In Memoriam: Chris Wood
Abstract
It is with great sadness that we heard of the loss of Chris Wood in 2021. Born in 1963, his death came much too early.
He was an excellent urologist and his knowledge and experience in kidney cancer made him one of the world’s leading experts in this field. His surgical approaches to advanced renal cell carcinoma, in particular, gave the kidney cancer community the backbone of our tool kit to treat this condition. Chris always communicated and published his results in a way that was as honest and straightforward as he was in person. In addition he liked to discuss individual cases, surgical strategies and complications. We remember the many panels at congresses where he gave his personal opinions on the pros and cons of surgery in different scenarios. He also saw the unmet need to cure kidney cancer at an advanced stage, and exploring neoadjuvant strategies, using resected tissue for analysis and new vaccine adjuvant strategies became the backbone of his clinical approaches in renal cell carcinoma. This greatly enhanced the prognosis of his patients, for whom he cared deeply.
With Chris we lose a great pioneer in kidney cancer, a widely respected colleague and a much valued associate editor for our relatively young journal. We offer our support and condolences to those he left behind: his family and friends, his colleagues, and his patients.
“PROBE”ing the Role of Cytoreductive Nephrectomy in Advanced Renal Cancer
Abstract
The Southwest Oncology Group (SWOG)1931 trial, also known as PROBE (ClinicalTrials.gov Identifier: NCT04510597) is a phase III study evaluating the role of cytoreductive nephrectomy (CN) in metastatic renal cell cancer (RCC). Kidney cancer presenting with synchronous metastases has demonstrated shorter survival outcome compared to the patients relapsing with metastases after nephrectomy. Previously, CN has been associated with survival improvement when interferon-based systemic therapy was used. In the setting of antivascular therapy sunitinib, a prospective randomized clinical trial demonstrated no benefit of CN. Immune checkpoint-based combination therapy has now become the standard-of-care in the frontline setting for RCC. The role of nephrectomy or primary resection has not been evaluated in the setting of immune checkpoint-based systemic therapy. The sequence and optimal timing of nephrectomy is also not established. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in RCC within the context of immune checkpoint-based combination regimens. The study requires starting with systemic therapy; any one of the FDA approved immunotherapy-based regimens at the time the study was activated are permitted. The disease status and response are evaluated at 9–12 weeks of therapy and then consented patients are randomized 1:1 to receive CN or to continue systemic therapy. The patients who have rapid disease progression are considered ineligible for randomization as they need a switch in systemic therapy. Both groups should continue systemic therapy as long as they are tolerating the treatment and continuing to derive clinical benefit. Quality-of-life, tumor genomic testing, microbiome, radiomics and circulating tumor DNA assessments as predictive biomarkers are planned as study correlatives.
Patient-Derived Renal Cell Carcinoma Xenografts Capture Tumor Genetic Profiles and Aggressive Behaviors
Abstract
BACKGROUND:
Patient-derived xenografts (PDX) have emerged as one of the most promising model systems to study cancer biology and to develop new antineoplastic drugs. Renal cell carcinoma (RCC) represents up to 90% of all kidney tumors, exhibits aggressive behavior, and has a propensity for metastasis. At diagnosis, 30% of patients with RCC have metastases, while up to 50% of those with localized disease treated with curative protocols experience recurrence.
OBJECTIVE:
This study aimed to establish an RCC PDX platform to identify novel clinical and molecular biomarkers of recurrence risk in order to facilitate precision medicine.
METHODS:
Tumor samples were obtained from surgical specimens of 87 RCC patients; fragments were implanted in immunodeficient NOD/SCID/gamma (NSG) mice. 17 Fragments were implanted subcutaneously in an initial group while a second group of 70 samples were implanted orthotopically in the subcapsular space.
RESULTS:
A total of 19 PDX developed only after orthotopic implantation, and included 15 cases of clear cell RCC subtype, 3 cases of papillary subtype, and 1 unclassifiable tumor. 1 PDX of clear cell RCC recapitulated the phenotype of vena caval tumor thrombus extension that had been diagnosed in the source patient. PDX characterization by immunohistochemistry and targeted sequencing indicated that all PDXs preserved RCC identity and major molecular alterations. Moreover, the capacity of tumor engraftment was a strong prognostic indicator for patients with locally advanced disease.
CONCLUSION:
Taken together, these results suggest that the orthotopic xenograft model of RCC represents a suitable tool to study RCC biology, identify biomarkers, and to test therapeutic candidates.
BRCA1-Associated Protein 1 (BAP-1) as a Prognostic and Predictive Biomarker in Clear Cell Renal Cell Carcinoma: A Systematic Review
Abstract
BACKGROUND:
The gene that encodes BRCA1-associated protein 1 (BAP1) has been reported to be dysregulated in several human cancers such as uveal melanoma, malignant pleural mesothelioma, hepatocellular carcinoma, thymic epithelial tumors, and clear-cell renal cell carcinoma (ccRCC). The gene is located on the human chromosome 3p21.3, encoding a deubiquitinase and acts as a classic two-hit tumor suppressor gene. BAP1 predominantly resides in the nucleus, where it interacts with several chromatin-associated factors, as well as regulates calcium signaling in the cytoplasm. As newer therapies continue to evolve for the management of RCC, it is important to understand the role of BAP1 mutation as a prognostic and predictive biomarker.
OBJECTIVE:
We aimed to systematically evaluate the role of BAP1 mutations in patients with RCC in terms of its impact on prognosis and its role as a predictive biomarker.
METHODS:
Following PRISMA guidelines, we performed a systematic literature search using PubMed and Embase through March 2021. Titles and abstracts were screened to identify articles for full-text and then a descriptive review was performed.
RESULTS:
A total of 490 articles were initially identified. Ultimately 71 articles that met our inclusion criteria published between 2012–2021 were included in the analysis. Data were extracted and organized to reflect the role of BAP1 alterations as a marker of prognosis as well as a marker of response to treatments, such as mTOR inhibitors, VEGF tyrosine kinase inhibitors, and immune checkpoint inhibitors.
CONCLUSIONS:
Alterations in BAP1 appear to be uniformly associated with poor prognosis in patients with RCC. Knowledge gaps remain with regard to the predictive relevance of BAP1 alterations, especially in the context of immunotherapy. Prospective studies are required to more precisely ascertain the predictive value of BAP1 alterations in RCC.
Comparative Evaluation of Safety and Efficacy of Alternate Schedule (AS) of Sunitinib in Asian and Non-Asian Patient Population for the Treatment of Metastatic Renal Cell Cancer (mRCC): A Meta-Analysis
Abstract
BACKGROUND:
Treatment of metastatic renal cell carcinoma (mRCC) using traditional schedule (TS, 4/2) of Sunitinib is associated with higher adverse effects compared to the alternate schedule (AS, 2/1 upfront or when switched from TS).
OBJECTIVE:
This meta-analysis aims to compare the safety, efficacy, and percentage of patients requiring dose reduction or dose interruption between Asian (AP) and non-Asian population (NAP) receiving AS of sunitinib.
METHODS:
Electronic databases (PubMed, EMBASE, Cochrane Library) were searched to identify studies published in the English language between May 2009- May 2019, which included patients (>18 years) with mRCC receiving AS of sunitinib. Data were analyzed using the random effect model and t-test. P < 0.05 was considered statistically significant.
RESULTS:
Of 1922, 16 studies were included (8 AP, 8 NAP). Among all grade AEs, mucositis (RR:0.22; 95% CI:0.12–0.40), cardiotoxicity (RR: 0.52; 95% CI: 0.31–0.88), nausea (RR:0.21; 95% CI: 0.10–0.44), hand-foot syndrome (RR:0.33; 95% CI:0.13–0.83), rash (RR: 0.52; 95% CI: 0.34–0.79), and aspartate transaminase (RR:0.57; 95% CI:0.33–0.98) were more common in AP. Leukopenia (RR:2.57; 95% CI:1.47–4.49), proteinemia (RR:4.45; 95% CI:2.12–9.33), and stomatitis (RR:4.33; 95% CI:2.6–7.23) occurred more commonly in NAP. Further, PFS was significantly longer in NAP, while longer OS was observed in AP (p < 0.001). Dose reduction was significantly higher in AP than NAP (52.08% vs. 40.6%, p = 0.0088).
CONCLUSION:
Safety profile of AS of sunitinib was similar with variations in the efficacy, dose reduction between AP and NAP. Sunitinib dose or schedule modification may mitigate AEs and enhance efficacy outcomes in mRCC by extending the treatment duration.
Systematic Review of Treatment of Metastatic Non-Clear Cell Renal Cell Carcinoma
Abstract
BACKGROUND:
Metastatic and unresectable non-clear cell renal cell carcinoma comprises more than a quarter of kidney cancers but does not have standardized treatment. Non-clear renal carcinoma consists of a variety of diverse histologic subtypes, including papillary, chromophobe, collecting duct, translocation, and medullary histologies, many of which carry a poor prognosis. Many prospective clinical trials exclude these kidney cancers, and for most clinical trials of non-clear cell renal cell carcinoma, only a small number of patients are enrolled.
OBJECTIVE:
To perform a systematic review of recently published and currently enrolling prospective clinical trials for advanced non-clear cell renal cell carcinoma.
METHODS:
A systematic search of Pubmed and MEDLINE (Ovid) was conducted as per PRISMA guidelines to identify recent prospective clinical trials in non-clear cell renal cell carcinoma. To ensure a thorough search, terms not only included non-clear cell renal carcinoma but also molecular subtypes. A review of currently enrolling clinical trials was conducted on Clinicaltrials.gov and the EU Clinical Trials Register as well.
RESULTS:
A total of 33 prospective clinical trials with published results and 10 currently enrolling clinicals trials were identified. About half (48.5%) of these studies were reported in 2020 or 2021, and 36.4% were in the first-line setting. Treatments investigated in these trials included mTOR inhibitors, VEGF- and MET-targeted tyrosine kinase inhibitors, immune checkpoint inhibitors, and combinatorial strategies. Outcomes from these data revealed a wide range of response rate and progression free survival, favoring TKIs and immune checkpoint inhibitors -based combination regimens.
CONCLUSIONS:
Novel targeted therapies and immunotherapies have changed the landscape of treatment for advanced non-clear cell renal cell carcinoma. Combination regimens may provide even further clinical benefit and warrant further investigation in larger, randomized prospective clinical trials.
Extended Disease Control with Unconventional Cabozantinib Dose Increase in Metastatic Renal Cell Carcinoma1
Abstract
BACKGROUND:
Cabozantinib is among the most potent tyrosine kinase inhibitors (TKIs) FDA-approved for metastatic renal cell carcinoma (mRCC). Effective treatments after progression on cabozantinib salvage therapy are limited. Dose escalation for other TKIs has been shown to afford added disease control.
OBJECTIVE:
We sought to evaluate whether dose escalation of cabozantinib (Cabometyx®) from conventional doses in select patients with limited treatment options offered additional disease control. We asked how cabozantinib dose increases may affect circulating drug levels.
METHODS:
We identified patients with mRCC at the University of Texas Southwestern Medical Center who were treated with cabozantinib dose escalation to 80 mg after progressing on conventional cabozantinib 60 mg. We then queried leading kidney cancer investigators across the world to identify additional patients. Finally, we reviewed pharmacokinetic (PK) data to assess how higher doses impacted circulating levels by comparison to other formulations (Cometriq® capsules).
RESULTS:
We report six patients treated at two different institutions with cabozantinib-responsive disease and good tolerability, where cabozantinib was dose escalated (typically to 80 mg, but as high as 120 mg) after progression on 60 mg, a strategy that resulted in added disease control (median duration, 14 months; 95% Confidence Interval [CI]: 8 –Not Estimable[NE]). Four patients (66.7%) had disease control lasting at least 1 year. No grade III/IV adverse events were identified in this small, select, cohort. A comparison of PK data to FDA-approved cabozantinib 140 mg capsules suggests that cabozantinib 80 mg tablets results in comparable exposures.
CONCLUSIONS:
mRCC patients with cabozantinib responsive disease and reasonable tolerability may benefit from dose escalation at progression.
Clinical Trials Corner: Nephrectomy in the New Year
Abstract
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
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.
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.
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.
