Kidney Cancer Journal | Volume 7, Issue 1

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

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.

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.

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.

BACKGROUND:
The historical standard of care for locally advanced renal cell carcinoma (RCC) is nephrectomy + active surveillance. Despite a high recurrence rate ( 40%), adjuvant therapy was previously not included in the standard of care. This review of adjuvant pharmacotherapy reflects conflicting results from multiple trials.

OBJECTIVE:
The objective of this review is to summarize the efficacy of therapy vs surveillance in resected early-stage intermediate to high-risk renal cell carcinoma.

METHODS:
We performed a systematic literature search using PubMed, EMBASE, and SCOPUS. Keywords such as “renal cell carcinoma”, “adjuvant therapy” and “nephrectomy” were used. In the literature search, 2,711 studies were identified and screened.

RESULTS:
We included a total of 21 publications. The most common histology seen in trials was clear cell carcinoma. A variety of interventions were reviewed including immunotherapy, medroxyprogesterone acetate, interferon alfa, and tyrosine kinase inhibitors. Most trials did not demonstrate a benefit in relapse-free survival (RPS) or overall survival (OS). Pembrolizumab demonstrated a significant difference in disease recurrence in the KEYNOTE-564 trial although median data was not reached. Blinded independent reviewers identified a benefit in disease-free survival (DFS) with Sunitinib in the S-TRAC trial.

CONCLUSION:
There was not a clear benefit in using adjuvant therapy broadly for resected locoregional RCC; however, further investigation should be done in the highest-risk group to elucidate potential benefit.

Objective:
To evaluate the effectiveness and safety profile of the tyrosine kinase inhibitor Axitinib for patients with advanced or metastatic renal cell carcinoma (a/mRCC) in a real-world setting.

Methods:
Adult patients from the German non-interventional post-approval multicenter STAR-TOR registry with a/mRCC (NCT00700258) were included if treated with Axitinib in second line or beyond. Overall survival (OS), progression-free survival (PFS) and adverse events were evaluated across subgroups using descriptive statistics and survival analyses.

Results:
Between November 2012 and December 2020, 75 study sites recruited 210 patients treated with Axitinib (69,6% male; median age 69 years; median Karnofsky Index 80%). Clear cell RCC was the most frequent histological subtype (81.0%). Axitinib was administered as second-line in 51.4%, third-line in 24.8%, and fourth-line treatment and beyond in 23.8% of the patients, respectively. MSKCC score was 15.0% favorable, 33.6% intermediate, and 51.3% poor risk. Median PFS was 5.6 months, and median OS 18.3 months. Patients with lactate dehydrogenase (LDH) levels > 300U/l had a nominally significantly shorter OS than patients with LDH≤300U/l (8.2 vs. 19.0 months, p = 0.008).

Drug related adverse and serious adverse events were reported in 56.7% and 17.6% of the patients, respectively (most common adverse event: gastrointestinal disorders; 37.6%).

Conclusions:
This real-world study confirms the clinical relevance of Axitinib in the second-line and beyond setting for a/mRCC with OS and PFS reported in concordance with pivotal trials, while demonstrating a favorable safety profile. A high LDH serum level could be a negative predictive marker for Axitinib effectiveness, which can aid in clinical decision making.

BACKGROUND:
The influence of age and comorbidities during decision-making for patients with renal cell carcinoma remains controversial.

OBJECTIVE:
To comprehensively review the available evidence regarding the impacts of age and comorbidities on the decision to perform partial nephrectomy (PN).

EVIDENCE ACQUISITION:
A systematic review was conducted in accordance with PRISMA and registered with PROSPERO (CRD42022344759). Only randomized control trials, prospective cohort studies, registry-based studies, or single/multi-institutional retrospective cohort studies comparing PN to other therapeutic options for cT1N0M0 renal masses were considered. The primary outcome was to assess differences in patients’ baseline characteristics between different treatments in order to investigate how those aspects have influenced clinical decision-making. Finally, perioperative outcomes were compared across the different options.

EVIDENCE SYNTHESIS:
Overall, patients who underwent PN were 3 to 11 years younger than those who underwent other treatments. Baseline renal function was slightly better in patients who underwent PN than in those who underwent radical nephrectomy (RN), active surveillance (AS), or tumor ablation. Patients undergoing PN had an average pre-treatment eGFR 4 to 6 points (mL/min/1.73 m2) higher than patients undergoing RN or tumor ablation. Likewise, the proportion of baseline chronic kidney disease (CKD) before treatment was higher in patients undergoing other treatments, with a rate of CKD between 6% and 56% higher compared with that for PN. A slightly higher proportion of baseline diabetes mellitus (DM) and cardiovascular comorbidities (CVD) were found in patients who underwent PN than in those who underwent RN (20% vs. 21% for DM and 37% vs. 41% for CVD). On average, patients who underwent AS and tumor ablation had more comorbidities, in terms of Charlson comorbidity index (CCI), DM, and CVD (50% vs. 38% for CCI ≥2; 25% vs. 20% for DM; and 43% vs. 37% for CVD). In terms of Eastern Cooperative Oncology Group (ECOG) Performance Status and American Society of Anesthesiologists (ASA) classification, no major differences were found between PN and other treatments, but a trend emerged whereby more fit patients underwent PN compared with RN (16% of ECOG >1 for PN vs. 18% for RN and 15% of ASA grade ≥3 for PN vs. 26% for RN). Again, tumor ablation was preferred for less fit patients (31% of ASA grade ≥3). No study included in our systematic review reported the baseline frailty status of patients treated for cT1 renal masses. The rates of perioperative complications and length of hospital stay (LOS) were similar between different techniques.

CONCLUSIONS:
Patients who underwent PN tended to be younger and fitter than those who underwent other available treatments for cT1 renal masses. Since this technique aims at reducing renal function impairment after surgery, a greater effort should be made to optimize patient selection to include more comorbid patients for whom PN might be useful.

BACKGROUND:
Papillary renal cell carcinoma (PRCC) has a relatively poor prognosis in the metastatic setting. In contrast to clear cell kidney cancer, there are limited treatment options specifically tested in PRCC. Alterations in the MET pathway are common in PRCC and may play a pivotal role in promoting tumor growth and the development of resistance to systemic therapy.

OBJECTIVE:
Current data on the efficacy of MET inhibitors over standard of care in PRCC is immature and evolving. The purpose of this systematic review is to assess and summarize the results and limitations of landmark trials of MET inhibitors for PRCC as well as to discuss barriers faced by trials of these drugs.

METHODS:
Manuscripts and abstracts were collected from PubMed, the American Society of Clinical Oncology (ASCO) historical abstracts and European Society for Medical Oncology (ESMO) historical abstracts. Included studies must have been either a clinical trial, systematic review or narrative review and included PRCC patients. Patients must have been treated with a selective or non-selective MET inhibitor. After the final application of criteria, 30 studies were included.

RESULTS/CONCLUSIONS:
Cabozantinib has the best evidence for use showing improved outcomes in PRCC. Other MET inhibitors, including savolitinib, crizotinib, and foretinib have shown possible benefit in patients with MET-positive disease, but the inconsistent definition of MET status and a low patient accrual rate prevented further extrapolation of the individual trial results. Future trials of single agent savolitinib, as well as combination MET inhibitor/ immuno-oncology (IO) therapies, have the potential to change the therapeutic landscape of using MET inhibitors for PRCC.

Immune checkpoint inhibitors (ICIs) have transformed the management of advanced renal cell carcinoma (RCC), but most patients still do not receive a long-term benefit from these therapies, and many experience off-target, immune-related adverse effects. RCC is also different from many other ICI-responsive tumors, as it has only a modest mutation burden, and total neoantigen load does not correlate with ICI response. In order to improve the efficacy and safety of immunotherapies for RCC, it is therefore critical to identify the antigens that are targeted in effective anti-tumor immunity. In this review, we describe the potential classes of target antigens, and provide examples of previous and ongoing efforts to investigate and target antigens in RCC, with a focus on clear cell histology. Ultimately, we believe that a concerted antigen discovery effort in RCC will enable an improved understanding of response and resistance to current therapies, and lay a foundation for the future development of “precision” antigen-directed immunotherapies.

An Open-label, Randomized, Phase 3 Study of MK-6482 in Combination With Lenvatinib (MK-7902) vs. Cabozantinib in Participants with Advanced Renal Cell Carcinoma Who Have Progressed After Prior Anti-PD-1/L1 Therapy

Status: Recruiting
Clinicaltrials.gov identifier: NCT04586231
Sponsor: Merck Sharp & Dohme LLC in collaboration with Eisai Inc
Enrollment: 708

Rationale: While there are limited data that demonstrate efficacy of cabozantinib after treatment with checkpoint inhibitor therapy, optimal second line treatment after first-line anti-PD-1 therapy remains an area of active clinical interest. Belzutifan (MK-6482) is an inhibitor of hypoxia-inducible factor-2α (HIF-2α), which has established efficacy in patients with von Hippel-Lindau disease, but remains under clinical study in patients with clear cell RCC. HIF-2α also regulates vascular endothelial growth factor (VEGF) expression and is involved in resistance to anti-VEGF therapy. Thus, there is interest in combining belzutifan with a VEGF tyrosine kinase inhibitor (TKI) such as lenvatinib.

Study Design: This open label, Phase 3, multicenter study enrolls patients with unresectable, locally advanced or metastatic clear cell RCC. Patients must have experienced disease progression on or after an anti-PD-1/PD-L1 therapy as either first or second-line treatment in the advanced setting, or as adjuvant or neoadjuvant therapy with progression within 6 months of the last dose. Patients may not have received more than 2 prior systemic regimens, and could only have received 1 prior anti-PD/PD-L1 therapy. Patients also must have never received belzutifan, lenvatinib or cabozantinib prior to enrollment. Patients who are enrolled to the study receive either belzutifan + lenvatinib or cabozantinib until disease progression or unacceptable toxicity.

Endpoints: The co-primary endpoints of this study are progression-free survival (PFS) and overall survival (OS). Secondary endpoints include objective response rate (ORR), duration of response (DOR), and toxicity.

BACKGROUND:
Renal cysts are the most frequently occurring incidental renal lesions. They are asymptomatic, which explains why they tend to be diagnosed incidentally as a result of imaging tests. In cases where malignancy is suspected, there are various therapeutic alternatives.

OBJECTIVE:
The objective of this study is to review the diagnostic and therapeutic alternatives for cystic renal lesions.

METHOD:
A systematic search was conducted in Pubmed, Science Direct, Scopus, and Google Scholar databases between May and October 2022. The review of articles was conducted following the methodological recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 Statement. As a result, 25 articles were selected.

RESULTS:
Thirteen studies focused on diagnostic management. In five of the cases ultrasound was used, multiparametric magnetic resonance imaging (mpMRI) was considered in six articles, and computerized tomography (CT) was studied in three. Eleven papers were retrospective series, one of the studies was prospective, and one was a simulated cost-effectiveness model. Among the 12 articles on treatment, five focused on surgery and one on the results of active surveillance, while three compared active surveillance with other treatments. Four articles assessed the percutaneous approach and radiofrequency ablation. All articles were retrospective cohorts.

CONCLUSIONS:
CT is the most standard of the tests. In doubtful cases, mpMRI and ultrasound can serve as complementary tests. Partial nephrectomy is currently the gold standard treatment and the results are similar for both open and laparoscopic approaches. Percutaneous radiofrequency treatments produce reasonable survival rates free of local recurrence and metastasis and are recommended in patients with high surgical risk.

Background:
Introduction of immune checkpoint inhibitors in the standard of care for metastatic renal cell carcinoma (mRCC) requires robust but yet simple biomarkers to predict efficacy of immunotherapy.

Objective:
The aim of this study was to evaluate the association between fibrinogen levels and efficacy of second-line therapy with nivolumab in mRCC.

Methods:
This is a prospective multicenter biomarker study. Fibrinogen levels were measured one week prior to second-line nivolumab therapy and six times monthly. A high fibrinogen level was defined as ≥5 g/L. Patients were divided into two cohorts: high (H) and normal (N) fibrinogen levels. The primary endpoint was overall survival (OS).

Results:
The median OS was 31.5 months (95% confidence interval [CI], 27.9 to 35.1) in cohort N vs. 20.9 months (95% CI, 18.1 to 23.7) in cohort H (hazard ratio [HR], 0.39; 98.5% CI, 0.21 to 0.7; P = 0.002). The median progression-free survival was 9.4 months (95% CI, 5.5 to 14.1) in cohort N and 4.0 months (95% CI, 2.9 to 5.1) in cohort H (HR, 0.65; 95% CI, 0.51 to 0.72; P <  0.001). The objective response rate was higher in N cohort (33% vs. 17% ; P = 0.012). No statistically significant changes of fibrinogen concentration during nivolumab therapy were found.

Conclusion:
The study demonstrated an association of hyperfibrinogenemia with worse clinical outcomes of second-line nivolumab monotherapy in patients with mRCC. Further validation of fibrinogen as a predictive biomarker for immunotherapy efficacy in patients with mRCC is warranted.

Background:
Non-clear cell renal cell carcinoma (nccRCC) is a diverse group of cancers that occurs in approximately 25% of patients with renal cell carcinoma. In the advanced/metastatic setting, survival in all nccRCC subtypes is considered poor, due to the inherent aggressiveness of these cancers, and a lack of effective systemic treatment options. Clinical trials of immune/targeted agents have predominantly focused on patients with ccRCC. There is no globally accepted standard of care for nccRCC; however, recently clinical trials have been initiated in this population.

Objective:
To perform a targeted literature review of published original observational studies reporting common real-world clinical outcomes (real-world overall response rate [rwORR], real-world progression free survival [rwPFS], real-world overall survival [rwOS]) in previously treatment naïve patients with advanced/metastatic nccRCC.

Methods:
A targeted search of MEDLINE and EMBASE was conducted per PRISMA guidelines to identify observational studies in previously treatment naïve patients with advanced/metastatic nccRCC. Publications with adequate information since 2010 and from select conferences since 2020 were considered.

Results:
27 studies across 29 publications were identified. Sample sizes ranged from 7-1,573 across these studies with differences in nccRCC subtypes included and treatments received. Real-world ORR ranged from 0–37%, median rwPFS from 2–17 months, and median rwOS from 3–30 months, across 19, 17, and 24 studies, respectively. These outcomes also varied with receipt/type of treatment and demographic/clinical subgroups with outcomes tending to be worse in patients with papillary RCC compared to chromophobe RCC.

Conclusions:
Clinical outcomes varied, as patient populations, eligible histologies, treatments and methods were heterogeneous.

Background:
Ipilimumab plus nivolumab is approved as a first-line treatment for intermediate or poor risk metastatic renal cell carcinoma (mRCC). However, ∼35% of patients progress within six months on ipilimumab plus nivolumab, and no validated genomic biomarkers predict the benefit. In this study, we explore the genomic and transcriptomic differences among patients with clear cell mRCC patients who either did or did not experience clinical benefit from first-line ipilimumab plus nivolumab therapy.

Method:
Patients with clear cell mRCC intermediate or poor IMDC risk scores, with available tumor whole exome with/without transcriptome sequencing before starting systemic therapy were included. Patients who developed a complete response, partial response, or stable disease for at least six months after initiating treatment were categorized into the ‘clinical benefit’ group, whereas the rest were classified as ‘no clinical benefit.’ Genomic alteration frequencies between the groups were assessed with a chi-square test. Differentially expressed genes and gene sets were identified via DeSeq2 and GSEA v4.2.3, respectively.

Result:
53 patients with clear cell mRCC (37 clinical benefit and 16 no clinical benefit) were eligible and included. No significant difference was found in the genomic alteration frequencies between these groups. Baseline tumor transcriptomic data were available for 14 patients (9 clinical benefit and 5 no clinical benefit). The apical surface and pathways downregulated by KRAS signaling were enriched in the clinical benefit group, whereas inflammatory pathways were enriched in the no clinical benefit group.

Conclusion:
These findings suggest that tumor specific gene expression as assessed by RNA sequencing could serve as a potential biomarker of response to ipilimumab plus nivolumab therapy.

Background:
The nephrotoxicity profile of contemporary first-line regimens for treatment of metastatic renal cell carcinoma (mRCC) has not been systematically studied in published clinical trials.

Objective:
To assess the rates of nephrotoxic events of contemporary first-line regimens for treatment of mRCC in comparison to vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) mono-therapy.

Methods:
We performed a systematic search of the literature looking for randomized clinical trials that contemplated National Comprehensive Cancer Network (NCCN) recommended first-line regimens for treating mRCC in which the control arm was a VEGF-TKI. Selected trials could either include an experimental arm of immune checkpoint inhibitor (ICI) plus VEGF-TKI combination or ICI-ICI combination. Nephrotoxic events were defined as proteinuria, hypertension, blood creatinine increase, acute kidney failure or nephritis, which were all described separately.

Results:
Five studies satisfied our inclusion criteria. Combination of ICI with VEGF-TKI showed a statistically significant higher degree of proteinuria compared to VEGF-TKI alone. There was no statistically significant difference in rates of hypertension between ICI-TKI and VEGF-TKI alone, but VEGF-TKI alone was statistically significantly more associated with hypertension than immunotherapy alone. Other renal toxicities, such as an increase in creatinine, acute kidney injury (AKI) and nephritis, were uncommon and not consistently reported in each trial.

Conclusions:
Contemporary regimens for first-line treatment of mRCC are associated with a higher grade of proteinuria than VEGF-TKI alone, while VEGF-TKI is more associated with hypertension than an ICI-ICI combination. Description of many renal toxicities across the studies reported have been diverse and a standardized definition across clinical trials would be helpful to reliably interpret the data regarding nephrotoxicity in the setting of treatment of renal cell carcinoma.

Background:
Approximately 30% of renal cell carcinoma (RCC) cases present with de novo metastatic disease, while 20% to 30% of those with localized disease will develop metastases following surgical resection. Various drug classes have been investigated to treat RCC, including cytokine-based therapies, small molecule Vascular Endothelial Growth Factor (VEGF) tyrosine kinase inhibitors (TKIs) and antibody-based therapies. Up to 58% of patients fail to respond to primary immune checkpoint inhibitor (ICI) therapy, and nearly all initial responders experience disease progression due to the development of secondary resistance. Consequently, novel treatment options are being investigated.

Objective:
Review the rapidly evolving ADC therapeutic landscape in metastatic RCC including recent trials, emerging ADCs targets, and future directions for ADCs in the treatment of advanced RCC.

Methods:
Literature review using the MEDLINE database on important trials and presentations from the American Society of Clinical Oncology (ASCO), and the European Society for Medical Oncology (ESMO) conferences. Key words used included “renal cell carcinoma,” “RCC,” “metastatic RCC,” “advanced RCC,” “antibody-based therapies,” “immunotherapy,” “clinical trials,” and “emerging drugs.” Specifically for review of ADCs in RCC, the following search string was used with additional review of bibliographies from retrieved papers: “((antibody drug conjugate) OR (antibody-dependent cellular cytotoxicity) OR (chimeric antigen receptor)) AND ((kidney cancer) OR (renal cell carcinoma))”.

Results:
Several promising targets including MMP14, EGFR, MCT4, CA9, MET, CDH13, B7-H3, and PSMA were identified with relevant preclinical and clinical studies reviewed.

Conclusions:
While ADCs therapeutics have not shown benefit to date for renal cell carcinoma, there are ample promising candidates and targets for future research.