Article Index

Feature: Updates in Advanced Renal Cell Carcinoma

Kelly M Brunk, PharmD, BCOP
Clinical Oncology Pharmacist
The University of Kansas Health System
Kansas City, KS

TJ Schieber, PharmD, MBA
PGY1 Pharmacy Resident
The Ohio State University Wexner Medical Center
Columbus, OH

Renal cell carcinoma (RCC) is the eighth most commonly di­agnosed cancer in the United States, with an estimated number of new cases and deaths of 76,080 and 13,780, respectively, in 2021.1 Over the past three decades, the treatment for advanced RCC (aRCC) has been transformed with antiangiogenic thera­pies, including anti-vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs), and immune checkpoint inhibitors (ICIs).2 Both treatment options have improved patient outcomes and modified the natural history of aRCC.3

Recently, two phase 3 trials—KEYNOTE-581 (CLEAR) and CheckMate-9ER—were published evaluating ICI and anti-VEGF TKI combinations in the treatment-naive setting.4,5 Additionally, tivozanib, a potent inhibitor and highly selective anti-VEGF TKI, received US Food and Drug Administration (FDA) approval in March 2021 for treatment of relapsed or refractory aRCC based on the TIVO-3 trial.6

To better appreciate how these new trials impact clinical decision making, we summarized the studies in the context of other guideline-recommended treatments. This article reviews the synergistic effect of ICIs and VEGF inhibition, provides a summary of each trial, and reviews investigational therapies that may contribute to the ever-evolving treatment landscape of aRCC.

Synergism of ICI and VEGF inhibition
Aberrations in proangiogenic factors, like VEGF, are a hallmark of RCC.3 VEGF stimulates blood vessel growth and causes immunosuppression by promoting T regulatory cells and inhibiting T effector cells.7 It may also induce changes in protein expression on endothelial cells that limit immune-cell tumor infiltration, leading to CD8+ T cells apoptosis, programmed death-ligand 1 or 2 (PD-L1/L2) upregulation, and hypoxia. In hypoxic conditions, cancer cells can recruit regulatory T cells and tumor-associated macrophages differentiate to an M2 phenotype, which can have immunosuppressive effects.8

Antiangiogenic drugs may restore the differentiation of den­dritic cells, reducing the level of myeloid-derived suppressor cells and decreasing the levels of regulatory T cells.7 These agents may also normalize the tumor vasculature and alleviate hypoxia, leading to increased immune-cell infiltration into tumors. As such, combination ICIs and anti-VEGF TKIs have a synergistic antitumor effect.

First-Line Systemic Therapy of Advanced Clear-Cell RCC
Prognostic tools currently used include the Memorial Sloan Kettering Cancer Center (MSKCC) Prognostic Model and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Criteria.3,9,10 Both models are used in clinical practice, but most current clinical trials use the IMDC model. Treatment recommendations are based on risk and are divided into two groups: favorable-risk and intermediate-/poor-risk. Patients without MSKCC or IMDC risk factors are categorized as favorable-risk, whereas those with at least one risk factor are categorized as intermediate-/poor-risk. The majority of patients (70-80%) have at least one risk factor, making them intermediate-/poor-risk.3

Per the National Comprehensive Cancer Network (NCCN), the preferred first-line systemic therapy recommendations for favorable-risk aRCC include axitinib plus pembrolizumab, cabozantinib plus nivolumab (category 1), lenvatinib plus pembrolizumab (category 1), pazopanib, and sunitinib.3 Options for intermediate-/poor-risk aRCC include axitinib plus pembroli­zumab (category 1), cabozantinib plus nivolumab (category 1), ipilimumab plus nivolumab (category 1), lenvatinib plus pem­brolizumab (category 1), and cabozantinib.

The most recent additions to the first-line treatment arma­mentarium are lenvatinib plus pembrolizumab and cabozantinib plus nivolumab. Lenvatinib plus pembrolizumab was studied in the phase 3 CLEAR trial and cabozantinib plus nivolumab was studied in the phase 3 CheckMate-9ER trial.

CLEAR: Lenvatinib + Pembrolizumab
CLEAR was a randomized, open-label, phase 3 trial that enrolled subjects with treatment naïve aRCC of clear cell histol­ogy.4 Patients were randomized 1:1:1 to pembrolizumab 200 mg every 21 days plus lenvatinib 20 mg daily (n=355), lenvatinib 18 mg daily plus everolimus 5 mg daily (n=357), or sunitinib 50 mg daily (4 weeks on with two weeks off per cycle) (n=357). The primary endpoint was progression free survival (PFS), and patients were stratified by region and IMDC risk category.

At a median follow up of 27 months, lenvatinib + pembroli­zumab demonstrated a significant improvement in PFS, overall survival (OS), and objective response rate (ORR) compared to sunitinib.4 The median PFS was 2.5 times longer with lenvatinib plus pembrolizumab (23.9 months vs. 9.2 months; hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.32-0.49, p<0.001). The median OS was not reached in either arm but favored lenvatinib plus pembrolizumab (HR 0.66, 95% CI 0.49-0.88, p=0.005). The confirmed ORR favored lenvatinib plus pembrolizumab over sunitinib (71% vs. 36.1%; HR 1.97, 95% CI 1.69-2.29), as did the complete response (CR) rates (16.1% vs. 4.2%).

Table 1. Pivotal randomized, phase 3 trials for treatment naïve advanced renal cell carcinoma

YearTrial NameAgentsPatients, nORR (%)CR (%)OS (mo)PFS (mo)Statistical Benefit
2017 CABOSUN11 CABO v SUN 157 33 v 12 1.3 v 0 26.6 v 21.1 8.2 v 5.6 ORR, PFS
2018 CheckMate-21412 IPI + NIVO v SUN 1096 42 v 27 9 v 1 NR 11.6 v 8.4 ORR, OS
2019 CLEAR4 AXI + PEM v SUN 861 59.3 v 35.7 5.8 v 1.9 NR 15.1 v 11.1 ORR, OS, PFS
2019 CLEAR4 AXI + AVEL v SUN 886 51.4 v 25.7 4.4 v 2.1 11.6 v 10.7 13.8 v 7.2 ORR, PFS
2021 CheckMate-9ER5 CABO + NIVO v SUN 651 54.8 v 28.4 9.3 v 4.3 NR 16.6 v 8.3 ORR, OS, PFS
2021 CLEAR4 LEN + PEM v SUN 1069 71 v 36.1 16 v 4.2 NR 23.9 v 9.2 ORR, OS, PFS

Abbreviations: AVEL, avelumab; AXI, axitinib; CABO, cabozantinib; CR, complete response; IPI, ipilimumab; LEN, lenvatinib; NIVO, nivolumab; NR, not reached; ORR, objective response rate; OS, overall survival; PEM, pembrolizumab; PFS, progression free survival; SUN, sunitinib

The CLEAR trial also evaluated lenvatinib plus everolimus in a third arm compared to sunitinib.4 Lenvatinib plus everolimus statistically outperformed sunitinib in PFS and ORR but showed no difference in OS. Efficacy results were numerically lower in all categories with lenvatinib plus everolimus compared to lenvati­nib plus pembrolizumab. While caution should be used compar­ing results between different studies, the PFS, ORR, and CR were the highest recorded in the lenvatinib plus pembrolizumab group compared to any other trial as seen in Table 1.4,5,11-14

Treatment-related adverse events (TRAEs) grade 3 or higher occurred more often with lenvatinib plus pembrolizumab than with sunitinib (71.6% vs. 58.8%).4 TRAEs leading to dose reduction also occurred more frequently in the lenvatinib plus pembrolizumab arm (67.3% vs. 49.7%). Discontinuation of at least one of the study drugs was seen in 37.2% of the lenvatinib plus pembrolizumab arm compared to 14.4% of the sunitinib arm.

Based on the results of the CLEAR trial, lenvatinib plus pem­brolizumab was added to the NCCN guidelines as a preferred, category 1 recommendation regardless of risk categorization.3 As of June 2021, however, this combination has not received FDA approval for treatment of aRCC.

CheckMate-9ER: Cabozantinib + Nivolumab
CheckMate-9ER was a randomized, open-label, phase 3 trial that enrolled subjects with treatment naïve aRCC of clear cell histology.5 Patients were randomized 1:1 to receive cabozantinib 40 mg daily plus nivolumab 240 mg every 14 days (n=323) or sunitinib 50 mg daily (4 weeks on with 2 weeks off per cycle) (n=328). The primary endpoint was PFS, and patients were stratified by region, IMDC risk category, and tumor expression of PD-L1.

At a median follow up of 18.1 months, cabozantinib plus nivolumab demonstrated a significant improvement in PFS, OS, and ORR compared to sunitinib.5 The median PFS was twice as long with cabozantinib plus nivolumab (16.6 months vs. 8.3 months; HR 0.51, 95% CI 0.41-0.64, p<0.001), and the median OS was not reached but favored the cabozantinib plus nivolumab group (HR 0.60, 95% CI 0.40-0.89, p=0.001). The confirmed ORR favored cabozantinib plus nivolumab over sunitinib (55.7% vs. 27.1%, p<0.001), as did the CR rates (8% vs. 4.6%). Survival and response benefits of nivolumab + cabozantinib were noted across all patient subgroups (e.g., IMDC risk status, PD-L1 expression level, bone metastases).

Cabozantinib plus nivolumab was associated with higher rates grade 3 or greater TRAEs (60.6% vs. 50.9%) and treatment discontinuation of at least one drug (19.7% vs. 16.9%).5 Dose reductions were not allowed with nivolumab but occurred more frequently with cabozantinib than with sunitinib (56.3% vs. 51.6%).

The FDA approved cabozantinib plus nivolumab for aRCC on January 22, 2021.15 This combination was added to the NCCN guidelines as a preferred, category 1 recommendation regardless of risk categorization.5

First-line Treatment Considerations
Many good options exist for first-line systemic treatment of aRCC. However, in some cases, there is not a clear choice regarding which therapy to try first. Clinicians must often weigh adverse event potential, financial toxicity, and patient prefer­ence when choosing therapy. Notably, some patients may not need systemic therapy. Many patients with favorable-risk and some intermediate-risk patients can survive for many years with or without therapy.3 For selected patients, a debulking nephrec­tomy or active surveillance can be considered.

Clinicians may consider combination ipilimumab plus nivolumab for patients with IMDC intermediate-/poor-risk disease, no significant autoimmune disease, VEGF contraindica­tions, and those who cannot tolerate the chronic adverse events of anti-VEGF TKIs.3 On the other hand, clinicians may consider combination ICI and anti-VEGF TKI therapy for patients with any IMDC risk disease, those with intermediate-/poor-risk dis­ease who need rapid response, and those who need to avoid the immune-related adverse events associated with dual ICI therapy.

Systemic Therapy for Relapsed/Refractory Advanced Clear-Cell RCC
Second-line treatment options for aRCC may include targeted therapies and ICIs, alone or in combination.3 Table 2 summarizes the pivotal randomized trials in aRCC following anti-VEGF TKI therapy.16-25

Per NCCN, the preferred regimens for relapsed/refractory aRCC include cabozantinib (category 1), nivolumab (category 1), and ipilimumab plus nivolumab.3 Other recommended regimens include axitinib (category 1), axitinib plus avelumab (category 1), axitinib plus pembrolizumab, everolimus, lenvatinib plus everolimus (category 1), pazopanib, sunitinib, and tivozanib.

The most recently approved drug for relapsed/refractory aRCC is tivozanib.6 Its approval was based on the results of the phase 3 TIVO-3 trial.

TIVO-3: Tivozanib
TIVO-3 was a randomized, open-label, phase 3 trial that en­rolled subjects with aRCC who failed two to three prior systemic regimens, one of which included an anti-VEGF TKI.24 Patients were stratified by IMDC risk category and type of prior therapy and randomized 1:1 to tivozanib 1.34 mg daily (21 consecutive days every 28 days) (n=175) or sorafenib 400 mg twice daily (n=175). The primary outcome was PFS.

At a median follow up of 19 months, tivozanib demonstrated significantly greater PFS (5.6 months vs. 3.9 months; HR 0.73, 95% CI 0.56-0.94, p=0.016) and ORR (18% vs. 8%, p=0.003; CR rates 0% vs. 0%) versus sorafenib in the intention to treat population, in the subset of patients treated with two prior anti-VEGF TKIs, and in patients treated with a prior anti-VEGF TKI and an ICI.24,25 Patients with favorable IMDC risk and those with intermediate IMDC risk had longer PFS with tivozanib than with sorafenib, whereas patients with a poor IMDC risk did not. The investigators hypothesized that patients with poor IMDC risk have tumors that are driven less by angiogenesis than their favorable- and intermediate-risk counterparts; therefore, pa­tients with poor-risk disease might derive less PFS benefit from a selective anti-VEGF TKI, like tivozanib. Median overall survival was not significantly different between groups (16.4 months vs. 19.7 months; HR 0.99, 95% CI 0.76–1.29, p=0.95).

The most common grade 3 or higher TRAE was hypertension, occurring in one-fifth of patients in both groups.24,25 Serious TRAEs occurred in 11% of patients with tivozanib and 10% of patients with sorafenib. Dose interruptions due to TRAEs occurred in 48% of patients treated with tivozanib and 63% of patients treated with sorafenib; TRAEs that led to dose reduc­tions were more common in the sorafenib arm (24% vs. 38%).

The FDA approved tivozanib for relapsed or refractory aRCC following two or more prior systemic therapies on March 10, 2021.6

Next-Line Treatment Considerations
Sequencing therapy remains a complicated issue for clini­cians. For patients with disease control greater than one year on first-line, single-agent VEGF inhibitor, switching to another sin­gle agent anti-VEGF TKI, such as cabozantinib or axitinib, may be appropriate.3 For patients with brief response to single-agent anti-VEGF TKI, clinicians may consider combination anti-VEGF TKI plus ICI therapy. If patients lack a response to first-line VEGF inhibition, dropping VEGF inhibition and switching to ICI therapy (e.g., ipilimumab plus nivolumab or nivolumab alone) can be considered.

For patients who did not respond to combination anti-VEGF TKI+ ICI therapy, clinicians may consider switching to a sec­ond-line anti-VEGF TKI, such as cabozantinib or axitinib, or combination lenvatinib plus everolimus.3 Notably, phase 3 data support sequential VEGF therapy; however, limited data support sequential ICI therapy.16-25

Ongoing Trials

Ipilimumab, Nivolumab, and Cabozantinib
COSMIC-313 (NCT03937219) is a randomized phase 3 trial of ipilimumab plus nivolumab with either cabozantinib or place­bo for patients with previously untreated IMDC intermediate-/ poor-risk aRCC.26 PDIGREE (NCT03793166) is also evaluating the combination of ipilimumab, nivolumab, and cabozantinib in the treatment naïve, IMDC intermediate-/poor-risk setting.27 However, unlike COSMIC-313, PDIGREE has an adaptive protocol. All patients receive up to four cycles of ipilimumab and nivolumab and are assessed at three months. Subsequent therapy is based on response. Patients that achieve a CR re­ceive nivolumab alone. Those with progressive disease receive cabozantinib alone. Patients who achieve either partial response or stable disease are randomized to either nivolumab alone or combination cabozantinib plus nivolumab.

Table 2. Pivotal randomized trials for relapsed/refractory advanced renal cell carcinoma following anti-VEGF TKI treatment

YearPhaseTrial NameAgentsPatients, nLine of TherapyORR (%)OS (mo)PFS (mo)Statistical Benefit
2008 3 RECORD16,17 EVE v PLA 410 2nd and beyond 1.8 v 0 14.8 v 14.4 4.9 v 1.9 PFS
2011 3 AXIS18,19 AXI v SOR 723 2nd 19 v 9 20.1 v 19.2 8.3 v 5.7 ORR, PFS
2015 3 METEOR20,21 CABO v EVE 658 2nd and beyond 21 v 5 21.4 v 17.1 7.4 v 5.3 ORR, OS, PFS
2015 3 CheckMate-02522 NIVO v EVE 821 2nd or 3rd 25 v 5 25 v 19.6 4.6 v 4.4 ORR, OS
2015 2 NCT0113673323 LEN + EVE v EVE 153 2nd 43 v 3 25.5 v 15.4 14.6 v 5.5 ORR, PFS, OS
2020 3 IVO-324,25 TIV v SOR 350 2nd and beyond 18 v 8 16.4 v 19.7 5.6 v 3.9 ORR, PFS

Abbreviations: AXI, axitinib; CABO, cabozantinib; EVE, everolimus; LEN, lenvatinib; NIVO, nivolumab; ORR, objective response rate; OS, overall survival; PFS, progression free survival; PLA, placebo; SOR, sorafenib; TIV, tivozanib; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor

PDIGREE will help clinicians understand the number of ipili­mumab cycles required as the protocol does not require comple­tion of all four cycles of ipilimumab plus nivolumab, as seen with CheckMate-214.12,27 PDIGREE will also address the feasibility of discontinuing treatment for patients who achieve CR at one year of treatment. To date, no other clinical trials have addressed this question of discontinuing therapy for patients achieving CR.

Belzutifan (MK-6482) is a novel hypoxia-inducible factor 2 alpha inhibitor that recently received a priority review from the FDA based on a phase 2 trial of patients with Von Hippel-Lindau Disease-associated RCC.28 This trial showed promising clin­ical activity for patients with treatment naïve disease (ORR 36.1%). Belzutifan is also being studied in combination with either cabozantinib, everolimus, or lenvatinib for patients with aRCC.29-31

Antiangiogenics and checkpoint inhibition have revolution­ized the treatment of aRCC. The CLEAR and CheckMate-9ER tri­als showed promising results in the first-line setting, supporting the use of lenvatinib plus pembrolizumab and cabozantinib plus nivolumab, respectively. Among the first-line treatment options, lenvatinib plus pembrolizumab demonstrated the highest ORR and PFS; however, caution should be used when comparing results between trials. The TIVO-3 trial demonstrated an ORR and PFS benefit with tivozanib in the relapsed/refractory setting and has been added to the treatment armamentarium. Ongoing trials are evaluating the use of combination ICI and anti-VEGF TKI, addressing sequencing of therapies, and investigating the use of novel therapies, such as inhibitors of hypoxia-inducible factor 2 alpha.


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