Clinical Trials Corner

Dear Readers,

The Clinical Trials Corner of the Kidney Cancer journal aims to present results from recently published trials and draw attention to ongoing studies in the field of renal cell carcinoma.

We hope that this section of the journal will help in the recruitment process of the trials and highlight new, possibly practice changing results. If you would like to inform us on a specific clinical trial, please do not hesitate to contact us on mbparikh@ucdavis.edu or kca@iospress.com.

Sincerely,

Mamta_Parikh_lr
Mamta Parikh, MD
Clinical Trials Corner Editor, Kidney Cancer
Assistant Professor, Hematology Oncology
UC Davis Comprehensive Cancer Center, Sacramento, CA, USA

A Multicenter, Double-Blind, Randomized Phase 3 Study to Compare the Efficacy and Safety of Belzutifan (MK-6482) Plus Pembrolizumab (MK-3475) Versus Placebo Plus Pembrolizumab, in the Adjuvant Treatment of Clear Cell Renal Cell Carcinoma (ccRCC) Post Neph

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT05239728
Sponsor: 
Merck Sharp & Dohme LLC
Enrollment: 
1600
Study Design: 
This Phase 3 study enrolls patients with clear cell RCC (with or without sarcomatoid features) with no evidence of disease (NED) after complete resection of primary tumor, if pathology confirms intermediate-high risk (pT2, Grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0), high risk (pT4, any Grade N0, M0; pT any stage, any Grade, N+, M0), or M1 NED (complete resection of a soft tissue metastasis at time of nephrectomy or < 2 years from nephrectomy). Eligible patients must have an Eastern Cooperative Oncology Group performance status of 0 to 1 within 10 days before randomization, must have undergone nephrectomy and/or metastasectomy < 12 weeks prior to randomization, and must have adequate organ function. Patients cannot have had a prior systemic treatment or radiotherapy for RCC, have pulse oximetry of <92% at rest or require supplemental oxygen. Following enrollment, patients are randomized to receive either belzutifan (120 mg orally once daily) for up to 54 weeks plus pembrolizumab (400 mg intravenously every 6 weeks) for up to 9 administrations or placebo plus pembrolizumab for the same duration. Patients will continue to be followed after the time of treatment discontinuation or completion.
Rationale: 
The KEYNOTE-564 study, a Phase 3 study evaluating the efficacy of pembrolizumab versus placebo in the adjuvant treatment of clear cell RCC post nephrectomy, extended disease-free survival (DFS) and has thus become an option for adjuvant therapy. Belzutifan, a small molecule hypoxia-inducible factor 2-alpha inhibitor, is a current treatment for patients with RCC associated with von Hippel-Lindau disease. It is possible that the combination of belzutifan and pembrolizumab may provide additive benefit to patients who are candidates for adjuvant therapy after nephrectomy.
Endpoints: 
The primary endpoint of this trial is disease-free survival (DFS). Key secondary outcomes include overall survival (OS), disease recurrence-specific survival, rate of study treatment discontinuation and rate of participants with one or more adverse events (AEs).
Comments: 
Pembrolizumab has recently become an option for adjuvant therapy for patients with intermediate to high-risk RCC after nephrectomy, based on establishing a disease-free survival benefit when compared to placebo. As with previous adjuvant trials in RCC with other systemic agents, overall survival benefit has not been demonstrated to date with pembrolizumab compared to placebo. Nevertheless, there remains interest in improving outcomes and preventing recurrences in patients with surgically resectable RCC. Combining pembrolizumab with belzutifan may provide additional benefit in adjuvant treatment as compared to pembrolizumab alone, which will be addressed in this clinical trial. The other important consideration in this study will be the additional toxicity that comes with addition of belzutifan, including development of hypoxia. Trials involving oral VEGF tyrosine kinase inhibitors in the adjuvant setting have been plagued with treatment discontinuation due to toxicity. Thus, the rate of discontinuation, a secondary endpoint, will be a meaningful finding. Ultimately, identifying patients most likely to benefit from adjuvant therapy should be an emphasis of all trials in resectable RCC, especially trials considering significant duration of multiple therapies. Thus, hopefully, correlative work will ensue from this trial to address that.

Multicenter Randomized Phase III Trial of Deferred Cytoreductive Nephrectomy in Synchronous Metastatic Renal Cell Carcinoma Receiving Checkpoint Inhibitors: a DaRenCa and NoRenCa Trial Evaluating the Impact of Surgery or No Surgery. The NORDIC-SUN-Trial.

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT03977571
Sponsor: 
Frede Donskov, Aarhus University Hospital
Enrollment: 
400
Study Design: 
This Phase III multi-site, randomized trial enrolls patients with histologically proven clear cell or non-clear cell synchronous metastatic RCC who have not previously received systemic therapy. Patients are eligible if considered to be appropriate for treatment with nivolumab plus ipilimumab according to the recommendations by the European Medicines Agency and national health authorities of any participating countries. Patients who have autoimmune disease requiring systemic corticosteroids, and patients with HIV, Hep B or Hep C are excluded from participation in this trial. Patients enrolled to study will be randomized to either be treated with nivolumab plus ipilimumab (every 3 weeks for 4 doses) then undergo cytoreductive nephrectomy followed by maintenance nivolumab every 4 weeks or be treated with nivolumab plus ipilimumab (every 3 weeks for 4 doses) followed by nivolumab every 4 weeks. All patients participating will have archival tissue collected as well as blood and stool specimens for translational biomarker research testing.
Rationale: 
The benefit of cytoreductive nephrectomy (CN) had previously been established among fit patients with metastatic renal cell carcinoma during the era of interferon alfa treatment. Subsequently, however, systemic therapy for mRCC evolved significantly. During the era of single agent anti-angiogenesis therapy as first-line treatment, the CARMENA trial supported the deferral of CN in patients receiving sunitinib who had intermediate or poor-risk disease. Yet at the same time, the current standard of care treatment for mRCC has evolved to include immune checkpoint inhibitors in first-line treatment. As such, the role of cytoreductive nephrectomy remains of question, prompting both the SWOG PROBE trial, and this trial, NORDIC-SUN.
Endpoints: 
The primary endpoint of this trial is overall survival (OS). The secondary outcomes include progression-free survival (PFS), objective response rate (ORR), and time to subsequent systemic therapy. Biomarker analyses will include evaluation of tumor infiltrating lymphocytes (TILs) at baseline and after surgery, immune subsets in blood measured by flow cytometry, genetic profile of circulating tumor DNA, and profile of gut microbiome.
Comments: 
This cooperative group sponsored multi-center Phase II trial evaluates RCC patients with bone metastases, a population with poor outcomes both in terms of morbidity and mortality. Importantly, while Radium-223 dichloride has been studied alone in patients with prostate cancer and in combination with antiangiogenesis agents in patients with mRCC, this study will better evaluate whether there is a benefit to Radium-223 added to treatment. Prior studies did not have a control arm, and this study has a cabozantinib-alone comparator arm. With correlative analysis of markers of bone turnover in this study, there is potential to further understanding of the mechanism of the effect of both Radium-223 dichloride and cabozantinib on osseous metastases. Importantly, the study chairs have recently updated the eligibility criteria as outlined in the Study Design, allowing now for patients who only have one untreated bony lesion and for patients who are asymptomatic from osseous metastases. The trial eligibility requirements have also been adjusted to allow for a hemoglobin threshold of > 9. These changes should encourage readers to consider this important trial when evaluating a patient with progressive osseous metastases. The challenge in this trial, of course, is that data from trials like METEOR have led to an increased use of cabozantinib early in the treatment of mRCC patients with bony metastases, and may lead some to even use first-line nivolumab plus cabozantinib on the basis of the CheckMate-9ER study. However, it is important to note that these studies stratified for osseous metastases, in contrast to the RADICAL study, which specifically studies mRCC patients with a preponderance of bony metastases.

A Phase II Randomized Trial of Radium-223 Dichloride and Cabozantinib in Patients with Advanced Renal Cell Carcinoma with Bone Metastasis (RADICAL)

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT04071223
Sponsor: 
Alliance for Clinical Trials in Oncology/National Cancer Institute
Enrollment: 
210
Study Design: 
This Phase II randomized trial enrolls patients with advanced RCC of any histologic subtype with at least 1 metastatic bone lesion that has not been previously irradiated. Patients may have had any number of prior lines of systemic therapy, but cannot have previously received cabozantinib. Prior Radium-223 dichloride treatment is also an exclusion criteria. Patients will be randomized to receive either Radium-223 dichloride every 28 days with cabozantinib 40 mg every day, or cabozantinib 40 mg every day. Patients in the combination arm will be treated with 6 treatments of Radium-223 dichloride and cabozantinib until disease progression or unacceptable toxicity; patients in the cabozantinib arm will be treated until disease progression or unacceptable toxicity.
Rationale: 
Roughly a third of patients with metastatic RCC have bone metastases, with the prevalence higher in patients with intermediate or poor risk disease. This leads to increased morbidity in these patients due to skeletal related events (SREs), and data suggest that these patients also have decreased survival. In the Phase III METEOR trial, cabozantinib appeared to particularly benefit the subset of patients with bone metastases compared to everolimus, both in terms of clinical endpoints as well as in changes in bone turnover markers. Radium-223, an alpha emitting radioisotope and calcium-mimetic, has been shown to decrease SREs in patients with metastatic castration resistant prostate cancer. An exploratory Phase I trial of Radium-223 combined with either sorafenib or pazopanib in patients with mRCC with at least one bone metastasis demonstrated significant declines in bone turnover markers. Given these findings suggesting combination activity of tyrosine kinase inhibitors with Radium-223, and the evidence suggesting benefit of cabozantinib in patients with bone involvement, this Phase II study evaluates whether there is benefit to addition of Radium-223 to cabozantinib.
Endpoints: 
The primary endpoint of this trial is symptomatic skeletal event (SSE)-free survival of the combination of Radium-223 and cabozantinib compared to cabozantinib alone. Secondary endpoints include SSE-free survival in predefined subgroups, progression free survival (PFS), overall survival (OS), time to first SSE, toxicity and objective response rate (ORR). The effect on markers of bone turnover will be examined as a correlative endpoint.
Comments: 
This cooperative group sponsored multi-center Phase II trial evaluates RCC patients with bone metastases, a population with poor outcomes both in terms of morbidity and mortality. Importantly, while Radium-223 dichloride has been studied alone in patients with prostate cancer and in combination with antiangiogenesis agents in patients with mRCC, this study will better evaluate whether there is a benefit to Radium-223 added to treatment. Prior studies did not have a control arm, and this study has a cabozantinib- alone comparator arm. With correlative analysis of markers of bone turnover in this study, there is potential to further understanding of the mechanism of the effect of both Radium-223 dichloride and cabozantinib on osseous metastases. Importantly, the study chairs have recently updated the eligibility criteria as outlined in the Study Design, allowing now for patients who only have one untreated bony lesion and for patients who are asymptomatic from osseous metastases. The trial eligibility requirements have also been adjusted to allow for a hemoglobin threshold of > 9. These changes should encourage readers to consider this important trial when evaluating a patient with progressive osseous metastases. The challenge in this trial, of course, is that data from trials like METEOR have led to an increased use of cabozantinib early in the treatment of mRCC patients with bony metastases, and may lead some to even use first-line nivolumab plus cabozantinib on the basis of the CheckMate-9ER study. However, it is important to note that these studies stratified for osseous metastases, in contrast to the RADICAL study, which specifically studies mRCC patients with a preponderance of bony metastases.

A Phase III, Multicenter, Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Atezolizumab Given in Combination With Cabozantinib Versus Cabozantinib Alone in Patients With Inoperable, Locally Advanced, or Metastatic Renal Cell Carcinoma

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT04338269
Sponsor: 
Hoffmann-La Roche
Enrollment: 
500
Study Design: 
This Phase III randomized trial enrolls patients with histologically proven clear cell or non-clear cell metastatic RCC, though those with chromophobe subtype must have sarcomatoid differentiation. Patients must have radiographic evidence of disease progression during or following treatment with an anti-PD-L1 or anti-PD1 antibody (including atezolizumab, avelumab, pembrolizumab, or nivolumab). Patients may not have received prior cabozantinib, or more than one anti-PD-L1 or anti-PD-1 therapy prior to enrollment. They also may not have received more than two prior lines of therapy in the locally advanced or metastatic setting. While brain metastases are not an exclusion, patients with symptomatic, untreated or actively progressing CNS metastases or leptomeningeal disease are not permitted on study. Patients enrolled to study will be randomized to receive either atezolizumab (1200 mg IV every 3 weeks) plus cabozantinib (60 mg PO daily) or cabozantinib 60 mg PO daily, until unacceptable toxicity or disease progression.
Rationale: 
In recent years, combination immune checkpoint inhibitor (ICI) therapy has become standard first-line treatment of mRCC. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib and nivolumab plus cabozantinib are all combinations that have been approved for use based on randomized trials in which these combinations demonstrated an overall survival benefit compared to sunitinib, regardless of risk stratification. Nivolumab plus ipilimumab has also demonstrated overall survival benefit in patients with intermediate- or poor-risk disease as compared to sunitinib, and thus is also an option for first-line treatment in select patients. Clinical data on sequencing further treatment after progression on initial immune checkpoint-based therapy is limited, and in particular whether there is further benefit to combining immune checkpoint inhibitor therapy with VEGF-directed therapies remains unclear. This trial seeks to interrogate that question..
Endpoints: 
The co-primary endpoints of this trial progression free survival (PFS) and overall survival (OS). The secondary outcomes include investigator-assessed PFS, investigator-assessed objective response rate (ORR), independently reviewed ORR, investigator-assessed duration of response (DOR) and independently reviewed DOR, as well as percentage of patients with adverse events.
Comments: 
As an increasing number of options emerge for the initial treatment of mRCC, selection of therapy becomes complicated, especially insofar as subsequent therapy is concerned. The most robust data for treatment after progression on ICI therapy is currently available for cabozantinib. There is also some data regarding the potential to treat with additional ICI therapy after progression on a prior ICI, but these data are limited to single-arm studies. This trial will both better characterize the response to cabozantinib after progression on ICI, and evaluate whether combining atezolizumab with cabozantinib provides benefit to patients previously treated with ICI. The trial allows prior treatment with atezolizumab, but does not allow prior cabozantinib exposure. As a result, this study will exclude those patients treated with nivolumab plus cabozantinib, a recently approved first-line combination treatment, but this is a necessary aspect of evaluating the clinical question at hand.

A Phase III Trial of Immunotherapy-Based Combination Therapy With or Without Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma (PROBE Trial)

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT04510597
Sponsor: 
Southwest Oncology Group
Enrollment: 
364
Study Design: 
This Phase III randomized trial enrolls patients with histologically proven clear cell or non-clear cell RCC. Patients may be treatment naïve or have initiated systemic therapy in the locally advanced or metastatic setting up to 12 weeks prior to registration as long as scans documented metastatic disease prior. Patients with symptomatic brain metastases, solitary kidney, or kidney transplantation are excluded. Patients without progression on combination immunotherapy-based systemic therapy at 12 weeks will be randomized to continue on systemic immunotherapy or to undergo cytoreductive nephrectomy while continuing on systemic immunotherapy.
Rationale: 
The benefit of cytoreductive nephrectomy (CN) had previously been established among fit patients with metastatic renal cell carcinoma. Subsequently, however, systemic therapy for mRCC evolved significantly. During the era of anti-angiogenesis therapy as first-line treatment, the CARMENA study supported the deferral of CN in patients receiving sunitinib who had intermediate or poor risk disease. However, subsequently, treatment of mRCC has further evolved, and with the new paradigm of immunotherapy-based combination treatment in the first-line setting, the role of cytoreductive nephrectomy remains in question.
Endpoints: 
The primary endpoint of this trial is comparison of overall survival between patients receiving immune checkpoint inhibitor-based combination therapy alone versus those who receive immune checkpoint inhibitor-based combination therapy and cytoreductive nephrectomy. The secondary outcomes include assessing complications of nephrectomy and post-randomization drug toxicities, objective response rate in metastatic sites between arms, and assessing change in diameter of primary tumor at week 12 disease assessment.
Comments: 
For over 50 years, spontaneous regression of sites of metastases have been reported in patients with mRCC after cytoreductive nephrectomy. In the era of interferon alfa-2b therapy, the benefit of nephrectomy was studied and shown to confer overall survival benefit in fit patients in Phase III SWOG and EORTC trials. With the advent of antiangiogenesis therapy for mRCC, clinical trials sought to determine whether cytoreductive nephrectomy prior to initiation of systemic therapy remained of benefit. These trials proved to be challenging to accrue. Phase III CARMENA results argued that deferred nephrectomy was the preferred approach, but results may have been complicated by patient selection overrepresenting those with poor risk disease. Ultimately, though, the relevance of this study was short-lived in that systemic therapy has dramatically evolved for mRCC in recent years with the incorporation of immune checkpoint inhibitor therapy in front-line treatment, again raising the question of whether cytoreductive nephrectomy might benefit patients with mRCC. The SWOG PROBE trial is designed pragmatically to allow for a variety of first-line immune checkpoint inhibitor therapy-based combinations and to allow for patients to have already initiated systemic therapy prior to enrollment. Patients in this study will not have upfront cytoreductive nephrectomy, but rather will be evaluated for benefit of cytoreductive nephrectomy after 12 weeks of systemic therapy. In addition to addressing the role of cytoreductive nephrectomy in treatment-naïve patients with mRCC who receive immune checkpoint inhibitor therapy, the study may shed further light on the impact of immunotherapy on the tumor microenvironment given that cytoreductive nephrectomy specimens will be collected in patients randomized to undergo surgery.

A Randomized, Double-Blind, Controlled Phase 3 Study of Cabozantinib in Combination with Nivolumab and Ipilimumab versus Nivolumab and Ipilimumab in Subjects with Previously Untreated Advanced or Metastatic Renal Cell Carcinoma of Intermediate or Poor Ris

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT03937219
Sponsor: 
Exelixis
Enrollment: 
676
Study Design: 
This Phase III randomized trial enrolls patients with advanced RCC with a clear-cell component, who must be intermediate- or poor-risk by International Metastatic RCC Database Consortium (IMDC) criteria. Patients may not have had previous systemic therapy in the locally advanced or metastatic setting, and will be excluded if they have underlying, recent autoimmune disorders requiring systemic treatment. Patients will be randomized to receive either cabozantinib + nivolumab + ipilimumab (with nivolumab + ipilimumab received for 4 doses) followed by cabozantinib + nivolumab (experimental arm) or placebo + nivolumab + ipilimumab (for 4 doses) followed by placebo + nivolumab (control arm). Patients will be treated until disease progression or unacceptable toxicity.
Rationale: 
The combination of nivolumab and ipilimumab was demonstrated to be superior to sunitinib in the treatment of patients with intermediate or poor risk advanced RCC in the CheckMate-214 trial, and thus has become an established therapy for these patients. Recently, the CheckMate 9ER trial demonstrated that the combination of nivolumab with cabozantinib was tolerated and was superior in radiographic progression free survival (PFS) and objective response rate (ORR) to sunitinib.
Endpoints: 
The primary endpoint of this trial is duration of PFS. The secondary outcome measure is duration of overall survival (OS).
Comments: 
While the COSMIC-313 study, sponsored by Exelixis, was initiated prior to the availability of results of CheckMate 9ER, it will inadvertently build on the findings recently reported by Dr. Choueiri at ESMO. While prior studies that combined sunitinib or pazopanib with checkpoint inhibitors have been plagued by toxicity that limited the evaluation of these combinations, the combination of cabozantinib and nivolumab has an acceptable toxicity profile. Prior Phase III studies, such as CheckMate 9ER, CheckMate 214, KEYNOTE 426, and JAVELIN Renal 100, have all utilized sunitinib as the comparator. In the current treatment landscape, however, for patients with intermediate or poor risk disease, sunitinib is not the optimal active comparator. The COSMIC-313 trial will provide meaningful results about the benefit of addition of cabozantinib to checkpoint inhibitors, particularly because the active comparator arm is nivolumab combined with ipilimumab, now a standard therapy for intermediate or poor risk advanced RCC. In addition, it will interrogate whether the combination of these three agents can be tolerated safely.

A Phase II Randomized Trial of Radium-223 Dichloride and Cabozantinib in Patients with Advanced Renal Cell Carcinoma with Bone Metastases

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT04071223
Sponsor: 
National Cancer Institute (NCI)
Enrollment: 
210
Study Design: 
This Phase II randomized trial enrolls patients advanced RCC of any histologic subtype with at least 2 metastatic bone lesions that have not been previously irradiated. Patients may have had 2 prior lines of systemic therapy, but cannot have received cabozantinib. Prior Radium-223 dichloride treatment is also an exclusion criteria. Patients will be randomized to receive either Radium-223 dichloride every 28 days with cabozantinib 40 mg every day, or cabozantinib 40 mg every day. Patients in the combination arm will be treated with 6 treatments of Radium-223 dichloride and cabozantinib until disease progression or unacceptable toxicity; patients in the cabozantinib arm will be treated until disease progression or unacceptable toxicity.
Rationale: 
Roughly a third of patients with metastatic RCC have bone metastases, with the prevalence higher in patients with intermediate or poor risk disease. This leads to increased morbidity in these patients due to skeletal related events (SREs), and data suggest that these patients also have decreased survival. In the Phase III METEOR trial, cabozantinib appeared to particularly benefit the subset of patients with bone metastases compared to everolimus, both in terms of clinical endpoints as well as in changes in bone turnover markers. Radium-223, an alpha emitting radioisotope and calcium-mimetic, has been shown to decrease SREs in patients with metastatic castration resistant prostate cancer. An exploratory Phase I trial of Radium-223 combined with either sorafenib or pazopanib in patients with mRCC with at least one bone metastasis demonstrated significant declines in bone turnover markers. Given these findings suggesting combination activity of tyrosine kinase inhibitors with Radium-223, and the evidence suggesting benefit of cabozantinib in patients with bone involvement, this Phase II study evaluates whether there is benefit to addition of Radium-223 to cabozantinib.
Endpoints: 
The primary endpoints of this trial is symptomatic skeletal event(SSE)-free survival of the combination of Radium-223 and cabozantinib compared to cabozantinib alone. Secondary endpoints include SSE-free survival in predefined subgroups, progression free survival (PFS), overall survival (OS), time to first SSE, toxicity and objective response rate (ORR). The effect on markers of bone turnover will be examined as a correlative endpoint.
Comments: 
This NCI-sponsored multi-center Phase II trial evaluates RCC patients with bone metastases, a population with poor outcomes both in terms of morbidity and mortality. Importantly, while Radium-223 dichloride has been studied alone in patients with prostate cancer and in combination with antiangiogenesis agents in patients with mRCC, this study will better evaluate whether there is a benefit to Radium-223 added to treatment. Prior studies did not have a control arm, and this study has a cabozantinib alone arm. This single-agent arm will also better characterize the outcomes of patients with osseous metastases treated with cabozantinib. With correlative analysis of markers of bone turnover in this study, there is potential to further understanding of the mechanism of the effect of both Radium-223 dichloride and cabozantinib on osseous metastases.

An Open-Label, Randomized Phase 3 Study of MK-6482 Versus Everolimus in Participants With Advanced Renal Cell Carcinoma That Has Progressed After Prior PD-1/L1 and VEGF-Targeted Therapies

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT04195750
Sponsor: 
Merck Sharp & Dohme Corp
Enrollment: 
736
Study Design: 
This Phase 3 randomized trial enrolls patients with locally advanced or metastatic clear cell RCC. Patients must have received systemic treatment in the advanced setting with a PD-1 or PD-L1 inhibitor and a VEGF targeted therapy, but must not have received more than 3 prior systemic regimens in this setting. Patients with significant cardiac disease are excluded from enrollment. Patients will be randomized to receive either MK-6482 or everolimus, both given once daily as oral therapies, until the time of disease progression or unacceptable toxicity.
Rationale: 
While numerous advances have been made in the treatment of mRCC in the past decade, our armament has been limited to three classes of drugs- immunotherapy, vascular endothelial growth factor (VEGF) inhibitors, and inhibitors of the mammalian target of rapamycin (mTOR). While it has long been recognized that hypoxia inducible factor-2 (HIF-2) is a key transcription factor driving clear cell RCC, attempts to develop an inhibitor of this target in the past have been thwarted. Results from a Phase 1/2 study of the oral HIF-2α inhibitor, MK-6482, in patients with refractory mRCC, however, recently objective response rate (ORR) of 24% with a disease control rate of 80%. Of note, 67% of the patients on this study had received both antiangiogenesis agents as well as anti-PD-1 inhibitors. On the basis of these promising results, a Phase 3 study has been initiated.
Endpoints: 
The co-primary endpoints of this trial are progression-free survival (PFS) and overall survival (OS). Secondary endpoints include ORR, duration of response, safety and impact to quality of life.
Comments: 
This multi-center industry-sponsored, registrational trial is designed to assess the activity of the oral HIF-2α inhibitor, MK-6482, in patients with refractory advanced clear cell RCC. The study design does provide a few challenges which should be noted. The limitation of prior systemic regimens to 3 is potentially challenging, as patients who receive nivolumab and ipilimumab as their initial treatment may normally be treated with more than 2 subsequent anti-VEGF agents before resorting to everolimus. On the other hand, limiting prior regimens to 3 does allow for a more uniform patient population, as most patients will have received 2-3 prior anti-VEGF agents and 1 prior immune checkpoint inhibitor. Patients with HIV, Hepatitis B and Hepatitis C have also been excluded from this trial. Notable safety signals seen in the Phase 1/2 trial, of anemia, dyspnea, and hypoxia will be further interrogated with the study of MK-6482 in a larger patient population. The study is expected to accrue well based on the unmet need of new classes of drugs in treating mRCC and on the promising results from the Phase 1/2 trial.

A Phase 3 Randomized Study Comparing Perioperative Nivolumab vs Observation in Patients with Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC)

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT03055013
Sponsor: 
National Cancer Institute (NCI) with Canadian Cancer Trials Group as Collaborators
Enrollment: 
805
Study Design: 
This Phase 3 study enrolls patients with clinical stage > T2 or node positive M0 RCC of any histology or patients with oligometastatic disease that can be resected or definitively treated. A tumor biopsy is mandatory prior to randomization. Patients randomized to one arm of the trial will receive two doses of perioperative nivolumab prior to nephrectomy, followed by 9 months of adjuvant nivolumab after nephrectomy. Patients randomized to the other, control arm of the trial will undergo nephrectomy followed by observation. Patients will be stratified by clinical T stage, node positivity, and histology.
Rationale: 
Despite multiple studies evaluating adjuvant therapy in patients with localized RCC after nephrectomy, largely involving vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs), there remains no standard adjuvant systemic therapy that increases overall survival. While a number of adjuvant trials are underway to determine if there is a role for immune checkpoint inhibitor therapy in treatment of localized RCC, it is hypothesized that neoadjuvant PD-1 priming may be necessary to maximize efficacy. Thus, the PROSPER RCC trial is a novel trial involving perioperative nivolumab in patients with RCC undergoing nephrectomy.
Endpoints: 
The primary endpoint of the trial is recurrence free survival (RFS), assessed up to 10 years. The secondary endpoints include overall survival (OS), RFS for patients with clear cell RCC, and incidence of toxicity. The study also plans to evaluate the primary tumor’s expression of PD-L1 as well as the expression of PD-L1 on tumor tissue at time of recurrence, among other potential correlative studies.
Comments: 
This multi-center NCI-sponsored trial continues to require the engagement of investigators treating patients with RCC. As mentioned, there is no adjuvant therapy established to prolong overall survival in patients with localized RCC. While sunitinib has been demonstrated to improve progression-free survival, toxicity concerns with long-term VEGF TKI use remains a major concern. Thus, the role of immune checkpoint inhibitor therapy in this context is critical. However, more importantly, unlike the other adjuvant immune checkpoint inhibitor trials, PROSPER RCC asks important questions about the tumor immune microenvironment and the impact of the primary tumor on the effects of nivolumab. Recent amendment to the protocol now allows for patients with oligometastatic disease as long as all sites of metastases are surgically resected or definitively treated within 12 weeks of nephrectomy. Another amendment now requires core tumor biopsy for patients randomized to the nivolumab arm only, rather than both arms of the trial. These amendments should further encourage patient enrollment.

PD-Inhibitor (Nivolumab) and Ipilimumab Followed by Nivolumab vs. VEGF TKI Cabozantinib With Nivolumab: A Phase III Trial in Metastatic Untreated Renal Cell Cancer [PDIGREE]

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT03793166
Sponsor: 
National Cancer Institute (NCI)
Enrollment: 
1046
Study Design: 
This Phase 3 study enrolls patients with newly diagnosed IMDC intermediate or poor risk advanced or metastatic RCC, who have not previously received any systemic therapy for RCC, who have histologically confirmed predominantly clear cell subtype RCC; patients with clear cell disease with sarcomatoid features are also included. Patients will be randomized to two arms. In both arms, patients will be treated with induction immune checkpoint inhibitor therapy, involving nivolumab and ipilimumab every 21 days. In Arm A, after induction therapy, if there is evidence of PD, patients will be treated with cabozantinib continuously; all other patients will continue on nivolumab treatment every 28 days until progression or unacceptable toxicity. In Arm B, after induction therapy, patients who have PD will be treated cabozanitinib until further progression or toxicity. Patients who achieve a complete response (CR) will remain on nivolumab alone. Patients who are found to have a partial response or stable disease will receive a combination of nivolumab with cabozantinib until progression or unacceptable toxicity.
Rationale: 
Based on the results of the CheckMate-214 trial, an overall survival (OS) advantage has been observed in patients with newly diagnosed metastatic RCC with intermediate- to poor-risk disease by International Metastatic RCC Database Consortium (IMDC) criteria when treated with nivolumab and ipilimumab as compared to sunitinib (OS not reached versus 26.0 months; hazard ratio (HR)= 0.63; p<0.001). The objective response rate (ORR) for the combination was 42%. Patients receiving nivolumab and ipilimumab receive 4 treatments with ipilimumab, after which, as long as there is no evidence of progressive disease (PD), they continue to receive nivolumab. Both the JAVELIN Renal 101 and KEYNOTE 426 trials demonstrated an advantage to combining a checkpoint inhibitor with axitinib as compared to treatment with sunitinib alone in Phase 3 trials, with some suggestion that ORR was higher with these combinations. An ongoing Phase 3 trial (CheckMate 9ER) is evaluating the combination of nivolumab plus cabozantinib versus sunitinib in patients with mRCC. It is unclear, after combination immune checkpoint inhibition, whether the combination of immune checkpoint inhibitor therapy and TKI is of benefit.
Endpoints: 
The primary endpoint of the trial is OS. The secondary endpoints include progression-free survival (PFS), CR at 12 months, ORR, and proportion of patients discontinuing protocol-directed treatment prior to 1 year. Incidence of adverse events will also be reported.
Comments: 
This multi-center trial brings us closer to understanding the role of combination of immune checkpoint inhibitor with TKI therapy. Ideally, a trial comparing dual immune checkpoint inhibition (nivolumab plus ipilimumab) to a checkpoint inhibitor with TKI (ie pembrolizumab plus axitinib) would help us to answer the question of optimal sequencing of therapy. However, such a trial would require large numbers of patients as well as extended follow-up, thus is likely not feasible in the short-term. As such, we currently have the option to treat patients with IMDC intermediate or poor risk mRCC with either nivolumab plus ipilimumab or a checkpoint inhibitor in combination with axitinib. For patients who are treated with nivolumab plus ipilimumab, this study will demonstrate the utility of incorporating cabozantinib in combination with checkpoint inhibitor before the time of overt progression. This will shed further light into the potential synergism of TKIs and immune checkpoint inhibitor, and may help guide sequencing therapy moving forward.

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