**7. Adjuvant therapy in the era of the new targeted therapy**

#### **7.1. Targeted therapy**

Systemic therapy for mRCC has particularly changed over the last decade with the introduction of targeted therapy and the evolvement of tyrosine kinase inhibitors (TKI) [7, 49–53]. This development has directly resulted from an improved understanding of the pathogenesis and molecular biology of RCC [49–54]. TKIs have provided a novel therapeutic approach for better managing the pathology through the inhibition of targets such as the mammalian target of rapamycin (mTOR) pathway and the vascular endothelial growth factor receptor (VEGFR), which consequently help inhibit processes that are critical for cancer progression [7, 49–53]. Particularly in cases of metastatic RCC, these inhibitors have been effective in increasing the overall survival and response rates than previously used immunotherapy and chemotherapy agents [7, 49–53].

Seven drugs are now approved for targeted therapy, and several others are being evaluated in clinical trials [50–53, 55]. At the molecular level, the mechanism of these drugs involves interrupting the molecular signal transduction of various signaling pathways which then ultimately affects pathogenic factors like tumor vascularity, growth and progression [50–53, 55]. Sunitinib and Pazopanib are currently the accepted standard of care for the management of metastatic RCC and are the most widely used first line agent due to their robust clinical efficacy and established toxicity profile [50–53, 55]. The current set of therapeutic agents used in targeted therapy exploit the Von Hippel-Lindau (VHL) and hypoxia-inducible factor (HIF) pathway associated with clear cell RCC pathogenesis [56, 57].

## **7.2. VHL-HIF pathway**

Clear Cell RCC (ccRCC) normally entails a biallelic inactivation of the VHL tumor suppressor gene at the 3p25-26 locus. VHL inactivation, which occurs due to factors such as mutation, hyper-methylation, or deletions, results in the formation of defective pVHL protein—ultimately leading to the activation and upregulation of HIF-1α [56, 57]. Activated HIF protein serves as a transcription factor for various pro-tumorigenic target genes such as vascular endothelial growth factor (VEGF), transforming growth factor-α and platelet-derived growth factor (PDGF) that are involved in pathogenic processes like angiogenesis, tumor cell proliferation and cell survival. [56, 57] Apart from this central pathway, the mTOR pathway also intersects with HIF pathway upstream of the VHL gene and hence also plays a critical role in influencing HIF process and function. [56, 57] Thus, inhibiting different targets in this pathway has yielded favorable results in mRCC cases [50–53, 55–57]. Given the success of targeted therapy agents in the metastatic setting, recent efforts have been focused into translating this into the adjuvant setting.

*7.3.2. ASSURE trial*

*7.3.3. S-TRAC trial*

The ASSURE trial, completed in 2016, was a randomized, double-blind, placebo-controlled, phase 3 clinical trial in which 1943 patients from 226 study centers in North America were assigned to one of three intervention arms—sunitinib, sorafenib or placebo in intermediate to high-risk patients [61]. Sunitinib patients received 50 mg for 54 weeks on a 4 of 6 week cycle; sorafenib recipients received 400 mg twice per day throughout each cycle, and placebo recipients were randomly assigned either the sunitinib placebo or the sorafenib placebo. The interventions were evaluated using DFS as the primary endpoint. Trial results indicated that the median DFS duration was approximately 5.8 years for sunitinib [HR: 1.02; 97.5% CI: 0.85–1.23; P = 0.8038], 6.1 years for sorafenib (HR: 0.97; 97.5% CI: 0.80–1.17; P = 0.7184), and 6.6 years for placebo—hence suggesting no survival benefit from the interventions relative to the placebo. Instead, the results further reported detrimental effects due to the increased toxicity of the treatment despite the dose reductions—suggesting no benefit of the particular TKI in the adjuvant setting. Of note, this trial had a higher number of TKI dose reductions (potentially suggesting suboptimal drug dosing) and more intermediate risk for recurrence patients than other trials.

Current Role of Adjuvant Therapy in High Risk for Recurrence Resected Kidney Cancer

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179

The S-TRAC study, also completed in 2016, was a prospective, randomized, double-blind, phase 3 clinical trial involving 615 patients from 21 countries [62]. Of the 615 patients who underwent randomization, 309 were assigned to the sunitinib arm and 306 to the placebo arm. These patients were all "high risk of recurrence." Sunitinib recipients received 50 mg for a

#### **7.3. Clinical trials: targeted therapy in adjuvant setting**

The contemporary endeavors to transpose targeted therapy in the adjuvant setting have been inspired by the increased clinical knowledge gained through the development and evaluation of interventions for stage IV disease [9, 10, 58, 59]. There are currently seven multicenter, double-blind, placebo-controlled, randomized adjuvant clinical trials, involving targeted therapy agents [9, 10, 58, 59]. Five of these trials involve tyrosine kinase inhibitors, while one involves an mTOR inhibitor and the other a monoclonal chimeric antibody [9, 10, 58–63]. So far, four of these trials have been completed including the, ARISER, ASSURE, S-TRAC and PROTECT trials while the other ones are still in progress [60–63].

#### *7.3.1. ARISER trial*

This ARISER trial, completed in 2014, evaluated the efficacy of girentuximab [60], a monoclonal antibody to carbonic anhydrase IX (a HIF downstream target gene), in the adjuvant setting for intermediate to high risk for recurrence patients. This multicenter, phase III trial involved 864 patients with resected clear cell tumors, who were randomized to receive either girentuximab or placebo, once a week, for 24 weeks. Girentuximab recipients received a 50 mg dose during the first week followed by a weekly dose of 20 mg for the next 23 weeks. The median disease free survival (DFS) duration for the participants in the intervention arm was 71.4 months (HR: 0.97; 95% CI, 0.79–1.18) while the endpoint was never reached for the placebo group. As such, the study indicated no interventional advantage but it recommended further investigation of adjuvant girentuximab in patients with high levels of CAIX in affected renal tissue.

endothelial growth factor (VEGF), transforming growth factor-α and platelet-derived growth factor (PDGF) that are involved in pathogenic processes like angiogenesis, tumor cell proliferation and cell survival. [56, 57] Apart from this central pathway, the mTOR pathway also intersects with HIF pathway upstream of the VHL gene and hence also plays a critical role in influencing HIF process and function. [56, 57] Thus, inhibiting different targets in this pathway has yielded favorable results in mRCC cases [50–53, 55–57]. Given the success of targeted therapy agents in the metastatic setting, recent efforts have been focused into translating this

The contemporary endeavors to transpose targeted therapy in the adjuvant setting have been inspired by the increased clinical knowledge gained through the development and evaluation of interventions for stage IV disease [9, 10, 58, 59]. There are currently seven multicenter, double-blind, placebo-controlled, randomized adjuvant clinical trials, involving targeted therapy agents [9, 10, 58, 59]. Five of these trials involve tyrosine kinase inhibitors, while one involves an mTOR inhibitor and the other a monoclonal chimeric antibody [9, 10, 58–63]. So far, four of these trials have been completed including the, ARISER, ASSURE, S-TRAC and

This ARISER trial, completed in 2014, evaluated the efficacy of girentuximab [60], a monoclonal antibody to carbonic anhydrase IX (a HIF downstream target gene), in the adjuvant setting for intermediate to high risk for recurrence patients. This multicenter, phase III trial involved 864 patients with resected clear cell tumors, who were randomized to receive either girentuximab or placebo, once a week, for 24 weeks. Girentuximab recipients received a 50 mg dose during the first week followed by a weekly dose of 20 mg for the next 23 weeks. The median disease free survival (DFS) duration for the participants in the intervention arm was 71.4 months (HR: 0.97; 95% CI, 0.79–1.18) while the endpoint was never reached for the placebo group. As such, the study indicated no interventional advantage but it recommended further investigation of adjuvant girentuximab in patients with high levels of CAIX

into the adjuvant setting.

178 Evolving Trends in Kidney Cancer

*7.3.1. ARISER trial*

in affected renal tissue.

**7.3. Clinical trials: targeted therapy in adjuvant setting**

PROTECT trials while the other ones are still in progress [60–63].

The ASSURE trial, completed in 2016, was a randomized, double-blind, placebo-controlled, phase 3 clinical trial in which 1943 patients from 226 study centers in North America were assigned to one of three intervention arms—sunitinib, sorafenib or placebo in intermediate to high-risk patients [61]. Sunitinib patients received 50 mg for 54 weeks on a 4 of 6 week cycle; sorafenib recipients received 400 mg twice per day throughout each cycle, and placebo recipients were randomly assigned either the sunitinib placebo or the sorafenib placebo. The interventions were evaluated using DFS as the primary endpoint. Trial results indicated that the median DFS duration was approximately 5.8 years for sunitinib [HR: 1.02; 97.5% CI: 0.85–1.23; P = 0.8038], 6.1 years for sorafenib (HR: 0.97; 97.5% CI: 0.80–1.17; P = 0.7184), and 6.6 years for placebo—hence suggesting no survival benefit from the interventions relative to the placebo. Instead, the results further reported detrimental effects due to the increased toxicity of the treatment despite the dose reductions—suggesting no benefit of the particular TKI in the adjuvant setting. Of note, this trial had a higher number of TKI dose reductions (potentially suggesting suboptimal drug dosing) and more intermediate risk for recurrence patients than other trials.

#### *7.3.3. S-TRAC trial*

The S-TRAC study, also completed in 2016, was a prospective, randomized, double-blind, phase 3 clinical trial involving 615 patients from 21 countries [62]. Of the 615 patients who underwent randomization, 309 were assigned to the sunitinib arm and 306 to the placebo arm. These patients were all "high risk of recurrence." Sunitinib recipients received 50 mg for a year on a 4 of 6 week cycle. The interventions were evaluated by comparing DFS, the primary endpoint of the study, between the two trial arms. The study results indicated that the median DFS duration was 6.8 years (95% CI: 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI: 3.8–6.6) in the placebo group (HR: 0.76; 95% CI: 0.59–0.98; P = 0.03). The adverse effects observed in sunitinib recipients were consistent with its known toxicity profile. As such, the results from this trial support the potential for sunitinib as a treatment option in the adjuvant setting with a DFS advantage. However, overall survival endpoints have not yet been reported.

that might have led to inconsistent outcomes include varying dose regimens, specifically with respect to the midtrial dose reductions for sunitinib, as well as differing trial criteria for estab-

Current Role of Adjuvant Therapy in High Risk for Recurrence Resected Kidney Cancer

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181

The development of therapy that targets oncogenic signaling pathways has advanced the treatment landscape for patients with advanced renal cell carcinoma. While nonspecific immunotherapy with IL-2 and IFN-α was the former mainstay in the management of metastatic disease, there was a shift away from it with the advent of targeted therapy which yielded relatively better response rates [32–34, 48–54, 65–68]. However, over the last couple of years, cancer immunotherapy has been revisited and, as a result, targeted immunomodulatory therapy, involving novel immunomodulating agents, has been reincorporated in combination therapy regimes for mRCC management—hence allowing for an induced immuonologic effect in addition to the inhibitory effect on tumor biology and microenvironment [69, 70]. This has been inspired in part by disease resistance that is progressively manifesting itself against standard targeted therapy in the landscape of metastatic disease management [69, 70]. Given that multiple mechanisms are employed by tumors to evade and suppress the immune system, research toward better understanding those mechanisms of immunomodulation has been critical in informing the therapeutic landscape [69, 71]. Particularly, an improved understanding of the factors regulating the antitumor immune response has led to the development a novel form of cancer immunotherapy involving checkpoint inhibitors and other immune therapies such as T-cell agonists, adoptive T-cell therapies and novel vaccines which are being

Immune checkpoints serve a critical protective function of preventing immune response against host cells through a series of complex interactions [71–73]. However, investigation into the pathogenic mechanisms of RCC revealed that cancer cells can induce similar interactions with host checkpoint receptors and can hence suppress the human immune response [71–73]. Immune checkpoint inhibitors counter these molecular mechanisms through which

Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) are currently the most well understood inhibitory checkpoint receptors [71–73]. The PD-1/PD-L1 axis involves an inhibitory interaction between a T-cell inhibitory ligand PD-L1, expressed on tumor cell surface, and a PD-1 receptor on the lymphocyte [71–73]. Hence, mimicking this interaction ultimately allows tumor cells to evade the adaptive immune response through suppression of T-cell function. The CTLA-4 pathway is similarly exploited by tumor cells [71–73]. During an adaptive immune response, immune activation occurs through an interaction between the T-cell receptor (TCR) and the antigen-presenting cell (APC) along with the co-stimulation of CD28 on the T cell [71–73]. This activation is negatively regulated by an inhibitory interaction between CTLA-4 and its ligands—CD80 or CD86 [71–73]. Thus, the targeted inhibition of these checkpoint receptors through targeted antibodies, in both the pathways mentioned above, could allow for T-cell activation and

lishing disease status and assessing primary end point status [61, 62, 64].

evaluated across different trials for metastatic RCC [69, 71].

**7.5. Immune checkpoint inhibitors**

effective immune function [71–73].

tumor cells evade immune recognition [71–73].

**7.4. Targeted immunomodulatory therapy**

#### *7.3.4. PROTECT trial*

The PROTECT study, completed recently in 2017, was a phase 3 randomized clinical trial that evaluated the efficacy of adjuvant pazopanib as compared to placebo in preventing RCC recurrence in intermediate to high-risk patients [63]. The trial enrolled 1538 participants and the majority of the pazopanib recipients received a revised dosage of 600 mg, daily for a year, following a dose reduction from 800 mg which caused severe side effects. The interventions were evaluated by comparing DFS as the primary endpoint measure between the two trial arms. The study did not meet its primary endpoint and indicated no significant benefit of pazopanib-600 mg in prolonging DFS as compared to placebo (HR: 0.86; 95% CI, 0.70–1.06; P = 0.165). However, a subgroup analysis of pazopanib-800 mg recipients indicated a 31% decline in DFS (HR, 0.69; 95% CI, 0.51–0.94; *P* = 0.02). While the DFS results were conflicting between the 600 mg and 800 mg groups, the study reported similar adverse event profiles between both the groups.

#### *7.3.5. Comparison of current adjuvant trial design*

The differing outcomes that have been indicated in the current set of completed trials may be accounted for by the distinct sample groups, dose regimens, risk assessment criteria and trial methods [60–63]. This collectively represents a fundamental limitation that underscores all current adjuvant clinical trials. First, the patient inclusion criteria characteristically differ, in multiple ways, across all adjuvant trials [60–63]. For example, in the S-TRAC trial, the selected sample exclusively included patients with late-stage, loco-regional, clear-cell RCC while other trials such as the ASSURE, ARTISER and PROTECT trials used a less restricted criteria and included patients with stage 1 or stage 2 tumors and non-clear-cell histologies [60–63]. In addition, another major cause of heterogeneity lies in the risk assessment and stratification criteria as the scoring system used in the current set of adjuvant trials are not standardized, and hence this invariably contributes to a varied assessment of recurrence risk [60–63]. With respect to the conflicting sunitinib trials (S-TRAC vs. ASSURE), additional sources of variation that might have led to inconsistent outcomes include varying dose regimens, specifically with respect to the midtrial dose reductions for sunitinib, as well as differing trial criteria for establishing disease status and assessing primary end point status [61, 62, 64].

#### **7.4. Targeted immunomodulatory therapy**

year on a 4 of 6 week cycle. The interventions were evaluated by comparing DFS, the primary endpoint of the study, between the two trial arms. The study results indicated that the median DFS duration was 6.8 years (95% CI: 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI: 3.8–6.6) in the placebo group (HR: 0.76; 95% CI: 0.59–0.98; P = 0.03). The adverse effects observed in sunitinib recipients were consistent with its known toxicity profile. As such, the results from this trial support the potential for sunitinib as a treatment option in the adjuvant setting with a DFS advantage. However, overall survival endpoints have not yet been reported.

The PROTECT study, completed recently in 2017, was a phase 3 randomized clinical trial that evaluated the efficacy of adjuvant pazopanib as compared to placebo in preventing RCC recurrence in intermediate to high-risk patients [63]. The trial enrolled 1538 participants and the majority of the pazopanib recipients received a revised dosage of 600 mg, daily for a year, following a dose reduction from 800 mg which caused severe side effects. The interventions were evaluated by comparing DFS as the primary endpoint measure between the two trial arms. The study did not meet its primary endpoint and indicated no significant benefit of pazopanib-600 mg in prolonging DFS as compared to placebo (HR: 0.86; 95% CI, 0.70–1.06; P = 0.165). However, a subgroup analysis of pazopanib-800 mg recipients indicated a 31% decline in DFS (HR, 0.69; 95% CI, 0.51–0.94; *P* = 0.02). While the DFS results were conflicting between the 600 mg and 800 mg groups, the study reported similar adverse event profiles

The differing outcomes that have been indicated in the current set of completed trials may be accounted for by the distinct sample groups, dose regimens, risk assessment criteria and trial methods [60–63]. This collectively represents a fundamental limitation that underscores all current adjuvant clinical trials. First, the patient inclusion criteria characteristically differ, in multiple ways, across all adjuvant trials [60–63]. For example, in the S-TRAC trial, the selected sample exclusively included patients with late-stage, loco-regional, clear-cell RCC while other trials such as the ASSURE, ARTISER and PROTECT trials used a less restricted criteria and included patients with stage 1 or stage 2 tumors and non-clear-cell histologies [60–63]. In addition, another major cause of heterogeneity lies in the risk assessment and stratification criteria as the scoring system used in the current set of adjuvant trials are not standardized, and hence this invariably contributes to a varied assessment of recurrence risk [60–63]. With respect to the conflicting sunitinib trials (S-TRAC vs. ASSURE), additional sources of variation

*7.3.4. PROTECT trial*

180 Evolving Trends in Kidney Cancer

between both the groups.

*7.3.5. Comparison of current adjuvant trial design*

The development of therapy that targets oncogenic signaling pathways has advanced the treatment landscape for patients with advanced renal cell carcinoma. While nonspecific immunotherapy with IL-2 and IFN-α was the former mainstay in the management of metastatic disease, there was a shift away from it with the advent of targeted therapy which yielded relatively better response rates [32–34, 48–54, 65–68]. However, over the last couple of years, cancer immunotherapy has been revisited and, as a result, targeted immunomodulatory therapy, involving novel immunomodulating agents, has been reincorporated in combination therapy regimes for mRCC management—hence allowing for an induced immuonologic effect in addition to the inhibitory effect on tumor biology and microenvironment [69, 70]. This has been inspired in part by disease resistance that is progressively manifesting itself against standard targeted therapy in the landscape of metastatic disease management [69, 70].

Given that multiple mechanisms are employed by tumors to evade and suppress the immune system, research toward better understanding those mechanisms of immunomodulation has been critical in informing the therapeutic landscape [69, 71]. Particularly, an improved understanding of the factors regulating the antitumor immune response has led to the development a novel form of cancer immunotherapy involving checkpoint inhibitors and other immune therapies such as T-cell agonists, adoptive T-cell therapies and novel vaccines which are being evaluated across different trials for metastatic RCC [69, 71].

#### **7.5. Immune checkpoint inhibitors**

Immune checkpoints serve a critical protective function of preventing immune response against host cells through a series of complex interactions [71–73]. However, investigation into the pathogenic mechanisms of RCC revealed that cancer cells can induce similar interactions with host checkpoint receptors and can hence suppress the human immune response [71–73]. Immune checkpoint inhibitors counter these molecular mechanisms through which tumor cells evade immune recognition [71–73].

Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) are currently the most well understood inhibitory checkpoint receptors [71–73]. The PD-1/PD-L1 axis involves an inhibitory interaction between a T-cell inhibitory ligand PD-L1, expressed on tumor cell surface, and a PD-1 receptor on the lymphocyte [71–73]. Hence, mimicking this interaction ultimately allows tumor cells to evade the adaptive immune response through suppression of T-cell function. The CTLA-4 pathway is similarly exploited by tumor cells [71–73]. During an adaptive immune response, immune activation occurs through an interaction between the T-cell receptor (TCR) and the antigen-presenting cell (APC) along with the co-stimulation of CD28 on the T cell [71–73]. This activation is negatively regulated by an inhibitory interaction between CTLA-4 and its ligands—CD80 or CD86 [71–73]. Thus, the targeted inhibition of these checkpoint receptors through targeted antibodies, in both the pathways mentioned above, could allow for T-cell activation and effective immune function [71–73].

The first checkpoint inhibitor which demonstrated a survival benefit in patients with metastatic RCC was nivolumab—an anti-PD1 monoclonal antibody [74]. The inhibitor, which received FDA approval in 2015 based on the results from a trial evaluating nivolumab versus everolimus, is effective in yielding positive response rates when used for treatment of advanced RCC in patients who have undergone prior anti-angiogenic therapy [74]. Apart from nivolumab, multiple other checkpoint inhibitors are being currently evaluated in different trials against advanced RCC [71–73].

**Adjuvant clinical trials in RCC using immune therapies**

Clark et al. [48] IL-2 vs. observation T3b-4 or N1-3 (LA)

IFN-α-NL vs. observation

IL-2 and IFN-α2a and intravenous 5 vs. fluorouracil

IL-2 and IFN-α2a and intravenous 5-fluorouracil

Messing et al. [33]

Atzpodien et al.

Aitchison et al.

[36]

[35]

**Authors Intervention Patient population Design No. of** 

pT3–4a and/or node-positive

pT3b/c pN0 or pT4pN0), pN, complete resection of tumor relapse or solitary metastasis (R0)

T3b-c,T4 or any pT and pN1 or pN2 or positive microscopic margins or microscopic vascular

invasion

or M1

**patients**

http://dx.doi.org/10.5772/intechopen.78684

69 total; 44 LA, 25M1 disease

Multicenter, randomized, controlled trial

Current Role of Adjuvant Therapy in High Risk for Recurrence Resected Kidney Cancer

Multicenter, randomized, controlled trial

Multicenter, randomized, controlled trial

Multicenter, randomized, controlled trial **Outcome**

283 At 10.4 years median follow-up: Median survival: 7.4 years (control) vs. 5.1 years (treatment) (P ¼ \_0.09). DFS: 3.0 years (control) vs. 2.2 years (treatment) (P ¼

\_0.33)

203 At median follow-up of 4.3 years: 2-year OS: 91% (control) vs. 81% (treatment) 5-year OS: 76% (control) vs. 58% (treatment) 8-year OS: 66% (control) vs. 58% (treatment) (P ¼ \_0.0278)

> 2-year DFS: 62% (control) vs. 54% (treatment) 5-year DFS: 49% (control) vs. 42% (treatment) 8-year DFS: 49% (control) vs. 39% (treatment) (P ¼ \_0.2398)

309 3-year DFS: 50%

(control) vs. 60% (treatment) (HR 0.87; 95% CI, 0.63–1.20) 5-year OS: 60% (control) vs. 68% (treatment) (HR 0.91; 95% CI, 0.60–1.38)

2-year DFS: 48% (control in LA patients) vs. 53% (treatment in LA patients) (P ¼ \_0.73) 2-year OS: 77% (control in LA patients) vs. 86%

183

#### **7.6. Immunomodulatory therapy in the adjuvant setting**

Given their recent development, many immune checkpoint inhibitors are still being evaluated for their efficacy and toxicity against metastatic RCC, and hence investigation of these inhibitors in the adjuvant setting has been limited. Currently, there are a few ongoing clinical trials that are evaluating different checkpoint inhibitors in both the adjuvant setting as well as the neo-adjuvant (presurgery) setting (**Table 3**) [75–78].

The *IMmotion*, *KEYNOTE-564*, and *CheckMate 914* are phase III trials evaluating the efficacy and safety of adjuvant atezolizumab, pembrolizumab, and nivolumab/ipilimumab (combinational regimen) respectively in prolonging the DFS of RCC patients who are at high risk of disease recurrence post nephrectomy [75, 77, 78]. In addition to the adjuvant trials, an ongoing study in the neo-adjuvant setting includes the PROSPER trial which is evaluating the efficacy of pre-nephrectomy nivolumab [75]. These trials, which have either started already or are expected to begin later this year, are currently in their recruitment or pre-recruitment phases and are anticipated to be completed by 2022–2024. [75, 77, 78] Apart from these clinical



The first checkpoint inhibitor which demonstrated a survival benefit in patients with metastatic RCC was nivolumab—an anti-PD1 monoclonal antibody [74]. The inhibitor, which received FDA approval in 2015 based on the results from a trial evaluating nivolumab versus everolimus, is effective in yielding positive response rates when used for treatment of advanced RCC in patients who have undergone prior anti-angiogenic therapy [74]. Apart from nivolumab, multiple other checkpoint inhibitors are being currently evaluated in different trials against

Given their recent development, many immune checkpoint inhibitors are still being evaluated for their efficacy and toxicity against metastatic RCC, and hence investigation of these inhibitors in the adjuvant setting has been limited. Currently, there are a few ongoing clinical trials that are evaluating different checkpoint inhibitors in both the adjuvant setting as well as the

The *IMmotion*, *KEYNOTE-564*, and *CheckMate 914* are phase III trials evaluating the efficacy and safety of adjuvant atezolizumab, pembrolizumab, and nivolumab/ipilimumab (combinational regimen) respectively in prolonging the DFS of RCC patients who are at high risk of disease recurrence post nephrectomy [75, 77, 78]. In addition to the adjuvant trials, an ongoing study in the neo-adjuvant setting includes the PROSPER trial which is evaluating the efficacy of pre-nephrectomy nivolumab [75]. These trials, which have either started already or are expected to begin later this year, are currently in their recruitment or pre-recruitment phases and are anticipated to be completed by 2022–2024. [75, 77, 78] Apart from these clinical

**patients**

Multicenter, randomized, controlled trial

Multicenter, randomized, controlled trial **Outcome**

(control) vs. 0.660 (treatment) (HR 1.040; 95% CI, 0.671–1.613, P ¼ \_0.861)

5-year DFS: 0.671 (control) vs. 0.567 (treatment) (HR 1.412; 95% CI, 0.927–2.149, P ¼ \_0.107)

(control) vs. 0.73 (treatment) 10-year DFS: 0.60 (control) vs. 0.73 (treatment) (HR 0.84; 95% CI, 0.54–1.33, P ¼ \_0.47)

247 5-year OS: 0.665

310 5-year DFS: 0.73

advanced RCC [71–73].

182 Evolving Trends in Kidney Cancer

**7.6. Immunomodulatory therapy in the adjuvant setting**

neo-adjuvant (presurgery) setting (**Table 3**) [75–78].

**Adjuvant clinical trials in RCC using immune therapies**

IFN-α2b vs. placebo

IL-2 and IFN-α \_v observation

Pizzocarro et al.

Passalacqua et al. [34]

[32]

**Authors Intervention Patient population Design No. of** 

Robson stages II and III (T3aN0M0 and T3bN0M0 or T2/3N1-3M0)

pT1, T2, T3 a-b-c; pN0-pN3,M0M


was taken in the context of the data from ASSURE. Results showed that only 1 out of 15 (6%) of the panel would change their standard of care when considering the DFS and OS closest to S-TRAC (DFS: HR 0.75, *p* < 0.05; OS: HR 1.0, *p* > 0.05). Standard practice would only be significantly influenced by a significant survival benefit. In addition, kidney cancer patients from the International Kidney Cancer Coalition (IKCC) participated in a questionnaire about

**size**

**size**

**Inclusion criteria (histology; stage/**

**Primary endpoint measure**

http://dx.doi.org/10.5772/intechopen.78684

DFS,OS 2014

DFS 2016

DFS 2016

DFS 2017

**Primary endpoint measure**

DFS 2019

DFS 2019

DFS 2021

**Estimated completion date**

**Completion date**

185

**grade)**

Current Role of Adjuvant Therapy in High Risk for Recurrence Resected Kidney Cancer

NX,MO, T2,N0, NX,MO (grade ≥ 3) (risk: intermediate-High)

1943 **Any**; pT1bN0M0 (grades 3–4), pT2- 4N1-3M0 (risk: intermediate-high)

> (grades 3–4) or pT3-4N0M0 or pTxN1M0 (risk: High)

(grades 3–4) or pT3-4N0M0 or pTxN1M0 (risk: intermediate-high)

**Inclusion criteria (histology; stage/**

(grade 4), pT1b N0M0 (grades 3–4), pT2-4N0M0, pT1b-4N1M (risk: intermediate-high)

4N0M0 or pTxN1M0 (risk:

high)

(grades 3–4) or pT2- 4N1-3M0 (risk: intermediate-high)

**grade)**

**Trial name. Trial ID Intervention Sample** 

ASSURE NCT00326898 Sorafenib or

**Table 4.** RCC adjuvant clinical trials that have been completed.

**Trial name. Trial ID Intervention Sample** 

SORCE NCT00492258 Sorafenib 1420 **Any**; pT1a N0M0

ATLAS NCT01599754 Axitinib 592 **ccRCC**; pT2-

EVEREST NCT01120249 Everolimus 1218 **Any**; pT1bN0M0

**Table 5.** Current set of adjuvant clinical trials that are still in progress.

ARISER NCT00087022 Girentuximab 864 **ccRCC**; T1b,N0,

Sunitinib

S-TRAC NCT00375674 Sunitinib 615 **ccRCC**; pT2N0M0

PROTECT NCT01235962 Pazopanib 1500 **ccRCC**; pT2N0M0

IFN, interferon; IL, interleukin; NL, neutral lymphoblastoid; LA, locally advanced; BCG, bacillus Calmette-Guérin; CI, confidence interval; LA, locally advanced; HR, hazard ratio; M, metastatic; OS, overall survival; DFS, disease-free survival.

**Table 3.** Adjuvant clinical trials in RCC using immune therapies.

studies, there are several checkpoint inhibitors that are in development as well as others that are currently being evaluated in trials for mRCC and would subsequently be assessed in the adjuvant setting [71–73] (**Tables 4**–**6**).

#### **7.7. Change of practice**

The European Association of Urology Renal Cell Cancer Guidelines Panel, which includes patient representatives and clinicians, considered a number of different scenarios to determine what would be required from S-TRAC to change practice. The decision on practice change


**Table 4.** RCC adjuvant clinical trials that have been completed.

was taken in the context of the data from ASSURE. Results showed that only 1 out of 15 (6%) of the panel would change their standard of care when considering the DFS and OS closest to S-TRAC (DFS: HR 0.75, *p* < 0.05; OS: HR 1.0, *p* > 0.05). Standard practice would only be significantly influenced by a significant survival benefit. In addition, kidney cancer patients from the International Kidney Cancer Coalition (IKCC) participated in a questionnaire about


**Table 5.** Current set of adjuvant clinical trials that are still in progress.

studies, there are several checkpoint inhibitors that are in development as well as others that are currently being evaluated in trials for mRCC and would subsequently be assessed in the

IFN, interferon; IL, interleukin; NL, neutral lymphoblastoid; LA, locally advanced; BCG, bacillus Calmette-Guérin; CI, confidence interval; LA, locally advanced; HR, hazard ratio; M, metastatic; OS, overall survival; DFS, disease-free

The European Association of Urology Renal Cell Cancer Guidelines Panel, which includes patient representatives and clinicians, considered a number of different scenarios to determine what would be required from S-TRAC to change practice. The decision on practice change

adjuvant setting [71–73] (**Tables 4**–**6**).

**Table 3.** Adjuvant clinical trials in RCC using immune therapies.

**Adjuvant clinical trials in RCC using immune therapies**

Autologous irradiated tumor cells and BCG vs. observation

irradiated tumor cells & BCG & hormone vs. hormone

tumor-derived heat-shock protein (glycoprotein 96)-peptide complex (HSPPC-96; vitespen) vs. observation

Autologous renal tumor cells (Reniale)

Galligioni et al.

184 Evolving Trends in Kidney Cancer

Adler et al. [40] Autologous

Wood et al. [41] Autologous,

Jocham et al. [42]

survival.

[39]

**Authors Intervention Patient population Design No. of** 

cT1b–T4 N0 M0, or cTanyN1- 2M0Multicenter

Stages I, II, and III Prospective,

All stages Prospective,

pT2–3b pN0–3 Multicenter,

randomized, controlled trial

randomized, controlled trial

Multicenter, randomized, controlled trial

randomized, controlled trial **patients**

**Outcome**

median follow-up: 5-year OS: 78% (control) vs. 69% (treatment) 5-year DFS: 72% (control) vs. 63% (treatment)

prolongation of DFS for stage I, II, and III

median follow-up: recurrence: 39.8% (control) vs. 37.7% (treatment) (HR 0.923; 95% CI, 0.729–1.169, P ¼ \_0.506) OS not mature

120 At 61 months

43 Trend for

819 At 1.9 years

(P o.1)

558 At 5-year follow-up: DFS: 67.8% (control) vs. 77.4% (treatment) (P ¼ \_0.0204). At 70-month follow-up: DFS: 59.3% (control) vs. 72% (treatment). HR for tumor progression: 1.58 (95% CI 1.05–2.37) and 1.59 (1.07–2.36) (P ¼ \_0.0204)

**7.7. Change of practice**


incorporating a genetic recurrence score to evaluate risk of relapse in patients, developing an adequate and an objectively standardized adjuvant trial design, identifying novel biomarkers

Current Role of Adjuvant Therapy in High Risk for Recurrence Resected Kidney Cancer

http://dx.doi.org/10.5772/intechopen.78684

187

That based on results from current trials, the "high risk for recurrence" RCC patient population (T3-T4, grade 3-4) may benefit from adjuvant sunitinib providing DFS advantage but pending OS results. Patients, in this category, interested in adjuvant therapy would benefit from a discussion with an oncologist regarding the potential benefits and risks of adjuvant treatment post kidney cancer surgery. Overall, the landscape of adjuvant treatment in nonmetastatic high-risk

[1] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide. Lyon, France: International Agency for

[2] Canadian Cancer Society's Advisory Committee on Cancer Statistics. Canadian Cancer

[3] Renal Cell Carcinoma. Cleveland Clinic. 2013. Available from: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/renal-cell-carcinoma/ [4] Kidney Cancer Association. About Kidney Cancer. October, 2016. Available from: http://

[5] National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis. Key Fact Available from: http://seer.cancer.gov/statfacts/html/kidrp.html (link is external) [6] Kidney Cancer—Mayo Clinic [Internet]. Mayoclinic.org. Available from: http://www. mayoclinic.org/diseases-conditions/kidney-cancer/basics/definition/con-20024753 [7] Abe H, Kamai T. Recent advances in the treatment of metastatic renal cell carcinoma.

[8] Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease.

and Anil Kapoor<sup>2</sup>

\*

RCC is expected to expand and to further develop in the coming years.

, Kiran Sharma<sup>1</sup>

2 Division of Urology, McMaster University, Hamilton, ON, Canada

Statistics 2015. Toronto, ON: Canadian Cancer Society; 2015

www.kidneycancer.org/knowledge/learn/about-kidney-cancer/

International Journal of Urology. Oct 2013;**20**:944-955

The Urologic Clinics of North America. 2003;**30**:843-852

and evaluating novel drug targets.

, Shahid Lambe1

1 McMaster University, Hamilton, ON, Canada

Research on Cancer; 2010

\*Address all correspondence to: akapoor@mcmaster.ca

**Author details**

Fadil Hassan1

**References**

**Table 6.** Ongoing adjuvant and neo-adjuvant clinical trials.

the implications for STRAC. The results lacked clarity. Twenty-two patient representatives from the IKCC network were asked what degree of PFS advantage would be needed to justify taking sunitinib for 1 year. Approximately one-third of patients favored not taking sunitinib when faced with the S-TRAC results [79].

Recently, on November 2017, the FDA approved the use sunitinib for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma following nephrectomy. The approval was based on (S-TRAC) trail.
