Non-metastatic Clear Renal Cell Carcinoma Research Articles

A phase II study of neoadjuvant tislelizumab and axitinib in patients with locally advanced non-metastatic clear cell renal cell carcinoma (accRCC).

420 Background: PD-1/PD-L1 combined with vascular endothelial growth factor (VEGF) inhibitors improves survival in patients with advanced renal cell carcinoma (RCC), but the role of perioperative application in patients with localized RCC has not been established. In this phase II trial, we investigate the safety and role of tislelizumab and axitinib in downsizing tumors in patients with non-metastatic clear cell RCC prior to surgical resection. Methods: In this investigator-initiated study, 20 patients with high-risk non-metastatic ccRCC (clinical stage T2a-4 and/or N1, M0 lesions) were enrolled to receive 12 weeks of neoadjuvant ticelizumab and axitinib prior to nephrectomy. The primary endpoint was the objective response rate (complete and partial response) after neoadjuvant treatment according to RECIST v1.1. Secondary endpoints were disease-free survival (DFS), overall survival (OS), surgical outcome and safety. Results: By September 2023,13 eligible pts were enrolled. 11 pts have completed neoadjuvant therapy, with a median age of 60 (range 45-73) years, among whom 9 pts underwent surgery as planned without any delay. One patient progressed during treatment and received further systemic therapy. In 9 pts evaluable for efficacy, the investigator-assessed confirmed ORR was 55.5%. The median reduction of primary renal tumor size was 26.2% (range 12.5-45%). Pathologic results showed that one patient (11.1%) achieved a complete response (CR) by RECIST 1.1 and four patients achieved a partial response (PR). One patient who was considered unresectable became resectable at the end of treatment. Two patients were converted from radical to partial nephrectomy. The most common neoadjuvant therapy-related AEs were hematologic toxicity, hypothyroidism, nausea, vomiting, decreased appetite, fatigue, diarrhea, and elevated ALT/AST. There were no Gr4/Gr5 TRAEs. No direct intraoperative complications and no drug-related surgical complications postoperatively. Conclusions: As a neoadjuvant therapy for accRCC, the combination of tislelizumab and axitinib has clinical efficacy and a manageable safety profile. Clinical trial information: NCT05172440 .

Outcomes of Patients With Advanced Renal Cell Carcinoma With Non-Clear Cell Histology Treated With Systemic Therapy

BackgroundPatients with nonclear cell renal cell carcinoma (RCC) and RCC with sarcomatoid differentiation have been under-represented in clinical trials. This study evaluates the outcomes and treatment patterns of patients with non-clear cell RCC and RCC with sarcomatoid features compared to those with clear cell RCC receiving systemic therapy. MethodsA single-center retrospective analysis of patients with advanced or metastatic RCC receiving systemic therapy was conducted. Patients were divided into groups based on histology: nonclear cell RCC, clear cell RCC, and RCC with and without sarcomatoid features. The primary endpoint was overall survival (OS) for each group calculated from the date of diagnosis of advanced or metastatic RCC to the date of last follow-up or death. Additionally, an exploratory analysis was conducted by nonclear cell type and type of first-line treatment. ResultsOverall, 251 patients were included, with most treated before 2018. First-line therapies included vascular endothelial growth factor monotherapy (68.5%), immunotherapy monotherapy (7.6%), immunotherapy combination therapy (16.7%), or other treatments (7.2%). Overall survival was shorter for patients with nonclear cell RCC compared to clear cell RCC (39.2 months vs. 81.1 months, hazard ratio (HR), 1.60, 95% Confidence Interval 1.0, 2.6, P = .04). Additionally, OS for patients with sarcomatoid differentiation was shorter compared to patients without sarcomatoid differentiation (43.4 vs. 75.0 months, HR 1.5, 95% CI 0.8, 2.6, P = .20). ConclusionWe demonstrate inferior outcomes among patients with advanced or metastatic nonclear cell RCC and RCC with sarcomatoid differentiation receiving systemic treatment. Further prospective studies are warranted testing immunotherapy combinations and novel treatments in patients with nonclear cell RCC.

Efficacy and safety evaluation of immunotherapy combined with targeted therapy as second-line treatment in patients with metastatic non-clear cell renal cell carcinoma

Objective: This study aimed to evaluate the efficacy and safety of programmed death-1 (PD-1) inhibitor combined tyrosine kinase inhibitor (TKI) therapy versus TKI monotherapy as the second-line regimen for patients with metastatic non-clear cell renal carcinoma (nccRCC) who failed first-line TKI therapy. Methods: The clinicopathological data of 67 patients with metastatic nccRCC who failed first-line TKI therapy between October 2011 and September 2020 were retrospectively analyzed, including 22 patients who received TKI monotherapy and 45 patients who received TKI plus PD-1 inhibitor as the second-line therapy. The efficacy was assessed according to Response Evaluation Criteria in Solid Tumors version 1.0/1.1 (RECIST 1.0/1.1), the Kaplan-Meier method was used to plot the survival curves, and the Log rank test was used to analyze the differences in the survival between the two groups. Treatment-related adverse events (AEs) after treatment were observed in both groups. Results: The overall objective response rate (ORR) and disease control rate (DCR) were 37.3% (25/67) and 56.7% (38/67), respectively. The overall second-line progression-free survival (PFS) was 7.7 months and Overall Survival (OS) was 25.2 months. The ORR and DCR of patients in the combination therapy group were 48.9% (22/45) and 71.1% (32/45), respectively, which were significantly improved compared with the TKI monotherapy group [13.6% (3/22) and 27.3% (6/22), respectively] (P=0.007 and P=0.001, respectively). The median PFS of 9.2 months for second-line treatment was longer in patients in the combination therapy group than in the TKI monotherapy group (5.2 months, P=0.001), but the median OS was not statistically different between the two groups (28.2 months vs 20.8 months, P=0.068). Common treatment-related AEs included hypertension, diarrhea, fatigue, stomatitis, hand-foot syndrome, and hypothyroidism. The incidence of hypothyroidism was higher in the combination therapy group [40.0% (18/45)] than in the TKI monotherapy group [22.7% (5/22), P=0.044]; the incidence of other treatment-related AEs between the two groups were not statistically significant (all P>0.05). Conclusion: Immune-targeted combination therapy was more effective than TKI monotherapy alone and was well tolerated in the treatment of metastatic nccRCC patients who failed first-line TKIs.

Prognostic Significance of Grade Discrepancy Between Primary Tumor and Venous Thrombus in Nonmetastatic Clear-cell Renal Cell Carcinoma: Analysis of the REMEMBER Registry and Implications for Adjuvant Therapy

BackgroundFurther stratification of the risk of recurrence of clear-cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) will facilitate selection of candidates for adjuvant therapy. ObjectiveTo assess the impact of tumor grade discrepancy (GD) between the primary tumor (PT) and VTT in nonmetastatic ccRCC on disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS). Design, setting, and participantsThis was a retrospective analysis of a multi-institutional nationwide data set for patients with pT3N0M0 ccRCC who underwent radical nephrectomy and thrombectomy. Outcomes measurements and statistical analysisPathology slides were centrally reviewed. GD, a bidirectional variable (upgrading or downgrading), was numerically defined as the VTT grade minus the PT grade. Multivariable models were built to predict DFS, OS, and CSS. Results and limitationsWe analyzed data for 604 patients with median follow-up of 42 mo (excluding events). Tumor GD between VTT and PT was observed for 47% (285/604) of the patients and was an independent risk factor with incremental value in predicting the outcomes of interest (all p < 0.05). Incorporation of tumor GD significantly improved the performance of the ECOG-ACRIN 2805 (ASSURE) model. A GD-based model (PT grade, GD, pT stage, PT sarcomatoid features, fat invasion, and VTT consistency) had a c index of 0.72 for DFS. The hazard ratios were 8.0 for GD = +2 (p < 0.001), 1.9 for GD = +1 (p < 0.001), 0.57 for GD = −1 (p = 0.001), and 0.22 for GD = −2 (p = 0.003) versus GD = 0 as the reference. According to model-converted risk scores, DFS, OS, and CSS significantly differed between subgroups with low, intermediate, and high risk (all p < 0.001). ConclusionsRoutine reporting of VTT upgrading or downgrading in relation to the PT and use of our GD-based nomograms can facilitate more informed treatment decisions by tailoring strategies to an individual patient’s risk of progression. Patient summaryWe developed a tool to improve patient counseling and guide decision-making on other therapies in addition to surgery for patients with the clear-cell type of kidney cancer and tumor invasion of a vein.

CABOSUN II: Results from a phase 2, open-label, multi-center randomized study of cabozantinib (CABO) vs. sunitinib (SUN) for non-clear cell renal cell carcinoma (NCCRCC).

4597 Background: NCCRCC are a diverse group of rare diseases with limited data to guide treatment. CABO is highly effective in clear cell RCC, but it is unknown whether it is superior to SUN, the historic standard of care for metastatic NCCRCC. Methods: CABOSUN II (NCT03541902) was a randomized phase II study at 3 centers for patients (pts) with metastatic NCCRCC. Sixty pts were planned to detect CABO as better than SUN with a 1-sided test. Pts were randomized 1:1 to CABO 60mg daily or SUN 50mg daily (4 weeks on, 2 weeks off). SUN dose modification to 2 weeks on, 1 week off was allowed for toxicity. Stratification was by papillary RCC (PRCC) vs. non-PRCC (NPRCC), good/intermediate vs. poor risk disease by IMDC criteria, and prior TKI use. The primary outcome was progression-free survival (PFS) by RECIST v1.1 compared between the 2 arms using the log-rank test. Secondary outcomes were objective response rate (ORR), overall survival (OS), and adverse event (AE) rates (2-sided tests). Results: 32 pts were randomized to CABO (N=15) or SUN (N=17) between 9/2018 and 6/2021. The trial stopped early due to a change in standard therapy for PRCC not based on these pts’ outcomes. Age range was 22-88 years with medians 57 and 61 for CABO and SUN. Pts were primarily white (84%) and male (72%), with good/intermediate risk (88%), and these were balanced between arms. More pts on the CABO arm had bone metastases (62% vs. 24%). NPRCC were chromophobe (N=6; 5 randomized to SUN), unclassified (N=5), and MiT family translocation (N=3; all randomized to CABO). With median follow-up of 33.3 months and 20 PFS events, median PFS for CABO vs. SUN was 8.2 vs. 13.8 months (1-sided p=0.96). There were no statistically significant differences in ORR or OS between the arms. AEs were in line with previous studies. Conclusions: CABO was not superior to SUN for metastatic NCCRCC in this study. Both arms had high rates of stable disease or better. Despite stratification by PRCC or NPRCC, there were major differences in NPRCC subtypes between the arms that may have impacted the results. More pts with chromophobe histology, an often indolent subtype, received SUN while all pts with MiT family translocation, a relatively aggressive subtype, received CABO. Permitted SUN dose modifications may have also influenced outcomes. While the PAPMET study showed CABO to be superior to SUN for PRCC, optimal treatments for rare, NPRCC remain a pressing need. Clinical trial information: NCT03541902 . [Table: see text]

Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Updated results from a phase 2 trial.

4537 Background: Identification of effective systemic therapy for non-clear cell renal cell carcinoma (RCC) remains a unmet need. We reported a two arm, phase 2 trial of cabozantinib plus nivolumab (CaboNivo) that showed promising efficacy in the treatment arm comprised primarily of papillary and unclassified histology. (Lee, JCO, 40: 2022). Herein, we report updated results with extended follow up. Methods: Patients had advanced non-clear cell RCC, 0 or 1 prior systemic therapies excluding prior immune checkpoint inhibitors, and measurable disease by RECIST. Cabo 40 mg/day plus Nivo 240 mg every 2 weeks or 480 mg every 4 weeks was given for both arms. Arm 1 was comprised of papillary, unclassified, or translocation associated RCC; and Arm 2 had chromophobe RCC (closed early for lack of efficacy). The primary endpoint was objective response rate (ORR) by RECIST; secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Arm 1 was a single stage design that met its primary endpoint and was expanded to produce more precise estimates of ORR. Correlative analyses by next generation sequencing were performed and will be presented. Results: A total of 40 patients were treated in Arm 1 (data cutoff: Dec 13, 2022). Median follow up time was 34 months (range 20, 51). Twenty-six patients (65%) were previously untreated, and 14 (35%) had 1 prior treatment line: 10 (25%) received prior VEGF-targeted therapy and 8 (20%) received prior mTOR-targeted therapy. ORR is 48% (95% CI 31.5–63.9). Median PFS is 13 months (95% CI: 7, 16). Progression-free survival is 51% (95% CI: 34, 65) at 12 months and 23% (95% CI: 11, 37) at 24 months. Median OS is 28 months (95% CI: 23, 43). Overall survival is 70% (95% CI: 53, 82) at 18 months and 44% (95% CI: 28, 60) at 36 months. PFS and OS were similar for previously treated and untreated patients. For responders, median DOR was 17 months (95% CI: 10, 36). Adverse effects of any grade were experienced by 35 patients (88%); grade 3/4 adverse events were experienced by 22 patients (55%). Grade 3/4 AST and ALT elevations were 18% and 23% respectively. Other common grade 3/4 adverse events were hypertension (5, 13%) and pain (4, 10%). Study therapy was discontinued in 9 patients (28%) for toxicity. Conclusions: Updated results with extended follow-up highlight efficacy and safety for CaboNivo in metastatic non-clear cell RCC pts with papillary, unclassified, or translocation associated histologies. Clinical trial information: NCT03635892 . [Table: see text]

Hemoglobin β Expression Is Associated with Poor Prognosis in Clear Cell Renal Cell Carcinoma.

The regulation of the redox balance in the tumor microenvironment is thought to be an adaptive response of tumor cells to hypoxic environments. In recent years, it has been reported that the hemoglobin β-chain (HBB), which is involved in scavenging reactive oxygen species (ROS), is expressed in several carcinomas. However, the relationship between HBB expression and the prognosis of renal cell carcinoma (RCC) remains unclear. HBB expression was immunohistochemically analyzed in 203 nonmetastatic clear cell RCC (ccRCC) cases. Cell proliferation, invasion, and ROS production were measured in ccRCC cell lines treated with HBB-specific siRNA. The prognosis of HBB-positive patients was worse than that of HBB-negative patients. Cell proliferation and invasion were inhibited, and ROS production was increased by treatment with HBB-specific siRNA. Oxidative stress increased HBB expression in cells exposed to H2O2. HBB expression in ccRCC contributes to cancer cell proliferation by suppressing ROS production under hypoxic conditions. Taken together with clinical results and in vitro experiments, HBB expression may serve as a new prognostic biomarker for RCC in the future.

Abstract 4459: Spatial profiling of the inflamed tumor microenvironment identifies novel prognostic subclasses in non-metastatic clear cell renal carcinoma patients

Abstract INTRODUCTION: Clear cell renal cell carcinoma (ccRCC) is highly vascularized and inflamed, and RNA signatures of angiogenesis/inflammation have been suggested as biomarkers for predicting progression and therapy benefit. Here, we explored as to how the spatial localization of endothelial cells and leukocytes and their mutual interactions contribute to disease progression. EXPERIMENTAL PROCEDURES: We applied multiplexed fluorescence IHC (mfIHC) to quantify CD45+ leukocytes, CD31+ endothelial cells, D2-40+ lymphatic cells, CD11b+ myeloid cells, CD3+ and CD20+ lymphocytes, as well as PDGFRB+ fibroblasts and epithelial cells (CK+/Ecadherin+/CAIX+) in two cohorts of non-metastatic primary ccRCC. Both the Helsinki (N=178) and Turku cohorts (N=241) contained TMA cores from tumor center, tumor border, and benign areas of each patient. mfIHC data were compared with clinical parameters, such as tumor stage (pT), Fuhrman grade, necrosis, and patient outcome (RFS, recurrence-free survival). RESULTS: CD31+ endothelial cells were associated with favorable (p&amp;lt;0.001) and CD45+ leukocytes with poor prognosis (p&amp;lt;0.001), high pT (p&amp;lt;0.05), high Fuhrman grade (p&amp;lt;0.05), and high necrosis (p&amp;lt;0.05) in TMA cores representing the tumor center and tumor border areas. CD45+ cells varied spatially with regards to CD31+ cells and EpiStain+ cells. For example, in tumor center cores, CD45+ cells co-localized with EpiStain+ cells ranging from 0.1 to 97% (median for both cohorts, 70.6% and 72.5%). The association of CD45+ leukocytes with poor prognosis was significant when counting the fraction of CD45+ cells not interacting with CD31+ or EpiStain+ cells, but not when including only the interacting cells. We then categorized patients into three classes based on the quantity of the cell types: 1) CD45+High/CD31+Low, 2) CD45+Low/CD31+High, and 3) Other. CD45+High/CD31+Low phenotype patients had a significantly lower 5-year RFS rate compared to that of CD45+Low/CD31+High patients (Helsinki: 37.9% vs. 92.0%; Turku: 50.0% vs. 93.5%; p&amp;lt;0.001, Log-rank test). CONCLUSIONS: In ccRCC, both the quantity and spatial localization of inflammatory cells with respect to vascular endothelial cells and tumor cells dictates its association with patient prognosis. Our results suggest that although CD45+ leukocyte infiltration associates with recurrent disease, the higher risk is only observed when CD45+ cells are not in contact with vasculature or tumor cells. This suggests how analysis of well-known prognostic biomarkers by IHC can be refined by using mfIHC and considering the spatial configurations of cells in the TME in ccRCC. Ongoing work is aimed to add further profiling of additional TME cell subset associations with inflammation, prognosis, and therapy response. Citation Format: Teijo Pellinen, Lassi Luomala, Kalle Mattila, Jenni Säilä, Annabrita Hemmes, Katja Välimäki, Oscar Bruck, Lassi Paavolainen, Harry Nisen, Petrus Järvinen, Olli Kallioniemi, Paula Vainio, Panu Jaakkola, Tuomas Mirtti. Spatial profiling of the inflamed tumor microenvironment identifies novel prognostic subclasses in non-metastatic clear cell renal carcinoma patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4459.

Transcriptomic signatures can aid in post-operative risk stratification of clear cell renal cell carcinoma.

383 Background: The ability to risk stratify patient’s post-nephrectomy is critical to select candidates for surveillance and adjuvant therapy. Whether transcriptomic information adds value to current prognostic information is unclear. Methods: Data from confirmed clear cell renal cell carcinoma (ccRCC) used in the TCGA Pan-RCC analysis was downloaded from cBioportal and GDC bioportal. Clinicopathologic variables were used to calculate the integrated staging system, SSIGN (stage, size, grade, and necrosis). The 16 gene recurrence score (RS) signature was generated as described in Rini 2015 using the TCGA data with log TPM normalization. The RS was stratified into high and low risk groups by median. SSIGN was divided into low (0-1) intermediate (2-4) and high ( &gt; = 5) risk groups. RS and SSIGN prognostic significance were evaluated using disease recurrence as an end point, censoring by death. Results: SSIGN and recurrence scores (RS) were calculated for 369 (71.2%) of 518 available TCGA subjects with non-metastatic clear cell renal carcinoma. On multivariable analysis, the RS (continuous variable) was independently associated with disease-free status (HR 1.18 [95%CI (1.02-1.37)], p = 0.031) for each 10 point increase in RS) after adjusting for SSIGN. Categorizing SSIGN into low, intermediate and high-risk groups showed 3.9%, 18.5% and 39.8% 3-year recurrence rates. Stratifying SSIGN risk groups by RS scores we found an RS to further risk stratify the SSIGN intermediate risk group (HR 1.60 [95%CI 1.21-2.12], p &lt; 0.001]). The AUC for at 3 years for SSIGN in the intermediate risk group was 0.68, for RS was 0.74 and the combination was 0.78 (with boot-strapping for optimism adjustment). At 3 years, patients with SSIGN intermediate risk disease (n = 135) with low RS had 3-year recurrence rate of 7.1% compared to 31.0% for those with high RS scores. Conclusions: Transcriptomic recurrence scores can risk stratify intermediate SSIGN clinical risk patients. Patients with intermediate risk disease but a high RS score had poorer outcomes similar to clinically high risk patients. Transcriptomic signatures may add value to existing clinicopathologic variables in ccRCC and clinical implementation is warranted.

Comparison of patients with high-risk nonmetastatic clear cell renal carcinoma in adjuvant therapy trials versus nonclinical trial patients.

361 Background: Characteristics of patients with high risk for recurrence non-metastatic renal cell carcinoma (nmRCC) participating in adjuvant therapy clinical trials post-nephrectomy have not been well described. We evaluated high risk nmRCC patients in the CKCis database to explore differences between trial and non-trial patients. Methods: Adult patients undergoing partial or radical nephrectomy for clear cell nmRCC between January 1, 2011 and March 31, 2021 were included. CKCis is a prospective cohort of patients from 14 Canadian academic institutions. Patients with high risk nmRCC (using modified UCLA Integrated Staging System) were included. Demographic, clinical, and survival statistics were analyzed for all patients and comparatively for the trial and non-trial groups. Results: 1459 patients, including 63 in adjuvant trials, were evaluated. 71% were male, 91% had pT3N0M0 disease. Disease characteristics including tumor size, stage, grade, location, necrosis, and margin status were similar between groups. Trial patients were younger (mean age 58.1 vs. 63.6; p &lt; 0.0001) and had lower Charlson Comorbidity Index scores (median 4 [3,6) vs. 5 [4,6] p &lt; 0.001). Estimated overall survival (OS) at 5 years was 80.8% (95% CI, 65,90) for trial patients and 74.8% (95% CI, 71,78.2) for non-trial patients. Recurrence-free survival at 5 years for trial patients was 48.6% (95% CI, 34,61.7) and 39.2% (95% CI, 35.2,43.1) for non-trial patients. Conclusions: Patients in adjuvant trials were younger and healthier at baseline than the average high risk nmRCC CKCis patient. Trial patients appear to have had longer time to recurrence and longer survival compared to non-trial patients, although not reaching statistical significance. Selection bias is common in clinical trials and evaluation of real-world population-based evidence of patients receiving adjuvant therapy will be important to ensure phase 3 trial results have external validity.

Phase 2 study of neoadjuvant cabozantinib in patients with locally advanced non-metastatic clear cell renal cell carcinoma.

340 Background: Cabozantinib is a small molecule inhibitor of the tyrosine kinases c-Met, AXL and VEGFR2 that has been shown to reduce tumor growth, metastasis, and angiogenesis. After the promising results from the METEOR, CABOSUN and Checkmate-9ER trials, cabozantinib was approved for use in patients with advanced renal cell carcinoma (RCC). The increased response rates with cabozantinib in metastatic RCC, along with the other neoadjuvant TKI data, support an expanded role for cabozantinib in the neoadjuvant setting. Methods: Patients with clinical stage ≥ T3Nx or TanyN+ or deemed unresectable by the surgeon with biopsy-proven clear cell RCC were eligible for this study, and received cabozantinib at a starting dose of 60 mg daily for 12 weeks. The primary outcome was objective response rate per RECIST v1.1 (complete and partial responses) at week 12 after the administration of cabozantinib as determined by independent radiologist review. Secondary outcomes included safety, tolerability, clinical outcome (DFS, OS), surgical outcome and quality of life. Results: As of 20 September 2021, 16 biopsy-proven clear cell RCC patients were treated with neoadjuvant cabozantinib. The median age was 56 years (range: 41-84 years) and 81.2% male. All patients completed 12 weeks of treatment, and 15 of them underwent surgery as planned without any delay after completion of 4 weeks wash-out. One patient refused to undergo surgery due to personal reasons and received further systemic treatment. Five patients (31.2%) experienced a partial response, and 11 patients had stable disease. There was no progression of disease while on cabozantinib. Median reduction of primary renal tumor size was 24% (range: 6-45%). The one patient who was deemed to be unresectable became resectable at the end of treatment. Two patients were converted from radical to partial nephrectomy. The most common AEs were diarrhea, nausea, fatigue, hypertension, anorexia, and palmar-plantar erythrodysesthesia syndrome. Intraoperatively, we did not experience any immediate complications. Postoperatively, no surgical complications related to the drug were noted. No treatment related grade 4 or 5 AEs related to cabozantinib or surgery occurred. Two patients had died at the time of analysis (1 due to COVID and 1 unknown cause). Conclusions: Cabozantinib was clinically active and safe in the neoadjuvant setting in patients with locally advanced non-metastatic clear cell RCC. Additional data will be reported including long term outcomes, correlative studies, quality of life, and frailty/sarcopenia indices. Clinical trial information: NCT04022343.

Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Results of a phase 2 trial.

4509 Background: Cabozantinib plus nivolumab (CaboNivo) improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) over sunitinib in a phase 3 trial for metastatic clear cell renal cell carcinoma (RCC). (Choueiri, abstract 6960, ESMO 2020) We report the results of a phase 2 trial of CaboNivo in patients (pts) with non-clear cell RCC. Methods: Pts had advanced non-clear cell RCC, 0 or 1 prior systemic therapies excluding prior immune checkpoint inhibitors, and measurable disease by RECIST. Cabo 40 mg/day plus Nivo 240 mg every 2 weeks or 480 mg every 4 weeks was given across two cohorts. Cohort 1: papillary, unclassified, or translocation associated RCC; Cohort 2: chromophobe RCC. The primary endpoint was ORR by RECIST; secondary endpoints included PFS, OS, and safety. Cohort 1 was a single stage design that met its primary endpoint and was expanded to produce more precise estimates of ORR. Cohort 2 was a Simon two-stage design that closed early for lack of efficacy. Correlative analyses by next generation sequencing were performed and to be presented. Results: A total of 40 pts were treated in Cohort 1, and 7 pts were treated in Cohort 2 (data cutoff: Jan 20, 2021). Median follow up time was 13.1 months (range 2.2 – 28.6). In Cohort 1, 26 (65%) pts were previously untreated, and 14 (35%) pts had 1 prior line: 10 (25%) received prior VEGF-targeted therapy and 8 (20%) received prior mTOR-targeted therapy. ORR for Cohort 1 was 48% (95% CI 31.5–63.9; Table). Median PFS was 12.5 months (95% CI 6.3–16.4) and median OS was 28 months (95% CI 16.3–NE). No responses were seen among 7 patients in Cohort 2 with chromophobe histology (Table). Grade 3/4 treatment emergent adverse events were consistent with that reported in the phase 3 trial; Grade 3/4 AST and ALT were 9% and 15%, respectively. Cabozantinib and nivolumab were discontinued due to toxicity in 17% and 19% of pts, respectively. Conclusions: CaboNivo had an acceptable safety profile and showed promising efficacy in metastatic non-clear cell RCC pts with papillary, unclassified, or translocation associated histologies whereas activity in patients with chromophobe RCC was limited. Clinical trial information: NCT03635892. [Table: see text]

Metastatic nonclear renal cell carcinoma current review in evolving treatment strategies.

Renal cell carcinoma (RCC) is the 6th most often diagnosed cancer in men and the 10th in women. Nearly 75% of the renal cancer cases are clear cell histologic subtype, whereas nonclear cell histologies represent the remaining 25%. Treatment options for clear renal type are well established. However, as nonclear RCC represents a heterogenous and less frequent group. Current treatment options for these tumors are limited and mostly based on evidence derived from small phase II clinical trials. The present review aims to provide an update of the available treatment options for nonclear RCC. In the past decade, the vascular endothelial growth factor tyrosine kinase inhibitor, sunitinib, and mammalian target of rapamycin inhibitors, everolimus, and temsirolimus, have demonstrated limited efficacy in nonclear RCC. Recent studies with MET inhibitors and immunotherapy-based combinations have proven promising activity, especially in certain subgroups of patients, such as patients with MET-driven disease or patients with sarcomatoid features RCC. Here, we report currently available data about biology and treatment of nonclear cell RCC.

Deep learning based prediction of prognosis in nonmetastatic clear cell renal cell carcinoma

Survival analyses for malignancies, including renal cell carcinoma (RCC), have primarily been conducted using the Cox proportional hazards (CPH) model. We compared the random survival forest (RSF) and DeepSurv models with the CPH model to predict recurrence-free survival (RFS) and cancer-specific survival (CSS) in non-metastatic clear cell RCC (nm-cRCC) patients. Our cohort included 2139 nm-cRCC patients who underwent curative-intent surgery at six Korean institutions between 2000 and 2014. The data of two largest hospitals’ patients were assigned into the training and validation dataset, and the data of the remaining hospitals were assigned into the external validation dataset. The performance of the RSF and DeepSurv models was compared with that of CPH using Harrel’s C-index. During the follow-up, recurrence and cancer-specific deaths were recorded in 190 (12.7%) and 108 (7.0%) patients, respectively, in the training-dataset. Harrel’s C-indices for RFS in the test-dataset were 0.794, 0.789, and 0.802 for CPH, RSF, and DeepSurv, respectively. Harrel’s C-indices for CSS in the test-dataset were 0.831, 0.790, and 0.834 for CPH, RSF, and DeepSurv, respectively. In predicting RFS and CSS in nm-cRCC patients, the performance of DeepSurv was superior to that of CPH and RSF. In no distant time, deep learning-based survival predictions may be useful in RCC patients.

Management of Metastatic Nonclear Renal Cell Carcinoma: What Are the Options and Challenges?

This case presents a 68-yr-old female patient with primary metastatic nonclear renal cell carcinoma (RCC) with multiple bone lesions. The patient underwent a single resection of skull bone lesion (diagnostic for poorly differentiated carcinoma of unknown origin) and cytoreductive nephrectomy. The pathology of the kidney specimen demonstrated an oncocytic papillary RCC. Within 3 mo, she developed skeletal progressive disease and was started on systemic therapy (sunitinib). After initial stabilization, bone metastasis progressed during the third cycle of sunitinib and required second-line therapy (cabozantinib). One of the major unmet needs in non–clear cell RCC is the lack of specific systemic therapy. Data on immunotherapy are still limited. Inclusion of these patients in clinical trials is strongly recommended. Patient summaryPatients with metastatic kidney cancer who present with the less common histological subtype (non–clear cell) have poor survival. In this case, the patient responded to second-line therapy. Very few therapies provide response to treatment. Patients should be offered participation in clinical trials testing combinations with immunotherapy.

Survival outcomes and practice trends for off-label use of adjuvant targeted therapy in high-risk locoregional renal cell carcinoma

ImportanceThe appropriate use of adjuvant targeted therapy (TT) for high-risk locoregional renal cell carcinoma (RCC) after nephrectomy is currently unclear due to mixed results from the relevant randomized controlled trials. National-level survival outcomes and practice trends for the use of adjuvant TT in the United States have not been reported. ObjectiveTo compare overall survival for patients who did and did not receive adjuvant TT after nephrectomy for high-risk locoregional RCC. Design, setting, and participantsThis cohort study reviewed the National Cancer Database from 2006 to 2015. Patients with nonmetastatic clear cell RCC who underwent nephrectomy with either stage pT3a or greater or pN+ were included. Main outcomes and measuresAdjuvant TT was defined as receipt of TT within 3 months of nephrectomy. The primary end point was overall survival from initial diagnosis to date of death or censored at last follow-up. Baseline characteristics were described, and a multivariable analysis identified associations for receipt of adjuvant TT. Nearest-neighbor propensity matching was performed to create similar groups for comparison. A survival analysis was performed using Kaplan-Meier analysis and log-rank test. ResultsThe final study population included 41,127 patients. Two thousand seventy-one patients (5.04%) received off-label adjuvant TT. Younger age, white race, private insurance, positive margins, pT4, and pN+ were associated with receipt of adjuvant TT. After nearest-neighbor propensity matching for clinically and statistically relevant covariates, 1,604 patients remained in the matched cohort, with statistically nonsignificant differences between the groups for all baseline characteristics. Median overall survival was 52 months for patients in the Adjuvant TT group versus 79 months for those who did not receive adjuvant TT (P < 0.001). Decreased overall survival for patients receiving adjuvant therapy was also seen in pathologic subgroups with and without lymph node involvement. ConclusionsThe propensity matched survival analysis revealed significantly decreased overall survival in patients who received off-label adjuvant TT for high-risk locoregional RCC.

Neutrophil-to-lymphocyte ratio as a predictor of oncologic outcomes in locally advanced non-metastatic clear cell renal carcinoma.

661 Background: An elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with worse oncologic outcomes in several malignancies, its prognostic role in kidney cancer, specifically in the non metastatic setting is controversial. We aimed to evaluate if an elevated NLR in patients with locally advanced non metastatic clear cell renal cell carcinoma (CCRCC) is associated with a worse survival and/or a higher cancer recurrence rate. Methods: We retrospectively identified 880 nephrectomies performed between 01/2009 to 12/2016 in a single center, reviewed data from 478 consecutive radical nephrectomies (RN) for kidney tumors and identified 187 patients with locally advanced non-metastatic CCRCC patients (pT3-T4 N0M0). The cut-off point of NLR = 2.5 was obtained using the receiver operating curve analysis (ROC). NLR was obtained preoperatively and calculated by dividing absolute neutrophil count by absolute lymphocyte count. Overall survival (OS) and recurrence-free survival (RFS) were evaluated using the Kaplan-Meier method. Cox regression models were utilized to evaluate predictors of recurrence and survival. Results: Median follow up was 48.7 months. The 3 year OS was significantly lower for patients with NLR ≥ 2.5 than those with NLR &lt; 2.5 (70% vs 85%, p = 0.049). In patients with a Fuhrman nuclear grade of differentiation of 3-4, the median time to recurrence was significantly shorter for patients with NLR ≥ compared to those with NLR &lt; 4 (24 vs 55 months p 0.045). On multivariable analysis adjusted for NLR ≥ 2.5, microvascular invasion, sarcomatoid differentiation, tumor size and body mass index, only nuclear grade of differentiation was found to be an independent predictor for recurrence (hazard ratio= 2.18; 95% confidence interval [CI]: 1.07 – 4.92, p = 0.03). Conclusions: Patients with non-metastatic CCRCC with higher nuclear grade of differentiation and a high preoperative NLR have shorter RFS and worse OS compared to patients with lower NLR.

Phase II efficacy trial of pazopanib in nonclear cell metastatic renal cell cancer (mRCC): PINCR.

696 Background: A number of treatments for metastatic renal cell carcinoma (RCC) have been FDA approved since December, 2005. Trials evaluating these agents excluded non-clear cell histologies and therefore the efficacy of these treatments remains unclear in patients (pts) with metastatic non-clear cell RCC (mncRCC). Methods: This is a single arm Phase II study designed to determine the efficacy of pazopanib in mncRCC. Treatment was pazopanib 800 mg by mouth daily until progression or intolerability of treatment. Dose reductions were allowed for toxicity with dose level -1 being 600 mg daily and dose level -2, 400 mg daily. Cycles were every 28 days. Main eligibility criteria included: (1) age ³ 18 years old; (2) histologic confirmation of ncRCC; (3) ECOG Performance Status (PS) 0, 1, or 2; (4) up to one prior treatment for mncRCC (5) measurable or non-measurable metastatic disease per RECIST criteria. The primary endpoint was overall survival rate at 12 months. Secondary endpoints were best tumor response rates after two cycles, PFS, OS and toxicity. Results: 38 pts were enrolled between May 16, 2013 and February 1, 2018. 35 pts were evaluable for primary endpoint. Median age 63 years old and 22/35 (62.9%) were male. Most common histology was papillary RCC, 14/35 (40%), and most common number of metastatic sites was 1. 29/35 (82.9%) had prior nephrectomy and 30/35 (85.7%) had no prior systemic therapy. Median number of cycles was 5. 12-month OS was 65.7% (90% CI, 50.5-78.9%). Best response in first 2 cycles: PR 11%, SD 60%, PD 9%, not evaluated 20%. Median PFS was 7.5 months (90% CI, 5.0-11.0); median OS 18.9 months (90% CI, 13.0-NE). Grade 3 / 4 AEs seen in 25 pts with hypertension, transaminitis and abdominal pain being most common (seen in &gt;10%). Conclusions: There are limited data about the efficacy of available therapies for mncRCC. This study shows that pazopanib has similar efficacy compared to historical data in clinical trials using other TKIs in mncRCC. The safety profile of pazopanib in pts with mncRCC was found to be similar to that found in prior clinical trials studying pazopanib. Our findings warrant further investigation into the utility of pazopanib in metastatic ncRCC. Clinical trial information: NCT01767636.

Efficacy of adjuvant vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (VEGFRi) in renal cell carcinoma (RCC): A systematic review and meta-analysis.

680 Background: To perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing the efficacy of adjuvant VEGFRi in locally advanced, non-metastatic clear renal-cell carcinoma (RCC). Methods:Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. We included studies that compared the addition of VEGFRi versus placebo, after nephrectomy. Analyzed endpoints were overall survival (OS) and disease-free survival (DFS). The data extracted from the studies were combined by using Hazard Ratio (HR) or Risk Ratio (RR) with their corresponding Confidence Intervals of 95% (CI95%). Results: Overall, 121 references were identified and screened. The final analysis included 5 trials (S-TRAC, ATLAS, ASSURE, PROTECT and SORCE) comprising 6,128 patients that underwent previous nephrectomy for RCC. The DFS was similar in patients who received VEGFRi (fixed effect: HR=0.94, CI95%=0.87 to 1.03; p=0.19), with no heterogeneity (Chi2 = 4.33, df = 5 (P=0.50); I2 = 0%). Overall survival also was not statistically better in patients who received VEGFR inhibitors (HR=1.01, CI95%=0.90 to 1.15; p=0.84), with no heterogeneity (Chi2= 3.57, df = 5 (P=0.61); I2 = 0%). In the final combined analysis of the higher-risk disease group (pT3, pT4, or N+ disease), patients who received VEGFRi had a longer DFS (fixed effect: HR=0.85, CI95%=0.74 to 0.97; p=0.02), with no heterogeneity (Chi2 = 2.46, df = 3 (P=0.48); I2 = 0%). Overall survival was not statistically different for these higher-risk disease patients (fixed effect: HR=0.93, CI95%=0.74 to 1.16; p=0.5). Conclusions: This is the first meta-analysis including the five available RCTs in the literature (the previous meta-analysis reviewed only four), comparing adjuvant VEGFRi versus placebo in patients submitted to nephrectomy with a locally advanced, non-metastatic RCC. Adjuvant VEGFRi did not increase the OS in this group of patients. Amodest benefit of DFS with the use of adjuvant VEGFR inhibitors was restricted to patients with the highest risk of relapse.

Pazopanib as a possible option for the treatment of metastatic non-clear cell renal carcinoma patients: a systematic review.

Background:Effective systemic treatment of non-clear cell renal carcinoma (nccRCC) is still an unmet clinical need, with few studies to support an evidence-based approach. To date, the only recommended standard first-line treatment is sunitinib. Pazopanib may also be used in nccRCC but its place in therapy is not clearly established. It has comparable efficacy and better tolerability than sunitinib in clear cell renal carcinoma. Our objective was to review the use of pazopanib in metastatic nccRCC.Methods:We conducted a systematic review according to PRISMA guidelines. Any type of study reporting the use of pazopanib in metastatic renal cell carcinoma including cases with non-clear cell histology was eligible.Results:In all, 15 studies were included in our analysis, including a total of 318 nccRCC patients treated with pazopanib. Most studies were retrospective (n = 12); three were prospective trials. The specific outcomes of nccRCC patients were reported by four studies. Pazopanib alone as first-line treatment gave overall response rates ranging from 27% to 33%, disease control rates of 81–89%, median progression free survival of 8.1–16.5 months and median overall survival of 17.3–31.0 months. Grade 3–4 adverse events rates were 21–55%.Conclusion:The present review provides for the first time a systematic summary of evidence about the possible use of pazopanib as first-line treatment for nccRCC, with a favorable outcome despite the low strength of evidence. Pazopanib could be considered as a possible therapeutic option in this setting.