*2.2.1. Temsirolimus*

Temsirolimus is an intravenous mTOR inhibitor, which inhibits the TORC1 complex by binding FKBP12 protein. Temsirolimus showed promising effectiveness in patients with mRCC in the early phase clinical trials [30, 31].

A phase III, multicenter open-label, clinical trial in untreated mRCC patients were carried out with three of six unfavorable prognosis factors. Six hundred and twenty six patients were randomized equally to three arms of treatment: IFN, temsirolimus, or IFN plus temsirolimus. The primary endpoint was OS. Patents were stratified with prior nephrectomy and geographic region. Patients who received temsirolimus alone experienced the best clinical outcome, showed a significant improvement in OS for 10.9 months (p = 0.008 vs. IFN 7.3 months) while the toxicity profile was acceptable. The combination group failed to improve the OS and PFS and also with increased adverse reactions [32]. About 20% of the patients included in this trial with nonclear cell RCC also benefited from temsirolimus.

Based on these data, in 2007, this drug was approved by both the FDA and the EMA as a category 1 recommendation for first-line treatment of poor-risk patients with relapsed or medically unresectable predominantly clear cell stage IV renal carcinoma.

## *2.2.2. Everolimus*

Everolimus is an orally administered inhibitor of mTOR, and it showed promising antitumor activity in patients with advanced RCC previously treated with cytokines [33]. Based on the results, a phase III, randomized, double-blind trial was designed (RECORD1) to evaluate the efficacy and toxicity of everolimus vs. placebo for the treatment of mRCC patients whose disease had progressed on the treatment of VEGFR inhibitors (sorafenib or sunitinib) [34]. The primary endpoint was PFS, and the secondary endpoints included OS and safety. The results of the second interim analysis indicated that the everolimus arm was associated with better PFS than the placebo arm (4.9 vs. 1.9 months; HR 0.33; p < 0.001). However, no significant differences exist in median OS between both arms (14.8 vs. 14.4 months; HR 0.87; p = 0.162). The most commonly AEs observed in the everolimus treatment arm were stomatitis (40%), rash (25%), and fatigue (20%), which were mostly mild or moderate in severity. Pneumonitis was caused in 8% of the patients with everolimus treated, eight of them reaching a grade 3 of severity.

A recent randomize phase III trial compares nivolumab with everolimus in patients with advanced mRCC who were previously treated, indicated that the OS was longer occurred with nivolumab than with everolimus (25.0 vs. 19.6 months, p = 0.002) [35]. In METEOR trial, which is also a phase III trial, randomized 658 patients to receive cabozantinib or everolimus; the result showed longer PFS with cabozantinib compared to everolimus (7.4 vs. 3.8 months; HR:0.58; p < 0.001) [36].

Based on the above data, in 2009, everolimus was approved by both the FDA and the EMA as a category 2A subsequent therapy option for the treatment of mRCC after antiangiogenics.

#### **2.3. Immunotherapy**

Bevacizumab plus IFN was registered in November 2007 and in August 2009 by the EMA and the FDA, respectively, for untreated patients with mRCC of good or intermediate risk (Memo-

TORC1 and TORC2 are two multiprotein complexes, which include a serine threonine kinase called mTOR, and they can regulate micronutrients, cell growth, apoptosis, and angiogenesis. mTOR inhibitor can inhibit small-molecule kinase, which lies downstream in the phosphati-

Temsirolimus is an intravenous mTOR inhibitor, which inhibits the TORC1 complex by binding FKBP12 protein. Temsirolimus showed promising effectiveness in patients with mRCC in

A phase III, multicenter open-label, clinical trial in untreated mRCC patients were carried out with three of six unfavorable prognosis factors. Six hundred and twenty six patients were randomized equally to three arms of treatment: IFN, temsirolimus, or IFN plus temsirolimus. The primary endpoint was OS. Patents were stratified with prior nephrectomy and geographic region. Patients who received temsirolimus alone experienced the best clinical outcome, showed a significant improvement in OS for 10.9 months (p = 0.008 vs. IFN 7.3 months) while the toxicity profile was acceptable. The combination group failed to improve the OS and PFS and also with increased adverse reactions [32]. About 20% of the patients included in this trial

Based on these data, in 2007, this drug was approved by both the FDA and the EMA as a category 1 recommendation for first-line treatment of poor-risk patients with relapsed or

Everolimus is an orally administered inhibitor of mTOR, and it showed promising antitumor activity in patients with advanced RCC previously treated with cytokines [33]. Based on the results, a phase III, randomized, double-blind trial was designed (RECORD1) to evaluate the efficacy and toxicity of everolimus vs. placebo for the treatment of mRCC patients whose disease had progressed on the treatment of VEGFR inhibitors (sorafenib or sunitinib) [34]. The primary endpoint was PFS, and the secondary endpoints included OS and safety. The results of the second interim analysis indicated that the everolimus arm was associated with better PFS than the placebo arm (4.9 vs. 1.9 months; HR 0.33; p < 0.001). However, no significant differences exist in median OS between both arms (14.8 vs. 14.4 months; HR 0.87; p = 0.162). The most commonly AEs observed in the everolimus treatment arm were stomatitis (40%), rash (25%), and fatigue (20%), which were mostly mild or moderate in severity. Pneumonitis was caused in 8% of the patients with everolimus treated, eight of them reaching a

rial Sloan Kettering Cancer Center (MSKCC) classification.

with nonclear cell RCC also benefited from temsirolimus.

medically unresectable predominantly clear cell stage IV renal carcinoma.

dylinositol 3-kinase (PI3K)-AKT pathway.

the early phase clinical trials [30, 31].

*2.2.1. Temsirolimus*

144 Evolving Trends in Kidney Cancer

*2.2.2. Everolimus*

grade 3 of severity.

**2.2. Targeting the mammalian target of rapamycin (mTOR) pathway**

T cells play an important role in anti-tumor activity through stimulatory and inhibitory system. Due to high mutation and other factors, immune system has been made to be self-tolerant by cancer cells, the most active immunotherapy recently be studied include: anti-PD1, anti-PDL1, and anti-CTLA-4. Immunotherapy with monoclonal antibodies against the programmed cell death 1 (PD-1) protein has become an important and effective therapy of advanced melanoma and nonsmall cell lung cancer and also is now being tested in a large number of malignancies. It has been tested in RCC with success results.

#### *2.3.1. Nivolumab*

Nivolumab is a fully human IgG4 antibody against PD-1. A phase I clinical trial was designed to determine the safety and tolerability of nivolumab with treatment-refractory solid tumor, one RCC patient previously treated experienced an overall PR that lasted more than 16 months after only three infusions of nivolumab [37]. These findings prompted the clinical development of this compound in the treatment of mRCC.

A randomized open-label phase III study CheckMate 025 compared nivolumab with everolimus in patients with previously treated mRCC. Eight hundred and twenty one patients were randomly assigned 1:1 to receive nivolumab or everolimus. The primary end point was OS. Patients in the experimental arm experienced better median OS of 25 vs. 19 months (HR 0.73; p = 0.002) and greater ORR (25 vs. 5%; p<0.001). Grade 3–4 toxicities occurred in 19 and 37% for patients receiving nivolumab and everolimus, respectively [35].

Based on the results of the CheckMate 025, nivolumab was approved by the FDA and the EMA as a category 1, preferred subsequent therapy option in November 2015 and February 2016, respectively for the treatment of RCC after progression to TKI therapy.

The clinical development of nivolumab in RCC is currently very intense, and multiple studies are testing the value of strategies in several ways. Phase I CheckMate 016 clinical trial evaluated the efficacy and safety of the combination of nivolumab with the anti-CTLA4 ipilimumab [38]. CheckMate 214 (NCT02231749) evaluates the role of ipilimumab in combination with nivolumab in patients who do not response after monotherapy of nivolumab, and results are highly awaited.

#### **2.4. Target therapy for nonclear cell RCC**

The only available category 1 preferred recommendation for systemic treatment of nonclear cell RCC (nccRCC) is temsirolimus, and it was commended in patients with poor-risk features [32]. Although other targeted agents against the VEGF and mTOR pathways are frequently used in the treatment of nccRCC, optimal first-line agent is much less defined and the outcomes are inferior to that in patients with ccRCC [39, 40]. Immune checkpoint inhibitors appear promising effect in early clinical trials and we look forward to a good result in the updating clinical trial.

recruiting, are going to test the effect of pembrolizumab in the neoadjuvant treatment for

Target Therapy for Kidney Cancer

147

http://dx.doi.org/10.5772/intechopen.73386

Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody against PD-L1. Avelumab binds to PD-L1 inhibiting its binding to PD-1 and therefore inhibiting its activation of T cells and restoring anticancer immune function. In an open-label, single-center, phase 1a trial, safety and activity of this compound was tested in multiple solid tumors including RCC and prompted the further research for this drug [45]. An open, randomized phase II trial SUAVE, which is recruiting is going to compare avelumab followed by sunitinib with the opposite sequence. The effect of avelumab in the combination therapy is also being evaluated. A phase III, multinational, randomized trial is going to compare avelumab with axitinib vs. sunitinib in

Atezolizumab (MPDL-3280A) is a PD-L1-specific monoclonal antibody, which inhibits the binding of PD-L1 to PD-1. Based on the promising date in the phase I clinical trial [46], a further phase II clinical trial IMmotion 150 enrolled untreated mRCC patients, and randomized them into three arms, atezolizumab alone, atezolizumab with bevacizumab, and sunitinib alone. Preliminary result showed no significant difference in PFS between the two arms with immunotherapy, PD-1+ patients showed a trend of survival benefit, although with no significant difference. The IMmotion 151 phase III trial is ongoing to assess the combination of

Ipilimumab is an antibody against CTLA-4 and it shows powerful antitumor activity and clinical experience in the treatment of patients with metastatic melanoma. Therefore, a phase II trial was conducted in patients with mRCC, observing a 10% partial RR, 33% of the patients experienced a grade III or IV immune-mediated toxicity [47]. The efficacy of ipilimumab combine with other drugs is also being evaluated in some trials, like the phase III, randomized study CheckMate 214, comparing the combination of nivolumab and ipilimumab with sunitinib monotherapy in previously untreated local advanced RCC or mRCC. Ipilimumab is also being investigated in association with other drugs for the treatment of advanced RCC, like Check-

Due to the remarkable development of the advanced in the molecular mechanism and cytogenetic of tumor in the last decade, targeted agents directed against VEGF, VEGFR, and mTOR have been important therapy in mRCC. Immune checkpoint inhibitors also appear promising power, and a lot of novel targets including small molecule TKIs and immunotherapies are entering clinical trials, which will update the treatment paradigms in the future time. It is hoped that with better understanding of the molecular diversity of RCC, more effective and personalized therapeutic strategies can be developed against mRCC to make the patients

localized RCC and in untreated mRCC, respectively as monotherapy.

advance renal cell cancer which is currently recruiting (NCT02684006).

*3.2.2. Avelumab*

*3.2.3. Atezolizumab*

*3.2.4. Ipilimumab*

atezolizumab with sunitinib in mRCC.

Mate 214 study or Keynote-29 study.

obtain the maximum benefit.
