Optimizing Treatment Approaches in Advanced Renal Cancer

Over the last decade, improved understanding of canonical pathways implicated in the unique biology of renal cell carcinoma (RCC) has fueled the development of several new approaches to treatment for this malignancy. Development of tyrosine kinase inhibitors; mammalian target of rapamycin inhibitors; and, more recently, targeted immunotherapies such as checkpoint inhibitors has had a major impact on the natural history of this disease. Clinical prognostic models also have played a central role in the management of metastatic disease, as well as in the design and interpretation of clinical trials. Currently, 11 regimens are approved by the US Food and Drug Administration for the treatment of advanced RCC, and there is a growing role for localized approaches, including surgery, in appropriately selected patients. This article reviews current registration data for approved agents, and offers an outlook on selected novel strategies. A practical perspective on the multidisciplinary management of advanced RCC is provided, with a focus on systemic therapy.

Introduction

Renal cell carcinoma (RCC) is characterized by a unique biology and poor response to conventional chemotherapy and radiation therapy. Over the last decade, a growing understanding of the underlying oncogenetic events and relevant molecular pathways has enabled significant advances in therapy for this disease. Inactivation of the von Hippel–Lindau (VHL) gene is the cardinal oncogenetic event in the pathogenesis of clear cell RCC. Loss of function in this tumor suppressor gene results in high levels of hypoxia-inducible factor (HIF) with activation of multiple downstream effectors involved in angiogenesis and cell proliferation, most prominently the vascular endothelial growth factor (VEGF).[1] Further, it is well understood that the phosphoinositide 3-kinase pathway, with its key enzymatic complex involving the mammalian target of rapamycin (mTOR), is commonly upregulated and actionable in this disease.[2] Lastly, a growing understanding of the unique immune microenvironment that is commonly hyperinfiltrated in RCC renders this disease targetable through reinvigoration of the patient’s immune system; this is evident historically by the success of cytokine therapy prior to the advent of molecularly targeted agents, and more recently by the successful application of checkpoint inhibitor blockade in this disease.[3] In addition to the successful development of 11 systemic regimens approved by the US Food and Drug Administration (FDA), a large body of work characterizing the heterogeneous nature of this disease has established clinical, laboratory, and molecular criteria to guide the management of RCC. This information can be integrated with individual patient data to inform decision making regarding the utility of systemic therapies, surgical interventions, and even active surveillance in the metastatic setting. This article provides a practical perspective on the management of advanced RCC, as well as insight into the current models of risk stratification and ongoing clinical trials. The discussion will focus on the currently available systemic therapies; other strategies that are beyond the scope of this article include active surveillance[4,5] and metastasectomy.[6,7]

Risk Stratification of Patients With Advanced RCC

Prognostic models

Even in the metastatic setting, the natural history of clear cell RCC is highly variable, and outcomes of systemic therapy are heterogeneous. Therefore, standardized determination of patient and disease characteristics that correlate with clinical outcomes has played a central role in this setting. Currently there are two well-established prognostic models-one from Memorial Sloan Kettering Cancer Center (MSKCC) and the other from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)-that have been developed and validated in large datasets of patients treated for metastatic RCC (Table 1). These have become critical in the design and interpretation of clinical trials and are commonly applied in retrospective analyses of large cohorts. Further, they have also been useful for patient prognostication and counseling. While the MSKCC and IMDC models typically do not facilitate selection of specific agents in the metastatic setting, they can guide decision making in several unique clinical scenarios, as we will outline in this article.

MSKCC and IMDC prognostic risk models for metastatic RCC

In 2002, we reported on the first developed and most widely used prognostic tool, the MSKCC risk criteria.[8] This model incorporates five prognostic factors that correlated independently with overall survival (OS) in patients treated with interferon alfa for metastatic disease: Karnofsky performance status scores of less than 80%, intervals of less than 1 year between diagnosis of RCC and initiation of treatment, lactate dehydrogenase levels more than 1.5 times the upper limit of normal, corrected serum calcium levels greater than 10 mg/dL, and hemoglobin levels below the lower limit of normal. This model was subsequently validated in an independent cohort of patients during the immunotherapy era[9] and ultimately in patients treated with sunitinib.[10] The MSKCC risk model has been applied to large clinical trial datasets multiple times, and it remains the most frequently used source of risk scores for stratification of patients enrolled in randomized clinical trials. Following the advent of targeted therapies, Heng et al, with the IMDC, compiled and retrospectively analyzed a large cohort of 645 patients with metastatic RCC treated with first-line tyrosine kinase inhibitor (TKI) therapy. The resulting clinical prediction model, commonly known as the IMDC model, provides a six-variable score that largely overlaps with the MSKCC model. The IMDC model also stratifies patients into “favorable-,” “intermediate-,” and “poor-risk” categories, while adding high absolute neutrophil and platelet counts as risk factors but excluding high lactate dehydrogenase level as a risk factor.[11]

Applicability of prognostic models beyond the first-line setting in clear cell RCC

Initially, these prognostic models were validated only in patients with metastatic RCC who were receiving first-line therapy. However, in 2004, the Cleveland Clinic group that previously reported on the MSKCC risk criteria conducted a study in which they pooled data from cytokine-pretreated patients receiving additional systemic therapies and proposed a separate model to stratify patients with prior therapies[4]; this MSKCC model included only three factors (Karnofsky performance status score, hemoglobin level below the lower limit of normal, and corrected serum calcium concentration). Similarly, the IMDC model was validated in patients in second-line therapy[12] and in patients with non–clear cell RCC.[13] More recently, use of prognostic gene expression signatures has improved the predictive power of the IMDC model and provided additional prognostic information in the setting of metastatic RCC.[14]

Prognostic models in specific clinical scenarios: active surveillance, cytoreductive nephrectomy, and first-line therapy options

Risk stratification tools have been applied to support decision making in several clinical scenarios. Data from a small trial prospectively studying active surveillance in patients with metastatic RCC suggests that integration of IMDC risk assessment and disease burden may enable clinicians to identify patients who are more likely to remain on active surveillance for a longer period of time.[5] Based on a large retrospective analysis, RCC patients being considered for cytoreductive nephrectomy appeared to gain an OS benefit from undergoing surgery before initiation of systemic therapy if they met three or fewer IMDC criteria preoperatively, whereas those with higher IMDC risk scores did not benefit from this strategy.[15] The only agent currently approved based on a pivotal trial performed in a “risk-defined” setting is temsirolimus, which was found to yield superior OS outcomes compared with interferon alfa in patients with three or more “poor-risk” features (as defined by the MSKCC criteria) and/or the presence of extensive metastatic disease.[16]

TKI registration trials, however, did enroll patients with poor-risk disease and showed clear treatment efficacy; hence, other approved first-line agents (such as sunitinib and pazopanib) are valid options in this setting. In fact, TKIs are commonly used in this setting, given the ease of oral administration (eg, compared with the need for weekly infusions for temsirolimus), the more robust radiographic response rates, and the superior efficacy of TKIs over rapalogs suggested by several randomized studies.[17-19] Finally, a recently published phase II trial in patients with previously untreated metastatic RCC and intermediate- or poor-risk disease per IMDC criteria reported superior progression-free survival (PFS) in those who received the novel TKI cabozantinib compared with those who received sunitinib.[20]

Systemic Therapy for Metastatic RCC: First-Line Options

A better understanding of the canonical pathways in RCC has led to the introduction of several molecularly directed therapies over the last 10 years, with these targeted treatment options replacing cytokine-based strategies as the standard of care in metastatic RCC. The availability of agents with known efficacy and safety profiles, as well as individual patient characteristics and physician preferences, all play a role in the selection of first-line and subsequent therapy (see the section in this article, “Choosing Between First-Line Option” and Table 2).[21]

TKIs as standard of care in the first-line setting

Sunitinib and pazopanib are the most commonly used first-line agents approved for the treatment of advanced RCC.[22] These small, orally available molecules are potent inhibitors of multiple tyrosine kinases, most relevantly VEGF receptor (VEGFR) 2, a key mediator of early-phase angiogenesis expressed on endothelial cells in the tumor microenvironment. In the pivotal phase III trial of first-line sunitinib, patients treated with this agent achieved longer PFS and higher objective response rates (ORRs) compared with those who received interferon alfa (median PFS, 11 months vs 5 months; hazard ratio [HR], 0.42; 95% CI, 0.32–0.54; P < .001; and ORR, 31% vs 6%, respectively).[23] Similarly, in its phase III registration trial, pazopanib demonstrated significant improvement in PFS and ORR when compared with placebo in patients with predominantly untreated advanced RCC (median PFS, 9.2 months vs 4.2 months; HR, 0.46; 95% CI, 0.34–0.62; P < .0001; and ORR, 30% vs 3%, respectively).[24]

A large subsequent phase III trial confirmed PFS noninferiority for pazopanib when compared with sunitinib in treatment-naive patients with metastatic disease (median PFS, 8.4 months vs 9.5 months; HR, 1.05; 95% CI, 0.99–1.22).[25] Similar OS outcomes were also reported in both groups in a subsequent analysis (median OS, 28.3 months vs 29.1 months, respectively; HR, 0.92; 95% CI, 0.79–1.06; P = .24).[26] Secondary analyses of this trial compared patients’ tolerance of pazopanib with that of sunitinib and reported distinctly different safety profiles. Patients receiving pazopanib were more likely to develop liver function test abnormalities, hair color changes, and weight loss. In contrast, adverse events were more frequently seen in the sunitinib-treated patients, including fatigue, hand-foot syndrome, and stomatitis. In the phase III trial, patient-reported quality-of-life scores predominantly favored pazopanib.[25] Similar results were reported in the phase II, randomized, double-blind, cross-over study that evaluated patients’ and physicians’ preferences for pazopanib vs sunitinib, with both groups significantly favoring pazopanib.[27]

Since the initial approval of sunitinib, several retrospective studies have evaluated alternative schedules (compared with the standard regimen of a 50-mg dose, for 4 weeks on treatment followed by 2 weeks off) in an effort to improve tolerance to the medication, optimize drug exposure, and maximize efficacy. While continuous administration of low-dose sunitinib was not found to be more effective than the standard schedule,[28] a growing body of retrospective data shows favorable outcomes with an alternative dosing schedule of 50 mg for 2 weeks on treatment/1 week off.[29-31] A small phase II randomized trial compared traditional sunitinib dosing with this new schedule and reported that the 2 weeks on treatment/1 week off approach was associated with less toxicity and superior failure-free survival at 6 months when compared with the standard schedule of 4 weeks on the drug followed by 2 weeks off.[32]

Emerging data: cabozantinib

Recent reports have prompted discussion of the potential future role of a novel TKI in the frontline setting. Cabozantinib is a small molecule that inhibits VEGFR. Unlike sunitinib, this agent also blocks the tyrosine kinases MET and AXL, which, in addition to being oncoproteins and HIF targets, have been associated with acquired resistance to antiangiogenic therapy.[33] In a recently reported randomized phase II trial, cabozantinib achieved superior PFS and increased ORR when compared with sunitinib in treatment-naive patients with IMDC-designated intermediate- or poor-risk disease.[20] While these are provocative data, it is important to note that this agent is presently FDA-approved in pretreated patients with advanced or metastatic RCC (see the section in this article, “Second-line options”).[34]

Use of mTOR inhibitors in the first-line setting

Temsirolimus, administered intravenously, is an allosteric inhibitor of mTOR. It binds to the intracellular protein FKBP12, forming a complex that inhibits mTOR complex 1 signaling. As previously noted, in a pivotal phase III Global Advanced Renal Cell Carcinoma trial, patients with poor-risk features who were treated with this agent demonstrated prolongation of OS compared with those who received interferon alfa (median OS, 10.9 months vs 7.3 months; HR, 0.73; 95% CI, 0.58–0.92; P = .008) (see the section, “Prognostic models in specific clinical scenarios”).[16] In the same study, the combination of temsirolimus plus interferon did not show additional benefit, likely because of limited drug exposure due to poor tolerance. Key side effects of temsirolimus include hyperglycemia, hyperlipidemia, and fatigue. The drug is used infrequently due to the need for weekly IV infusions. It has not been compared directly with sunitinib or pazopanib in the first line; however, several randomized studies have suggested that VEGF-targeting TKIs achieve an antitumor effect superior to that of mTOR complex 1 inhibitors when given alone in treatment-naive and pretreated patients.[17,18,35]

Bevacizumab plus interferon alfa

Bevacizumab is a monoclonal antibody that binds to VEGF-A and prevents its interaction with VEGFRs, halting angiogenesis. Two phase III clinical trials conducted in untreated patients with advanced clear cell RCC have shown that the combination of interferon alfa with bevacizumab results in significant improvement of PFS vs treatment with interferon alfa alone (median PFS, 10.2 months vs 5.4 months; HR, 0.63; 95% CI, 0.52–0.75; P = .0001).[36] The median PFS (8.5 months vs 5.2 months; HR, 0.71; 95% CI, 0.61–0.83; P < .001)[37] and ORR (25.5% vs 13.1%, respectively)[37] seen in the second trial led to approval of the combination. However, due to the unfavorable adverse event profile and the infusions required for interferon, and the frequent injections (of bevacizumab), the regimen is not commonly used in the clinic.

Cytokine-based immunotherapies: high-dose interleukin-2

High-dose interleukin-2 remains a first-line option in a selected group of patients with metastatic RCC. It was initially approved by the FDA in 1992, based on the results of a pool of seven nonrandomized phase II clinical trials with meaningful, durable response rates in a small portion of patients.[38] Despite this evidence, the potential benefits of high-dose interleukin-2 must be balanced cautiously with the significant morbidity associated with this agent, which requires hospital admission and is frequently administered in the intensive care unit setting to allow close patient monitoring. More recently, the prospective phase II SELECT study reported an ORR of 25% based on World Health Organization criteria[39] in treatment-naive patients,[40] but the investigators failed to confirm certain histopathologic features tested for their utility in selecting patients.

Choosing Between First-Line Options

With the exception of data from the COMPARZ trial that inform decision making regarding the use of sunitinib vs pazopanib for the treatment of metastatic RCC,[25] head-to-head comparisons of approved first-line therapies have not been performed. Selection of the appropriate agent, particularly the consideration of a non-TKI option, should be individualized. The following factors should be taken into account:

• Patient performance status may determine which treatment is selected (eg, high-dose interleukin-2 should only be considered in patients with excellent performance status, and temsirolimus is a valid option in patients with poor performance status).

• Patient intolerance to oral medications and/or the presence of gastrointestinal symptoms (nausea, vomiting) would favor the use of intravenous infusions of temsirolimus or of bevacizumab plus interferon alfa.

• Certain patient comorbidities (eg, poorly controlled cardiovascular comorbidities, including recent cardiac or cerebrovascular events) may raise the level of safety concerns regarding the use of anti-VEGF therapies.

• Finally, clinical trials should be considered in well-fitted treatment-naive patients (not only pretreated patients), given promising results in ongoing investigational strategies (see section, “Novel strategies”).

Second-Line Options

Following the initial wave of first- or second-line regimens that were approved by the FDA before 2010 for the treatment of advanced or metastatic RCC, subsequent efforts and all subsequent approvals have targeted pretreated patients. The National Comprehensive Cancer Network currently lists four therapeutic options as category 1 treatments (Table 3)[41]; notably, two agents, nivolumab and cabozantinib, are designated as preferred options by the committee, given that the large phase III registration trials for both agents demonstrated an OS benefit.

Axitinib

Axitinib, an inhibitor of VEGFR1, VEGFR2, and VEGFR3, has greater potency and narrower target specificity than the VEGFR inhibitors sunitinib and pazopanib. In the phase III AXIS trial, axitinib was associated with longer PFS when compared with sorafenib in patients with metastatic RCC who progressed after just one prior line of systemic therapy (median PFS, 6.7 months vs 4.7 months; HR, 0.66; 95% CI, 0.54–0.81; P < .0001).[42] Importantly, the study population included a subset of patients who were treated with cytokine-based therapy in the first line, and who therefore were TKI-naive at the time of study entry; as expected, in a subgroup analysis, the benefit in patients who progressed after cytokine-based therapy was greater than that observed in sunitinib-pretreated patients, with reported median PFS of 4.8 months vs 3.4 months, respectively. The toxicity observed for axitinib in the AXIS trial was similar to prior reports of TKI-related adverse effects in patients with advanced and metastatic RCC; the most common adverse events were diarrhea, hypertension, and fatigue.[42] Notably, AXIS is the only registration trial in RCC to use dose escalation based on tolerance, with the dose of axitinib increased in patients who tolerated the medication without developing significant treatment toxicities during the initial weeks of treatment. A separate randomized study testing this concept has provided further support for this approach,[43] which is included in the FDA product insert.

Cabozantinib

This novel multitargeted TKI potently inhibits not only VEGFR2, but also MET and AXL, two kinases that have been implicated in the development of cancer in humans. Notably, both MET and AXL are HIF targets, and they have been found to be upregulated in RCC cells during the development of acquired resistance to sunitinib.[33] The pivotal phase III METEOR trial compared cabozantinib with everolimus in patients with metastatic RCC who had previously received treatment with at least one VEGFR-targeting TKI; notably, there was no restriction on the number or type of prior lines of therapy, with the exception of mTOR inhibitors. Patients treated with cabozantinib achieved superior outcomes compared with those who received standard-dose everolimus, in terms of PFS (median PFS, 7.4 months vs 3.8 months; HR, 0.58; 95% CI, 0.45–0.75; P < .001),[34] OS (median OS, 21.4 months vs 16.5 months; HR, 0.66; 95% CI, 0.53–0.83; P = .0003), and ORR (17% vs 3%).[19,34] Secondary analyses suggest that these differences extend to various subgroups, including patients who have received multiple lines of prior therapy, those with metastatic involvement of multiple organs, and those with osseous involvement.[19] The toxicity profile, which included diarrhea, hypertension, fatigue, and hand-foot syndrome, was consistent with adverse events seen in patients who have undergone treatment with VEGF TKIs. Although the rate of dose adjustments for cabozantinib was notable (58% of patients required first-level dose reduction), only 10% of patients discontinued the drug due to toxicity, a rate similar to that reported for patients in the everolimus arm of the study and comparable to other approved agents.

Nivolumab

Interaction between the programmed death 1 (PD-1) receptor expressed in T cells, and its ligands programmed death ligand 1 (PD-L1) and 2 (PD-L2) expressed on tumor and antigen-presenting cells, confers inhibition of the cellular immune response towards malignant cells.[44] Nivolumab is a fully human immunoglobulin G4 inhibitor that competitively binds to PD-1 and reinvigorates suppressed effector T cells in the tumor microenvironment. Earlier studies had confirmed activity in clear cell RCC,[45-47] providing a rationale for the phase III CheckMate 025 study,[48] which pursued OS as the primary endpoint. In CheckMate 025, 822 patients with clear cell RCC who had received one to three prior lines of therapy (including at least one but no more than two VEGF-directed therapies) were randomized in a 1:1 ratio to receive nivolumab or standard-dose everolimus. The trial showed nivolumab was associated with improved OS (median OS, 25 months with nivolumab vs 19.6 months with everolimus; HR, 0.73; 95% CI, 0.57–0.93; P = .002) and ORR (25% vs 5%, respectively).[48] There were no differences in PFS (median PFS, 4.6 months vs 4.4 months; HR, 0.88; 95% CI, 0.75–1.03; P = .11). Grade 3 or 4 treatment-related adverse events were less frequent with nivolumab than with everolimus (occurring in 19% vs 37% of patients, respectively). While the individual rate of high-grade immune-related organ-specific adverse events was low (individual toxicities were seen in fewer than 5% of patients), the dynamics of immune-mediated toxicity are uniquely different from those of toxicities associated with previously approved targeted agents, since the onset of the former can be significantly delayed from the time of treatment initiation.[49] The quality-of-life scores assessed in CheckMate 025 favored nivolumab over everolimus at each assessment point through the 2-year study period.[48]

Lenvatinib plus everolimus

One strategy for delaying resistance to VEGF- or mTOR-targeted therapies is to combine both classes of drugs. A recent randomized phase II study tested lenvatinib, a novel multitargeted TKI inhibiting both VEGFR and fibroblast growth factor receptors, on its own and in combination with the oral mTOR inhibitor everolimus. A total of 153 patients with clear cell RCC who had progressed after treatment with just one VEGF-targeted therapy were randomized in a 1:1:1 ratio between lenvatinib, everolimus, or the combination of both agents given at reduced doses, as previously established in a phase I study.[50] The combination resulted in significant prolongation of PFS when compared with everolimus alone (median PFS, 14.6 months vs 5.5 months; HR, 0.40; 95% CI, 0.24–0.68; P = .0005).[35] Similarly, treatment with lenvatinib alone also was associated with improvement of PFS when compared with everolimus alone (median PFS, 7.4 months vs 5.5 months; HR, 0.61; 95% CI, 0.38–0.98; P = .048). The superiority of lenvatinib-based regimens extended to secondary analyses for ORR (which showed an ORR of 27% with lenvatinib alone, compared with 22% with lenvatinib and everolimus in combination and 6% with everolimus alone) and OS (median OS of 25.5 months in patients treated with lenvatinib in combination with everolimus, 18.4 months with lenvatinib alone, and 17.5 months with everolimus alone; HR, 0.51; 95% CI, 0.30–0.88; P = .024). Not unexpectedly, the combination of lenvatinib with everolimus was associated with a notable increase in toxicity, specifically for overlapping class-specific adverse events (eg, a 19% incidence of grade 3 or 4 diarrhea), and limitations in drug delivery (with dose reductions needed in 71% of patients treated with the lenvatinib/everolimus combination vs 62% of those treated with lenvatinib alone vs 26% of patients treated with everolimus alone; permanent treatment discontinuation for toxicity was needed in 24% vs 25% vs 12% of patients, respectively). Ultimately, however, the strong efficacy signal, even in the phase II setting, led to FDA approval of this novel combination in 2016.

Sequencing Regimens: Second-Line Treatments and Beyond

With a growing number of treatment options approved, particularly for pretreated patients, treating physicians must choose one drug over the other. While the more recently approved therapies have numerically achieved the highest efficacy in their registration trials, direct comparisons cannot be made across trials, and it is important to bear in mind the previously discussed differences in entry criteria for these studies, particularly the extent of prior therapies.

For instance, while some studies evaluated patients who had been treated with a limited number of prior therapies,[35,42] the METEOR trial demonstrated persistent benefit of cabozantinib in heavily pretreated patients with advanced RCC.[19] Additionally, the AXIS trial demonstrated less benefit of axitinib in sunitinib-pretreated patients than in those treated with cytokine-based therapies[42] (see section, “Second-line options: axitinib”). Taken together, data from several studies have led clinicians to the important conclusion that monotherapy with everolimus no longer has a role in second- and third-line treatment of advanced RCC, since single-agent everolimus has proven to be inferior to TKIs, checkpoint inhibitors, and administration of everolimus in combination therapy.[34,35,48]

Beyond this, instead of using a sequencing algorithm, clinicians should follow an individualized approach to the selection of second-line and subsequent therapies for patients with advanced or metastatic RCC. Several factors can help to guide such decision making:

• Patient comorbidities should be considered; for example, poorly controlled diabetes that could worsen with use of mTOR inhibitors (including in combination therapy); cardiovascular disease, including hypertension with preexisting end-organ damage, which could be aggravated further with anti-VEGF therapies; and preexisting autoimmune diseases in patients being considered for checkpoint-directed therapy.

• Information about an individual patient’s tolerance to prior therapy and whether the patient has fully recovered from previous treatment-related adverse effects can be instructive. Patients whose performance status and quality of life are still compromised are likely to benefit from switching mechanism of action and toxicity profile, recognizing that these do not overlap between TKI and checkpoint inhibitor therapy.

• Finally, the pace of metastatic disease can be a relevant factor-in that for some patients, such as those who are symptomatic from local effects, the need for timely tumor regression is more pressing than for others. It is important to note that checkpoint blockade with nivolumab in RCC has shown a more variable time to response when compared with other diseases such as bladder cancer.[48] The median time to response in CheckMate 025 was 3.5 months[48]; over one-third of patients were reported to have progressive disease as their best response on the study,[48] a proportion that is likely partially due to delayed responses and pseudoprogression,[51] but nonetheless is substantially higher when compared with other approved regimens (with reported rates of progressive disease at 12% for cabozantinib[19] and at 14% for combination treatment with lenvatinib plus everolimus).[35]

Novel Strategies

With the successful development of the first targeted immunotherapy for the treatment of RCC, and due to the considerable benefit from checkpoint inhibitor–based regimens seen across various solid tumors, there has been high interest in developing combination strategies that pair these targeted agents with other therapies. In patients with metastatic kidney cancer, early-phase trials have shown the promise of regimens with a backbone of monoclonal antibodies directed at PD-1 and PD-L1. This includes combinations with TKIs, including sunitinib, pazopanib, and axitinib,[52-55] among others. While the efficacy signal seen with all of these combinations supports the concept of pairing checkpoint inhibition with VEGF-directed TKIs, it has become apparent that some combinations are more toxic than others.[55] There has been rapid development of the regimens proven to be tolerable in early-phase trials, with several phase III studies now testing combinations in the first-line setting (Table 4). The monoclonal VEGF-A–directed antibody bevacizumab has been paired successfully with the PD-L1–specific antibody atezolizumab. A randomized three-arm phase II trial comparing this combination with monotherapy using sunitinib or atezolizumab failed to reach its primary endpoint,[56] but the study generated a wealth of correlative data, which ultimately suggest that molecularly defined subgroups of patients might predict favorable response to antiangiogenic treatment vs therapy directed at the immune microenvironment.[57] Lastly, numerous other immunomodulatory targets on cancer cells, stromal cells, and immune cells are currently under investigation in clinical trials, with an emphasis on testing these in combination with PD-1–directed checkpoint inhibition. The best example and furthest in development for this disease is the combination of nivolumab plus ipilimumab, which showed promise in a large RCC-only phase I trial[58] and is being compared with standard sunitinib in an ongoing phase III trial of first-line therapy (see Table 4).

It is notable that despite the multitude of molecularly targeted agents approved for advanced or metastatic RCC, the search for predictive biomarkers in patients with clear cell histology has largely been unsuccessful. Numerous candidate biomarkers have been tested for their utility in predicting the outcome of approved therapies. These investigations, however, have failed to change clinical practice. Past efforts have included profiling of gene mutations in the VHL/HIF pathway,[59,60] germline single nucleotide polymorphisms,[61,62] circulating proteins,[63,64] next-generation sequencing of frequently mutated genes in tumor tissue,[65,66] and PD-L1 expression by immunohistochemistry.[48,67] With an ever-increasing number of available systemic agents, together with the advent of novel assays to investigate tumor and host tissue, more sophisticated computational tools, and a decrease in the cost of nucleotide sequencing, every effort should be made to integrate biomarker development in all prospective trials of novel treatment strategies.

Conclusion

Over the last decade, there have been significant advances in the understanding of some of the most relevant molecular pathways implicated in RCC, leading to the development of targeted therapies that have improved the clinical outcomes of patients with this disease. Treatment selection from the currently available therapeutic options should follow an individualized approach, with consideration of factors such as the patient’s comorbidities, functional status, tolerance of prior agents, and rate of disease progression. The recent advent of immunotherapy has further expanded the pool of treatment opportunities, with large randomized trials of combination approaches now challenging the present standards of care. As we look to the future, there is a strong need to emphasize the development and application of biomarkers that will help us to optimize the sequential use of available agents and inform the design and interpretation of new clinical trials.

Financial Disclosure:Dr. Voss is a consultant to Eisai, Exelixis, and Novartis, and receives research funding from Bristol-Myers Squibb and Roche/Genentech. Dr. Motzer is a consultant to, and receives research support from, Eisai, Exelixis, and Novartis; he also receives research support from Bristol-Myers Squibb. Dr. Osorio has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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