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

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.

A Phase 3b, Randomized, Double-blind Study of Nivolumab Combined with Ipilimumab Versus Nivolumab Monotherapy for Patients With Previously Untreated Advanced Renal Cell Carcinoma and Intermediate- or Poor-Risk Factors

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT03873402
Sponsor: 
Bristol-Myers Squibb
Enrollment: 
418
Study Design: 
This Phase 3b study enrolls patients with newly diagnosed 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 must have intermediate or poor risk disease based on the International Metastatic RCC Database Consortium (IMDC) criteria. They cannot have received any immune checkpoint or T-cell co-stimulation therapy. Patients will be randomized to receive, in a double-blinded manner, either nivolumab and ipilimumab or nivolumab and placebo.
Rationale: 
The CheckMate-025 trial, evaluating nivolumab versus everolimus in patients with metastatic RCC progressed after antiangiogenesis therapy, established an overall survival benefit with the use of nivolumab; the objective response rate (ORR) for nivolumab in that trial was 25%. Subsequently the combination of nivolumab and ipilimumab was compared to sunitinib in the CheckMate-214 trial in patients with newly diagnosed metastatic RCC with intermediate- to poor-risk disease by International Metastatic RCC Database Consortium (IMDC) criteria; the study demonstrated a median overall survival advantage with nivolumab plus ipilimumab compared to sunitinib (not reached versus 26.0 months; hazard ratio (HR)= 0.63; p<0.001). The ORR for the combination was 42%. The combination of nivolumab plus ipilimumab led to 46% Grade 3 and higher adverse events (AEs); 35% of patients in the nivolumab plus ipilimumab group required treatment with high-dose glucorticoids due to immune-related AEs. Pembrolizumab was also studied as monotherapy, in patients with previously untreated advanced RCC, in the KEYNOTE-427 trial. In this single arm study, the ORR was 33.6%. Nivolumab has not been studied in the first-line setting, and increased toxicity is observed with the combination of nivolumab plus ipilimumab, driving the design of this trial.
Endpoints: 
The primary endpoint of the trial is progression-free survival (PFS) and ORR. Secondary endpoints include overall survival, disease control rate (DCR), duration of response (DOR), time to objective response (TTR), as well as AEs.
Comments: 
This multi-center international trial asks an important question regarding the role of intensification of immune checkpoint inhibition in the treatment of intermediate- and poor-risk advanced RCC. While treatment of advanced RCC now involves several options for dual therapy, including nivolumab plus ipilimumab and pembrolizumab plus axitinib, both of which have demonstrated improvement in overall survival in comparison to sunitinib, these combination approaches come with increased toxicity that can be discouraging to the patient as well as the practicing oncologist. While the KEYNOTE-427 trial (Cohort A) did show an impressive ORR of ~34%, this was a single-arm trial. This randomized, double blind trial has the potential to address the true benefit of combination immune checkpoint inhibition versus anti-PD-1 therapy alone, as well as to better assess the true toxicity of the combination versus nivolumab alone. Ultimately, this study could provide oncologists the option to treat with anti-PD-1 therapy alone in the first-line setting in intermediate- and poor-risk patients, though the study will require some time to mature in order to evaluate the results meaningfully.

Prospective Phase II Study of Gemcitabine Plus Platinum Salt in Combination with Bevacizumab (Avastin) for Metastatic Collecting Duct Carcinoma

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT02363751
Sponsor: 
UNICANCER
Enrollment: 
41
Study Design: 
This is a phase 2 open label European multi-site study enrolling patients with metastatic collecting duct or medullary carcinoma which is histologically confirmed, who are treatment naïve in the metastatic setting, > 18 years of age, and with adequate end organ function. Once enrolled, patients receive gemcitabine plus a platinum salt plus bevacizumab. If patients achieve disease control on this regimen, with either stable disease or a partial or complete response, then treatment is continued with bevacizumab monotherapy until progression.
Rationale: 
Though there is increasing awareness of the heterogeneity of RCC, collecting duct carcinoma has long been recognized as a separate entity, amounting to <1% of all kidney cancers. This subtype has been noted because of its aggressive behavior, and low likelihood of responding to conventional RCC regimens. Platinum-based chemotherapy has typically been used, extrapolating largely from treatment of urothelial carcinoma. As such, and on the basis of a preceding Phase I trial, a Phase II trial is evaluating the combination of gemcitabine, platinum agent, and bevacizumab in patients with metastatic collecting duct carcinoma.
Endpoints: 
The primary outcome of the trial is a composite endpoint of objective response rate (RR) and progression-free survival (PFS) rate at 6 months. Secondary endpoints include PFS, overall survival (OS), and toxicity.
Comments: 
This study is noteworthy in that collecting duct kidney cancer is rare, aggressive and has only been studied in a limited manner in clinical trials. Typically these patients are excluded from trials evaluating regimens for mRCC, or are enrolled in too small numbers to derive any conclusions. Given the similarities collecting duct kidney cancer shares histopathologically with urothelial carcinoma, the use of platinum-based chemotherapy is rational. On the other hand, the study is permitting enrollment of patients with medullary RCC. Though this subtype has some overlapping features with collecting duct kidney cancer, it is a distinct entity. For example, while it does also confer a poor prognosis with an aggressive phenotype, medullary RCC occurs more frequently in patients with sickle cell disease and is characterized by loss of INI1 expression. Thus, there could be some potential confounding with enrollment of both subtypes into this trial. Nevertheless, it is commendable to evaluate this rare subset of patients with platinum-based chemotherapy. Immune checkpoint inhibitors, having now demonstrated efficacy in both urothelial and renal cell carcinomas, are being studied in patients with non-clear cell RCC as a broad category, which will also provide additional information about new potential approaches towards these aggressive subtypes.

A Randomized Phase 2 Trial of Axitinib/Nivolumab Combination Therapy vs Single Agent Axitinib or Nivolumab for the Treatment of TFE/Translocation Renal Cell Carcinoma (tRCC) Across All Age Groups

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT03595124
Sponsor: 
National Cancer Institute (NCI)
Enrollment: 
87
Study Design: 
This phase 2, randomized, multicenter, open-label trial (ECOG AREN1721) is enrolling patients with histologically confirmed unresectable or metastatic tRCC of patients age >1 years, as long as Body Surface Area is >0.53 m2. Patients may not have received VEGF-targeted therapies or anti-PD-1 or anti-PD-L1 antibodies, but other therapies are allowed. Patients will be randomized to 1 of 3 arms, receiving either axitinib and nivolumab (Arm A), axitinib alone (Arm B), or nivolumab alone (Arm C). Patients will be treated to progression or until 2 years if there is disease control. A total of 4 years of follow-up is planned.
Rationale: 
Translocation Renal Cell Carcinomas (tRCC), characterized by Xp11.2 translocation or TFE3 gene fusions, represent a rare subset of metastatic RCC with a poor prognosis. Patients tend to present at a younger age, and while rare in adults, tRCC represent about half of all pediatric RCCs. Historically, patients with this RCC subtype have highly aggressive disease, which tends to be refractory to typical RCC therapies. However, there are no formal treatment recommendations for this disease, and previously, no prospective trials had been conducted to study this subtype.
Endpoints: 
The primary endpoint of the trial is PFS. Antitumor immune response and stability of T cell activation will be studied in an exploratory fashion. The study will also study the clinical behavior for up to 4 years of translocation morphology renal cell carcinoma.
Comments: 
This study is the first prospective trial studying patients with tRCC, and will require awareness and participation from all oncologists treating genitourinary malignancies to successfully accrue. While the study will undoubtedly include a large pediatric cohort, adult patients also need to be studied to see if clinical behavior and response to therapies are similar. The study may help to better elucidate the pathophysiology of this particular subtype to better explain its aggressive behavior. It may also contribute to our understanding of response or lack of response to targeted and immune checkpoint therapies for this patient population.

Phase II Study of Optimized Management of Nivolumab Based on Response in Patients with Advanced Renal Cell Carcinoma (OMNIVORE Study)

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT03203473
Sponsor: 
Dana-Farber Cancer Institute
Enrollment: 
58
Study Design: 
This Phase II, open-label study enrolls patients with treatment-naïve or previously treated aRCC with either clear cell or non-clear cell disease. Prior immune checkpoint inhibitor therapy is not permitted. All patients enrolled receive nivolumab every 2 weeks initially, with subsequent management outlined based on RECIST response within the first 6 months of nivolumab. If patients have a confirmed partial response (PR) or complete response (CR), nivolumab will be discontinued and patients will be observed. At the time of progression, these patients will be treated again with nivolumab, and if there is further progression, 2 treatments with ipilimumab every 3 weeks will be given in addition to nivolumab (which will be given every 3 weeks when combined with ipilimumab). These patients will be considered part of ‘Arm A.’ If, instead, patients are found to have stable disease (SD) or progression (PD) after initial nivolumab treatment, 2 treatments with ipilimumab every 3 weeks will be given while continuing nivolumab, with these patients constituting ‘Arm B.’
Rationale: 
Nivolumab is an established therapy for treatment of advanced RCC (aRCC) after progression on antiangiogenic therapy after the findings of the CheckMate-025 study. The CheckMate-214 trial established the efficacy of nivolumab combined with ipilimumab in intermediate- to poor-risk metastatic RCC but with the tradeoff of increased toxicity as compared to single agent immune checkpoint inhibition. There are also no studies which have addressed the optimal duration of this type of therapy in mRCC, and it is not known if the benefit of combining nivolumab with ipilimumab is derived from combined treatment upfront, if these drugs can be sequenced, or if ipilimumab can convert a non-responder to nivolumab to a responder.
Endpoints: 
There are co-primary endpoints in this trial – the proportion of patients with durable CR/PR at 1 year after nivolumab discontinuation in Arm A and proportion of patients with SD or PD who convert to CR/PR at 1-year after addition of ipilimumab to nivolumab (Arm B). Progression-free survival (PFS), OS, salvage therapy-free interval, safety and immune related objective response rate (irORR) will also be determined as secondary endpoints.
Comments: 
The findings of this Phase II study will help to guide the design of future trials evaluating immune checkpoint inhibitor therapy. For example, if Arm A indicates that a favorable proportion of patients have a durable CR/PR after discontinuation of nivolumab, this would warrant a more robust trial to determine the optimal duration of nivolumab. If Arm B of this trial finds that a promising proportion of patients convert to CR/PR after the addition of ipilimumab, this could indicate that we may be able to spare some patients from the toxicity of combined immunotherapy without sacrificing efficacy.

A Phase III, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study of Atezolizumab (Anti-PD-L1 Antibody) as Adjuvant Therapy in Patients with Renal Cell Carcinoma at High Risk of Developing Metastasis Following Nephrectomy

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT03024996
Sponsor: 
Hoffmann-La Roche
Enrollment: 
664
Study Design: 
This phase III, randomized, double-blind, multicenter trial (IMmotion010) is enrolling patients with clear cell or sarcomatoid RCC at high risk for RCC recurrence after radical or partial nephrectomy, with lymphadenectomy allowed in select patients, high risk defined as T2N0M0 Fuhrman Grade 4, T3aN0M0 Fuhrman Grade 4 or higher, T3b/c & T4 with any Fuhrman grade, or any T stage or Fuhrman grade with lymph node positive disease. Similar to the KEYNOTE-564 trial, complete resection of limited synchronous or metachronous metastases is permitted. Patients are randomized 1:1 to receive either atezolizumab or placebo every 3 weeks for 16 cycles or 1 year unless there is unacceptable toxicity or disease progression. Patients will be stratified by stage and PD-L1 status.
Rationale: 
Much as the aforementioned study, this study seeks to evaluate the role of immune checkpoint inhibitor therapy in the adjuvant setting. Atezolizumab, an anti-PD-L1 antibody, has demonstrated activity in the metastatic setting in RCC, in particular in combination with bevacizumab in the IMmotion150 and IMmotion151 trials.
Endpoints: 
The primary endpoint of IMmotion010 will be DFS as assessed by independent review facility (IRF). The secondary endpoints will be overall survival, and investigator-assessed DFS. IRF-assessed and investigatory-assessed DFS will also be evaluated based on tumor-infiltrating immune cell (IC) levels.
Comments: 
The KEYNOTE-564 and IMmotion010 trials will evaluate the role of immune checkpoint inhibitor therapy after definitive surgical intervention, but the results of these trials will be of particular interest to contrast to the ongoing PROSPER trial which was discussed in the last issue of Kidney Cancer. PROSPER is based on the hypothesis that the primary tumor and its microenvironment is critical to the effectiveness of immune checkpoint inhibitor therapy; thus, that trial is administering nivolumab, an anti-PD-1 antibody, for two cycles prior to proceeding to nephrectomy. All three trials are evaluating DFS as a primary endpoint, though all will report OS as a secondary endpoint. The results of these trials may be revealing in terms of the interplay between the tumor microenvironment and immunotherapy, with potential to optimally treat localized RCC and reduce the risk of recurrence and mortality from the disease.

A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post Nephrectomy (KEYNOTE-564)

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT03142334
Sponsor: 
Merck Sharp & Dohme Corp
Enrollment: 
950
Study Design: 
This is a phase III, randomized, double-blind, multicenter trial (KEYNOTTE-564) evaluating the efficacy of pembrolizumab compared to placebo in improving survival in patients who have undergone a partial nephroprotective or radical complete nephrectomy with intermediate- to high-risk clear-cell RCC, as defined as pT2N0M0 disease of Fuhrman Grade 4 or with sarcomatoid features, pT3N0M0 disease of any grade, pT4N0M0 disease of any grade, or any pT stage with N+, M0 disease. Patients with M1 disease who have completely resectable disease in a synchronous or metachronous fashion are also eligible. Those with residual thrombus post-nephrectomy in the renal vein or vena cava are excluded. Surgery must have been performed within 12 weeks prior to randomization. Patients will be randomized 1:1 to receive either placebo or pembrolizumab every 3 weeks for up to 17 cycles unless there is disease recurrence or unacceptable toxicity. Patients will be stratified by metastasis stage.
Rationale: 
While strides have been made in the treatment of metastatic RCC, there remains no standard adjuvant systemic therapy that has demonstrated an overall survival benefit in the non-metastatic setting. Most patients with intermediate- to high-risk advanced RCC will progress within 3 years following nephrectomy. Pembrolizumab, an anti-PD-1 antibody, has demonstrated benefit in treating metastatic RCC. It is thought that there may be benefit to immune checkpoint inhibitor therapy after resection of localized disease, the hypothesis being that such therapy may allow for eradication of micrometastatic disease and thus translate to improvements in disease-free (DFS) and overall survival (OS).
Endpoints: 
The primary outcome of the trial is DFS by investigator assessment, with OS as a secondary endpoint. OS will also be assessed by PD-L1 expression status.

A Phase III, Open Label, Randomised, Controlled, Multi-Centre Study To Assess the Efficacy and Safety of Savolitinib Versus Sunitinib in Patients With MET-Driven, Unresectable and Locally Advanced, Or Metastatic Papillary Renal Cell Carcinoma (PRCC)

Status: 
Recruiting
Clinicaltrials.gov identifier: 
NCT03091192
Sponsor: 
AstraZeneca + Hutchinson MediPharma
Enrollment: 
180
Study Design: 
This is a phase III, open label, randomised, multicentre study investigating the efficacy and safety of savolitinib compared to sunitinib in patients with MET-driven, unresectable and locally advanced or metastatic papillary renal cell carcinoma (pRCC). Patients can have had treatment previously (not sunitinib or MET inhibitors) or be treatment naïve.
Rationale: 
pRCC carries a poor prognosis and typically responds less well to standard therapies than clear cell RCC. It is frequently excluded from large scale clinical trials and as such there is little data on the use of specific therapies in this patient population. A single arm phase II study (NCT02127710) evaluating savolitinib, a new MET inhibitor, in pRCC showed an overall response rate of 7% with good tolerability. The response rate was better in those patients with MET-driven tumours irrespective of pathological classification.
Endpoints: 
The primary endpoint for this study is progression free survival (PFS) defined as the time from randomisation to progression or death. There are several secondary endpoints in this study including overall survival (OS), defined as time from randomisation to death by any cause; objective response rate including all patients with complete or partial responses based on RECIST 1.1 criteria; the duration of any response achieved and the disease control rate (number of patients achieving complete or partial responses or stable disease according to RECIST 1.1).
Results: 
No results are currently available.
Comments: 
Papillary cell cancer is poorly represented in clinical trials and the inclusion of patients with papillary cell cancer in this trial provides an interesting option for a difficult to treat subtype of RCC. Standard therapies have typically performed poorly in pRCC and savolitinib may provide a more effective and well tolerated option for MET-driven pRCC.

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