Targeted therapy for metastatic RCC: introduction
Ronald M. Bukowski , Robert A. Figlin, Robert J. Motzer (Eds). Renal cell carcinoma. Molecular targets and clinical applications. 3 Ed. Springer Science+Business Media New York (2015)
Renal cancer accounts for 3 % of all malignant tumors and is the sixth leading cause of death in the United States. In 2014, an estimated 63,920 new cases with 13,860 deaths secondary to RCC are predicted . At diagnosis, patient ages range from 40 to 70 years, with a male to female predominance persists (1.6–1.0) . Renal cell carcinoma generally arises from the renal epithelium and accounts for approximately 85 % of all renal malignancies . Fifteen to 20 % of patients present with locally advanced or metastatic disease , and approximately 20–40 % of those who undergo surgical resection of the primary tumor will develop metastatic disease .
Histologically, renal cell cancers represent a group of subtypes with unique morphologic and genetic characteristics. Clear-cell renal carcinoma (ccRCC) is the most common type and accounts for approximately 80–90 % of renal epithelial malignancies . It arises from the proximal convoluted tubule and histologically is characterized by clear cytoplasm with occasional areas of eosinophilia. The majority of sporadic clear-cell renal tumors are associated with defects in the VHL gene . In the past 5 years, efforts to characterize other genetic abnormalities in ccRCC have been an important and crucial focus of research in this area. The recognition of the various histologic subtypes and, in some instances, associated genetic alterations now provides the opportunity to develop specific and potentially personalized approaches to therapy.
Molecular genetics: RCC
Renal cell carcinoma represents a collection of distinct diseases that can be distinguished histologically and genetically. Recent work has focused primarily on clear cell RCC, the most common subtype. This is a vascular neoplasm, with recent studies revealing the molecular basis of this phenotype. In a recently published dataset from 417 patients, 19 genes were identified as significantly mutated (q < 0.05) in clear-cell tumors . Mutations in eight genes emerged as significant, including VHL, PBRM1, SETD2, KDMRC (lysine (K)-specific demethylase 5C), PTEN, BAP1, mTOR, and TP53. The VHL gene and its product function as a tumor suppressor. Functions of the VHL protein include ubiquitination and proteasome degradation  of hypoxia-inducible factor (HIF). HIF-α is a key regulator of the hypoxic response and is the primary target of this protein. Under hypoxic conditions or the presence of abnormal VHL function, the VHL protein does not bind to HIF-α, resulting in its accumulation. This activates the transcription of hypoxia-inducible genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-α (TGF-α), and erythropoietin (EPO). Morphologically, renal cancers are very vascular tumors and have a rich tumor-associated vasculature. The VHL gene controls this process and suppresses angiogenesis; however, loss of VHL gene function in clear-cell tumors results in the increased production of VEGF, PDGF, and TGF-α producing the vascular phenotype characteristic of these tumors.
Recent studies using newer sequencing technologies have reported mutations in VHL wild-type tumors in TCEB1, which encodes elongin C, a protein that binds to VHL and is required for its function . As noted previously, mutations in additional tumor suppressor genes in the region of the VHL on chromosome 3p have also been identified, including SETD2, BAP1, and PBRM1. Mutations of BAP1 and PBRM1 appear mutually exclusive and may be associated with different patient outcomes .
Finally, mTOR pathway mutations are uncommon, with reported mutation frequency of mTOR, TSC1, PIK3CA, and PTEN of less than 10 % in RCC patients [7, 10]. Expression of activated mTOR however has been reported in 60 % of tumors . These initial observations will hopefully provide the rationale for the future to development of molecularly oriented approaches to therapy of advanced RCC.
Prognostic factors in renal cell carcinoma
Retrospective analysis of untreated and previously treated patients with metastatic RCC has identified clinical characteristics that can be used to categorize patients into prognostic groups. For previously untreated patients, an initial prognostic model, which included five clinical characteristics, was developed at Memorial Sloan Kettering Cancer Center  and later validated and expanded by Cleveland Clinic investigators . These criteria were then utilized in the pivotal phase III clinical trials of the oral tyrosine kinase inhibitors (TKIs), bevacizumab, and temsirolimus. This scheme was updated and modified by Heng and colleagues  utilizing patients receiving targeted therapy. These prognostic schemes have clinical utility, but in the future incorporation of tissue-based markers and genomic characteristics of tumors will be required.
Management of patients with advanced RCC
The management of patients with metastatic RCC has undergone dramatic changes, and a new treatment paradigm is in place. Blockade of the VEGF pathway and the functions of HIF are now utilized as primary therapeutic strategies. In the past, cytokine administration utilizing either interleukin IL-2 and/or IFNα was the standard approach. Clinical trials [15, 16] demonstrated responses were best with high-dose, intravenous IL-2 (21 %) compared to low-dose intravenous (11 %) or subcutaneous IL-2 (10 %). No progression-free survival (PFS) or overall survival (OS) advantages were observed however. A comparison of overall response rates (ORR) with high-dose IL-2 (23.2 %) to subcutaneous IL-2 plus IFNα (9.9 %) suggested some differences; however, no significant improvement in PFS or OS was found . In contrast, administration of IFNα produced a survival advantage compared to methoxyprogesterone in a prospective randomized trial . Additionally, a median OS of 13.1 months and median PFS of 4.7 months for IFNα-treated patients were reported in a retrospective review . Ultimately, IFNα monotherapy became the standard of care for patients with advanced RCC, in view of these results and the toxicity associated with high-dose IL-2.
Bevacizumab (Avastin®) is a fully humanized monoclonal antibody that binds all the isoforms of VEGF. The antitumor activity of the bevacizumab and IFNα combination in patients with advanced clear-cell carcinoma was demonstrated in a sequence of phase III randomized trials [19, 20]. In these studies, the combination of bevacizumab and IFNα proved superior to monotherapy with IFNα, with increased overall response rates and progression-free survival; however, no survival advantage was detected in either trial. These reports demonstrated that an agent inhibiting VEGF could change the natural history and biologic behavior of RCC when administered with IFNα.
Sorafenib (Nexavar®) is an orally bioavailable inhibitor of Raf-1, a member of the RAF/MEK/ERK signaling pathway, as well as of multiple growth factor receptors including VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, Flt-3, and c-KIT . In preclinical models, this multitargeted TKI blocked the RAF/MEK/ERK signaling pathway and inhibited tumor angiogenesis. The pivotal study with this agent was a randomized phase III placebo-controlled study  in cytokine-refractory patients. Results demonstrated prolongation of PFS in sorafenib-treated patients. Subsequently, a phase II randomized trial in treatment-naïve patients with advanced clear-cell carcinoma  compared sorafenib to IFNα. The final analysis demonstrated no differences in PFS for the sorafenib patients and IFNα-treated individuals (5.7 vs. 5.6 months, respectively, HR 0.88, p = 0.504). Subsequently, sorafenib has been utilized as a comparator treatment in including comparisons to axitinib, temsirolimus, and tivozanib [24–26]. The results from these studies suggest the overall response rates and PFS in earlier trials may have been underestimated.
Sunitinib (Sutent®) is a multitargeted oral TKI of VEGFR-2, PDGFR with less potent activity against ?broblast growth factor receptor-1 tyrosine. In preclinical studies, direct antitumor activity was reported in cells dependent on signaling through PDGFR, KIT, and FLT3, as well as presence of significant anti-angiogenic effects . A sequence of phase II clinical trials demonstrated the activity of this agent in patients with cytokine-refractory metastatic RCC . These trials accrued 168 patients, and the ORR was 40 % (investigator assessment) and 25.5 % (independent review). The majority of responses were partial. Median time to progression was 8.7 months (95 % confidence interval [CI]: 5.5–10.7) and 8.1 months (95 % CI: 7.6–10.4), respectively, in the two trials, and the median OS 16.4 months in trial 1. Based on these results, and the ability of this agent to induce objective and meaningful responses, the FDA granted accelerated approval to sunitinib for the treatment of advanced RCC in January 2006.
A large randomized trial in 750 untreated patients with metastatic clearcell carcinoma was then conducted, which compared sunitinib to IFNα .
Patients receiving sunitinib had superior outcomes including improved median PFS (11.0 vs. 5.0 months) and median OS (26.0 vs. 21.0 months) and a response rate over 40 % (investigator assessment). These results established sunitinib as a reference standard for first-line treatment of advanced RCC patients with clear-cell carcinoma.
The third oral TKI agent investigated in advanced RCC patients was pazopanib (Votrient®), an oral multitargeted TKI, with potent inhibitory activity against the VEGF and PDGF receptors . A pivotal double-blind, phase III study in 435 patients with advanced RCC  was conducted. Patients were randomized in 2:1 fashion to pazopanib or a placebo. Pazopanib was found to significantly improve PFS (9.2 vs. 4.2 months), in both untreated and cytokine-refractory patients regardless of performance status, prognostic score, or age. This agent was approved for the treatment of advanced RCC patients in October 2009. The toxicity profile of pazopanib was acceptable, and the data have supported its use as first-line therapy as an alternative to sunitinib.
The most recent TKI studied in RCC patients is axitinib (Inlyta®). It is a potent oral indazole derivative that inhibits all the VEGFR, PDGFR-Я, and c-kit . It was evaluated in the AXIS trial , a two-arm, randomized, open-label, multicenter phase III study comparing the PFS of 723 patients with advanced clear-cell RCC receiving either axitinib or sorafenib following failure of prior systemic first-line therapy (sunitinib, bevacizumab ± IFNα, temsirolimus, or cytokines). The secondary end points included OS, ORR, safety, and tolerability of axitinib. The results demonstrated a superior PFS for the axitinib-treated patients (6.7 vs. 4.7 months), improved ORR (19.4 % vs. 9.4 %), and similar survival. The side profile of axitinib was moderate and acceptable. The results supported the FDA approval of axitinib as second-line therapy in January 2012 for patients with refractory RCC.
mTOR inhibitors: temsirolimus
A third group of medications investigated in advanced RCC patients are the mTOR kinase inhibitors. mTOR is an intracellular kinase that has a central role in controlling cellular functions, including cell division and metabolism . mTOR is a downstream component in the phosphoinositide 3-kinase (PI 3-kinase)/Akt pathway and acts by regulating translation, protein degradation, and protein signaling. VEGF-mediated endothelial cell proliferation requires the activity of PI 3-kinase . mTOR has also been identified as an upstream activator of HIF, stabilizing the molecule, preventing its degradation, and thereby increasing HIF activity . Rapamycin was the first mTOR inhibitor developed. It was derived from Streptomyces hygroscopicus and was initially developed as an antifungal agent . Subsequently, the mTOR inhibitors were developed to delay and/or prevent graft rejection of solid organ transplant patients. Despite early evidence from in vitro and in vivo studies demonstrating rapamycin possessed cytostatic activity against cancer cells, it was not extensively tested in this area until the late 1990s . These studies suggested this group of drugs may have utility in cancer treatment, with direct anticancer effects as well as producing inhibition of angiogenesis. Recent studies suggest mTOR is phosphorylated and activated in over 60 % of RCC metastatic lesions , providing additional evidence that this kinase is a logical therapeutic target in RCC.
Based on the results of a phase 2 randomized trial of intravenous temsirolimus (Torisel®) in treatment-refractory patients , a phase III trial investigating temsirolimus was designed. This randomized trial was conducted in patients with poor risk features. Six hundred and twenty-six patients with a poor prognosis and any histology received either intravenous temsirolimus, IFNα monotherapy, or the combination as first-line treatment . The definition of poor risk required =3 risk factors, including metastases to multiple organs. Patients receiving temsirolimus monotherapy demonstrated improved median OS and PFS compared to IFNα. This was not seen in the group treated with the combination of temsirolimus + IFNα. A subset analysis suggested OS and PFS were increased in temsirolimus-treated patients regardless of histologic subtype, and the effect was the most pronounced in patients with non-clear RCC. This drug was approved by the FDA for treatment of advanced RCC in May 2007. In Europe, temsirolimus was approved for therapy of advanced RCC patients with a poor prognosis.
A second mTOR inhibitor investigated in advanced RCC was oral agent everolimus (A?nitor®). A pivotal clinical trial was conducted in patients who had failed previous TKI therapy including sunitinib and/or sorafenib . At the time this trial was conducted, patients progressing on TKI therapy were been seen frequently by medical oncologists. And a need to define the effects of therapy in this treatment-refractory group was recognized. A randomized, blinded, placebo-controlled phase III trial (RECORD 1) was conducted in 421 patients with progressive disease following sunitinib and/or sorafenib therapy. The results demonstrated everolimus increased the median PFS compared to placebo, 4.9 (95 % CI, 0.25–0.48) vs. 1.9 months (95 % CI, 1.8–1.9) (HR 0.33, p < 0.0001). Everolimus was approved by the FDA for treatment of patients failing sunitinib and/or sorafenib in March 2009.
The evolving treatment landscape for RCC
The TKIs studied in clear-cell RCC were first shown to have activity in cytokinerefractory patients as second-line therapies, with follow-up trials demonstrating their efficacy in the frontline setting. Both VEGF and mTOR pathway inhibitors have received FDA approval based on their ability to prolong either median PFS or OS in large randomized trials. VEGF pathway inhibitors which have shown a high level of clinical evidence supporting their use in metastatic RCC include sunitinib , sorafenib , pazopanib , axitinib , and bevacizumab . mTOR pathway inhibitors which have a high level of evidence include temsirolimus  and everolimus . These drugs have all been approved as single agents with the exception of bevacizumab, which has been approved in combination with interferon. The TKI tivozanib was investigated in a randomized phase 3 trial and compared to sorafenib . Despite the significant PFS improvement seen, tivozanib was not approved by the FDA secondary to concerns regarding the overall survival data. Although these targeted therapies appear to have better toxicity profiles and improve either PFS or OS compared to cytokine therapy, complete responses uncommon, and survival improvements are measured in months. The need to re?ne and improve the current paradigm and provide information on the comparative efficacy and toxicity of the available agents is clear.
Comparative clinical trials
In the treatment-naïve RCC population, therapy with these agents has improved patient outcomes. The efficacy of the various agents in terms of PFS prolongation, response rates, survival appears similar; however, additional clinical studies were needed to provide this evidence. Therefore, differences in patient tolerability and outcomes have been explored in several studies. In treatment-naïve individuals, clinical trials of sunitinib vs. pazopanib [40, 41] and tivozanib vs. sorafenib  suggest similar levels of efficacy with variable toxicity and patient acceptance.
The COMPARZ study which represents an important trial comparing sunitinib and pazopanib as first-line treatment for patients with clear-cell, metastatic RCC has recently been completed . One thousand one hundred and ten patients with clear-cell, metastatic RCC were randomized to receive continuous daily pazopanib or intermittent sunitinib. The primary end point was PFS as assessed by independent review. The study was powered to show the non-inferiority of pazopanib vs. sunitinib. Secondary end points included overall survival, safety, and quality of life. Pazopanib was reported as non-inferior to sunitinib in median PFS (8.4 months, 95 % CI, 8.3–10.9 vs. 9.5 months, 95 % CI, 8.3–11.1, respectively). The hazard ratio for progression of disease or death from any cause was 1.05 (95 % CI, 0.90–1.22), which met the predefined non-inferiority margin (upper bound of the 95 % confidence interval, <1.25). ORRs were 31 % for pazopanib and 24 % for sunitinib.
Quality of life analysis favored pazopanib during the first 6 months of treatment, particularly with regard to fatigue, mouth soreness, and hand-foot syndrome. Final OS data are similar (hazard ratio 0.92, 95 % CI 0.79–1.06; p, 0.24) in both patient groups, 28.3 months for the pazopanib cohort (95 % CI, 26.0–35.5), and 29.1 months for patients randomized to sunitinib (95 % CI, 25.4–33.1).
Another second innovative clinical trial comparing these two TKIs in treatmentnaïve RCC patients has also been reported . In the PISCES phase II trial, 169 patients were randomized to either sunitinib or pazopanib. The primary end point was patient preference for a specific treatment, which was assessed by questionnaire at the end of the two treatment periods. In 114 patients meeting prespecified intent to treat criteria, significantly more patients preferred pazopanib (70 %) over sunitinib (22 %) (p < 0.001); 8 % expressed no preference. These two trials comparing pazopanib and sunitinib have addressed the issues of comparability and patient acceptance; however, the design, analysis, and interpretation of the results have been criticized. Nevertheless, they represent an important milestone in the field and provide comparative data on the administration of TKIs to similar patient populations.
In treatment-refractory patients, results from trials comparing axitinib vs. sorafenib  and sorafenib vs. temsirolimus  have demonstrated differences in efficacy end points such as median PFS and OS, respectively. In the AXIS trial  discussed previously, axitinib therapy was associated with prolongation of the median PFS by 2.0 months and an improved ORR. No survival differences were noted. In the INTORSECT trial , 512 patients who had progressed on first-line sunitinib treatment were randomly assigned to receive intravenous temsirolimus once weekly or oral sorafenib. The analysis revealed no significant difference between the primary end point, PFS (hazard ratio, 0.87; 95 % CI, 0.71–1.07; p = 0.19) or ORR. Median PFS in the temsirolimus and sorafenib arms was 4.3 and 3.9 months, respectively. Interestingly, a significant difference in OS in favor of the sorafenib group (hazard ratio, 1.31; 95 % CI, 1.05–1.63; two-sided p = 0.01) was found. The median OS in the temsirolimus and sorafenib arms was 12.3 and 16.6 months, respectively. The authors speculated that the longer OS observed with sorafenib therapy suggested sequential VEGF inhibition may be important factor in determining patient outcomes.
Overall, the recent results suggest improved efficacy compared to the previous decade, but treatment remains palliative for the vast majority of patients. Therefore, re?nement of patient selection for therapy and continued attempts to combine agents are relevant investigative approaches. Initial attempts to combine sunitinib with bevacizumab  or sorafenib with IFNα  in RCC patients demonstrated enhanced toxicity. Preclinical studies suggested the combination of an mTOR inhibitor such as temsirolimus and bevacizumab was associated with increased efficacy, and the results from a small phase I/II study  in previously treated patients demonstrated an acceptable safety profile for combination at full doses, as well as promising activity (7/12 partial responses). Based on these findings, a randomized, open-label, multicenter, phase 3 study (INTORACT) was initiated in patients with untreated clear-cell RCC . 791 patients received either temsirolimus or IFNα with bevacizumab. The primary end point was independently assessed PFS.
In patients receiving temsirolimus + bevacizumab vs. IFN + bevacizumab, the median PFS was 9.1 and 9.3 months, respectively (hazard ratio, 1.1; 95 % CI, 0.9–1.3; p = 0.8). Likewise, there were no significant differences in overall survival (25.8 vs. 25.5 months) or ORR (27.0 % vs. 27.4 %). The toxicity associated with temsirolimus and bevacizumab combination was more severe. Similar results were reported in a phase 2 randomized trial (TORAVA) in 171 previously untreated patients . In this study the temsirolimus + bevacizumab combination resulted in higher toxicity than anticipated, which limited the duration of treatment. A median PFS of 8.2 months and ORR of 27 % with temsirolimus + bevacizumab were lower than with IFNα + bevacizumab (16.8 months and 43 %, respectively). These data demonstrate the dif?culty encountered in developing combinations of targeted agents, and importantly the lack of evidence demonstrating improved efficacy. These approaches remain investigational.
Sequential therapy RCC
The results reported in the AXIS , RECORD 1 , and INTORSECT  trials address some of the issues encountered in evaluating sequential therapy in RCC. The clinical effects of this approach are of interest, since data have suggested patients receiving previous therapy with various targeted agents may respond to a second VEGFR TKI . These preliminary observations suggested sequential TKI therapy may be possible, and cross-resistance may not develop. The issue of whether second-line therapy in RCC should involve a TKI inhibiting the VEGF pathway or an agent with a different mechanism of action has attracted interest. The INTORSECT trial  results are therefore of interest and suggest sequential administration of agents inhibiting VEGFR may produce superior OS. Another important study investigating sequential therapy is the RECORD 3 trial . This study involved comparison of sunitinib and everolimus. Patients with mRCC (clear or non-clear cell) with no prior systemic therapy were randomized to receive either everolimus or sunitinib. At disease progression, patients then crossed over and continued on the alternate drug until subsequent progressive disease developed. The primary objective was to assess PFS non-inferiority of everolimus compared to sunitinib. The median PFS for the everolimus group was 7.9 months (95 % CI, 5.6–8.2) compared to 10.7 months (95 % CI, 8.2–11.5) for the sunitinib-treated cohort. Importantly, a trend in favoring OS for the sunitinib group was noted and awaits confirmation. In the setting of TKI-refractory disease, a study comparing of mTOR inhibitor such as everolimus with a TKI such as axitinib would be appropriate.
Continuing investigations of the molecular genetics of RCC and the development of novel drugs recognizing new biologically relevant targets are needed. The development of a rationale molecular-oriented approach to therapy utilizing the genetic background of RCC represents the next step in the evolution of the current treatment paradigm. This will involve discovery of relevant biomarkers, understanding at a molecular level the factors producing resistance to VEGF-targeted therapy, and incorporation of genetic and molecular factors in treatment and prognostic factor schemes.
The previous experience with cytokines in the therapy of RCC and recognition that tumors can overwhelm the immune system utilizing strategies such as altering antigen expression and interfering with T cell activation have resulted in a renewed interest in the role of immunotherapy for this neoplasm . The normal immune response requires two signals for T cell activation and proliferation. The first signal consists of antigen presentation by an antigen-presenting cell and interaction with T cells. The second signal required for immune system activation can involve several costimulatory molecules such as CTLA-4 and PD-1 . These inhibitors are dysregulated in various malignancies such as RCC and can therefore impair immune recognition of tumor cells. Targeting the immune system with monoclonal antibodies producing checkpoint inhibition may impact tumor growth and proliferation. This approach has been utilized successfully in patients with metastatic melanoma and is now being explored in advanced RCC. The area of Immunoncology is now focused on therapy that may improve the body’s ability to generate an immune response against cancer. The use of PD1/PDL1 blocking monoclonal antibodies represents a novel investigational approach to immune checkpoint inhibition. Currently several PD1/PDL1 inhibitors are being investigated and clinical trials in advanced RCC are underway. The results of a phase 1 trial  utilizing nivolumab, a fully human IgG4 monoclonal antibody directed against PD-1, which included 34 patients with RCC, have been reported. Ten of 34 (29 %) patients had major clinical responses.
These data resulted in initiation of a phase III trial comparing nivolumab to everolimus in TKI-refractory patients with clear-cell RCC . Checkpoint inhibition with agents such as nivolumab will provide data on a new and novel target in RCC, and in view of its favorable toxicity profile, combination therapy with other targeted agents may be possible.
The renewed interest in the immunology of RCC has been accompanied by attempts to develop tumor vaccines for patients with advanced RCC. Ongoing phase III trials involve either an RNA-based autologous tumor vaccine  or a peptide-based vaccine  administered with sunitinib. The control arm in each study is sunitinib alone, with the primary end point being OS. It is unclear whether these approaches which are based on the reported immunoregulatory functions of sunitinib  will succeed; however, the availability of the immune checkpoint inhibitor class of agents should provide a biologically rationale approach and stimulate continued interest in vaccine therapy for advanced RCC.
The need to extend ongoing studies in clear-cell RCC to non-clear-cell RCC variants is recognized. Additional information on therapy, prognosis, and classification of this uncommon group of tumors is required. The limited numbers of patients with these neoplasms make this a challenge, perhaps best met in a cooperative setting.
Finally, postoperative adjuvant therapy has not been demonstrated as useful in preventing relapse following nephrectomy for completely resected, localized RCC. Multiple trials are now in progress to assess the role of targeted therapy in the adjuvant setting. One randomized phase III adjuvant trial compares sorafenib (for either 1 or 3 years) to a placebo , and a second National Cancer Institute sponsored phase III trial compares sorafenib and sunitinib to a placebo . Data from these trials should be available in the near future.
Significant progress has been made in understanding the biology and molecular characteristics of RCC, as well as development of a new treatment paradigm for patients with advanced disease. The chapters in this book were designed to present in detail the clinical, biologic, and genetic features of renal cancer, the molecular targets identified in the various histologic subtypes, and the rationale for the use of the targeted agents. The clinical applications of these agents, as well as novel targeted strategies, are reviewed. The advances in this field have been significant both at the basic and clinical levels and clearly demonstrate that renal cancer continues to represent a model for application of targeted therapeutic approaches.
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