To outline current practices and challenges in the systemic management of patients with advanced renal cell carcinoma (RCC).

We conducted a focused review of hallmark randomized controlled trials informing the systemic treatment of patients with RCC. We concentrated on trials informing the use of combination therapies, therapy in both treatment-naïve and previously treated patients, sequential treatment strategies, and schedules.

The systemic treatment of advanced RCC has experienced tremendous progress over the past 15 years. An improved understanding of the canonical pathways implicated in RCC pathogenesis has resulted in the development of molecularly targeted and immunotherapy options for patients. These therapies have replaced cytokine-based treatments as the standard of care for patients with advanced RCC. Until recently, sequential vascular endothelial growth factor (VEGF)–targeted therapy or VEGF-targeted therapy followed by mammalian target of rapamycin inhibition has been the prevailing treatment paradigm for patients. However, newer agents such as cabozantinib and nivolumab have challenged this traditional approach. In addition, combination treatments including nivolumab plus ipilimumab and atezolizumab plus bevacizumab have transformed the RCC treatment landscape, and other doublet combinations in clinical testing will likely continue to alter the treatment paradigm in RCC. Currently, factors that inform treatment selection between different therapy options include performance status, comorbidities, prognostic risk stratification, treatment adverse event profile, and mode of administration, with no Level I evidence for predictive biomarker use in clinic.

The treatment options for advanced RCC are rapidly evolving since the introduction of VEGF-targeted therapy, immunotherapy with checkpoint blockade and, more recently, combination regimens. Despite the success of these regimens, advanced RCC remains a largely incurable disease, and additional strategies are warranted.

Renal cell carcinoma (RCC) is responsible for more than 14,400 deaths per year in the United States.1 It is a heterogeneous disease clinically divided into two histologic categories: clear cell and non–clear cell RCC, also called “rare RCC histologies or variants.” Approximately 70% to 80% of tumors are clear cell, whereas non–clear cell histology such as papillary, translocation, medullary, chromophobe, collecting duct, unclassified RCC, and an expanding list of additional subtypes make up the remaining histologies.2 In metastatic RCC (mRCC), two prognostic models have been validated and adopted to stratify mRCC patients in clinical trials: The Memorial Sloan Kettering Cancer Center model3,4 and the International mRCC Database Consortium (IMDC).5,6 Both models categorize patients into favorable-, intermediate-, and poor-risk groups, each group with distinct survival outcomes. This risk stratification has been important in understanding outcomes of patients in clinical trials and informing patient prognostication and counseling, even for standard agents.

Most patients with mRCC require systemic therapy for disease control. Before 2005, interferon-α and high-dose interleukin-2, commonly referred to as cytokines, were the only available treatments to have demonstrated efficacy in a small subset of patients.7 As our understanding of the key role of angiogenesis in the pathogenesis of mRCC improved, therapies targeting the vascular endothelial growth factor (VEGF) pathway replaced cytokines as the mainstay of treatment. The treatment armamentarium continued to expand as therapies targeting the mammalian target of rapamycin (mTOR) pathway and, more recently, immune checkpoint blockers (ICBs) and targeted agents that deal with resistance pathways improved outcomes for patients. These classes of agents have shaped the therapeutic landscape for mRCC in both treatment-naïve and previously treated patients.8

Early loss of function of the von Hippel Lindau (VHL) gene during tumorigenesis of clear cell RCC causes the accumulation of hypoxia-inducible factor which results in excessive production of proangiogenic factors such as VEGF, fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF).9 Oral multitargeted tyrosine kinase inhibitors (TKIs) such as sunitinib, pazopanib, sorafenib, and axitinib oppose this proangiogenic milieu and induce tumor cell death by inhibiting downstream signaling of VEGF as well as other tyrosine kinases. Similarly, cabozantinib and lenvatinib target the VEGF receptors in addition to kinases implicated in resistance such as MET, AXL, and FGFR. The selective monoclonal antibodies against VEGF also target angiogenesis and impede tumor growth by binding to circulating VEGF (Fig 1).

Constitutive activation of the mTOR signaling pathway also plays an important role in tumorigenesis and growth of many malignancies including RCC. Cancer cells can activate the mTOR pathway via different mechanisms, including loss of p53, paracrine production of growth factors, mutations in the upstream components of PI3K, or mTOR complexes themselves such as TSC1/2, Lkb1, PTEN, and Nf1.10,11 Rapalogs blunt the sustained activation of the mTOR pathway by inhibiting the phosphorylation of mTOR and alter the translation of messenger RNA that codes for proteins involved in cell survival, cell proliferation, and angiogenesis10 (Fig 1).

ICBs have demonstrated clinical activity against a host of malignancies and constitute the latest therapeutic advancement in the field of mRCC. Under physiologic conditions, the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) checkpoints attenuate T-cell activation and are critical to maintain the balance between self-defense and self-tolerance.12 This balance can be dysregulated by tumor expression of checkpoint proteins such as PD-L1 that promote immune tolerance of cancer cells. Thereby, blockers of PD-1/PD-L1 and CTLA-4 axes invigorate exhausted T cells to foster antitumor immunity13 (Fig 1).

The overwhelming majority of practice-changing clinical trials in the field have been limited to patients with clear cell mRCC (Table 1). Although results of these trials are often extrapolated to non–clear cell mRCC in practice, these tumors have a distinct biology and response to therapies.35 Enrollment in clinical trials should be the preferred option for patients with non–clear cell mRCC.8,35a

Table

Table 1. Practice-Changing Trials in Advanced and Metastatic Clear Cell RCC

Interleukin-2 stimulates the cytotoxic activity of T lymphocytes against malignant cells. It was first used against mRCC in the mid-1980s and subsequently approved in 1992. High-dose interleukin-2 was associated with an objective response rate (ORR) of 15%, including 5% durable complete response.36 The High-Dose Aldesleukin (IL-2) Trial for Patients With Metastatic Renal Cell Carcinoma (SELECT) trial, a more recent single-arm biomarker study of high-dose interleukin-2, reported ORR of 25%, including 7.5% complete responses, and a median response duration of 20.6 months.37 High-dose interleukin-2 mandates careful selection of patients with good performance status and organ function because it is associated with serious toxicity such as capillary leak syndrome, hypotension, and end-organ failure that can be fatal. It should be reserved for designated centers of expertise with intensive care support.38 Since the approval of several efficacious and better tolerated treatments, the use of high-dose interleukin-2 has decreased steadily,39 and its role is even less prominent with the advent of combination ICBs.

Several multitargeted TKIs against VEGF receptors have been evaluated in patients with mRCC. In the first-line setting, the best evidence supports the use of sunitinib or pazopanib. In a phase III trial against interferon-α, sunitinib (50 mg per day, 4 weeks on/2 weeks off) significantly improved median progression-free survival (PFS; 11 v 5 months) with a hazard ratio (HR) of 0.42 (95% CI, 0.32 to 0.54) and ORR of 31% versus 6%.14 In a phase III placebo-controlled trial conducted in good- and intermediate-risk patients, pazopanib improved PFS in treatment-naïve or cytokine-treated patients (HR, 0.46; 95% CI, 0.34 to 0.62).16,17 The median PFS was 11 versus 2.8 months in the subset of treatment-naïve patients. In the noninferiority phase III COMPARZ trial, pazopanib was compared with sunitinib and was found to be noninferior to sunitinib for both PFS (HR, 1.05; 95% CI, 0.9 to 1.22) and death (HR, 0.91; 95% CI, 0.76 to 1.08).18 Eleven of 14 health-related quality-of-life domains favored pazopanib. Fatigue, hand-foot syndrome, and thrombocytopenia were more frequent with sunitinib, whereas pazopanib was associated with higher rates of transaminitis.18 Alternate dosing schedules of sunitinib have been proposed to improve tolerance to sunitinib.39,40-43

Bevacizumab is a monoclonal antibody against VEGF given intravenously every 2 weeks. Two phase III trials, AVOREN and CALGB 90206, assessed bevacizumab 10 mg/kg with interferon-α (9 MIU subcutaneously three times per week) versus interferon-α. In both studies, bevacizumab plus interferon-α prolonged PFS compared with interferon-α with HRs of 0.63 (95% CI, 0.52 to 0.75) in the AVOREN study and 0.71 (95% CI, 0.61 to 0.83) in the CALGB 90206 study.19,20

Cabozantinib is an oral small molecule against the VEGF receptor in addition to MET and AXL, which have been implicated as mechanisms of resistance against anti-VEGF therapies.44,45 The randomized phase II CABOSUN trial compared cabozantinib 60 mg orally once per day to sunitinib at standard dosing in IMDC intermediate- and poor-risk patients.46 Both median PFS (8.2 v 5.6 months; HR, 0.66; 95% CI, 0.46 to 0.95) and ORR (33% v 12%) favored cabozantinib. The results were subsequently confirmed by independent radiology review,21 and cabozantinib was approved as a first-line option for mRCC. The most common toxicities of cabozantinib included fatigue, hypertension, diarrhea, palmar-plantar erythrodysesthesia, stomatitis, and transaminitis.

Temsirolimus is an inhibitor of the mTOR complex-1. In the phase III Global ARCC three-arm trial, temsirolimus 25 mg once per week was compared with interferon-α 3 MIU three times per week (titratable up to 18 MIU) and the combination of temsirolimus 15 mg once per week plus interferon-α 3 MIU three times per week in untreated poor-risk patients with mRCC, including 18% with non–clear cell histology.22 The overall survival (OS) was superior in the temsirolimus arm (HR, 0.73; 95% CI, 0.58 to 0.92), but not the combination arm compared with interferon-α alone. Notable adverse effects with temsirolimus include fatigue, pneumonitis, hyperglycemia, and hyperlipidemia. Although no trial has directly compared temsirolimus to either sunitinib or pazopanib, randomized studies have demonstrated that VEGF TKIs may be superior to mTOR inhibitors.

CheckMate-214 is the first phase III trial to demonstrate the clinical activity of combination ICBs in the first-line setting.23 The study compared the combination of ipilimumab (an anti-CTLA-4 inhibitor) plus nivolumab (an anti-PD-1 inhibitor) to sunitinib in IMDC intermediate- or poor-risk patients. Nivolumab 3 mg/kg was administered once every 3 weeks with ipilimumab 1 mg/kg for four doses, and then nivolumab monotherapy was continued once every 2 weeks. The co-primary end points were ORR, PFS, and OS. Median OS was not reached at 26 months, and the HR for death was 0.63 (99.8% CI, 0.44 to 0.89) in favor of the ipilimumab plus nivolumab in intermediate- and poor-risk patients. Median PFS by independent review was 11.6 versus 8.4 months (HR, 0.82; 99.1% CI, 0.64 to 1.05; P = .03), and the ORR was 42% versus 27% (9% v 1% complete response) in the combination compared with sunitinib, respectively. PFS did not meet the prespecified threshold (P = .009) for statistical significance. Subset analyses of favorable-risk patients showed superior ORR (29% v 52%) and PFS (15.3 v 25.1 months; HR, 2.18; 99.1% CI, 1.29 to 3.68) in favor of sunitinib. Grade 3 to 4 immune-related adverse events included hepatitis (6%), colitis (5%), rash (3%), hypophysitis (3%), adrenal insufficiency (3%), nephritis (2%), pneumonitis (2%), and diabetes (1%). In the combination arm, 35% of patients received high-dose glucocorticoids (≥ 40 mg of prednisone per day or equivalent). Seven (1.3%) treatment-related deaths were reported with the combination compared with four (0.7%) with sunitinib. Although the magnitude of benefit was greater in PD-L1–positive patients (defined by ≥ 1% PD-L1 expression; 27.5% of the intermediate- and poor-risk population), this biomarker was not entirely predictive of response to and OS from nivolumab plus ipilimumab.

Historically, first-line phase III trials in metastatic clear cell RCC were compared with interferon-α, and comparative trials between agents did not have superiority efficacy end points as a primary outcome. Nivolumab plus ipilimumab is the first therapy to demonstrate superiority over sunitinib in treatment-naive patients with clear cell RCC, challenging the treatment paradigm of first-line VEGF TKIs in RCC. However, there are several questions and barriers regarding the clinical implementation of this combination. And there are questions regarding the appropriate patient population, given differential outcomes on the basis of IMDC risk stratification, a risk model using clinical parameters for risk stratification as opposed to biomarkers that inform pathogenesis. In addition, this trial did not allow crossover; thus, the utility of the combination in previously treated patients remains in question. Finally, the toxicity profiles of ICBs compared with TKIs are vastly different. For integration into clinical practice, management guidelines have been created to help physicians manage the specific immune-mediated adverse events associated with ICB.46a

Early-phase trials indicate that the combination of ICBs with antiangiogenic therapies is safe, and is associated with encouraging antitumor activity.47-50 Five phase III trials comparing different combinations of ICBs and antiangiogenic agents against sunitinib are currently ongoing (Table 2).24 The recently reported phase III IMmotion-151 study, which compared atezolizumab (a PD-L1 inhibitor given intravenously once every 3 weeks) plus bevacizumab (15 mg/kg once every 3 weeks) to sunitinib. The study met its primary end point of investigator-assessed PFS in the subgroup of patients with tumor expression of PD-L1 (HR, 0.74; 95% CI, 0.57 to 0.96). However, the PFS was not significant by independent radiology review (HR, 0.88; 95% CI, 0.74 to 1.04]. The survival data were immature at the time of data cutoff, but they showed a trend in favor of atezolizumab plus bevacizumab in both tumors expressing PD-L1 and in the intention-to-treat population. ORR was not different in these groups. Forty percent of patients experienced treatment-related grade 3 to 4 adverse events compared with 54% in the sunitinib arm. Hypertension, hand-foot syndrome, diarrhea, gastrointestinal adverse events, and stomatitis were more frequent in the sunitinib arm, whereas the incidence of proteinuria was higher with the combination. Sixteen percent of patients who received atezolizumab plus bevacizumab required systemic corticosteroids as a result of toxicity.

Table

Table 2. Ongoing Phase III Trials of Immune-Based Combination Therapies

Despite major treatment advancements, the majority of patients progress on first-line therapy, and alternative strategies are required. Sorafenib was the first agent to demonstrate efficacy in patients progressing on cytokine therapy in the placebo-controlled TARGET trial.25,26 The phase III AXIS trial was the first phase III trial to compare two VEGF TKIs. Patients were randomly assigned to axitinib 5 mg twice per day (titratable to 7 mg, then 10 mg on the basis of blood pressure response) or sorafenib 400 mg twice per day.27 Independently assessed ORR (19% v 11%) and PFS (HR, 0.67; 95% CI, 0.54 to 0.81) favored axitinib in the intention-to-treat population, as well as the cytokine- (12.1 v 6.5 months) and sunitinib-pretreated (4.8 v 3.4 months) subsets. There was no difference in OS between the arms.28

The mTOR inhibitor everolimus also demonstrated efficacy in patients who progressed on sunitinib or sorafenib in the phase III placebo-controlled RECORD-1 trial. Everolimus improved PFS (median, 4.9 v 1.9 months) but not OS in patients for whom treatment with sunitinib, sorafenib, or both failed.29,30 Noticeable adverse events associated with everolimus included stomatitis, fatigue, rash, hyperglycemia, hyperlipidemia, and pneumonitis. By comparison, temsirolimus did not improve PFS or ORR versus sorafenib 400 mg twice per day in the phase III INTORSECT trial.51 Furthermore, sorafenib was associated with longer OS (HR for death, 1.31; 95% CI, 1.05 to 1.63).51

Lenvatinib is approved in combination with everolimus in patients receiving second-line treatment who progressed on one VEGF-targeted agent. In a phase II randomized three-arm trial of 153 patients, everolimus (control arm) was compared with lenvatinib 24 mg/day or lenvatinib 18 mg plus everolimus 5 mg/day.31 Median PFS was longer with the combination compared with everolimus (14.6 v 5.5 months; HR, 0.40; 95% CI, 0.24 to 0.68). The ORR was 43% versus 6% with the combination compared with everolimus. The rate of grade 3 to 4 adverse events and discontinuation associated with lenvatinib plus everolimus was 71% and 24% compared with 50% and 12% with single-agent everolimus.

The efficacy of cabozantinib was evaluated in the phase III METEOR trial, which compared cabozantinib 60 mg once per day to everolimus 10 mg once per day in VEGF-refractory patients (two or more VEGF-targeted therapies failed for 27% of patients).32 Both the PFS (7.4 v 3.8 months; HR, 0.58; 95% CI, 0.45 to 0.75) and ORR (21% v 5%) were in favor of cabozantinib. An updated analysis also demonstrated superior median OS (21.5 v 16.5 months; HR, 0.66; 95% CI, 0.53 to 0.93) with cabozantinib.33 Sixty percent of patients required a dose reduction (median average dose per day of 43 mg), and 12% discontinued cabozantinib as a result of toxicity compared with 11% with everolimus.

Finally, the phase III CheckMate-025 trial was a pivotal study that randomly assigned patients to either nivolumab 3 mg/kg intravenously once every 2 weeks or everolimus 10 mg once per day in VEGF-refractory patients. Twenty-eight percent of patients had progressed to 2 or more lines of therapy.34 The primary end point of the study was OS. Treatment with nivolumab resulted in improved OS compared with everolimus (25 vs 19.6 months; HR, 0.73; 98.5% CI, 0.57 to 0.93) as well as improved ORR (25% v 5%). Nivolumab was better tolerated and improved health-related quality of life compared with everolimus.52 Grade 3 to 4 adverse events associated with nivolumab included fatigue (2%), anemia (2%), pneumonitis (1%), dyspnea (1%), hyperglycemia (1%), and diarrhea (1%), among others. As of March 2018, the US Food and Drug Administration approved nivolumab 480 mg intravenously once every 4 weeks as an alternate dosing schedule.53

For a decade, the sequential use of VEGF-targeting agents or VEGF followed by mTOR blockade was the classic paradigm for mRCC. Given limited comparative efficacy data between agents, factors considered for patient selection for an individual therapy included patient characteristics (eg, comorbidities and preferences), tumor characteristics (eg, histology and prognostic risk group), and drug pharmacology (eg, route of administration and toxicity).

The paradigm is now shifting as treatments with distinct mechanisms of action and combinatorial regimens are integrated into the treatment armamentarium (Table 3). Changes in the landscape started with nivolumab, cabozantinib, and levantinib plus everolimus, which all improved outcomes compared with everolimus in previously treated patients. Second, the face of first-line therapy is rapidly changing, with (at the time this manuscript was submitted) three trials meeting their primary end points versus standard sunitinib. But for now, only the combination of nivolumab plus ipilimumab has improved OS, considered by many experts as the gold standard end point in oncology trials.

Table

Table 3. Pharmacology of Systemic Therapies Approved for Advanced and Metastatic Renal Cell Carcinoma

First-line treatment will continue to evolve because other combinatorial therapies of ICBs with antiangiogenic agents and immunotherapy doublets are being explored (Table 2). Early results from axitinib plus ICB combinations (with the PD-1 inhibitor pembrolizumab48 or the PD-L1 inhibitor avelumab47) showed tolerability and encouraging preliminary activity (Table 4). The efficacy of current second-line options after new first-line therapies is unknown, and the optimal sequencing is uncertain pending new data to inform practice. Despite the multiple regimens available for patients with advanced RCC, predictive biomarkers to better inform therapy selection are largely lacking. Although the initial experience of the utility of tumor PD-L1 expression from CheckMate-025 showed that this marker is prognostic rather than predictive of nivolumab efficacy, this biomarker will continue to be of interest across ICB trials, especially in the context of the recent CheckMate-214 data.

Table

Table 4. Early-Phase Trials of Combination Antiangiogenic Agents With Immune Checkpoint Blockade

The current treatment landscape for patients with metastatic clear cell RCC is rapidly evolving (Fig 2). For treatment-naïve patients, the combination of nivolumab plus ipilimumab can be considered for patients with IMDC intermediate- and poor-risk disease. Cabozantinib can also be used in the first-line space for patients with intermediate- and poor-risk disease, particularly select patients with bone metastases. For patients with good-risk disease, standard VEGF TKIs such as sunitinib and pazopanib remain active options. The treatment strategy in the second-line space will be dependent on the first-line treatment. For ICB-naïve patients, nivolumab monotherapy or VEGF TKIs that include cabozantinib, axitinib, or lenvatinib plus everolimus, can be considered. For patients who have received prior nivolumab plus ipilimumab, VEGF TKIs are acceptable considerations. It is also important to consider clinical trials for patients when appropriate in both the treatment-naïve and previously treated settings.

The continuously evolving therapeutic landscape for mRCC raises many questions regarding the appropriate sequence and selection of treatment of patients who have mRCC. The development of biomarkers predictive of response will be critical to improve treatment individualization. As combination therapy moves into the first line of treatment, the efficacy of subsequent lines of treatment will become more uncertain. Future and ongoing clinical trials (eg, NCT03203473; Optimized Management of Nivolumab Based on Response in Patients With Advanced RCC [OMNIVORE Study]) that optimize treatment strategies on the basis of response will help clarify how to best sequence and use current therapies.

© 2018 by American Society of Clinical Oncology

Conception and design: Rana R. McKay, Dominick Bossé

Collection and assembly of data: Rana R. McKay, Dominick Bossé

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

Evolving Systemic Treatment Landscape for Patients With Advanced Renal Cell Carcinoma

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Rana R. McKay

Consulting or Advisory Role: Novartis, Janssen, Tempus

Research Funding: Pfizer (Inst), Bayer AG (Inst)

Dominick Bossé

No relationship to disclose

Toni K. Choueiri

Honoraria: National Comprehensive Cancer Network, UpToDate

Consulting or Advisory Role: Pfizer, Bayer AG, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Peloton Therapeutics, Exelixis, Prometheus Laboratories, Alligent, Ipsen, Corvus Pharmaceuticals

Research Funding: Pfizer (Inst), Novartis (Inst), Merck (Inst), Exelixis (Inst), TRACON Pharmaceuticals (Inst), GlaxoSmithKline (Inst), Bristol-Myers Squibb (Inst), AstraZeneca (Inst), Peloton Therapeutics (Inst), Genentech (Inst), Celldex (Inst), Agensys (Inst), Eisai (Inst)

ACKNOWLEDGMENT

We thank Julie Boucher, MD, for graphic design.

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COMPANION ARTICLES

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ARTICLE CITATION

DOI: 10.1200/JCO.2018.79.0253 Journal of Clinical Oncology 36, no. 36 (December 20, 2018) 3615-3623.

Published online October 29, 2018.

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