-risk disease and substantial disease burden who are symptomatic and/or have more rapidly progressive disease, we offer initial treatment with immunotherapy-based regimens. This treatment approach is discussed separately. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Substantial disease burden'.)

For those who are ineligible for or choose to forego initial treatment with immunotherapy-based regimens, we prefer antiangiogenic treatment that incorporates a VEGFR inhibitor. Options include lenvatinib plus everolimus, sunitinib, pazopanib, or cabozantinib. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Lenvatinib plus everolimus' and 'Sunitinib' above and 'Pazopanib' above and 'Cabozantinib' above.)

•Intermediate- or poor-risk disease – For patients with intermediate- or poor-risk disease, we offer initial treatment with immunotherapy-based regimens. This treatment approach is discussed separately. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Intermediate- and poor-risk disease'.)

For those who are ineligible for or choose to forego initial treatment with immunotherapy-based regimens, we offer antiangiogenic therapy that incorporates a VEGFR inhibitor. Preferred options include lenvatinib plus everolimus or cabozantinib. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Lenvatinib plus everolimus' and 'Cabozantinib' above.)

●Subsequent treatment – For patients who progress after initial therapy, the choice of subsequent treatment depends on prior therapy and often includes antiangiogenic and/or molecularly targeted therapy. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Subsequent therapy'.)

•Prior immunotherapy – For patients who progress after initial immunotherapy and have not previously received antiangiogenic therapy, we suggest VEGFR-targeted therapy rather than a mechanistic target of rapamycin (mTOR) inhibitor as a single agent (Grade 2B). Options include axitinib, cabozantinib, sunitinib, pazopanib, or the combination of lenvatinib plus everolimus. Treatment options incorporating further immunotherapy are discussed separately. (See 'Preferred VEGFR inhibitors' above and "Systemic therapy of advanced clear cell renal carcinoma", section on 'Subsequent therapy'.)

•Prior immunotherapy plus a VEGFR inhibitor – For patients who progress after initial treatment with both immunotherapy and a VEGFR inhibitor (either in sequence or in combination), options include single-agent cabozantinib, axitinib, tivozanib, or the combination of lenvatinib plus everolimus, depending upon prior therapy. In general, when choosing treatment, we often avoid VEGFR inhibitors that have been used in prior lines of therapy. Treatment options incorporating further immunotherapy are discussed separately. (See 'Cabozantinib' above and 'Axitinib' above and 'Tivozanib' above and 'Lenvatinib plus everolimus' above and "Systemic therapy of advanced clear cell renal carcinoma", section on 'Subsequent therapy'.)

•Prior VEGFR inhibitor alone – For patients who progress after initial treatment with a VEGFR inhibitor without previous exposure to immunotherapy, we offer single-agent nivolumab. Nivolumab plus ipilimumab is an alternative option. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Nivolumab'.)

For those not eligible for immunotherapy, we offer an alternative VEGFR inhibitor. (See 'Preferred VEGFR inhibitors' above.)