Correspondence: Takao Kamai M.D., Department of Urology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan. Email: firstname.lastname@example.org
In the past 5 years, the treatment of patients with metastatic renal cell carcinoma has changed dramatically from being largely cytokine-based with the emergence of targeted therapy. Following the elucidation of various molecular pathways in renal cell carcinoma, targeted agents (particularly vascular endothelial growth factor-targeting antiangiogenic agents) now form the backbone of most therapeutic strategies for patients with metastatic renal cell carcinoma and the outcome of treatment has improved. However, many tumors eventually develop resistance to targeted therapy due to secondary mutation of the target protein or compensatory changes within the target pathway that bypass the site of inhibition. On the other hand, there are new forms of immunotherapy that hold the promise of improving the outcome for patients with metastatic renal cell carcinoma. In this article, we describe some of these new therapies, including the anti-vascular endothelial growth factor monoclonal antibody bevacizumab, several receptor tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib, axitinib, and tivozanib), the mammalian target of rapamycin inhibitors temsirolimus and everolimus, and new immunotherapy modalities, such as anti-cytotoxic T-lymphocyte-associated antigen 4 antibody and anti-programmed cell death 1/programmed cell death-ligand 1 antibody. We also discuss their role in the current management of patients with metastatic renal cell carcinoma.
mitogen-activated protein kinase/extracellular signal-regulated kinases kinase
metastatic renal cell carcinoma
median survival time
mammalian target of rapamycin
overall response rate
programmed cell death
platelet-derived growth factor
phosphatidylinositol 3'kinase-dependent kinase-1
phosphatidylinositol 3'kinase-dependent kinase-2
programmed cell death-ligand 1
von-hippel Lindau protein
rapidly accelerated fibrosarcoma
renal cell carcinoma
tyrosine kinase inhibitors
time to progression
vascular endothelial growth factor
vascular endothelial growth factor receptor
The incidence of RCC is steadily increasing and it now accounts for 2–3% of all adult malignancies. RCC is classified histologically as clear cell carcinoma (70–80%), papillary carcinoma (10–15%), chromophobe carcinoma (5–10%) and collecting duct carcinoma (<1%). Approximately 40% of RCC patients die of metastasis, because metastases are often present at diagnosis, and relapse after nephrectomy is common.[1-3] Patients with distant metastases have a poor prognosis and their 5-year survival rate is less than 10%.[2, 3] Although localized RCC is curable by surgery, the prognosis is poor once distant metastases have developed. Approximately 30% of all patients with RCC have metastatic disease at presentation. After complete resection of the primary tumor, recurrence occurs in another 30% of patients. Until the past decade, the treatment options for patients with mRCC have been extremely limited, as it is notoriously resistant to cytotoxic chemotherapy and radiotherapy.[1-3] As RCC is considered to be an immunogenic tumor, immunotherapy has usually been used to treat patients with metastatic disease. Although few patients with metastatic disease, especially those with lung metastases and previous nephrectomy, achieve long-lasting complete remission, cytokine-based therapy provides modest response rates and a modest survival benefit. IFN-α is the most frequently used cytokine, and it achieves an objective response rate of 7.5% and a median OS time of 13 months.
In the past 5 years, the introduction of targeted therapy has dramatically changed the treatment armamentarium of mRCC and has significantly improved the prospects for patients with this disease. Beginning with approval in the USA in 2005, the first targeted agent, the receptor tyrosine kinase inhibitor sorafenib, had been approved in many countries for the treatment of patients with cytokine-refractory disease. Since then, other targeted agents have also been approved for the treatment of mRCC, including the receptor tyrosine kinase inhibitor sunitinib (and more recently pazopanib and axitinib), the mTOR inhibitors temsirolimus and everolimus, and the anti-VEGF monoclonal antibody bevacizumab in combination with IFN-α. Currently, these agents have replaced immunotherapy in the majority of patients. However, many tumors eventually develop resistance to targeted therapy as a result of a secondary mutation of the target protein or compensatory changes within the target pathway that bypass the site of inhibition. In contrast, there are new immunotherapy modalities that diverge from this paradigm and hold the promise of improving therapeutic outcomes for patients with mRCC. This article reviews the current treatment strategies for patients with mRCC in the era of targeted therapy. In particular, we describe the anti-VEGF monoclonal antibody bevacizumab, the receptor TKI sorafenib, sunitinib, pazopanib axitinib and tivozanib, the mTOR inhibitors temsirolimus and everolimus, and new immunotherapy options that include anti-CTLA4 antibody and anti-PD-1/PD-L1 antibody.
Biological pathways in RCC
Improved understanding of the biology of RCC has led to the identification of two cellular signaling pathways that are relevant for molecular-targeting therapy, which are the VEGF pathway and the mTOR pathway (Fig. 1). The von Hippel-Lindau (VHL) gene appears to function as a tumor suppressor gene, and biallelic inactivation increases the risk of developing malignancies, as its activity is very low or absent in tumors from individuals with von Hippel-Lindau syndrome. In addition, LOH has been found in more than 90% of sporadic clear cell RCC, resembling a classic Knudson “two-hit” model. The other VHL allele is inactivated through either gene mutation (in approximately 80% of clear cell RCC) or through gene silencing by methylation (in approximately 19%).[9, 10] Defective VHL gene function leads to overexpression of a series of proteins that are potential targets for treatment. It has been suggested that pseudo-hypoxia is the mechanism of tumorigenesis associated with VHL gene dysfunction, as defective VHL gene function inhibits the action of prolyl hydroxylase on HIF. As a result, HIF remains unhydroxylated and avoids degradation, allowing it to upregulate the transcription of several genes involved in angiogenesis and cell proliferation. These genes include those for VEGF and PDGF, which can be used as targets for treatment. VEGF is a potent proangiogenic protein that plays a key role in tumor angiogenesis and acts by binding to the VEGFR on endothelial cells. RCC is usually a highly vascular tumor, so several drugs affecting VEGF signaling have been approved for the treatment of metastatic disease. VEGF activity can be inhibited by bevacizumab, which is a monoclonal antibody that binds circulating VEGF and thereby prevents it from binding to its receptor. TKI, including sorafenib, sunitinib, pazopanib, axitinib and tivozanib, inhibit VEGF signaling by targeting the intracellular domain of the VEGFR.
The rapamycin-sensitive mTOR-raptor (regulatory-associated protein of mTOR) complex controls cell growth by regulating protein synthesis, so mTOR-raptor signaling is a potential target for antitumor therapy and mTOR inhibitors are currently under investigation for the treatment of various human cancers. mTOR also interacts with rictor (rapamycin-insensitive companion of mTOR) and recent findings have suggested that the rapamycin-insensitive effect of mTOR on cell viability is upregulated in many cancers. Thus, mTOR has dual rapamycin-sensitive (mTORC1) and rapamycin-insensitive (mTORC2) functions, indicating that treatment with inhibitors of the rapamycin-sensitive component (temsirolimus and everolimus) will not completely block mTOR activity.[13, 14] PI3K, serine/threonine kinase Akt, and the mTOR pathway are all overactive in human cancers, and mTOR is frequently activated in RCC.[15, 16] Temsirolimus and everolimus are two rapamycin derivatives or rapalogs, which have been approved for the treatment of mRCC as mTOR inhibitors. Temsirolimus and everolimus bind to an intracellular protein called FKBP-12, and form a complex that inhibits the mTOR serine-threonine kinase. Consequently, these agents induce cell cycle arrest and also inhibit tumor angiogenesis by reducing the synthesis of VEGF.
Phosphorylation at two sites is required for full activation of Akt, as it is phosphorylated by PDK1 at a threonine residue in the catalytic domain (Thr-308) and by PDK2 at a serine residue (Ser-473) in the carboxy-terminal hydrophobic motif. It has been reported that mTORC2 regulates the actin cytoskeleton and also possesses PDK2 activity that phosphorylates Ser-473 in the carboxy-terminus of Akt, making it essential for activation of Akt. Importantly, activation of Akt might promote cell viability after inhibition of mTORC1, or could potentially increase VEGF production, because PI3K/Akt signaling induces tumor angiogenesis by regulating VEGF through both HIF1α-dependent and -independent mechanisms. It has been reported that HIF1α expression is dependent on both raptor and rictor, whereas HIF2α expression only depends on rictor and that HIF2α is more important in RCC. These findings suggest that phosphorylation of Ser-473 in Akt is a key molecular step in the progression of RCC and could be a potential target for treating these tumors.[23, 24]
Role of sequential versus combination therapy
Combination therapy has two (or more) target points that block a single pathway or else block multiple pathways. Although combination therapy might be expected to increase the cure rate through an increase of complete responses, it is associated with more severe toxicity and there is no clear improvement of the response rate or disease stabilization. Ongoing phase II and III studies might be informative, because we might have failed to detect a response so far as toxicity prevented the use of optimal dosages. In contrast, sequential therapy targets resistant pathways that have been upregulated by prior therapy. Thus, sequential therapy is expected to maintain stable disease and decrease toxicity by diminishing drug interactions. So far, no major issues with toxicity have been reported, but the ideal sequence is still unknown. Reducing toxicity and maximizing efficacy are the key points, and ongoing randomized trials will provide data regarding the optimal sequencing of existing agents.
In 1999, two randomized controlled studies were published on the efficacy of IFN-α for mRCC.
The Medical Research Council Renal Cancer Collaborators investigated the effect of IFN-α on the survival of patients with mRCC in a multicenter randomized trial. Enrolled patients were randomly assigned subcutaneous IFN-α at a dose of 10 MU three times per week (n = 174) or oral MPA at 300 mg once daily (n = 176). The risk of death was reduced by 28% in the IFN-α group (HR 0.72; 95% CI 0.55–0.94; P = 0.017). IFN-α improved the 1-year survival rate by 12% (31% with MPA vs 43% with IFN-α) and improved MST by 2.5 months (6 vs 8.5 months). Pyrhonen et al. reported the results of a prospective randomized study that compared IFN-α-2a plus vinblastine versus vinblastine alone in patients with advanced RCC. The MST of patients receiving IFN-α-2a plus vinblastine and vinblastine alone was 67.6 weeks vs 37.8 weeks for those given vinblastine alone (P = 0.0049), and ORR were 16.5% and 2.5%, respectively (P = 0.0025). These results established the IFN-α as a treatment for advanced RCC.
Naito et al. studied prognostic factors in 1463 Japanese patients with mRCC. In that study, the median OS was 21.4 months, and the MST of patients receiving continuous cytokine therapy was longer than that of patients in whom cytokine therapy was discontinued at disease progression (18.2 vs 13.2 months; P = 0.0232). In a prospective study, Eto et al. found an association between a single nucleotide polymorphism of the signal transducer and activator of transcription 3 and the clinical response of IFN-α in Japanese patients with mRCC.
IFN-α and IL-2 have been used together as combination therapy for advanced RCC. Negrier et al. carried out a randomized trial to determine the effect of IL-2 and IFN-α independently or combined. The response rates of the groups receiving IL-2, IFN-α-2a and IL-2 plus IFN-α-2a were respectively 6.5%, 7.5% and 18.6% (P = 0.01), whereas the 1-year event-free survival rates were 15%, 12% and 20%, respectively (P = 0.01). However, there were no significant differences of OS among the three groups. Akaza et al. studied the effect of combination immunotherapy using low-dose IL-2 and IFN-α. The ORR was 26.1%, whereas it was a high 38.7% in the patients who had undergone nephrectomy and only had lung metastases. Additionally, the associations between the clinical or molecular markers and the clinical response of this combination immunotherapy were reported in Japanese patients with mRCC, namely pretreatment serum sodium level and the expression levels of HLA-DQA1 and HLA-DQB1, respectively.
These data encourage the use of cytokines for selected patients with mRCC, especially in east Asian populations.
During the cytokine era, the efficacy of cytoreductive nephrectomy for metastatic disease was thoroughly investigated. Mickisch et al. studied the effect of carrying out nephrectomy before immunotherapy in patients with mRCC. Enrolled patients were randomly assigned to receive nephrectomy plus immunotherapy or immunotherapy alone. The TTP (5 vs 3 months; HR 0.60, 95% CI 0.36–0.97) and the MST (17 vs 7 months; HR 0.54; 95% CI 0.31–0.94) were both significantly better in the combined treatment group. Also, five of 42 patients showed a complete response to nephrectomy plus IFN-α, whereas one of 43 patients responded to IFN-α alone. Flanigan et al. reported similar results. The MST of 120 patients assigned to surgery followed by IFN therapy was 11.1 months, whereas that of 121 patients receiving IFN alone was 8.1 months (P = 0.05). Flanigan et al. also reported a combined analysis of these two prospective randomized trials. They found that the MST of patients who had nephrectomy plus IFN was 13.6 months (95% CI 9.7–17.4) versus 7.8 months (95% CI 5.9–9.7) for patients given IFN alone. This difference represents a 31% decrease in the risk of death in the nephrectomy arm (P = 0.002). Excluding for patients with severe comorbidities, poor performance status or unresectable disease, as well as elderly patients because of their high perioperative mortality rate, these data suggest that cytoreductive nephrectomy should be considered in patients with mRCC.[37, 38]
Currently, two randomized controlled trials are ongoing to confirm the benefits of cytoreductive nephrectomy combined with targeted therapy. The Clinical Trial to Assess the Importance of Nephrectomy is investigating the value of carrying out cytoreductive nephrectomy before sunitinib treatment. In addition, a phase III study carried out by the European Organisation for Research and Treatment of Cancer is investigating the timing of cytoreductive nephrectomy in relation to sunitinib therapy. So far, although presurgical targeted therapy has been considered to be tolerable, its effect has yet to be elucidated. The European Organisation for Research and Treatment of Cancer phase III study will go a way towards defining the role of this treatment.
Bevacizumab is a recombinant humanized monoclonal antibody that inhibits VEGF. In the Cancer and Leukemia Group B study, bevacizumab plus IFN was compared with IFN monotherapy. Medical treatment-naive patients with mRCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN (9 million U subcutaneously three times weekly) or IFN monotherapy by the same regimen. The median PFS was 8.5 months for patients receiving bevacizumab plus IFN (95% CI 7.5–9.7 months) versus 5.2 months (95% CI 3.15.6 months) for patients given IFN monotherapy (P = 0.0001; Table 1).[43, 44] Escudier et al. reported the results of a randomized, double-blind, phase III trial in patients with previously untreated mRCC. They were randomly assigned to receive either IFN-α-2a (9 million U subcutaneously three times weekly) plus bevacizumab (10 mg/kg every 2 weeks) or IFN-α-2a plus placebo. The median PFS was significantly longer in the bevacizumab plus IFN-α group than in the control group (10.2 vs 5.4 months; HR 0.63; 95% CI 0.52–0.75; P = 0.0001). Median OS was 23.3 months with bevacizumab plus IFN-α versus 21.3 months with IFN-α plus placebo (unstratified HR 0.91; 95% CI 0.76–1.10; P = 0.3360; stratified HR 0.86; 95% CI 0.72–1.04; P = 0.1291).
Table 1. Key phase III studies of targeted therapy in mRCC
In patients previously treated with IL-2, a randomized, double-blind, phase II trial compared placebo plus bevacizumab at doses of 3 or 10 mg/kg every 2 weeks. The median TTP was 4.8 months in the high dose group, which was significantly longer than in the placebo group (2.5 months; P < 0.001).
In the phase II TORAVA trial (bevacizumab plus temsirolimus vs sunitinib vs bevacizumab plus IFN), the median PFS achieved with bevacizumab plus IFN was 16.8 months. These data show that longer survival was achieved than in other randomized trials of bavacizumab plus IFN as first-line therapy, and this treatment option seems to be suitable for patients with favorable and intermediate risk profiles.
Sorafenib is an oral multikinase inhibitor that targets VEGFR-2, -3, PDGFR-β, cKIT and Raf-1 (Table 2). In a phase II randomized trial, patients who underwent primary cytokine therapy received oral sorafenib (400 mg twice daily) during a 12-week run-in period, after which patients with stable disease were randomly assigned to sorafenib or placebo for an additional 12 weeks. At 24 weeks, 50% of the sorafenib-treated patients showed no progression versus just 18% of the placebo-treated patients (P = 0.0077). Median PFS from randomization was significantly longer in the sorafenib group than the placebo group (24 vs 6 weeks; P = 0.0087).
The Treatment Approaches in Renal Cancer Global Evaluation Trial was a phase III study, which showed that the median PFS was 5.5 months in the sorafenib group versus 2.8 months in the placebo group after failure of IFN therapy (HR for disease progression in the sorafenib group: 0.44; 95% CI 0.35–0.55; P < 0.01). Although the final OS of patients receiving sorafenib was comparable with that of patients receiving placebo (17.8 vs 15.2 months; HR 0.88; P = 0.146), when placebo survival data from after cross-over were censored, the difference became significant (17.8 vs 14.3 months; HR 0.78; P = 0.029). Guidelines for RCC recommend sorafenib as second-line therapy after failure of IFN based on the results of this study.
In the Japanese nonrandomized, open-label, phase II study for patients with mRCC who had undergone nephrectomy and failed at least one cytokine-containing regimen, the median PFS was 224 days (95% CI 178–280 days).
Sunitinib is a highly potent, selective inhibitor of certain protein tyrosine kinases, including VEGFR-2, PDGFR, fms-related tyrosine kinase-3 and cKIT.[53, 54] Motzer et al. reported the efficacy of sunitinib for cytokine-failure patients. A total of 25 of 63 patients (40%) treated with sunitinib achieved a partial response, and 17 other patients (27%) had stable disease for longer than 3 months. The median TTP of the 63 patients was 8.7 months.
In a randomized, phase III trial of sunitinib compared with IFN-α, the median PFS was significantly longer in the sunitinib group (11 months) than in the IFN-α group (5 months), corresponding to a HR of 0.42 (95% CI 0.32–0.54; P < 0.001). Sunitinib also achieved a higher ORR than IFN-α (31% vs 6%, P < 0.001). Median OS was longer in the sunitinib group than in the IFN-α group (26.4 vs 21.8 months; HR 0.821; 95% CI 0.673–1.001; P = 0.051) as shown by primary analysis with the unstratified log–rank test (P = 0.013 by the unstratified Wilcoxon test). With the stratified log–rank test, the HR was 0.818 (95% CI 0.669–0.999; P = 0.049). On the basis of these data, sunitinib has emerged as a front-line agent for mRCC.
The safety and efficacy of the sunitinib therapy were confirmed in an expanded-access trial. Discontinuation of treatment because of adverse events occurred in 8% of the patients, and clinical benefit (objective response or stable disease for at least 3 months) was achieved in 76%. In this trial, sunitinib was also found to be active against non-clear cell RCC, and the median PFS of this subgroup was 7.8 months. Sunitinib was also found to be active in the subgroups of patients with brain metastasis (n = 320; median PFS: 5.6 months), poor performance status (Eastern Cooperative Oncology Group Performance Status ≥2; n = 582; median PFS: 5.1 month), and an age ≥65 years (n = 1442; median PFS: 11.3 months).
Escudier et al. investigated the efficacy and tolerability of continuous sunitinib therapy (37.5 mg per day for 6 weeks) in patients with cytokine-refractory metastatic RCC, and found similar results to those achieved with an intermittent administration schedule (50 mg per day for 4 weeks and 2 weeks off). Barrios et al. reported similar results in the first-line setting.
In a Japanese phase II trial of treatment-naive patients and cytokine-refractory patients, the median PFS was 12.2 and 10.6 months for first-line and pretreated patients, respectively. A total of 14 patients died in each group (56% and 54%), and the median OS was 33.1 and 32.5 months, respectively. Although the number of subjects was small, the results of this study suggested that sunitinib can also be considered as second-line therapy after the failure of cytokines in Japanese patients with mRCC.
Pazopanib is an oral multi-targeted TKI of VEGFR-1, −2 and −3, PDGFR-α, -β, and cKIT. A randomized, double-blind, placebo-controlled phase III study was carried out in 435 patients, of whom 233 were treatment naive (54%) and 202 had received cytokine therapy (46%). PFS was significantly prolonged by pazopanib compared with placebo in the overall study population (median PFS was 9.2 vs 4.2 months; HR 0.46; 95% CI 0.34–0.62; P = 0.0001), as well as in the treatment-naive population (median PFS was 11.1 vs 2.8 months; HR 0.40; 95% CI 0.27–0.60; P = 0.0001) and the cytokine-treated population (median PFS was 7.4 vs 4.2 months; HR 0.54; 95% CI 0.35–0.84; P = 0.001). Based on these results, guidelines recommend pazopanib for both first-line therapy and as a second-line agent after cytokine therapy.
Grade 3 hepatotoxicity might be more common with pazopanib. Powles et al. reported there was no significant difference in the overall number of toxic events (grade 1–4) as a result of sunitinib and pazopanib (the mean number of events per patient was 1.97 vs 1.96, P > 0.05). There were more grade 2–4 events with sunitinib therapy (HR 1.67; 95% CI 1.11–2.56; P < 0.03) in two sequential prospective single-arm phase II studies that investigated 12 weeks of sunitinib treatment (n = 43) or pazopanib administration (n = 34) before nephrectomy for patients with untreated mRCC.
Ongoing phase III trials, including COMPARZ (pazopanib vs sunitinib as first-line therapy for locally advanced and/or mRCC in a head-to-head comparison) and PISCES (pazopanib vs sunitinib as first-line therapy for mRCC in a cross-over trial) might help to define the role of pazopanib in the treatment of mRCC.
Axitinib is a low molecular weight indazole derivative that is an orally active, potent, and highly selective inhibitor of VEGFR-1, -2 and -3.
In a phase II study, 52 patients with cytokine-refractory mRCC received axitinib (5 mg twice daily while fasting) as 28-day treatment cycles until progression or unacceptable toxicity occurred, and the median TTP was 15.7 months (95% CI 8.4–23.4).
Rini et al. reported the results of another phase II study that included 62 patients with histologically documented mRCC of any subtype, prior nephrectomy and prior failure of sorafenib. A total of 16 patients (25.8%) had also received one other prior therapy regimen, and 46 patients (74.2%) had been treated with at least two prior regimens. The majority of the patients (85.5%) received sorafenib as their only or final treatment before starting axitinib therapy. The median PFS and OS was 7.4 months (95% CI 6.7–11.0 months) and 13.6 months (95% CI 8.4–18.8 months), respectively. These phase II results suggested that axitinib could be an effective second-line treatment for advanced RCC.
A randomized phase III trial (AXIS) was carried out to directly compare the efficacy and safety of axitinib versus sorafenib in patients with advanced RCC who had shown progression after initial systemic therapy. A total of 723 patients with advanced RCC from 175 hospitals or outpatient clinics in 22 countries were randomly assigned to receive axitinib or sorafenib. Among them, 389 patients (54%) had previously received sunitinib, 251 patients (35%) had received cytokines, 59 patients (8%) had been given bevacizumab and 24 patients (3%) had used temsirolimus. The median PFS was 6.7 months with axitinib versus 4.7 months with sorafenib. Among patients who had previously received cytokines, the median PFS was 12.1 months with axitinib and 6.5 months with sorafenib (HR 0.464; 95% CI 0.318–0.676; P < 0.0001). In patients previously treated with sunitinib, the median PFS was 4.8 months with axitinib and 3.4 months with sorafenib (HR 0.741; 95% CI 0.573–0.958; P = 0.0107).
These findings show that axitinib should be considered as one of the first choices after prior therapy with cytokines or TKI, as recommended in guidelines.
Regarding toxicity, both hand–foot syndrome and proteinuria were more frequent in the Japanese trial than in the Western trial, and this difference might influence the efficacy of axitinib.
Tivozanib is a selective VEGFR inhibitor that shows greater than approximately 10-fold higher potency against all three VEGFR subtypes (VEGFR-1,2,3) versus other kinases (e.g. cKIT, PDGFR-β, fms-related tyrosine kinase-3) in cell-based assays.
The phase II trial enrolled 272 patients with locally advanced or metastatic RCC. The majority of the patients (83%) had clear cell carcinoma and 73% of all patients had undergone nephrectomy. Approximately half of the patients (54%) were untreated, whereas the remaining patients had received prior therapy with cytokines, vaccines, chemotherapy or other agents. In patients with clear cell carcinoma who had undergone nephrectomy, tivozanib showed stronger antitumor activity with an ORR of 30% (95% CI 23–37%) and a median PFS time of 14.8 months (95% CI 10.3–19.2 months).
The phase III trial of tivozanib is ongoing. As in the AXIS trial, an active comparator (sorafenib) is being utilized and a total of 500 patients have been randomized (1:1) to receive either sorafenib or tivozanib. The results of this trial are expected to clarify the role of tivozanib in treatment strategy of mRCC.
Temsirolimus is a derivative of sirolimus (rapamycin) that inhibits mTOR, a non-receptor TK in the PI3K-Akt pathway controlling the translation of specific messenger RNA.
Hudes et al. reported the results of a phase III trial that compared temsirolimus alone or temsirolimus plus IFN-α with IFN-α alone for the treatment of mRCC. This study included a total of 626 treatment-naive patients with poor risk features. It was open to all histological subtypes, and even enrolled patients with treated brain metastases. All participants had at least three of the following six predictors of poor survival: (i) serum lactate dehydrogenase >1.5 times the upper limit of normal; (ii) hemoglobin less than the lower limit of the normal range; (iii) corrected serum calcium >10 mg/dL; (iv) interval from initial diagnosis of RCC to randomization <1 year; (v) Karnofsky performance score of 60 or 70; and (vi) metastases involving multiple organs. In this study, patients who received temsirolimus alone had a longer OS (HR 0.73; 95% CI 0.58–0.92; P = 0.008) and longer PFS (P < 0.001) than patients who received IFN alone. The median OS time of the IFN group, the temsirolimus group, and the combination therapy group was 7.3, 10.9 and 8.4 months, respectively. Based on these results, guidelines recommend temsirolimus as a first-line treatment for poor risk RCC patients.
Everolimus is an orally active mTOR inhibitor that binds with high affinity to its intracellular receptor (FKBP12) at the same point in the mTOR pathway as temsirolimus. In a phase II clinical trial, 33 out of 37 patients (89%) had received prior systemic immunotherapy, chemotherapy and/or TKI therapy. A total of 21 of the 37 patients (57%) showed no progression for at least 6 months, with a median PFS of 11.2 months (95% CI 1.7–36.2 months) and a median OS of 22.1 months (95% CI 1.4–36.4 months).
The phase III trial (RECORD-1) was carried out at 86 centers in Australia, Canada, Europe, Japan and the USA. The study population consisted of patients with mRCC that had a clear cell component, and had shown progression within 6 months of stopping treatment with sunitinib and/or sorafenib. The median PFS was 4.9 months (95% CI 4.0–5.5 months) with everolimus and 1.9 months (95% CI 1.8–1.9 months) with placebo (HR 0.33; 95% CI 0.25–0.43; P < 0.001). Median OS was 14.8 months for patients randomized to everolimus versus 14.4 months for patients randomized to placebo (HR 0.87; 95% CI 0.65–1.15; P = 0.162). RECORD-1 is the prospective, randomized phase III trial of an mTOR inhibitor for patients with TKI failure. Thus, guidelines for RCC use everolimus as second-line therapy after TKI failure. In the subgroup analysis of 24 Japanese patients (15 received everolimus and 9 received placebo), median PFS was 5.75 months (95% CI 4.90 to not reached) with everolimus and 3.61 months (95% CI 1.91–9.03 months) with placebo (HR 0.19; 95% CI 0.05–0.83). Median OS was not reached with everolimus and was 14.9 months (95% CI 11.0–16.8) with placebo (HR 0.30; 95% CI 0.07–1.27).
Adverse events of targeted therapy
It is well known that targeted agents present specific toxicity profiles that differ from conventional chemotherapeutic agents. Bevacizumab is associated with potentially fatal gastrointestinal perforation and thrombovascular events. Sunitinib is associated with hypothyroidism and cardiovascular toxicity, whereas mTOR inhibitors cause hyperglycemia and interstitial pneumonitis. Proteinuria occurs with the second-generation TKI, pazopanib and axitinib. Hypertension and cutaneous reactions (i.e. hand–foot syndrome) are common adverse effects of anti-angiogenic agents. Furthermore, in a clinical trial of sunitinib, hypertension was an independent predictor of PFS and OS (P < 0.001). In a trial of axitinib, a diastolic blood pressure >90 mmHg was significantly associated with longer median OS (P < 0.001). These reports suggest that skilful management of adverse events can maximize patient outcomes by achieving optimal dosing.
Therapeutic targets identified by resistance mechanisms
Targeted therapies act by blocking essential biochemical pathways or mutant proteins that are required for tumor cell growth and survival. These drugs can arrest tumor progression and can induce striking regression in particular subsets of patients. Numerous investigations of the genetic pathways driving tumor proliferation have uncovered additional oncoproteins that are crucial for tumor viability, such as VEGFR. Although the low molecular weight inhibitors of these kinases, including sorafenib, sunitinib and axitinib, achieve impressive responses in selected patients, the majority of RCC possess the intrinsic ability to survive the immediate insult of hypoxia and nutrient deprivation induced by the loss of tumor vasculature, and are able to activate escape pathways that restore adequate perfusion, possibly because of the emergence of drug-resistant variants. Elucidating the mechanisms by which RCC develops resistance to VEGF-targeting therapy would be extremely useful. It could be that the identification of critical signaling pathways that mediate both intrinsic resistance to anti-angiogenic agents and delayed restoration of microvasculature, so-called “angiogenic escape,” will identify novel therapeutic targets in RCC. Resistance usually involves secondary mutation of a target protein or compensatory changes within a target pathway that bypass the site of inhibition. Accordingly, targeted therapy might achieve dramatic tumor regression, but this is generally short-lived, limiting their overall clinical benefit.
Emerging immunotherapeutic strategies
Cytotoxic T lymphocytes recognize and selectively kill autologous RCC cells, and tumor-specific T cells can be detected in the blood of RCC patients. Because some RCC evoke an immune response, immunotherapy has traditionally been used to treat patients with metastatic disease.
More recently, improved understanding of cancer progression has shed light on new immunotherapy options. Important insights into the limitations of T cell-based anticancer immunotherapy have come from the discovery of inhibitory pathways that are termed “immune checkpoints”. Blockade of such immune checkpoints might be a promising approach to activating antitumor immunity. Immune checkpoints refer to a plethora of inhibitory pathways in the immune system that are crucial for maintaining self-tolerance, and modulating the duration and amplitude of physiological immune responses. It is clear that tumors utilize such immune checkpoints as a resistance mechanism, particularly against T cells that specifically target tumor antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by the use of recombinant ligands or receptors. The B7 family consists of activating and inhibitory costimulatory molecules that positively and negatively regulate immune responses in the tumor microenvironment, among which the inhibitory B7 molecules include CTLA4 and PD-1. CTLA4 antibodies were the first of this class of immunotherapy agents to achieve USA Food and Drug Administration approval. Preliminary clinical findings obtained with blockers of additional immune checkpoint proteins, such as PD-1, show that there are diverse opportunities to enhance antitumor immunity and the potential to achieve durable clinical responses.
Pharmacological blockade of CTLA-4, also known as CD152, prevents induction of T cell anergy, which occurs when CTLA-4 on the T cell surface binds to B7 on antigen-presenting cells (Fig. 2). Ipilimumab is a monoclonal antibody directed at CTLA-4 that was recently examined in a phase II study of patients with metastatic clear cell RCC using two dosing regimens. Of 21 evaluable patients treated at the lower dose, one patient showed a PR. In contrast, five out of 40 patients (12.5%) treated at the higher dose achieved a PR. The patients who developed autoimmune toxicities, such as enterocolitis, hypophysitis, hepatitis, uveitis and pancreatitis, showed a higher response rate (30%).
PD-1 and PD-L1 inhibition
PD-1, also known as CD279, is an inhibitory receptor that is expressed on antigen-activated and exhausted T and B cells. B7-H1/PD-L1 is the ligand of PD-1, and it acts as the predominant mediator of PD-1-dependent immunosuppression. B7-H1 is massively upregulated in many murine and human tumors (either in tumor cells or non-transformed cells in the tumor microenvironment, such as antigen-presenting cells), and its expression is associated with a poor outcome for patients with RCC. These findings have focused attention on PD-1:B7-H1 blockade as a possible strategy for antitumor immunotherapy. A phase II study of BMS-936558 (formerly MDX-1106) recently showed that this agent was safe, and obtained a response in nine out of 33 patients with advanced RCC (27%), including durable responses. A phase I study is currently assessing an anti-PD-L1 antibody for patients with advanced cancer, including 17 patients with mRCC, and an objective response (complete or partial response) has been observed in two out of 17 patients (28%).
Targeted therapy aims to inhibit molecular pathways that are crucial for tumor growth and survival, whereas immunotherapy endeavors to stimulate a host immune response that will lead to long-term tumor destruction. Targeted agents also modulate immune system, which raises the possibility that such agents might be effectively combined with immunotherapy to improve clinical outcomes. Several studies of these combinations are ongoing.
Bevacizumab promotes DC maturation so that there is a shift towards mature DC, and it increases DC priming of T cells. A phase III trial of bevacizumab plus IFN-α for metastatic RCC showed that the combination achieved an improved objective response rate compared with that of patients receiving IFN-α alone.[43-45, 54]
Sunitinib blocks multiple tumor-associated tyrosine kinases (including VEGFR and PDGFR), as well as blocking signal transducer and activator of transcription 3, and decreasing the number and activity of regulatory T cells and myeloid-derived suppressor cells. In a phase I trial of sunitinib plus IFN-α for 25 patients with mRCC, three patients (12%) showed a partial response, and 20 (80%) had stable disease, but all patients suffered from grade 3/4 treatment-emergent adverse events.
It has also been reported that combined treatment with IFN-α plus sorafenib is more effective for suppressing proliferation and VEGF production in several RCC cell lines than either agent alone.[97, 98] Although the efficacy of combination therapy with IFN-α and sorafenib requires clarification, the outcome of patients with metastatic disease might be improved by combining IFN-α and sorafenib, as the adverse effects of such regimens are related to the doses of each agent and are not additive.[23, 24, 99-101]
Although significant strides have been made in the treatment of mRCC over the past several years, many challenges remain to be overcome in order to further improve the therapeutic outcome. Many of the agents recently approved in many countries including the USA, Europe, Japan and other Asian countries for the treatment of advanced RCC have potentially distinct mechanisms of action. We require a better understanding of the tumor biology of RCC to determine the optimal dosing strategies, sequences or combinations for administering these agents, as well as to develop patient selection strategies for directing the most appropriate therapies to individual patients. Furthermore, recent studies have given rise to new prospects for cancer immunotherapy. Whereas targeted therapy aims to inhibit molecular pathways that are crucial for tumor growth and survival, immunotherapy has the objective of stimulating a host immune response that will lead to long-term tumor destruction. Although the efficacy of many of these targeted therapy and immunotherapy agents has yet to be established, once this has been achieved, integrating such new therapies should be attempted.