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Open accessObituaryFirst published March 15, 2022pp. 1-1
Open accessReview articleFirst published March 15, 2022pp. 3-9The 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.
The study hypothesis is that CN will improve OS in synchronous metastatic RCC when surgery is performed after starting systemic immune checkpoint-based combination therapy. A potential mechanism leading to improved survival is the broader antigen spread and higher neoantigen load enabled by the primary tumor enhancing the efficacy of the immune therapy. CN after initial systemic therapy would help select the patient subset most likely to benefit and will potentially enable eradication of immune resistant clones within the primary tumor.
Open accessResearch articleFirst published March 15, 2022pp. 11-22Patient-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.
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.
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.
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.
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.
Open accessReview articleFirst published March 15, 2022pp. 23-35The 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
We aimed to systematically evaluate the role of
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.
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
Alterations in
Open accessReview articleFirst published March 15, 2022pp. 37-51Treatment 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).
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.
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
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 (
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.
Open accessReview articleFirst published March 15, 2022pp. 53-68Metastatic 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.
To perform a systematic review of recently published and currently enrolling prospective clinical trials for advanced non-clear cell renal cell carcinoma.
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.
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,
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.
Open accessCase reportFirst published March 15, 2022pp. 69-79Cabozantinib 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.
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.
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).
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.
mRCC patients with cabozantinib responsive disease and reasonable tolerability may benefit from dose escalation at progression.
Open accessOtherFirst published March 15, 2022pp. 81-82