1. Molina, Ana M. MD

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Renal cell carcinoma (RCC) is the most common malignancy of the kidney and is expected to account for 63,340 new cases and 14,970 deaths in the U.S. during 2018 (CA Cancer J Clin 2018;68(1):7-30). Unfortunately, between 20 and 40 percent relapse after nephrectomy and approximately one-third of patients have evidence of metastasis at initial diagnosis. The majority of these patients will proceed with systemic therapy during the course of disease.

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A better understanding of the pathophysiology of RCC has led to the discovery and clinical development of targeted agents, checkpoint inhibitors, and combination therapies that have expanded treatment options and improved prognosis for patients metastatic RCC.


Identification of the von Hippel-Lindau (VHL) tumor-suppressor gene and that its inactivation in clear cell RCC leads to increased expression of hypoxia-inducible factor (HIF-[alpha]) and angiogenesis-related proteins such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor B chain (PDGF-B) led to the development of targeted therapies that specifically inhibit VEGF signaling pathways.


Strategies to target the VEGF pathway include small molecule tyrosine kinase inhibitors (TKIs) (e.g., sunitinib, pazopanib, axitinib, sorafenib, cabozantinib, lenvatinib) or anti-VEGF antibodies (e.g., bevacizumab) that act on multiple targets of RCC. Activation of the PI3K/Akt pathway, and in turn the mTOR kinase, is another important pathway in RCC. Inhibitors of the mTOR (e.g., everolimus, temsirolimus) are used in the management of RCC.


More recently, the clinical development of immune checkpoint inhibitors has led investigators to re-visit the role of immunotherapy in RCC. Monoclonal antibodies target and block the inhibitory T-cell receptor PD-1, PD-L1, or CTLA-4 signaling to restore tumor specific T-cell immunity (N Engl J Med 2012;366(26):2517-2519). Immune checkpoint inhibitor monotherapy and combination therapy have quickly been incorporated into the treatment paradigm in the past few years.


Finally, prognostic factors are instrumental for the purposes of clinical trial design, risk-directed therapy, and patient counseling. The most recent prognostic model, International mRCC Database Consortium, retrospectively collected population-based data on 645 patients with metastatic RCC treated with targeted therapy (J Clin Oncol 2009;27(34):5794-5799). A KPS<80 percent, a diagnosis of RCC to treatment interval <1 year, anemia, hypercalcemia, neutrophilia, and thrombocytopenia were all independent predictors for overall survival.


Patients in the favorable-risk group have zero factors with a median overall survival (OS) that was not reached (43.4 months in the external validation cohort). Those in the intermediate-risk group have one or two risk factors (median OS, 22.5 months), and those in the poor-risk group have three or more risk factors (median OS, 7.8 months) (Lancet Oncol 2013;14(2):141-148). This relationship between pretreatment factors and survival can be applied to directing therapy and interpreting the results of clinical trials for patient with advanced RCC.


Herein, we review targeted agents, immunotherapy, combination therapy and pivotal phase III trials that have led to the current paradigm of treatment of patients with metastatic RCC.


First-Line Therapy in RCC

Sunitinib, a TKI, was approved by the FDA in 2006 for the treatment of patients with mRCC and became a standard first-line therapy. Pazopanib, another multi-kinase inhibitor targeting VEGFR, PDGFR, and c-Kit, was approved in 2009 by the FDA for the treatment of advanced RCC.


The COMPARZ phase III study compared the efficacy and safety of pazopanib and sunitinib as first-line therapy (N Engl J Med 2013;369(8):722-731). In this trial, objective response rates were 31 percent for pazopanib and 24 percent for sunitinib. Pazopanib was noninferior to sunitinib with a median progression-free survival (PFS) of 8.4 months and 9.5 months, respectively. Overall survival was similar in the two groups.


Bevacizumab, a humanized VEGF-neutralizing antibody, was FDA-approved in 2009 based on two multicenter phase III studies comparing bevacizumab plus IFN to IFN alone as first-line treatment in patients with mRCC (Lancet 2007;370:2103-2111, J Clin Oncol 2010;28(13):2137-2143). Both studies demonstrated a significant improvement in PFS in patients receiving bevacizumab (10.2 vs. 5.4 months and 8.5 vs. 5.6 months), as well as an increase in the objective tumor response rate (30.6% vs. 12.4% and 25.5% vs. 13.1%).


Based on these phase III trials, sunitinib, pazopanib, and bevacizumab plus IFN are each considered an option for first-line therapy in patients with mRCC (Eur Urol 2017; doi: 10.1016/j.eururo.2017.11.016). Of note, the majority of the patients treated on these trials had either "favorable" or "intermediate" MSKCC risk features.


Nivolumab plus ipilimumab (anti-CTLA-4) was approved by the FDA in April 2018 for patients with intermediate- or poor-risk advanced RCC based on a multicenter, randomized, phase III study (CheckMate-214), which compared the combination to sunitinib. This study showed a survival superiority for the combination with a median OS not reached with the combination versus 26 months with the previous standard of care first-line agent sunitinib.


The overall response rate was 41.6 percent in the combination compared with 26.5 percent in the sunitinib arm (p< .0001) (N Engl J Med 2018;378(14):1277-1290). The data remains immature in favorable-risk patients and, therefore, anti-angiogenesis agents (e.g., pazopanib, sunitinib) remain the favored agents for this subgroup of patients. This is the first immunotherapy combination approved in the first-line setting for RCC patients.


Second-Line Therapy

Although VEGF-targeted agents have significantly impacted patients with mRCC, the search for newer agents and/or combinations has continued because robust tumor reductions are rare and patients ultimately develop resistance to therapy.


Everolimus until 2012 was the only second-line therapy to demonstrate improvement in PFS after first-line anti-VEGF therapy. Axitinib, a VEGFR TKI, was approved in 2012 for the treatment of mRCC following failure of a prior systemic therapy based on results from the AXIS trial, a global, randomized phase III trial comparing axitinib with sorafenib as second-line therapy in patients with treatment-refractory mRCC (Lancet 2011;378(9807):1931-1939). Median PFS was significantly longer in patients treated with axitinib versus sorafenib (6.7 vs. 4.7 months).


Cabozantinib, a small-molecule TKI that targets VEGFR, as well as MET and AXL, each of which has been implicated in the development of resistance to anti-VEGF drugs, demonstrated impressive anti-tumor activity in heavily pretreated RCC patients (N Engl J Med 2015;373(19):1814-1823, Ann Oncol 2014;25(8):1603-1608). The phase III METEOR trial compared the efficacy of cabozantinib with everolimus in patients with RCC that had progressed after VEGFR-targeted therapy. Patients treated with cabozantinib had increased OS, delayed disease progression, and improved objective responses compared to everolimus (Lancet Oncol 2016;17(7):917-927).


Nivolumab is a human monoclonal antibody that targets the coinhibitory receptor, PD-1, which is expressed on activated T cells (Curr Opin Investig Drugs 2010;11(12):1354-1359). Upregulation of PD-1 expression in tumor lymphocytes is associated with aggressive disease and poor prognosis in RCC (Clin Cancer Res 2007;13(6):1757-1761). Nivolumab first demonstrated anti-tumor activity and durable responses in phase I and II (N Engl J Med 2012;366(26):2443-2454, J Clin Oncol 2015;33(13):1430-1437).


A randomized phase III trial (CheckMate 025) compared nivolumab with everolimus in patients with RCC previously treated with one or two anti-angiogenic regimens (N Engl J Med 2015;373(19):1803-1813). In this trial, patients treated with nivolumab demonstrated a 25 percent objective response rate, median PFS of 4.6 months, and OS of 25 months, while patients treated with everolimus experienced a 5 percent objective response rate, a median PFS of 4.4 months, and OS of 19.6 months. Based on these results, nivolumab was approved by the FDA in 2015.


Lenvatinib, a multi-targeted TKI in combination with everolimus, was approved by the FDA in 2016 in the treatment of advanced RCC following one prior anti-angiogenic therapy. The approval was based on the results of a randomized phase II study in which patients previously treated with anti-angiogenic therapy were randomized to receive lenvatinib plus everolimus, lenvatinib, or everolimus (Lancet Oncol 2015;16(15):1473-1482). The combination of lenvatinib plus everolimus demonstrated numerically superior PFS, objective response rate, and OS, compared to lenvatinib monotherapy.


Nivolumab, cabozantinib, and the combination of lenvatinib and everolimus are used commonly for second-line treatment of RCC.


Changing Paradigm for Treatment

The introduction of targeted therapies and more recently checkpoint inhibitors for the treatment of mRCC has vastly changed the treatment landscape of this disease. Now, with the availability of nine approved targeted agents and two approved immunotherapy agents, clinicians must consider the best way to incorporate these therapies into management of patients with mRCC.


Clinicians are now faced with questions such as how many therapies a patient can receive and what is the optimal sequence of treatment. Results from recent phase III clinical trials have established the role of both targeted agents and immunotherapy in the management of advanced RCC in the first- and second-line setting.


Ongoing studies are investigating optimal sequential therapy and combination therapy with existing and novel targeted and immunotherapy agents. In addition, studies identifying new prognostic factors, biomarkers, and mechanisms of resistance are underway.


ANA M. MOLINA, MD, is GU Medical Oncologist at Weill Cornell Medicine and NewYork-Presbyterian.

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