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Oncologist. 2018 May; 23(5): 540–555.
Published online 2018 Feb 27. doi:10.1634/theoncologist.2017-0534
PMCID: PMC5947457
PMID: 29487224
Nizar M. Tannir,*a Sumanta K. Pal,b and Michael B. Atkinsc
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This article reviews second‐line treatments for patients with clear‐cell renal cell carcinoma, focusing on everolimus, axitinib, nivolumab, cabozantinib, and the lenvatinib‐everolimus combination. Pivotal studies that led to regulatory approval of these agents are discussed, and strategies for selecting second‐line treatments are considered.
Keywords: Renal cell carcinoma, Everolimus, Axitinib, Nivolumab, Cabozantinib, Lenvatinib
Abstract
The management of advanced clear‐cell renal cell carcinoma has steadily improved over the past decade with the introduction of antiangiogenic and targeted therapies. Recently, three new therapies have been approved for use as second‐line options that further advance the treatment armamentarium: nivolumab, a monoclonal antibody targeting the programmed cell death receptor; cabozantinib, a small‐molecule tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR), MET, and AXL; and lenvatinib, a small‐molecule TKI of VEGF and fibroblast growth factor receptors that is used in combination with everolimus, an inhibitor of the mechanistic target of rapamycin. Together, these and previously approved second‐line treatments offer clinicians the ability to better individualize treatment for patients after progression on first‐line VEGFR‐targeted therapies. In this comprehensive review, we discuss the efficacy and safety results from the pivotal trials of these newly approved therapies, including the quality of study design, the level of evidence, subgroup analyses, and how these data can help to guide clinicians to select the most appropriate second‐line therapy for their patients.
Implications for Practice.
This review article provides the reader with a comprehensive overview of current treatment options for patients with advanced clear‐cell renal cell carcinoma (RCC) whose disease has progressed after their first therapy. As many patients with RCC experience disease progression with initial treatments, effective second‐line therapies are critical. Nivolumab, cabozantinib, and lenvatinib plus everolimus have recently been approved as second‐line treatments. The new agents discussed in this review increase the therapeutic options available and provide physicians with opportunities to individualize treatments for their patients, with a view to improving disease control and survival outcomes.
Keywords: Renal cell carcinoma, Everolimus, Axitinib, Nivolumab, Cabozantinib, Lenvatinib
Introduction
The management of advanced renal cell carcinoma (RCC) remains a clinical challenge. When the disease is detected early, patients with RCC can be effectively treated by radical or partial nephrectomy alone [1], with a 5‐year survival rate of up to 93% [2]. However, up to 30% of patients present with advanced disease at diagnosis, and 10%–20% treated for early‐stage disease experience recurrence [2], [3], [4]. As RCC advances, the 5‐year survival rate drops to 67% for patients with regional metastases and 12% for those with distant, metastatic disease [2]. Despite these challenges, treatment of advanced RCC has steadily improved with the introduction of antiangiogenic and targeted therapies [5], [6]. In recent years, specialized centers have reported 5‐year survival rates as high as 23% for patients with metastatic RCC [7].
Preferred front‐line therapies for advanced clear‐cell RCC, the most common type of kidney cancer [8], include the tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib [1]. Both inhibit the vascular endothelial growth factor (VEGF) pathway, and both demonstrated improvement in progression‐free survival (PFS) in pivotal trials [9], [10]. In the second‐line setting, treatment strategies have focused on continuing VEGF inhibition or switching toward inhibition of mechanistic target of rapamycin (mTOR). Established second‐line therapies include axitinib, a selective VEGF receptor (VEGFR) TKI [11], [12], and the mTOR inhibitor everolimus [13], [14]. Since 2015, three new second‐line treatments have become available—nivolumab, a checkpoint inhibitor (CPI) [15], [16]; cabozantinib, a TKI [17], [18]; and lenvatinib, a TKI used in combination with everolimus [19], [20].
Given the expanding options for second‐line therapy, clinicians can more readily individualize treatment. When choosing therapies, clinicians should consider a number of patient factors, including age, comorbidities, and prior therapy, as well as treatment attributes [21]. Herein, we review second‐line treatments for patients with clear‐cell RCC, focusing on everolimus, axitinib, nivolumab, cabozantinib, and the lenvatinib‐everolimus combination. We discuss pivotal studies that led to regulatory approval of these agents and consider informed strategies to select second‐line treatment for individual patients.
Materials and Methods
We reviewed prescribing information for each agent and conducted a MEDLINE search for pivotal trial publications and a search of presentations at meetings of the American Society of Clinical Oncology and the European Society for Medical Oncology through March of 2017.
Treatment Characteristics
As most patients with advanced RCC will require multiple therapies over the course of their disease, it is important for clinicians to understand the clinical and molecular attributes of each treatment (Table (Table1).1). Axitinib, cabozantinib, and lenvatinib all target VEGFR 1–3 (Fig. (Fig.1A)1A) [11], [12], [17], [18], [19], [20]. VEGF is an established target in clear‐cell RCC because of the prevalence of von Hippel‐Lindau (VHL) loss‐of‐function mutations [22], [23]. These mutations lead to overexpression of VEGF through the intermediary hypoxia inducible factor (HIF), a constitutively active transcription factor [24]. Under normoxic conditions, the VHL protein targets HIF for proteasome degradation, whereas under hypoxic conditions, VHL is inactivated and HIF accumulates. Loss of VHL function by somatic mutation dysregulates HIF with subsequent upregulation of VEGF even under normoxic conditions, promoting tumor angiogenesis. Cabozantinib also targets receptor kinases MET and AXL [17], [25], which are also upregulated by VHL loss [26], [27]. MET and AXL play a role in RCC pathogenesis by supporting alternative proangiogenic and proproliferative pathways and may contribute to resistance to VEGFR‐TKI therapy [28], [29], [30]. Lenvatinib also inhibits fibroblast growth factor receptors (FGFRs) 1–4 [19], [31]. Preclinical studies indicate that the benefit of lenvatinib‐everolimus is likely through combined inhibition of angiogenesis, through VEGFR and FGFR, and inhibition of proliferation, through mTOR [32].
Therapeutic targets in advanced renal cell carcinoma (RCC). (A): Established second‐line targets: activation receptor tyrosine kinases, including VEGFR [22], MET [28], AXL [29], and FGFR [88], can promote tumorigenesis and angiogenesis [22], [88], [89], [90]; AXL, MET, and FGFR may also act as compensatory mechanisms of angiogenesis [30], [32]; PD‐L1/PD‐L2 on tumor cells and APCs suppress effector T‐cell activity in the tumor microenvironment, facilitating tumor immune evasion [33]. (B): Immunomodulatory targets for tyrosine kinase inhibitors (TKIs)—rationale for combination with checkpoint inhibitors in RCC. TKIs have been shown, generally in ex vivo or non‐VHL tumor models, to modulate (suppress [red line] or stimulate [green arrow]) the activity of immune cells (e.g., activation, migration, proliferation, expansion, recruitment) involved in the tumor‐immune response, including CD8+ T cells [91], [92], CD4+ T cells [92], [93], Treg cells [91], [92], [93], [94], [95], [96], APC [97], [98], [99], tumor‐associated macrophages [91], MDSC [91], [93], [96], [100], [101], and NK cells [102].
Abbreviations: APC, antigen‐presenting cell; CD, cluster of differentiation; CTLA‐4, cytotoxic T‐lymphocyte‐associated protein 4; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; GAS6, AXL receptor tyrosine kinase ligand; HGF, hepatocyte growth factor; HIFα, hypoxia‐inducible factor alpha; IL‐10, interleukin 10; MDSC, myeloid‐derived suppressor cell; MHC, major histocompatibility complex; mTOR, mechanistic target of rapamycin; NK, natural killer; PD‐1, programmed cell death receptor 1; PDGF, platelet‐derived growth factor; PDGFR, platelet‐derived growth factor receptor; PD‐L1/L2, programmed cell death‐ligand 1 or 2; TCR, T‐cell receptor; Teff, effector T cell; TGF‐β, transforming growth factor‐β; Treg cell, regulatory T cell; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptors; VHL, von Hippel‐Lindau.
Table 1.
Treatment attributes
Abbreviations: —, not reported; Ab, antibody; CYP, cytochrome; ESRD, end‐stage renal disease; EU, European Union; FGFR, fibroblast growth factor receptor; Ig, immunoglobulin; IV, intravenous; mTOR, mechanistic target of rapamycin; PD1‐1, programmed cell death receptor 1; PD‐L1/L2, programmed cell death‐ligand 1 and −2; PDGFR, platelet‐derived growth factor receptor; PgP, P‐glycoprotein; RCC, renal cell carcinoma; US, United States of America; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
Nivolumab targets the programmed cell death (PD‐1) receptor [15], [16], [33]. Interaction between PD‐1 on T cells and its ligands, PD‐ligand 1 (L1) and 2, on tumor cells and antigen‐presenting cells is thought to inhibit specific antitumor immunity. Blocking this interaction can unleash a pre‐existing antitumor immune response.
Clinical Outcomes from Pivotal Trials
Table Table22 summarizes key design information from the pivotal studies, including the phase III studies RECORD‐1 (everolimus) [34], AXIS (axitinib) [35], CheckMate 025 (nivolumab) [36], METEOR (cabozantinib) [37], and the randomized phase II study E7080‐G000‐205 (Study 205; lenvatinib‐everolimus combination) [38]. Although there are similarities across these studies, there are also important differences. Variation in study design, including patient eligibility, response criteria and assessment (investigator vs. independent radiology review [IRR]), can affect outcomes and limit comparisons across studies.
Table 2.
Study design of pivotal trials
aCheckMate 025 was stopped early at the interim analysis and participants in the everolimus groups could be assessed for a crossover to nivolumab (ClinicalTrials.gov, NCT01668784).
bMSKCC prognostic risk groups based on three risk factors (anemia, hypercalcemia, and poor performance status).
cFor CheckMate 025, MSKCC prognostic risk groups based on the presence of the three risk factors: 0, favorable; 1 or 2, intermediate; and 3, poor; for all other studies, 0 was favorable, 1 was intermediate, and 2 or 3 was poor.
Abbreviations: DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; Hb, hemoglobin; HR, hazard ratio; IFN, interferon; IL, interleukin; IRR, independent radiology review; MSKCC, Memorial Sloan Kettering Cancer Center; mTOR, mechanistic target of rapamycin; ORR, objective response rate; OS, overall survival; PFS, progression‐free survival; PK, pharmaco*kinetics; Q8W, once every 8 weeks; Q12W, once every 12 weeks; QOL, quality of life; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria in Solid Tumors; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
Key baseline characteristics across the pivotal studies were typical for patients with RCC, but some differences are worth noting (Table (Table3).3). Although randomization was stratified by Memorial Sloan Kettering Cancer Center (MSKCC) risk criteria for CheckMate 025 and METEOR, the definition of intermediate‐ and poor‐risk groups differed [36], [37]. Sunitinib was the most common prior therapy across all studies, but other prior therapies varied because of availability and study design restrictions.
Table 3.
Patient baseline characteristics from pivotal trials
aFor CheckMate 025, MSKCC prognostic risk groups based on the presence of the three risk factors: 0, favorable; 1 or 2, intermediate; and 3, poor; for all other studies, 0 was favorable, 1 was intermediate, and 2 or 3 was poor.
Abbreviations: —, not reported; CPI, checkpoint inhibitor; ECOG, Eastern Cooperative Oncology Group; MSKCC, Memorial Sloan Kettering Cancer Center.
Table Table44 summarizes key efficacy data for these pivotal studies, and safety data are shown in Table Table5.5. Comparisons across studies should be approached with caution, but some general aspects are worth mentioning. Median PFS (mPFS) in the everolimus arm was similar across studies (4.4–5.5 months by investigator assessment), whereas median overall survival (mOS) had a wider range (14.8–19.6 months) [34], [36], [37], [38], [39], [40], [41], [42]. This may reflect differences in study population or treatment after the study. There was also a range in response rates, but achievement of complete responses remained elusive across studies. Given their common role in VEGFR inhibition, the types and rates of adverse events (AEs) associated with TKIs were generally consistent with variations, likely reflecting additional targets unique to each agent [35], [37], [38]. In CheckMate 025, nivolumab was well tolerated [36], but clinicians should be aware that CheckMate 025 and RECORD‐1 reported only treatment‐related AEs (TRAEs) [34], [36].
Table 4.
Efficacy data from pivotal trials
aStatistical comparisons presented are for lenvatinib + everolimus vs. everolimus.
bIRR analyses were ad hoc.
cPrimary endpoint.
dFor METEOR study, primary endpoint was PFS (IRR) in the first 375 randomized patients for cabozantinib vs. everolimus: median of 7.4 vs. 3.8 months (HR = 0.58, 95% CI 0.45–0.75; p < .001).
e98.5% CI.
fEstimated from data provided in Rini et al. [35].
Abbreviations: —, not reported; CI, confidence interval; CR, complete response; HR, hazard ratio; IRR, independent radiologic review; NE, not evaluated; NS, nonsignificant (significant boundary of p ≤ .0019); ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression‐free survival; PR, partial response; SD, stable disease.
Table 5.
Safety and tolerability data from pivotal trialsa
aIncludes most common grade 3–4 AEs from experimental arms of each study (primary analysis); additional data of AEs that overlap with other studies provided when available; some rates are estimated from data provided in the primary analysis.
bAll‐causality AE rates are available in everolimus and nivolumab product label.
cAXIS study reported any grade and grade ≥3.
dAll lenvatinib dose reductions (one patient also had a everolimus dose reduction).
eEstimated from upper or lower respiratory tract infection.
Abbreviations: —, not reported; AE, adverse event; NA, not applicable (dose reductions not permitted for nivolumab); NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PPES, palmar‐plantar erythrodysesthesia.
In the following sections, we provide more detailed discussion of key clinical data from each trial, including subgroup analyses. However, we emphasize that subgroup data are informative but not definitive.
Everolimus
In the primary analysis of RECORD‐1, everolimus significantly improved PFS (IRR) versus placebo with a 70% reduction in the rate of progression or death (hazard ratio [HR] = 0.30, 95% confidence interval [CI] = 0.22–0.40, p < .0001), with the PFS benefit maintained in subgroups defined by MSKCC risk, prior therapy, and age [34]. The major benefit of everolimus was disease stabilization at a rate of 63% versus 32% for placebo. There was no improvement in objective response rate (ORR) or in overall survival (OS), the latter likely confounded by crossover of placebo patients to everolimus [39].
The most common TRAEs of any grade in the everolimus arm included stomatitis (40%), rash (25%), asthenia (18%), and fatigue (20%), and the most common grade 3–4 TRAEs were stomatitis (3%), infections (3%), pneumonitis (3%), and fatigue (3%) [34]. Everolimus was associated with myelosuppression, including grade 3–4 anemia (9%) and lymphopenia (16%). Dose reductions were infrequent (5%), although dose interruptions were more common (34%); 10% of patients discontinued everolimus because of TRAEs. In an updated analyses, safety and tolerability were generally maintained, although grade 3–4 infections increased to 10% [39].
Everolimus delayed time to decline in performance status [39]. The median time to a 10% decline in Karnofsky Performance Status was 5.78 months for everolimus versus 3.84 months for placebo (HR = 0.66, 95% CI = 0.49–0.90, p = .004).
Axitinib
In the pivotal phase III AXIS study, axitinib demonstrated a significant improvement in PFS (IRR) and ORR (IRR) versus sorafenib without an OS benefit [35], [43]. Axitinib was associated with a 33% improvement in PFS relative to sorafenib (HR = 0.665, 95% CI = 0.544–0.812, p < .0001) [35]. The PFS benefit was maintained in subgroups defined by performance status, MSKCC risk, and age. In subgroup analysis by prior therapy, the effect size of the PFS benefit was substantial in patients with prior cytokine therapy (median 12.1 vs. 6.5 months; HR = 0.464, 95% CI = 0.318–0.676) but less robust in patients with prior sunitinib (median 4.8 vs. 3.4 months; HR = 0.741, 95% CI = 0.573–0.958).
The most common AEs (all causality) in the axitinib arm of any grade and grade ≥3, respectively, included diarrhea (55% and 11%), hypertension (40% and 16%), fatigue (39% and 11%), and decreased appetite (34% and 5%) [35]. Hypertension of any grade was more common with axitinib versus sorafenib (40% vs. 29%), as was nausea (32% vs. 22%), whereas the rate of grade 3–4 palmar‐plantar erythrodysesthesia (PPES) was lower (5% vs. 16%). Dose reductions were less frequent with axitinib than with sorafenib (31% vs. 52%), as were AE‐related discontinuations (4% vs. 8%). After longer follow‐up, safety results were generally similar [43].
Patient‐reported outcomes were comparable between axitinib and sorafenib [35], [44]. There was a 17% reduction in the risk of time to deterioration (TTD) by Functional Assessment of Cancer Therapy‐Kidney Symptom Index (FKSI)‐15 for axitinib versus sorafenib and a 16% reduction in risk by FKSI‐Disease‐Related Symptoms (DRS) [35].
Nivolumab
CheckMate 025 enrolled patients with advanced clear‐cell RCC and prior antiangiogenic therapy [36]. At interim analysis, minimum follow‐up was 14 months. Nivolumab was associated with a significant OS benefit versus everolimus, with a 27% reduction in mortality (HR = 0.73, p = .002). In OS subgroup analyses, nivolumab was favored over everolimus irrespective of MSKCC risk group, number, type or duration of prior therapy, and number or site of metastases [36], [45]. The extent of the OS benefit was notable for patients with poor MSKCC risk (HR = 0.47, 95% CI = 0.32–0.73), although this represented a relatively small subgroup (n = 124) [36]. Nivolumab was not favored in patients ≥75 years of age (HR = 1.23, 95% CI = 0.66–2.31), but this subgroup was also small (n = 74).
There was no statistical difference in PFS for nivolumab compared with everolimus (HR = 0.88; p = 0.11), although ORR (investigator assessed) was higher for nivolumab (25% vs. 5%, p < .001). Median duration of response was 12 months in each arm, although 49 patients receiving nivolumab had an ongoing response at data cutoff versus 10 receiving everolimus [36]. Conversely, there was a high incidence of nivolumab‐refractory patients (35%).
The most common TRAEs with nivolumab were fatigue (33%), nausea (14%), and pruritus (14%) [36]. Grade 3–4 TRAEs were infrequent—the most common being fatigue (2%). The rate of nivolumab discontinuations due to TRAEs was 8%, and no deaths were associated with nivolumab treatment.
Nivolumab was associated with significant improvement in quality of life (QOL) measures versus everolimus [46]. The rate of improvement by FKSI‐DRS was 55% for nivolumab versus 37% for everolimus (p < .0001).
Cabozantinib
METEOR initially assessed PFS in the first 375 randomized patients and then OS in the overall study population (n = 658) after additional follow‐up [37], [40]. In the primary analysis of the first 375 randomized patients, cabozantinib was associated with a 42% improvement in PFS (IRR) versus everolimus (median 7.4 vs. 3.8 months; HR = 0.58, 95% CI = 0.45–0.75, p < .001) after a minimum follow‐up of 11 months [37]. PFS in the overall study population was consistent with the primary analysis [40]. ORR (IRR) in the overall population favored cabozantinib over everolimus (17% vs. 3%; p < .0001), with a low incidence of cabozantinib‐refractory patients (12%). After additional follow‐up (median ≥18.7 months), cabozantinib was associated with a significant improvement in OS with a 34% reduction in mortality (HR = 0.66, 95% CI = 0.53–0.83, p = .00026) [40].
Cabozantinib was consistently favored for OS and PFS in subgroup analyses, including age, MSKCC risk group, prior nephrectomy, tumor burden, number and site of metastases, and number and type of prior therapy [40]. There was a notable PFS and OS benefit in patients with bone metastases, with an mPFS of 7.4 months for cabozantinib versus 2.7 months for everolimus (HR = 0.33, 95% CI = 0.21–0.51) and mOS of 20.1 versus 12.1 months (HR = 0.54, 95% CI = 0.34–0.84), and a lower rate of skeletal‐related events in patients with a history of such events (16% vs. 34%) [47].
The most common all‐causality AEs (any grade and grade 3–4) in the cabozantinib arm included diarrhea (74% and 11%), fatigue (56% and 9%), nausea (50% and 4%), decreased appetite (46% and 2%), PPES (42% and 8%), and hypertension (37% and 15%) [37]. Dose reductions were common (60%), but only 9% of patients discontinued cabozantinib because of AEs. One treatment‐related death occurred in the cabozantinib arm and two in the everolimus arm. The safety profile was similar in the updated analysis [40].
The overall QOL profile for cabozantinib was comparable with that of everolimus [48]. In exploratory analysis, cabozantinib delayed the TTD by FKSI‐DRS versus everolimus (median 5.5 vs. 3.7 months; HR = 0.65, 95% CI = 0.54–0.78, p < .0001).
Lenvatinib‐Everolimus Combination
Study 205 randomized patients to three treatment arms: lenvatinib‐everolimus, lenvatinib alone, and everolimus alone [38]. At data cutoff, median follow‐up was ≥16.5 months. Combination treatment was associated with a 60% improvement in investigator‐assessed PFS versus single‐agent everolimus (HR = 0.40, 95% CI = 0.24–0.68, p = .0005). The PFS benefit of the combination over single‐agent everolimus was maintained in subgroup analysis by MSKCC risk group, tumor burden, and metastatic site, with a notable effect for patients with favorable MSKCC risk (median 20.1 vs. 9.8 months; HR = 0.25, 95% CI = 0.08–0.76) [42]. The ORR (investigator assessed) was 43% for the combination treatment, 27% for single‐agent lenvatinib, and 6% for single‐agent everolimus [38]. Analyses of OS suggested a trend of improvement with the combination versus single‐agent everolimus, but statistical outcomes were too varied to reach definitive conclusion, underscoring the need for adequate study size to assess OS [38], [42].
Based on regulatory agency requests, a retrospective analysis of PFS was conducted using IRR [41]. ORR by IRR was 35% for the combination, 0% for everolimus, and 39% for lenvatinib alone, and mPFS was 12.8, 5.6, and 9.0 months, respectively. Statistical significance was maintained for the combination versus single‐agent everolimus (HR = 0.45, 95% CI = 0.27–0.79, p = .0029) but lost for the comparison between single‐agent arms (HR = 0.62, 95% CI = 0.37–1.04, p = .12), underscoring the relevance of blinded assessment.
The most common grade 3–4 AEs (all causality) during Study 205 included constipation (37% for the combination vs. 0% for single‐agent everolimus vs. 0% for single‐agent lenvatinib), diarrhea (20% vs. 2% vs. 12%), fatigue or asthenia (14% vs. 2% vs. 8%), hypertension (14% vs. 2% vs. 17%), and hypertriglyceridemia (8% vs. 8% vs. 4%) [38]. The rate of dose reductions was 71%, 26%, and 62%, respectively, and the rate of discontinuations due to AEs was 24%, 12%, and 25%. There was one treatment‐related death with the combination and one with single‐agent lenvatinib.
Selecting a Treatment
The National Comprehensive Cancer Network recommends nivolumab and cabozantinib as Preferred Category 1 agents for second‐line treatment, axitinib and the lenvatinib‐everolimus combination as Category 1, and everolimus as Category 2A [1]. Although guidelines are useful for the general population, clinicians are challenged with selecting treatments for individual patients. Clinicians must consider a range of factors when selecting a treatment, from comorbidities and prior therapy to less obvious but central issues in the daily life of the patient. Convenience can be important for patients who face difficulties reaching cancer centers.
Table Table66 outlines our recommendations for specific patient populations. We emphasize that these are opinions that will evolve as more data and treatments become available. As there is a lack of head‐to‐head comparisons, our recommendations rely on subgroup analyses from pivotal studies, other prospective or retrospective studies, and our own clinical experience. Cost‐effectiveness analyses have been published by the National Insitutue of Health and Care Excellence in the UK, with the exception of the lenvatinib‐everolimus combination, which is in development [49], [50], [51], [52], [53].
Table 6.
Second‐line treatment recommendations based on available clinical evidence and expert opinion
Key to recommendations: 
preferred first option; 
preferred second option; 
option(s) after preferred therapies; 
subsequent option(s); 
no data available; 
should be used with caution.
aTreatment is associated with cardiovascular events.
bTreatment is associated with hypertension.
cTreatment is associated with new‐onset diabetes.
dTreatment is associated with thyroid dysfunction.
eDose adjustments may be needed.
fIncremental cost‐effectiveness ratio (ICER) for everolimus + best supportive care (BSC) vs. BSC alone £49,300 ($64,910) per quality‐adjusted life year (QALY) gained.
gICER for axitinib vs. BSC of £55,284 ($72,790) per QALY gained after failure of a cytokine and £33,538 ($44,160) per QALY gained after failure of sunitinib.
hICER for nivolumab vs. axitinib, everolimus, or BSC <£50,000 ($65,830) per QALY gained.
iICER for cabozantinib vs. axitinib <£50,000 ($65,830) per QALY gained vs. axitinib, and in incremental analyses, cabozantinib was more effective and less expensive vs. nivolumab.
Key to supportive evidence: A1, phase III randomized controlled trial (RCT); A2, phase II RCT; B1, expert opinion supported by subgroup data from phase III RCT; B2, expert opinion supported by subgroup data from phase II RCT; B3, expert opinion supported by patients’ inclusion in RCT; C, expert opinion supported by prospective clinical trial(s); CE, cost‐effectiveness anlaysis reported in NICE technical assessment; D, expert opinion supported by retrospective studies or case reports; E, expert opinion; PL, product label.
Other abbreviations: MSKCC, Memorial Sloan Kettering Cancer Center; NA, not applicable; NICE, National Institute for Health and Care Excellence; PD‐1, programmed cell death receptor 1; PD‐L1, programmed cell death‐ligand 1; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor receptor.
Sources: Everolimus [13], [14], [34], [39], [53], [54], [56], [57], [103], [104]; axitinib [11], [12], [35], [43], [49], [56], [57], [58], [74], [104]; nivolumab [15], [16], [36], [45], [51], [59], [60], [61], [64], [105]; cabozantinib [17], [18], [37], [40], [47], [52], [56], [57], [73], [74], [75], [106]; lenvatinib + everolimus [19], [20], [38], [41], [42], [50], [56], [57], [104].
Everolimus
Although everolimus will likely move to later lines of therapy, it still has a therapeutic space in second‐line therapy. Everolimus could be considered for patients who are TKI intolerant or refractory [54] and not appropriate for nivolumab, as will be discussed. Molecular investigations may eventually identify mutational profiles that support the use of everolimus in select patients [55]. Everolimus may also be considered in patients requiring dialysis. Bleeding disorders in dialysis patients may preclude the use of VEGFR TKIs, although limited data are available for dialysis patients [56], [57].
Axitinib
Given the difference in PFS for patients in the axitinib arm who had received prior sunitinib (4.8 months) compared with prior cytokine treatment (12.1 months) [35], [58], prior therapy is an important consideration for axitinib. Safety and tolerability data for axitinib were generally consistent with TKIs but showed lower rates for some AEs, including dermatologic AEs, and better tolerability than sorafenib. Axitinib may be an appropriate second‐line option for patients who are at risk for specific AEs associated with other treatment options or for patients previously treated with cytokines, particularly those with factors associated with favorable risk [35].
Nivolumab should be preferred for patients in whom prior VEGFR‐TKI therapy was not well tolerated. It will be important to determine if switching the mechanism of action toward PD‐1 inhibition can re‐establish or enhance sensitivity to subsequent VEGFR inhibition for treatment sequencing.
Nivolumab
Nivolumab should be considered a second‐line option for most patients. The lack of a PFS benefit needs to be better understood, but the OS and ORR benefits versus everolimus in a phase III setting make it a preferred treatment [36]. Nivolumab was active across nearly all subgroups, with a notable OS benefit in the MSKCC poor‐risk subgroup [36], [45]. The safety and tolerability of nivolumab were better than that of everolimus, and nivolumab appears to be more tolerable than TKIs, although comparisons are difficult given that CheckMate 025 reported only TRAEs. Nivolumab should be preferred for patients in whom prior VEGFR‐TKI therapy was not well tolerated. It will be important to determine if switching the mechanism of action toward PD‐1 inhibition can re‐establish or enhance sensitivity to subsequent VEGFR inhibition for treatment sequencing. Nivolumab should be the treatment of choice for patients <65 years of age, for patients with factors associated with poor risk, and for patients with renal impairment or those receiving dialysis (although data are limited) [36], [45], [59], [60].
Oncologists using nivolumab should have expertise in managing immune‐related AEs, such as dermatitis, hepatitis, colitis, endocrine deficiencies, and pneumonitis [61]. There are no contraindications in the nivolumab label [15], but other treatments should be considered for patients with neuromuscular disorders or a history of Guillain‐Barré syndrome [62], [63]. Caution is warranted for patients at risk for immune‐related AEs (e.g., organ transplant or uncontrolled autoimmune disease) until more data become available [61], [64]. Patients with conditions requiring glucocorticoids were excluded from CheckMate 025 [36]. A recent analysis also suggests that antibiotics may impair CPI activity, but more definitive data are needed before implementing changes to clinical practice [65].
Although tolerability data support nivolumab in elderly patients [66], the lack of an OS benefit in the CheckMate 025 elderly subgroup needs to be resolved [36]. We also need to better understand the lack of a PFS benefit and high incidence of refractory patients. In contrast to VEGFR TKIs, the clinical impact of immunotherapy appears to be durability of response in select patients. PFS is likely not an adequate indicator of nivolumab's overall efficacy because of the high rate of progressors, whereas a subset experiences durable responses [67]. We await updated analyses from CheckMate 025, noting that a small number of patients maintained response even after discontinuing nivolumab [36].
CheckMate 025 also allowed treatment beyond progression if the patient was deriving clinical benefit. In an analysis by the U.S. Food and Drug Administration, 156 patients assigned to nivolumab were treated beyond progression and were evaluable, with 5 patients (3.2%) achieving a reduction of ≥30% [68]. However, it is unclear how these data can be applied to the general population because of selection bias. Furthermore, cases of hyperprogressive disease have been reported in patients with advanced tumors receiving CPIs and warrant careful study [69].
Predictive biomarkers for nivolumab are vital, but PD‐L1 expression on tumor cells has not proven a reliable biomarker in patients with previously treated RCC [36]. Investigations continue, including analyses of PD‐L1 with tumor‐infiltrating lymphocytes, mutational burden, neoantigens, and others [70], [71]. Analysis of metastatic lesions (as opposed to nephrectomy specimens) may provide a better assessment of the potential to respond to nivolumab [72].
Cabozantinib
Cabozantinib should be considered a preferred second‐line option across the population of patients with RCC. Cabozantinib demonstrated a benefit versus everolimus for all three key efficacy endpoints (OS, PFS, and ORR), and analyses support cabozantinib in all subgroups investigated [37], [40]. This is reinforced by the low incidence of refractory patients. Cabozantinib should be the preferred choice for patients with high tumor burden or bone metastases, patients previously treated with a CPI, and elderly patients [40], [47], [73], [74], [75].
With regard to prior therapy, cabozantinib was favored over everolimus for both OS and PFS for patients previously treated with sunitinib or pazopanib, and in a small subgroup with prior nivolumab treatment [40]. In patients with sunitinib as their only prior VEGFR TKI (n = 267), mPFS was 9.1 months for cabozantinib versus 3.7 months for everolimus (HR = 0.43, 95% CI 0.32–0.59), and mOS was 21.4 versus 16.5 months (HR = 0.66, 95% CI 0.47–0.93) [73]. An exploratory analysis by age showed that outcomes in elderly patients (≥75 years) were consistent with the overall population, with an mPFS of 9.4 months for cabozantinib versus 4.4 months for everolimus (HR = 0.38, 95% CI = 0.18–0.79) and an mOS of 18.4 versus 14.0 months (HR = 0.57, 95% CI = 0.28–1.14), although dose reductions were common (85%) [75].
With regard to prior therapy, cabozantinib was favored over everolimus for both OS and PFS for patients previously treated with sunitinib or pazopanib, and in a small subgroup with prior nivolumab treatment.
The high rate of dose reductions with cabozantinib raises tolerability concerns, but discontinuations due to AEs were infrequent, indicating that AEs were manageable with dose reductions [37], [40]. Cabozantinib's safety profile was generally consistent with other TKIs in RCC [76]. Cabozantinib has not been evaluated in patients with severe hepatic or renal impairment [17], [18], and cabozantinib may be inappropriate for patients who experienced intolerable AEs with a prior TKI that overlap with cabozantinib (e.g., gastrointestinal events, hypertension, PPES).
Lenvatinib‐Everolimus Combination
Across the studies discussed here, the lenvatinib‐everolimus combination had the longest mPFS at 14.6 months [38]. However, this was a phase II study in patients with only one prior VEGF‐targeted therapy, and PFS was investigator‐assessed. The limitations of the trial design became apparent in the IRR analysis of ORR and PFS and inconsistencies across OS analyses [38], [41]. Regardless, this was a highly active combination, but more data are needed to support use across specific subgroups, and definitive OS outcomes are needed in an adequately powered study.
Activity in the overall study population and subgroup analyses support the use of the lenvatinib‐everolimus combination for patients with symptomatic tumors or poor‐risk disease, those with heavy tumor burden who require rapid disease control, and those with lymph node involvement [38], [42]. In Study 205, patients with lymph node metatases had a median PFS of 14.7 months with the combination versus 5.5 months with everolimus (HR = 0.28, 95% CI 0.14–0.58) [42]. However, this should be considered along with the level of evidence of a phase II study and the safety profile. There were high rates of gastrointestinal‐related AEs with the combination, and discontinuation due to AEs occurred in 24% of patients [38]. The combination may not be appropriate for frail patients or patients for whom tolerability may be of concern.
Future Directions
The RCC treatment paradigm will continue to evolve as the newer second‐line agents are assessed in the first‐line settings and novel treatment strategies are developed. Recently, CABOSUN, a randomized phase II study, demonstrated a PFS benefit for front‐line cabozantinib versus sunitinib in patients with advanced clear‐cell RCC who had intermediate‐ or poor‐risk disease [77]. In addition, CheckMate 214, a phase III trial in patients with untreated metastatic RCC, compared the nivolumab‐ipilimumab combination with sunitinib. An interim analysis demonstrated a significant OS benefit with the combination in intermediate‐ and poor‐risk patients—mOS not reached versus 26 months for sunitinib (HR = 0.63, 99.8% CI = 0.44–0.89, p < .0001) [78].
A major focus of future strategies will be immunotherapy combinations. Given the durability of response with CPIs in select patients but the low level of complete response and high rate of refractory disease, investigations have centered on combining CPIs to improve response in a broader population. Investigators have identified relevant targets in the immune‐cancer cycle that could enhance the antitumor immune response, including other checkpoint molecules and targets of TKIs [79]. VEGFR TKIs have demonstrated immunomodulatory activity that might facilitate the antitumor immune response with CPIs (Fig. (Fig.1B)1B) and could also provide more immediate tumor control for patients who experience delayed immune responses. Ongoing studies are combining CPIs with VEGFR TKIs, including axitinib, cabozantinib, and lenvatinib, and have demonstrated clinical activity with the combinations and acceptable tolerability [80], [81], [82], [83]. Studies with sunitinib and pazopanib in combination with CPIs have demonstrated activity but also intolerable toxicities [84], [85].
As treatments continue to advance, we need to better understand the mechanism of resistance to current therapies, targets of antitumor immune response, and combination strategies [79], [86]. Complete response rates and durability of response must improve. Predictive biomarkers are urgently needed. There is also need for more data to guide clinicians in the treatment of patients who tend to be under‐represented in clinical studies, including minority populations, elderly patients, and those with significant comorbidities [87].
Conclusion
The recent approval of three new agents for second‐line treatment of patients with advanced RCC enables clinicians to better individualize treatment. Clinicians should be aware of similarities and differences among approved therapies to make informed decisions with their patients. Clinicians should consider the level of evidence supporting approved treatments; efficacy benefits; availability and quality of subgroup data; safety and tolerability, including risk of AEs based on pre‐existing conditions and prior treatment; impact on QOL; and treatment convenience. Recent studies, including CheckMate 214 and CABOSUN, will likely change the second‐line treatment landscape as the nivolumab‐ipilimumab combination and cabozantinib become available as first‐line options.
Acknowledgments
Medical writing and editorial assistance provided by Isabella Milton and Michael Raffin (Fishawack Communications, Conshohocken, PA, USA), which was supported by Exelixis, Inc. (South San Francisco, CA, USA).
Author Contributions
Conception/design: Nizar M. Tannir, Sumanta K. Pal, Michael B. Atkins
Provision of study material or patients: Nizar M. Tannir, Sumanta K. Pal, Michael B. Atkins
Collection and/or assembly of data: Nizar M. Tannir, Sumanta K. Pal, Michael B. Atkins
Data analysis and interpretation: Nizar M. Tannir, Sumanta K. Pal, Michael B. Atkins
Manuscript writing: Nizar M. Tannir, Sumanta K. Pal, Michael B. Atkins
Final approval of manuscript: Nizar M. Tannir, Sumanta K. Pal, Michael B. Atkins
Disclosures
Nizar M. Tannir: Argos Therapeutics, Bristol‐Myers Squibb, Calithera Biosciences, Exelixis, Nektar, Novartis, Pfizer (C/A, H, other: travel expenses), Bristol‐Myers Squibb, Epizyme, Exelixis, Miranti, Novartis (RF); Sumanta K. Pal: Aveo, Bristol‐Myers Squibb, Exelixis, Genentech, Myriad Pharmaceuticals, Novartis, Pfizer (C/A), Astellas Pharma, Medivation, Novartis (H); Michael B. Atkins: Alexion, Argos Therapeutics, Astra Zeneca, Aveo, Bristol‐Myers Squibb, Eisai, Exelixis, Genentech, Merck, Nektar, Novartis, Pfizer, X‐4 Pharma (C/A), Bristol‐Myers Squibb (H).
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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