**4. Monoclonal antibodies and renal cell carcinoma**

Renal cell carcinoma is one of the urologic cancers that has lower incidence rates and poor prognosis. About 30% are diagnosed in their metastatic stage. It is a type of cancer that originates in the PCT. Therapy considered for this form of cancer include nephrectomy, radiation therapy, chemotherapy and embolization. The role of mAbs in Renal cell carcinoma is undertaken and studied in clinical trials treatment has not been very successful. Several trials have been carried out to check for its efficacy the details of which have been mentioned below as renal cell carcinoma (RCC) is a largely chemotherapy-resistant disease. It is immune responsive disease; therefore, checkpoint inhibitors can be considered as agents for the treatment of RCC [15].

The pivotal drug trial Checkmate 214 showed good objective responses in case of poor and intermediate risk patients in combination immunotherapy (Nivolumab/ Ipilimumab) vs. the tyrosine kinase inhibitor sunitinib and can be considered as a first line treatment in these subjects for RCC. However, for favorable high-risk patients, the single agent sunitinib showed more response rate. Survival rates were similar in both arms. In another clinical trial Keynote 426, Pembrolizumab (anti-PD-1) plus axitinib, the responses were good and this led to its approval by leading to Food and Drug Administration (FDA) first line treatment. In another trial named, Javelin 101 Renal, avelumab (anti-PD-L1) plus axitinib vs. sunitinib the OS was not significantly different between the two arms [16].

In addition to this, there are many clinical trials that are underway for RCC (**Table 1**). Nivolumab was approved advanced clear-cell RCC by the FDA and is under investigation as pre- and postoperative therapy in mRCC. Combinatorial treatments with various drugs are also being studied in various clinical trials. Atezolizumab phase I trial involving 17 mRCC patients showed promising results as 7 had stable disease for more than 24 weeks. In another phase Ia study, of the 63 patients with clear-cell RCC whose OS was 28.9 months. Pembrolizumab is currently being investigated in two randomized phase II trials of mRCC patients. It has been found to be acceptable for safe use [17]. Several trials evaluating pembrolizumab in combination with various agents are also undergoing. Avelumab showed an acceptable usage when used in patients with advanced solid tumors and safety profile. Two ongoing trials are still being evaluated for avelumab in combination with axitinib Durvalumab. There are ongoing trials evaluating durvalumab in combination with other drugs, including tremelimumab for patients with advanced malignancies including RCC. Ipilimumab: Phase-II studies have been undergoing and the results are found to be partial response with adverse events being reported. In addition, Ipilimumab and nivolumab is being investigated and found to be favorable [18].

**131**

**Table 1.**

*Therapeutic Applications of Monoclonal Antibodies in Urologic-Oncology Management…*

Atezolizumab Bevacizumab Ib Untreated, advanced clear cell RCC

adjuvant pilot

Nivolumab Temsirolimus Ib/II Metastatic RCC, prior therapy allowed Pembrolizumab Pazopanib I/II Untreated, advanced clear cell RCC Pembrolizumab Axitinib Ib Untreated, advanced clear cell RCC Pembrolizumab Bevacizumab Ib/II Metastatic clear cell RCC treated with

Pembrolizumab Aflibercept I Metastatic RCC treated with at least one

Avelumab Axitinib Ib Untreated, advanced clear cell RCC Atezolizumab Bevacizumab III Untreated, advanced clear cell RCC Avelumab Axitinib III Untreated, advanced clear cell RCC Pembrolizumab Axitinib III Untreated, advanced clear cell RCC *RCC: Renal cell carcinoma; VEGF: Vascular Endothelial Growth Factor; TKI: Tyrosine kinase inhibitors.*

I Advanced RCC, prior cytokine therapy

Metastatic clear cell RCC, prior therapy

failure of at least one prior therapy

prior VEGF TKI

allowed

allowed

**mAbs Targeted therapy Phase Population**

*DOI: http://dx.doi.org/10.5772/intechopen.96911*

Pazopanib

Nivolumab Bevacizumab Neo-

Nivolumab Sunitinib

**5. Monoclonal antibodies and bladder cancer**

*List of the Clinical trials that are underway for RCC.*

higher in America when compared to other forms of malignancy.

Bladder cancer is one of the common cancers which develop in the tissues of the bladder. It is a type of Urolethial cancer. There are several methods which have been developed as a cancer therapy for bladder cancer and the most common being the, Bacillus Calmette-Guerin which has a very high success rate. The role of immunotherapy in Bladder cancer has been detailed in a number of case report and clinical trial studies [19]. The incidence of Bladder cancer is comparatively found to be

Here are the various monoclonal antibodies that have been considered as a cancer therapy for the bladder cancer. 2016-Atezolizumab, was the first mAb to be approved by the FDA and also accepted by the European Association of Urology (EUA) as second-line therapy for patients with advanced Bladder Cancer. It is a PD-1/PD-L1 checkpoint inhibitor It has been used for subjects even with metastatic or advanced bladder cancer. 2017-Avelumab was also approved by FDA for urothelial cancers. It acts against PD-L1. A phase Ib clinical trial had been carried out with metastatic urothelial cancer which showed inconvincing results. However in the phase II trial, avelumab exhibited a good antitumor response in patients with advanced urothelial cancer whose tumors progressed during or after platinum-based chemotherapy 2017-Durvalumab has also received approval by FDA for the treatment of Bladder cancer. Studies in phases I and II patients have confirmed the effectiveness of durvalumab: It has shown responses in a number of clinical trial studies. It is a drug that acts against the PD-L1. 2017-Nivolumab is a FDA and EUA approved human mAb that acts against the PD-1. It was accepted on the basis of a single-arm phase trial for 270 platinum pretreated patients. The result has been 20% response rate [20].

Nivolumab was also tested on advanced or metastatic Bladder cancer subjects. In this study many adverse events were reported. Unlike the above mentioned

*Therapeutic Applications of Monoclonal Antibodies in Urologic-Oncology Management… DOI: http://dx.doi.org/10.5772/intechopen.96911*


**Table 1.**

*Monoclonal Antibodies*

plus nivolumab has been gaining responses as being reported in a phase 2 trial on metastatic castration resistant prostate cancer. Pembrolizumab is also an immune checkpoint inhibitor [13]. It has received approval from FDA for the treatment of prostate cancer. In these solid tumors, microsatellite instability (MSI) and mutations in mismatch repair genes (MMR) has been observed. Pembrolizumab is evaluated for in a patient after other effective treatments (such as sipuleucel-T, abiraterone, enzalutamide, docetaxel, cabazitaxel, radium-223, etc.) has been ruled out [14]. Combination therapies either with multiple immunotherapies or with immunotherapy and chemotherapy/RT, are currently being evaluated in prostate cancer. The optimal timing of immunotherapy in prostate cancer also remains unclear. Although much work remains to be done, the promise of prostate cancer immunotherapy remains unclear. There have been modern advances in the treatment of prostate cancer, however there is no curative treatment option once prostate becomes metastatic.

Renal cell carcinoma is one of the urologic cancers that has lower incidence rates and poor prognosis. About 30% are diagnosed in their metastatic stage. It is a type of cancer that originates in the PCT. Therapy considered for this form of cancer include nephrectomy, radiation therapy, chemotherapy and embolization. The role of mAbs in Renal cell carcinoma is undertaken and studied in clinical trials treatment has not been very successful. Several trials have been carried out to check for its efficacy the details of which have been mentioned below as renal cell carcinoma (RCC) is a largely chemotherapy-resistant disease. It is immune responsive disease; therefore, checkpoint inhibitors can be considered as agents for the treatment of RCC [15].

The pivotal drug trial Checkmate 214 showed good objective responses in case of poor and intermediate risk patients in combination immunotherapy (Nivolumab/ Ipilimumab) vs. the tyrosine kinase inhibitor sunitinib and can be considered as a first line treatment in these subjects for RCC. However, for favorable high-risk patients, the single agent sunitinib showed more response rate. Survival rates were similar in both arms. In another clinical trial Keynote 426, Pembrolizumab (anti-PD-1) plus axitinib, the responses were good and this led to its approval by leading to Food and Drug Administration (FDA) first line treatment. In another trial named, Javelin 101 Renal, avelumab (anti-PD-L1) plus axitinib vs. sunitinib the OS

In addition to this, there are many clinical trials that are underway for RCC (**Table 1**). Nivolumab was approved advanced clear-cell RCC by the FDA and is under investigation as pre- and postoperative therapy in mRCC. Combinatorial treatments with various drugs are also being studied in various clinical trials. Atezolizumab phase I trial involving 17 mRCC patients showed promising results as 7 had stable disease for more than 24 weeks. In another phase Ia study, of the 63 patients with clear-cell RCC whose OS was 28.9 months. Pembrolizumab is currently being investigated in two randomized phase II trials of mRCC patients. It has been found to be acceptable for safe use [17]. Several trials evaluating pembrolizumab in combination with various agents are also undergoing. Avelumab showed an acceptable usage when used in patients with advanced solid tumors and safety profile. Two ongoing trials are still being evaluated for avelumab in combination with axitinib Durvalumab. There are ongoing trials evaluating durvalumab in combination with other drugs, including tremelimumab for patients with advanced malignancies including RCC. Ipilimumab: Phase-II studies have been undergoing and the results are found to be partial response with adverse events being reported. In addition, Ipilimumab and nivolumab is being investigated and found to be favorable [18].

**4. Monoclonal antibodies and renal cell carcinoma**

was not significantly different between the two arms [16].

**130**

*List of the Clinical trials that are underway for RCC.*

#### **5. Monoclonal antibodies and bladder cancer**

Bladder cancer is one of the common cancers which develop in the tissues of the bladder. It is a type of Urolethial cancer. There are several methods which have been developed as a cancer therapy for bladder cancer and the most common being the, Bacillus Calmette-Guerin which has a very high success rate. The role of immunotherapy in Bladder cancer has been detailed in a number of case report and clinical trial studies [19]. The incidence of Bladder cancer is comparatively found to be higher in America when compared to other forms of malignancy.

Here are the various monoclonal antibodies that have been considered as a cancer therapy for the bladder cancer. 2016-Atezolizumab, was the first mAb to be approved by the FDA and also accepted by the European Association of Urology (EUA) as second-line therapy for patients with advanced Bladder Cancer. It is a PD-1/PD-L1 checkpoint inhibitor It has been used for subjects even with metastatic or advanced bladder cancer. 2017-Avelumab was also approved by FDA for urothelial cancers. It acts against PD-L1. A phase Ib clinical trial had been carried out with metastatic urothelial cancer which showed inconvincing results. However in the phase II trial, avelumab exhibited a good antitumor response in patients with advanced urothelial cancer whose tumors progressed during or after platinum-based chemotherapy 2017-Durvalumab has also received approval by FDA for the treatment of Bladder cancer. Studies in phases I and II patients have confirmed the effectiveness of durvalumab: It has shown responses in a number of clinical trial studies. It is a drug that acts against the PD-L1. 2017-Nivolumab is a FDA and EUA approved human mAb that acts against the PD-1. It was accepted on the basis of a single-arm phase trial for 270 platinum pretreated patients. The result has been 20% response rate [20].

Nivolumab was also tested on advanced or metastatic Bladder cancer subjects. In this study many adverse events were reported. Unlike the above mentioned

mAbs,PD-L1 overexpression among patients was not significant. In another phase II clinical trial with subjects also receiving platinum-based chemotherapy showed a two-month progression-free period. In patients with PD-L1 overexpression compared to patients with low-expression, a difference in drug effects was observed. Many subjects did show adverse events [21].

Pembrolizumab has been showing positive responses in cases of advanced bladder cancer. It is a humanized monoclonal antibody used in the treatment of bladder cancer and is approved by the FDA and EAU. In a study conducted by on pembrolizumab by Bellmunt et al., it was observed that this mAb showed lower adverse events and longer survival by about 3 months which was significant when compared to chemotherapy drugs such as docetaxel and paclitaxel [22]. In a case report mentioning the treatment with pembrolizumab as reported by McDermott et al., it was observed that adverse events were not observed after 8 months and hence suggested that pembrolizumab can be considered as a PD –I inhibitor [23]. In patients with DNA repair defects, pembrolizumab can also be considered for treatment. This drug not only reduced the risk of developing newer cancers but also prevented premalignant hyperplastic lesion. This shall be a rational therapy. Pembrolizumab is also shown better survival rates when compared to chemotherapy as mentioned farina and his colleagues.

A novel murine monoclonal antibody KMP1 has been studied by cheng and his colleagues [24]. The study was conducted both in vitro and in vivo settings It identified the CD44 epitope on bladder cancer cells and bound to it due to O-linked glycosylation and thereby exhibit antitumor potential in both settings. Future studies may be recommended to understand the exact glycolsylation mechanism also produce humanized forms and also conjugate types for better therapeutics. Enfortumab vedotin delivers toxic drugs to tumors. It is an antibody-drug conjugate that targets the Nectin-4 pathway, it has been approved for further study in case of bladder cancer. Immunotherapy has significantly reduced the risk of recurrence for bladder cancer while also increasing the percentage of patients who see a complete response post-surgery. Investigational bladder cancer immunotherapies also have the capacity change the outcomes positively for patients with this disease.
