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

Randomized Phase II Stereotactic Ablative Radiation Therapy (SABR) for Metastatic Untreated Renal Cell Carcinoma (RCC) Receiving Immunotherapy (SAMURAI)

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT05327686
Sponsor: 
NRG Oncology
Enrollment: 
240
Study Design: 
This randomized Phase II multicenter study enrolls patients with a histologically or cytologically proven diagnosis of RCC with radiographically node-positive or metastatic disease, with IMDC intermediate or poor risk disease. Patients must be candidates to receive standard of care therapy with either nivolumab plus ipilimumab or an immune checkpoint inhibitor (CPI) and vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). The primary renal tumor must measure 8 cm or less, and cytoreductive nephrectomy should be deemed as not recommended by the investigator or should be declined by the patient. Patients are ineligible for enrollment if planned therapy would be definitive such that it would render the patient without extra-renal measurable disease. Patients must not have untreated or unstable brain metastases, and cannot have had prior systemic therapy for mRCC, though prior chemotherapy for a different cancer completed 3 years prior to registration is permitted. Patients who are enrolled to the study will be randomized to Arm A, consisting of standard of care immunotherapy or CPI + VEGF TKI, or Arm B, in which patients receive standard of care of immunotherapy or CPI + VEGF TKI as well as SABR delivered in 3 fractions for a total of 42 Gy over 1-3 weeks.
Rationale: 
While the SWOG PROBE trial (S1931) is currently evaluating the role of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma (mRCC) receiving immunotherapy, a significant number of patients presenting with mRCC are either not candidates for surgical intervention or refuse surgical resection. There are data suggesting that stereotactic ablative radiotherapy (SABR) to the primary tumor in RCC can be safe and highly effective. In addition, there are hypothesized to be immunomodulatory effects of SABR, but these have not been studied prospectively in RCC. Thus, the SAMURAI study aims to test the ability of SABR to adequately treat the primary tumor with local cytoreduction and potentially modulateimmunotherapy.
Endpoints: 
The primary endpoint of this study is nephrectomy and radiographic progression-free survival (nrPFS). Key secondary endpoints include safety, objective response rate (ORR), overall survival, treatment-free survival, and second-line therapy-free survival. The rate of cytoreductive nephrectomy per arm will also be captured as a secondary endpoint.
Comments: 
For years, cytoreductive nephrectomy was a clinical standard for patients with mRCC, supported by randomized clinical trials in the cytokine era of mRCC treatment. Since then, as systemic therapy for mRCC evolves, the pendulum has swung away from cytoreductive nephrectomy based on trials in the VEGF TKI era of mRCC treatment. While the S1931 PROBE study will further evaluate the role of cytoreductive nephrectomy in the current era of mRCC treatment, the role of radiation therapy to the primary tumor is a more recent question. In recent years, the role of radiation therapy in mRCC has been better appreciated, but still requires rigorous study. The SAMURAI study serves as a complement to PROBE, in that this Phase II study enrolls patients who are not candidates for nephrectomy or have declined it. Both the PROBE and SAMURAI studies will provide important information on the interplay between immunotherapy, treatment modality, and the primary tumor. Both studies also face challenges in optimal accrual. For SAMURAI, patients must have primary tumors less than 8 cm in size and be considered non-candidates for surgical resection. At the same time, patients must have adequate end organ function to receive systemic therapy on the study. Thus, finding the patient who best meets enrollment criteria may be difficult. Nevertheless, this cooperative group trial is addressing an important question in a rigorous way, which must be commended.

Multicenter Phase II Study of Axitinib +/- Pembrolizumab in First Line Treatment of Patients with Locally Advanced or Metastatic Papillary Renal Cell Carcinoma (pRCC)

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT05096390
Sponsor: 
Centre Leon Berard
Enrollment: 
72
Study Design: 
This randomized Phase II multicenter study enrolls patients with histologically proven Type 2 or mixed PRCC that is either locally advanced or metastatic. Patients must have adequate organ and hematologic function and good performance status. Participants cannot have received prior systemic therapy for RCC even in the adjuvant setting, and cannot have untreated brain metastases. Patients are randomized to receive either axitinib (5 mg orally twice daily) plus pembrolizumab (200 mg every 3 weeks intravenously) or axitinib (5 mg orally twice daily) until the time of disease progression or unacceptable toxicity. Axitinib dosing may be increased to up to 10 mg twice daily if patents tolerate.
Rationale: 
The optimal treatment of advanced papillary RCC (PRCC), which constitutes <15% of all RCCs, remains in question. The Axipap Phase II study evaluated axitinib in patients with advanced papillary RCC, and demonstrated a 35.7% investigator assessed response rate in the Type 2 subgroup of PRCC. Pembrolizumab has also been studied in non-clear cell RCC patients, including those with papillary RCC. In PRCC patients, in a single-arm study of pembrolizumab, an objective response rate of 28% was observed. As such, this study seeks to examine whether the combination of pembrolizumab plus axitinib could improve outcomes in Type 2 PRCC patients.
Endpoints: 
The primary endpoint of this study is 6-month objective response rate (ORR), evaluating the efficacy of axitinib + pembrolizumab versus axitinib alone. The secondary outcomes include duration of response, best overall response, progression-free survival, overall survival and incidence of adverse events.
Comments: 
As mentioned in the previous issue of Clinical Trials Corner, defining optimal treatments for non-clear cell RCC histologic subtypes is challenging. The Phase II PAPMET study was a landmark trial in that it was the first randomized trial assessing targeted therapies in patients with PRCC, and in this study cabozantinib was found to have a longer progression free survival compared with sunitinib. However, axitinib was not one of the comparator arms in that study. While the Axipap Phase II study was a single-arm study of axitinib, the efficacy demonstrated in this study was encouraging, in particular in patients with Type 2 PRCC. Of note, the PAPMET2 study that is currently accruing in the United States of America enrolls patients with both Type 1 and 2 PRCC to receive either cabozantinib alone or in combination with atezolizumab. Thus, if both of these trials successfully accrue, there will be much more insight into the role of immune checkpoint inhibition, as well as the role of axitinib and cabozantinib, in patients with advanced PRCC.

A Phase II Randomized Trial of Cabozantinib (NSC#761968) With or Without Atezolizumab (NSC#783608) in Patients with Advanced Papillary Renal Cell Carcinoma (PAPMET2)

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT05411081
Sponsor: 
National Cancer Institute
Enrollment: 
200
Study Design: 
This study enrolls patients with metastatic histologically confirmed pRCC (either Type 1 or Type 2) with radiographically measurable disease who are ICI- and cabozantinib-naïve and who have been treated with one or fewer targeted therapies for pRCC. Following enrollment, patients are randomized to receive either 60 mg of cabozantinib orally or 60 mg of cabozantinib orally plus atezolizumab 1200 mg intravenously every 3 weeks, until the time of disease progression or unacceptable toxicity.
Rationale: 
The Phase II PAPMET was a landmark study in that it was the first randomized trial assessing targeted therapies in patients with papillary renal cell carcinoma (pRCC), a rare histologic subtype observed in 15% of patients with RCC. In the study, cabozantinib was found to have a longer progression free survival (PFS) compared with sunitinib in patients with metastatic pRCC. Since the initiation of that trial, immune checkpoint inhibitors (ICIs) have become a vital foundation of first-line treatment of advanced clear cell RCC, and some trials of ICI combinations have included a non-clear cell RCC cohort, a heterogeneous population. Thus, SWOG has initiated a clinical trial evaluating a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI) cabozantinib with or without a checkpoint inhibitor in this specific patient population.
Endpoints: 
The primary endpoint of this trial is progression-free survival (PFS). Key secondary outcomes include overall survival (OS), objective response rate (ORR), and quantitative & qualitative adverse events observed in each treatment arm.
Comments: 
Treatment for metastatic clear cell RCC has evolved over the last decade, incorporating ICI therapy, often in combination with a VEGF TKI. Since non-clear cell RCC is less common, studying patients with these histologic subtypes has been more challenging. The Phase II PAPMET study was a landmark trial that impressively enrolled patients with metastatic pRCC and demonstrated a superior PFS with cabozantinib compared to sunitinib. However, many of the combinations that have established activity in clear cell RCC have trials enrolling non-clear cell RCC. PAPMET2 will thus face some increased challenges with accrual, especially as a Phase II study of nivolumab combined with cabozantinib enrolled mostly pRCC patients and established activity of this combination. As such, PAPMET2 having an arm that does not include an ICI may give some investigators pause. Similarly, the choice of atezolizumab may also cause hesitation, as this ICI has not demonstrated superior OS in combination with VEGF TKIs as of yet in clear cell RCC. Another interesting aspect of this trial is the choice of dose of cabozantinib, as trials combining nivolumab with cabozantinib have treated patients with 40 mg of cabozantinib daily; in this study, the dose will be 60 mg in both arms. Thus, tolerance of this dose level in combination with ICI will be an important observation. The strength of this study is its uniformity in enrolling patients with pRCC, which is important as retrospective studies have reflected heterogeneity in outcomes based on histologic subtypes undoubtedly in part due to differences in responses to currently available therapies.

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.

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