**3. Upcoming therapies in RCC**

#### **3.1. Last generation for targeting VEGF/VEGFR**

#### *3.1.1. Dovitinib*

Dovitinib (TKI-258) is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. In a multicenter phase III study, patients who previously received VEGF-targeted therapy or mTOR inhibitor were randomized to dovitinib or sorafenib. The results indicated that the mPFS was 3.7 months in dovitinib group vs. 3.6 months in sorafenib group, showing improvement in mPFS, however, with no significant difference [41]. A phase II clinical trial has been designed to find out the usefulness of dovitinib in the initial treatment for patients with advanced kidney cancer, and the study will additionally look for changes in the genetic makeup of tumor cells.

#### *3.1.2. Trebananib*

Angiopoietin-2 (Ang2) exhibits broad expression in the remodeling vasculature of tumors but not in the normal tissues. Trebananib (AMG-386) can bind to angiopoietin 1 and 2 and block their union with the Tie2 receptor tyrosine kinase, showing its antiangiogenic effect. In preclinical and clinical phase I studies, AMG-386 showed a good safety profile in inhibiting tumor growth [42]. A randomized phase II trial showed that AMG-386 plus sorafenib reach a RR of 38% in RCC patients previously treated [43].

#### **3.2. Immunotherapy**

#### *3.2.1. Pembrolizumab*

Pembrolizumab (MK-3475) is a highly selective IgG4-humanized monoclonal antibody, which prevents the binding of PD-1 with PD-L1 and PD-L2. A phase I study evaluated the safety, tolerated does, and antitumor effect of pembrolizumab in patients with advanced solid tumors. It showed durable antitumor activity in multiple solid tumors including RCC [44]. There are two clinical trials NCT02212730 and NCT02853344, both of which are currently recruiting, are going to test the effect of pembrolizumab in the neoadjuvant treatment for localized RCC and in untreated mRCC, respectively as monotherapy.

#### *3.2.2. Avelumab*

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

**3. Upcoming therapies in RCC**

**3.1. Last generation for targeting VEGF/VEGFR**

38% in RCC patients previously treated [43].

updating clinical trial.

146 Evolving Trends in Kidney Cancer

*3.1.1. Dovitinib*

makeup of tumor cells.

*3.1.2. Trebananib*

**3.2. Immunotherapy**

*3.2.1. Pembrolizumab*

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

Dovitinib (TKI-258) is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. In a multicenter phase III study, patients who previously received VEGF-targeted therapy or mTOR inhibitor were randomized to dovitinib or sorafenib. The results indicated that the mPFS was 3.7 months in dovitinib group vs. 3.6 months in sorafenib group, showing improvement in mPFS, however, with no significant difference [41]. A phase II clinical trial has been designed to find out the usefulness of dovitinib in the initial treatment for patients with advanced kidney cancer, and the study will additionally look for changes in the genetic

Angiopoietin-2 (Ang2) exhibits broad expression in the remodeling vasculature of tumors but not in the normal tissues. Trebananib (AMG-386) can bind to angiopoietin 1 and 2 and block their union with the Tie2 receptor tyrosine kinase, showing its antiangiogenic effect. In preclinical and clinical phase I studies, AMG-386 showed a good safety profile in inhibiting tumor growth [42]. A randomized phase II trial showed that AMG-386 plus sorafenib reach a RR of

Pembrolizumab (MK-3475) is a highly selective IgG4-humanized monoclonal antibody, which prevents the binding of PD-1 with PD-L1 and PD-L2. A phase I study evaluated the safety, tolerated does, and antitumor effect of pembrolizumab in patients with advanced solid tumors. It showed durable antitumor activity in multiple solid tumors including RCC [44]. There are two clinical trials NCT02212730 and NCT02853344, both of which are currently 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 advance renal cell cancer which is currently recruiting (NCT02684006).

#### *3.2.3. Atezolizumab*

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 atezolizumab with sunitinib in mRCC.

#### *3.2.4. Ipilimumab*

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-Mate 214 study or Keynote-29 study.

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 obtain the maximum benefit.
