Abstract
Since the approval of sorafenib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), in December 2005, seven drugs have been introduced that have provided a high level of clinical efficacy in patients with mRCC, with a median survival ~30 months in an unselected patient population that generally fits trials eligibility1. Despite such success, advancements in therapies have reached a plateau: different combinations of targeted agents have not demonstrated additional benefit mainly due to toxicity concerns, and some novel agents have failed to show benefit over approved drugs in clinic.
In this review, we aim to focus on optimizing selection of agents in mRCC after progression on first-line TT. We will also review how new drugs may transform existing guidelines and break through the current plateau reached with approved agents.
Keywords: Sequence, systemic therapy, Renal Cell Carcinoma
1.0 Introduction
Until the development of TT, immunotherapy was the mainstay of treatment in mRCC, with high-dose interleukin-2 (HD-IL2) being the only approved drug. However, in the last decade, the use of TT led to a significant increase in survival, from 9 months in 1995 with interferon alpha2 to 28–29 months in 20131 with either sunitinib or pazopanib, both VEGFR-tyrosine kinase inhibitors (TKIs). Currently, seven approved agents exist to treat mRCC. Six of these agents were approved by the US Food and Drug Administration (FDA) between 2006 and 2010. Over the past five years however, only one additional agent, axitinib, has become available. Currently, novel drugs targeting the PD-1 /PD-L1 pathway and the discovery of drugs that target mechanisms of resistance to anti-angiogenic therapy seem to hold promise for improving the management of mRCC.
2.0 Consideration for selection of second-line/Salvage therapy
2.1 Does selection of patients depend on molecular alterations and/or clinical factors?
The identification of potentially targetable molecular alterations in different tumors has affected patient outcomes, but only in a few selected settings in oncology.3 Several genes have been reported to be associated with RCC, including VHL, PBRM1, SETD2 and BAP1.4 However, these molecular alterations do not currently guide treatment selection.
Nevertheless, clinical prognostic factors can guide the choice of systemic therapy in pretreated patients, as well as treatment-naive patients. The International Metastatic Database Consortium (IMDC) prognostic factors have been validated in previously treated patients5 and provide a reasonable stratification in patients treated with targeted agents and a glance on the natural biology of disease. A slight modification of the traditional Memorial Sloan Kettering Cancer Center (MSKCC) criteria have been used to selected poor-risk patients for the pivotal trial evaluating temsirolimus in treatment-naïve patients. At present, these criteria represent an appropriate tool to identify patients for first-line temsirolimus therapy, although subset analyses from trials of VEGF-directed agents suggest comparable benefit in patients with poor-risk disease. Eventually, we should be able to integrate a molecular and clinical classification in order to achieve a tailored treatment selection. Currently, IMDC or MSKCC criteria alone are not sufficient to delineate the optimal second- or third-line approach.
2.2 Does intolerance to first-line therapy impact the choice for further line of therapy?
Up to 24% of patients stop receiving standard first-line VEGF-TT due to toxicity concerns.6 Whether these patients should switch to different VEGF targeting agents is not yet clear since they may have not acquired resistance to VEGF-TKIs and can subsequently continue to benefit from VEGF inhibition. To date, there are no trials that address this question. However, the efficacy of second-line TT with mammalian target or rapamycin (mTOR) inhibitors in mRCC patients previously treated with VEGF-TKIs was assessed in the RECORD-1 trial, a randomized, placebo-controlled, phase III trial. As the only trial to include patients intolerant to VEGF-TKIs, primarily sunitinib, RECORD-1 shows that treatment with everolimus is associated with a significantly higher PFS than placebo.7
2.3 Can patients’ preferences play a role in therapy choice?
There are several available TKIs that have been approved by the FDA for both first- and second-line management of mRCC. Although efficacy and survival are the ultimate endpoints when considering potential second-line treatment options, patients’ preferences remain an important factor, especially when one particular therapy may have only a slight efficacy edge over another. Generally, no standardized methodologies are available to evaluate “patients’ preferences” and data collection methods are rather heterogeneous.9 Escudier et al.10 completed the first randomized study to evaluate patients’ preferences in patients with mRCC, albeit in a first-line setting. The PISCES study enrolled 169 patients with mRCC and randomly assigned them to either 800-mg pazopanib for 10 weeks followed by a 2-week washout and then crossover to 50-mg sunitinib per day for 10 weeks, or the reverse sequence. They found that 70% of patients reported preferring pazopanib compared to 22% preferring sunitinib (P <.001); 8% reported no preference. Less fatigue and a better overall quality of life were the most common reasons for patient preference of pazopanib. The main reason for sunitinib preference was the lower frequency of diarrhea over pazopanib.
2.4 The impact on the type of prior treatment: published evidence
2.4.1 Cytokines
Cytokine therapy, particularly high-dose interleukin-2 (HD-IL2) or interferon-alfa (IFN-α), was the standard treatment for mRCC until late 2005. However, poor overall response rates and significant toxicities limited their applicability.11 Despite its drawbacks, HD-IL2 remains indicated for a highly selected population of patients in specialized centers.2 Several attempts to identify reliable and predictive biomarkers of response to cytokine therapy have failed12. When HD-IL2 (or IFN-α, mainly outside the US) are given as a first-line treatment, there is evidence supporting the sequence of a VEGF-TT as second-line treatment. Several anti- angiogenic drugs have shown a benefit in cytokine pre-treated patients with mRCC, including sunitinib, pazopanib,13 bevacizumab,14 and tivozanib.15 In particular, sorafenib16 has the most extensive supporting data and axitinib has the most remarkable PFS. Escudier et al.17 reported that sorafenib as a second-line treatment (after IL-2 or IFN-α) achieved better outcomes than placebo (PFS of 5.5 and 2.8 months and overall survival (OS) of 19.3 and 15.9 months in the sorafenib and placebo arms, respectively). In the AXIS trial18 and when stratified by previous treatment, patients previously treated with cytokines had significantly longer PFS in the axitinib group (12.2 months; 95% CI, 10.2–15.5) than in the sorafenib group (8.2 months; 95%CI, 6.6–9.5; HR: 0.505; 95 % CI, 0.373–0.684; p<0.0001). Pazopanib19 and sunitinib20 showed a PFS of 7.4 and 8.3 months, respectively, in cytokines-pretreated patients.
Little data exist regarding the use of mTOR-inhibitors as a second-line treatment after cytokines. Small studies showed that temsirolimus and everolimus can show some benefits.21, 22
2.4.2 VEGF TT Refractory
Both mTOR and VEGFR inhibitors have enough level of evidence to be used as second-line therapy after progression on VEGF-TT.
2.4.2.1 mTOR inhibitors after VEGF-TT
Everolimus was the first TT to receive approval for second-line treatment after TKIs (sunitinib and/or sorafenib) in mRCC. Cancer guidelines and recommendations across the U.S.23 and Europe24 include everolimus as a standard second-line therapy after TKI failure. In the RECORD-1 trial,7 everolimus had a longer PFS than placebo (4.9 and 1.9 months, respectively; p < 0.001; HR 0.30; 95% CI, 0.22–0.40). However, in the RECORD-1 trial, sunitinib was the first line treatment in only 16% of patients enrolled.
Temsirolimus is approved as a first-line therapy in patients with poor prognosis mRCC. The INTORSECT study was the first randomized clinical trial comparing an mTOR-inhibitor – temsirolimus – to a VEGFR TKI – sorafenib – as second-line treatments. The patients were randomized after progression of disease on sunitinib. The primary endpoint did not show any difference in PFS between both arms: 4.28 months for temsirolimus versus 3.91 months for sorafenib (p = 0.193).25 Interestingly, median OS favored sorafenib over temsirolimus. The median OS was 16.64 months with sorafenib compared to 12.27 months with temsirolimus; (P = 0.01). The results remain puzzling: baseline characteristics between arms, treatment discontinuation related to toxicity and the receipt of third line therapies were similar between both groups.
2.4.2.2 VEGF-TKIs after initial VEGF-TT
The AXIS trial18 was the first randomized clinical trial to compare two VEGF-TKIs as second-line therapies. First-line agents included mainly sunitinib and interferon-alpha with a small minority receiving bevacizumab or temsirolimus. The median PFS was significantly longer with axitinib compared to sorafenib (6.7 and 4.7 months, respectively; p < 0.0001). In the sunitinib pre-treated population, the PFS for axitinib and sorafenib patients was 4.8 months and 3.4 months, respectively (p = 0.0107), modestly favoring axitinib. OS was 15–16 months in both arms.
Data from the SWITCH-I26, another trial assessing the use of VEGF-TKIs as second line treatment following first line VEGF TT, addressed the hypothesis of whether sequential use of sorafenib followed by sunitinib in mRCC would produce longer PFS. This study enrolled 365 treatment-naive patients and switched over to the alternate therapy (sunitinib-sorafenib versus sorafenib-sunitinib), which the patients received until progression or intolerable toxicity. The trial did not show any difference in either PFS or OS between the two sequences. The median total PFS duration reached 12.5 months in the sorafenib-sunitinib arm and 14.9 months in the sunitinib-sorafenib arm. Median OS showed comparable outcomes, with 31.5 months in the sorafenib-sunitinib arm and 30.2 months in the sunitinib-sorafenib arm.
Most of the studies on second-line therapies are based on sunitinib as a first-line therapy. Results from the COMPARZ trial1 demonstrate that pazopanib is not inferior to sunitinib. Pazopanib is commonly used in the first-line setting in mRCC, with its sales increasing worldwide by 50% from 2012 to 2013.27 Unfortunately, there are no prospective randomized trials assessing the efficacy of targeted agents following first line treatment of pazopanib. A small retrospective study showed that VEGF-TKIs were more effective than mTOR inhibitors after disease progression on pazopanib, although OS was not significantly different between both groups.28
2.4.3 mTOR inhibitors refractory
2.4.3.1 VEGFR-TKIs after mTOR inhibitors
In clinical practice, the use of mTOR inhibitors as first-line therapy is limited to patients with poor prognosis29 or intolerance to VEGF-TT. In addition, poor-risk patients are unlikely to receive subsequent lines.30
The sequence of everolimus to sunitinib versus sunitinib to everolimus was studied in the RECORD-3 trial31. First-line PFS, combined PFS, and OS favored the sequence of sunitinib followed by everolimus. The OS was 22.4 months for everolimus followed by sunitinib versus 32 months for sunitinib followed by everolimus (HR 1.24; 95% CI, 0.94–1.64).32 The sequence of sunitinib to everolimus was also favored in select subsets of patients, such as poor-risk mRCC or non-clear cell RCC. Notably, next generation sequencing (NGS) studies paired to RECORD-3 provide some of the most important insights to date with respect to potential predictors of response to mTOR- versus VEGF-directed therapy. The study suggested that patients with PBRM1 alteration may have a prolonged response to everolimus, while patients with KDM5C alteration may have a prolonged response to sunitinib.
2.4.3.2 mTOR inhibitors after mTOR inhibitors
The use of a rapalog as a second-line treatment following progression on a first-line rapalog is not currently recommended. Interestingly, a study enrolling only 12 patients showed that this sequence may result in some benefit.33 However, due to the small cohort size, this sequence should not be recommended unless the patient did not experience real progression on the first rapalog.
3.0 Novel treatment approaches after progression on first-line targeted therapy
3.1 Immune checkpoint inhibition
The immunogenic nature of RCC has led to exploration of several strategies to stimulate an anti-tumor immune response. The promising results and approval of ipilimumab, anti-(cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) blocker, in melanoma revived an interest in immunotherapy, with a particular focus on immune checkpoint inhibition.33,34 Central to the concept of tumor immune evasion is the presence of co-inhibitory molecules, such as CTLA-4 and programmed cell death protein-1 (PD-1) receptors expressed on T-lymphocytes’ surface.35 The interaction between these receptors and their respective ligands expressed on antigen-presenting cells (APCs) results in an inhibitory signal on activated T cells.36 PD-1 ligand (PD-L1) may be expressed in tumor cells or in the surrounding microenvironment constitutively due to an activated oncogenic pathway or as part of an adaptive immune resistance mechanism. Furthermore, the expression of PD-L1 specifically in RCC has been associated with a more aggressive behavior and a worse survival.37 In mRCC, targeting the PD-1/PD-L1 pathway has thus far been promising.38
3.2 Anti PD-1/PD-L1 monotherapy
Recent strategies targeting the PD-1/PD-L1 pathway in mRCC showed potential efficacy in early phase clinical trials. Topalian et al.38 conducted a large phase I study of nivolumab (an Ig4 antibody against PD-1) in 296 patients with treatment-refractory advanced solid tumors, including 34 patients with mRCC. A notable objective response rate (ORR) of 27% was reached, and 5 out of 8 patients achieved durable responses of 24 months or more. The long-term follow up results from this cohort of patients showed a median duration of response of 12.9 months. Serious adverse events were 18%, including 9% immune-mediated adverse events.39 In another phase I trial of BMS-936559 enrolling 17 patients with previously treated mRCC, an ORR of 12% was observed40.
In a three arm, randomized, phase II clinical trial exploring 3 different doses of nivolumab in 168 TKI-refractory patients with mRCC, the median PFS ranged from 2.7 to 4.2 months. When immune-response PFS was assessed, PFS ranged from 4.3 to 6.9 months. The overall response rate (ORR) ranged from 20% to 22%. The median OS ranged from 18.2 to 25.5 months, raising high expectations considering the acceptable safety profile of nivolumab.40 In comparison, expected survival from trials in the same setting (RECORD-1, AXIS) is around 15–16 months. In another biomarker study of nivolumab including both previously-treated and treatment-naive patients, efficacy results were similar. Nivolumab also showed an immunomodulatory effect, with a significant increase in the number of effector T cells and their transcripts in sequential biopsies.41 Notably, response rate was modestly higher in patients with PD-L1 positivity (22% versus 8%), and OS appeared to be prolonged (NR versus 23.4 mos). With these results in mind, PD-L1 expression should be explored as a potential biomarker of response in forthcoming studies. CheckMate 025, a large, phase III clinical trial finished accruing over 800 pre-treated mRCC patients and compares nivolumab monotherapy versus standard of care everolimus (NCT01668784). This trial assumes a median OS of 14.8 months for everolimus compared to 19.5 months for nivolumab.
Alternatively, PD-L1 inhibition with the advantage of sparing PD-1/PD-L2 interaction has been investigated as well. MPDL3280A, a monoclonal antibody against PD-L1, was tested in a phase I trial with 69 mRCC patients, 26% of which were poor prognosis patients by MSKCC criteria and only 13% were treatment-naive. The median PFS was 24 weeks (95% CI, 38–63 weeks) and the ORR was 15%. ORR for Fuhrman grade 4 or sarcomatoid clear cell RCC (n = 18) was 22%. Treatment-related grade 3 AEs occurred in 11 patients (16%).42
3.3 Combined immune checkpoint strategies
Monoclonal antibodies against CTLA-4 have been widely used in several tumors, mainly melanoma and non small cell lung cancer (NSCLC)43 A phase II trial of ipilimumab was conducted in 61 patients with mRCC.44 A partial response rate of 10% was observed, mostly at the higher dose of 3 mg/kg every 3 weeks.45 Several trials investigating the combination of PD-1 and CTLA-4 blockade have been conducted as well, following the impressive data seen in metastatic melanoma. Hammers et al.45 reported the use of dual immune checkpoint blockade in 44 patients with mRCC, with most patients having received prior systemic therapy. Patients were assigned to receive either nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg (N3+I1), or nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg (N1+I3) then nivolumab at 3 mg/kg every 2 weeks until progression/toxicity. ORRs ranged between 29%–39% in both arms. The toxicity profile favored the lowest dose of ipilimumab (24% of grade 3/4 related AEs in the N3+I1 arm versus 61% in the N1+I3 arm). Currently, multiple studies are assessing the combination of CTLA4 and PD1 blockade. CheckMate214 (NCT02231749) is a phase 3, randomized, open-label trial investigating nivolumab combined with ipilimumab versus sunitinib monotherapy in subjects with previously untreated mRCC. The combination of ipilimumab and pembrolizumab (anti-PD1) is currently being studied in a phase I-II clinical trial (NCT02089685).
3.4 Dual Immune checkpoint and VEGF blockade
1.1.1 VEGF may play a role in the immune response through the induction of myeloid-derived suppressor cells that suppress both T-cell and dendriticcell functions47. VEGF inhibition also regulates the immune response by increasing cytokines and tumor-infiltrating T cells, increasing T cell access into tumors48 and developing CD8+ and CD4+ central memory T cells49. Despite achieving notable results, immune checkpoint inhibitors are effective only in a subgroup of patients. Therefore, the combination of both approaches targeting VEGF and PD-1/PD-L1 together, although still under investigation, is promising and exciting.
The combination of nivolumab with either sunitinib or pazopanib showed an ORR that is higher than expected with either nivolumab or VEGF-TKIs in monotherapy (52% and 45% with sunitinib and pazopanib respectively, both started at full dose) in predominantly pre-treated patients. However, grade 3–4 related adverse events were observed in 73% and 60% with sunitinib and pazopanib respectively50.
Results of the dual VEGF and PD-L1 blockade has been reported with the combination of bevacizumab and MPDL3280 in 10 patients with mRCC enrolled in a phase I trial.52 Among these 10 patients, 4 experienced a partial response and only 1 patient experienced a high-grade adverse event related to MPDL3280. A prospective phase II study of 300 treatment naive mRCC patients compares this combination with single-agent MPDL3280 and standard-of-care sunitinib (NCT01984242) and just finished accrual.
3.5 Dual MET and VEGF blockade: Reverting resistance to VEGF-targeted agents?
The Majority of patients eventually develop resistance to VEGF TKIs. While heterogeneity may play an important role, unexpectedly acquired mutations are uncommon causes of resistance.52–54 Mechanisms of resistance to VEGF inhibition remain under investigation. The upregulation of alternative pro-angiogenic and pro-invasive signaling pathways is thought to play a major role. For example, MET activation was shown to be upregulated following VEGFR inhibition in several tumor models54, as a mechanism of resistance. Moreover, high MET expression levels have been associated with a worse outcome.56 Therefore, the combined inhibition of the VEGF and MET might overcome resistance to VEGF inhibition, thus increasing the efficacy achieved by VEGF inhibition alone. Cabozantinib is a new TKI with potent activity against MET and VEGFR2, as well as other receptor tyrosine kinases including RET, KIT, AXL, and FLT.57 It was first studied in mRCC in a Phase I trial with 25 patients who had at least one prior systemic therapy including VEGF and mTOR inhibitors. Single agent cabozantinib treatment showed antitumor activity with PFS of 12.9 months and response rate of 28%.58 METEOR is a randomized phase III trial that compares cabozantinib to standard everolimus in patients with VEGF-TKI refractory mRCC (NCT01865747).
4.0 Future directions
Existing guidelines suggest that everolimus and axitinib are reasonable choices for second-line treatment, based on results of previously described phase III trials. In the absence of head-to-head trials comparing axitinib and everolimus, it is challenging to be dogmatic about which agent should be used first. Based on the data cited from INTORSECT, we propose that VEGF-directed therapy may be preferred second-line in patients with a prolonged response to VEGF-directed therapy in the front-line setting. However, the choice of VEGF versus mTOR inhibition in the second-line setting may become antiquated with the emergence of several phase III studies. Drugs targeting PD-1/PD-L1 pathways and mechanisms of resistance to VEGF-inhibitors may represent the next milestone in the management of mRCC. Checkmate 025 and METEOR, two randomized, phase III clinical trials assessing the efficacy of nivolumab and cabozantinib respectively, have recently had press releases to show positive results. CheckMate 025 has stopped prematurely because the study has met the primary endpoint demonstrating increased overall survival compared to the control arm – everolimus – in patients with previously-treated mRCC.59 METEOR has also met primary endpoint, showing that cabozantinib reduces the risk of disease progression or death by 42% (HR 0.58, [p < 0.0001] compared to everolimus).60 Moreover, the interim analysis of overall survival has shown a trend favoring cabozantinib (HR 0.67, [p = 0.005] compared to everolimus). Mature results are awaited to make further conclusions regarding therapeutic sequencing.
Careful selections of patients, toxicity profiles, and long-term survival data, as well as identification of predictive biomarkers, remain critical keys to guides therapeutic decision making. Many patients will still progress and require further systemic therapy after novel agents. One study61 retrospectively reviewed the data on 56 patients who received subsequent TT after anti-PD-1/PD-L1 therapies. Overall median time to treatment failure (TTF) was 6.6 months after progression on PD1/PD-L1 inhibitors. Median TTF was 6.9 and 5.7 months in patients treated with VEGF and mTOR inhibitors, respectively. Median OS after the initiation of subsequent therapy was 17.5 months. A further retrospective study with 63 patients reached similar results.62 This data suggests that targeting PD-1/PD-L1 should not affect the efficacy of further VEGF-TT.
In summary and despite no new approved therapies in mRCC since 2011, pending large phase 3 pivotal trials in the refractory setting with novel agents may finally lead to new options for our mRCC patients.
Table 1.
Agent | Comparator | N | 1o EP | Comments |
---|---|---|---|---|
Everolimus | Placebo | 410 | PFS |
|
Axitinib | Sorafenib | 723 | PFS |
|
Cabozantinib | Everolimus | 658 | PFS |
|
Nivolumab | Everolimus | 821 | OS |
|
Table 2.
Combination regimen |
Treatment groups | Phase | Trial number |
---|---|---|---|
PD-1 and VEGF inhibition | Pembrolizumab with axitinib | I | NCT02133742 |
Pembrolizumab with Pazopanib | I/II | NCT02014636 | |
Nivolumab with sunitinib vs. nivolumab with pazopanib | I | NCT01472081 | |
PD-1 and CTLA4 inhibition | Prembrolizumab vs. pembrolizumab with ipilimumab vs. pembrolizumab with peglylated IFN-a2b | I/II | NCDT02089685 |
Nivolumab vs. nivolumab with bevacizumab vs. nivolumab with ipilimumab | II | NCT02210117 | |
Nivolumab with ipilimumab vs. sunitinib | II | NCT02231749 | |
PD-L1 and VEGF inhibition | MPDL3280A vs. MPDL3280A with bevacizumab vs. MPDL3280A with sunitinib | II | NCT01984242 |
Summary.
The introduction of molecularly targeted therapies (TT) has transformed the management of metastatic renal cell carcinoma (mRCC). Within a relatively short period of time, systemic treatment of mRCC has evolved from a disease only treated by cytokines to a disease where TT is the cornerstone of patient management.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
REFERENCES
- 1.Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N. Engl. J. Med. 2014;370:1769–1770. doi: 10.1056/NEJMc1400731. [DOI] [PubMed] [Google Scholar]
- 2.Fyfe G, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 1995;13:688–696. doi: 10.1200/JCO.1995.13.3.688. [DOI] [PubMed] [Google Scholar]
- 3.Solomon BJ, et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N. Engl. J. Med. 2014;371:2167–2177. doi: 10.1056/NEJMoa1408440. [DOI] [PubMed] [Google Scholar]
- 4.Brugarolas J. Molecular Genetics of Clear-Cell Renal Cell Carcinoma. J. Clin. Oncol. 2014;32:1968–1976. doi: 10.1200/JCO.2012.45.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Ko JJ, et al. The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study. Lancet Oncol. 2015;16:293–300. doi: 10.1016/S1470-2045(14)71222-7. [DOI] [PubMed] [Google Scholar]
- 6.Motzer RJ, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N. Engl. J. Med. 2013;369:722–731. doi: 10.1056/NEJMoa1303989. [DOI] [PubMed] [Google Scholar]
- 7.Motzer RJ, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449–456. doi: 10.1016/S0140-6736(08)61039-9. [DOI] [PubMed] [Google Scholar]
- 8.Rini BI, et al. Hypertension among patients with renal cell carcinoma receiving axitinib or sorafenib: analysis from the randomized phase III AXIS trial. Target. Oncol. 2015;10:45–53. doi: 10.1007/s11523-014-0307-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Garnick MB. How to Interpret Patient Preferences in Selecting the Best Drug: Are the Current Measurements up to the Job? J. Clin. Oncol. 2014;32:1392–1393. doi: 10.1200/JCO.2014.55.1911. [DOI] [PubMed] [Google Scholar]
- 10.Escudier B, et al. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2014;32:1412–1418. doi: 10.1200/JCO.2013.50.8267. [DOI] [PubMed] [Google Scholar]
- 11.Hutson TE. Targeted Therapies for the Treatment of Metastatic Renal Cell Carcinoma: Clinical Evidence. The Oncologist. 2011;16:14–22. doi: 10.1634/theoncologist.2011-S2-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.McDermott DF, et al. The High-Dose Aldesleukin ‘Select’ Trial: A Trial to Prospectively Validate Predictive Models of Response to Treatment in Patients with Metastatic Renal Cell Carcinoma. Clin. Cancer Res. 2015;21:561–568. doi: 10.1158/1078-0432.CCR-14-1520. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Sternberg CN, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur. J. Cancer Oxf. Engl. 1990. 2013;49:1287–1296. doi: 10.1016/j.ejca.2012.12.010. [DOI] [PubMed] [Google Scholar]
- 14.Yang JC, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 2003;349:427–434. doi: 10.1056/NEJMoa021491. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Nosov DA, et al. Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2012;30:1678–1685. doi: 10.1200/JCO.2011.35.3524. [DOI] [PubMed] [Google Scholar]
- 16.Escudier B, et al. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2009;27:3312–3318. doi: 10.1200/JCO.2008.19.5511. [DOI] [PubMed] [Google Scholar]
- 17.Escudier B, et al. Sorafenib in Advanced Clear-Cell Renal-Cell Carcinoma. N. Engl. J. Med. 2007;356:125–134. doi: 10.1056/NEJMoa060655. [DOI] [PubMed] [Google Scholar]
- 18.Motzer RJ, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013;14:552–562. doi: 10.1016/S1470-2045(13)70093-7. [DOI] [PubMed] [Google Scholar]
- 19.Sternberg CN, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2010;28:1061–1068. doi: 10.1200/JCO.2009.23.9764. [DOI] [PubMed] [Google Scholar]
- 20.Motzer RJ, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006;295:2516–2524. doi: 10.1001/jama.295.21.2516. [DOI] [PubMed] [Google Scholar]
- 21.Dutcher JP, et al. Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med. Oncol. Northwood Lond. Engl. 2009;26:202–209. doi: 10.1007/s12032-009-9177-0. [DOI] [PubMed] [Google Scholar]
- 22.Motzer RJ, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer. 2010;116:4256–4265. doi: 10.1002/cncr.25219. [DOI] [PubMed] [Google Scholar]
- 23.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. [Accessed January 22, 2015];Kidney Cancer [serial online] 2015 version.3. Available at http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. in. [Google Scholar]
- 24.Escudier B, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. ESMO. 2012;23(Suppl 7):vii65–vii71. doi: 10.1093/annonc/mds227. [DOI] [PubMed] [Google Scholar]
- 25.Hutson TE, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2014;32:760–767. doi: 10.1200/JCO.2013.50.3961. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Maurice Stephan Michel. SWITCH: A randomized sequential open-label study to evaluate efficacy and safety of sorafenib (SO)/sunitinib (SU) versus SU/SO in the treatment of metastatic renal cell cancer (mRCC) J Clin Oncol. 2014;32(Suppl 4) Abstr 393. [Google Scholar]
- 27. http://www.evaluategroup.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=37359&componentID=1002. [Google Scholar]
- 28.Bellmunt J, et al. Sequential targeted therapy after pazopanib therapy in patients with metastatic renal cell cancer: efficacy and toxicity. Clin. Genitourin. Cancer. 2014;12:262–269. doi: 10.1016/j.clgc.2014.03.002. [DOI] [PubMed] [Google Scholar]
- 29.Hudes G, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 2007;356:2271–2281. doi: 10.1056/NEJMoa066838. [DOI] [PubMed] [Google Scholar]
- 30.Heng DYC, et al. Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials. Ann. Oncol. 2014;25:149–154. doi: 10.1093/annonc/mdt492. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Motzer RJ, Barrios CH, Kim TM, et al. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC) ASCO Meet. Abstr. 2013 Jun 17; 20133115suppl4504. [Google Scholar]
- 32.Motzer RJ, et al. Phase II Randomized Trial Comparing Sequential First-Line Everolimus and Second-Line Sunitinib Versus First-Line Sunitinib and Second-Line Everolimus in Patients With Metastatic Renal Cell Carcinoma. J. Clin. Oncol. 2014;32:2765–2772. doi: 10.1200/JCO.2013.54.6911. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Brahmer JR, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012;366:2455–2465. doi: 10.1056/NEJMoa1200694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Harshman LC, Drake CG, Choueiri TK. PD-1 blockade in renal cell carcinoma: to equilibrium and beyond. Cancer Immunol. Res. 2014;2:1132–1141. doi: 10.1158/2326-6066.CIR-14-0193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat. Rev. Cancer. 2007;7:95–106. doi: 10.1038/nrc2051. [DOI] [PubMed] [Google Scholar]
- 36.Butte MJ, Peña-Cruz V, Kim M-J, Freeman GJ, Sharpe AH. Interaction of human PD-L1 and B7-1. Mol. Immunol. 2008;45:3567–3572. doi: 10.1016/j.molimm.2008.05.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Thompson RH, et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2007;13:1757–1761. doi: 10.1158/1078-0432.CCR-06-2599. [DOI] [PubMed] [Google Scholar]
- 38.Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 2012;366:2443–2454. doi: 10.1056/NEJMoa1200690. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.McDermott DF, et al. Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2015 doi: 10.1200/JCO.2014.58.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Drake CG, et al. Survival, safety, and response duration results of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase I trial in patients with previously treated metastatic renal cell carcinoma (mRCC): Long-term patient follow-up. J. Clin. Oncol. 2013;31 [Google Scholar]
- 41.Motzer RJ, et al. Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J. Clin. Oncol. 2014 doi: 10.1200/JCO.2014.59.0703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.McDermott DF, Mario Sznol, Sosman JA. Immune correlates and long term follow up of a phase Ia study of MPDL3280A, an engineered PD-L1 antibody, in patients with metastatic renal cell carcinoma (mRCC) Ann Oncol Abstr. 2014;809O [Google Scholar]
- 43.Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010;363:711–723. doi: 10.1056/NEJMoa1003466. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Yang JC, et al. Ipilimumab (Anti-CTLA4 Antibody) Causes Regression of Metastatic Renal Cell Cancer Associated With Enteritis and Hypophysitis: J. Immunother. 2007;30:825–830. doi: 10.1097/CJI.0b013e318156e47e. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Hammers Jans J. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC) J Clin Oncol. 2014;32(suppl):5s. doi: 10.1200/JCO.2016.72.1985. abstr 4504)). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Campbell MT, et al. Phase I Trial of Sunitinib and Temsirolimus in Metastatic Renal Cell Carcinoma. Clin. Genitourin. Cancer. 2014 doi: 10.1016/j.clgc.2014.10.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Noman MZ, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 2014;211:781–790. doi: 10.1084/jem.20131916. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Shrimali RK, et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 2010;70:6171–6180. doi: 10.1158/0008-5472.CAN-10-0153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Butler MO, et al. Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells. Sci. Transl. Med. 2011;3:80ra34. doi: 10.1126/scitranslmed.3002207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Asim Amin. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC) J Clin Oncol. 2014;32:5s. (suppl; abstr 5010)). [Google Scholar]
- 51.Lieu C, Bendell J. SAFETY AND EFFICACY OF MPDL3280A (ANTI-PDL1) IN COMBINATION WITH BEVACIZUMAB (BEV) AND/OR CHEMOTHERAPY (CHEMO) IN PATIENTS (PTS) WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS. Ann Oncol. 2014;25(suppl 4):iv361. [Google Scholar]
- 52.Bielecka Z, Czarnecka A, Solarek W, Kornakiewicz A, Szczylik C. Mechanisms of Acquired Resistance to Tyrosine Kinase Inhibitors in Clear - Cell Renal Cell Carcinoma (ccRCC) Curr. Signal Transduct. Ther. 2014;8:219–228. doi: 10.2174/1574362409666140206223014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Gerlinger M, et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat. Genet. 2014;46:225–233. doi: 10.1038/ng.2891. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Gerlinger M, et al. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. N. Engl. J. Med. 2012;366:883–892. doi: 10.1056/NEJMoa1113205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Sennino B, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012;2:270–287. doi: 10.1158/2159-8290.CD-11-0240. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Gibney GT, et al. c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. ESMO. 2013;24:343–349. doi: 10.1093/annonc/mds463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Kurzrock R, et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2011;29:2660–2666. doi: 10.1200/JCO.2010.32.4145. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Choueiri TK, et al. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. ESMO. 2014;25:1603–1608. doi: 10.1093/annonc/mdu184. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.CheckMate-025, a Pivotal Phase III Opdivo (nivolumab) Renal Cell Cancer Trial, Stopped Early. 2015 at < http://news.bms.com/press-release/checkmate-025-pivotal-phase-iii-opdivo-nivolumab-renal-cell-cancer-trial-stopped-early>. [Google Scholar]
- 60.Exelixis Announces Positive Top-Line Results from METEOR, the Phase 3 Pivotal Trial of Cabozantinib versus Everolimus in Patients with Metastatic Renal Cell Carcinoma. 2015 at< http://www.exelixis.com/investors-media/press-releases>. [Google Scholar]
- 61.Laurence Albiges, Andre Fay & Wangling Xie. Efficacy of targeted therapies after PD1/PD-L1 inhibitors in metastatic clear cell renal cell carcinoma (mRCC): A multi-institution retrospective cohort. J Clin Oncol. 2015;33(Suppl 7) Abstr 45662. [Google Scholar]
- 62.Rosa Nadal, Asim Amin & Daniel M. Geynisman. Efficacy and safety of endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKI) after programmed cell death 1 (PD-1) inhibitor treatment in patients with metastatic clear cell renal cell carcinoma (mccRCC) J Clin Oncol. 2015;33 doi: 10.1093/annonc/mdw160. (suppl; abstr 4566)). at < http://meetinglibrary.asco.org/content/152564-156>. [DOI] [PMC free article] [PubMed] [Google Scholar]