Non-clear Cell Histology Research Articles

Efficacy and Safety of Pembrolizumab plus Axitinib combination for Metastatic Renal Cell Carcinoma in a Real-World Scenario: Data From the Prospective ProPAXI Study

BackgroundPembrolizumab/Axitinib combination is approved as first-line therapy in mRCC. The aim of this study is to evaluate outcomes of PAXI combo in the real-world in Italy. MethodsThis is a prospective study including patients diagnosed with mRCC who received combination as first-line therapy in recruiting Italian Centers. Data about patient characteristics, safety and outcome were collected. Results170 pts have been treated from December 2020 to September 2023. The majority had clear-cell histology (83%). Sarcomatoid feature was present in 33%of available cases. About one half of patients (55%) had synchronous metastasis. In 58% of cases nephrectomy was performed, of which 27% were cytoreductive and 4% were deferred nephrectomies. Lung metastases were identified in 106 patients (62%), bone and liver involvement in 66 and 29 patients (38.8% and 17.1%) respectively. Stratifying by IMDC criteria, 32 patients (18.8%) were at favorable-risk, 106 (62.4%) at intermediate-risk, and 32 (18.8%) at poor-risk. At time of analysis, treatment was ongoing in 49% of patients. Progression occurred in 45% of patients. Median PFS was 19.2 months (95% CI: 15-NR). With a median follow-up of 19.3 months (range 1.3-34.5), at 24-months and 36-months landmark analysis 62% (95% CI, 53-70) and 58% (95% CI, 47-69) of treated patients are still alive respectively. Disease control rate was achieved in 84.6% of patients: 4.3% reached a complete response, 52% had a partial response and 28.8% a stable disease. Primary progression was observed in 15.3% of patients. In the multivariate analysis, the prognostic significance of age ≥ 65 years, non-clear cell histology, IMDC score, and adverse events and gender interaction as predictors of worse OS were confirmed. ConclusionThis is the first available prospective study on first-line Pembrolizumab/Axitinib combination in real world scenario. Our findings support the effectiveness and safety of first-line this combination in mRCC and reveal that gender emerged as a prognostic factor in relation to the occurrence of adverse events.

Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study

The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

Real-World Impact of Upfront Cytoreductive Nephrectomy in Metastatic Non-Clear Cell Renal Cell Carcinoma Treated with First-Line Immunotherapy Combinations or Tyrosine Kinase Inhibitors (A Sub-Analysis from the ARON-1 Retrospective Study).

About 20% of patients with renal cell carcinoma present with non-clear cell histology (nccRCC), encompassing various histological types. While surgery remains pivotal for localized-stage nccRCC, the role of cytoreductive nephrectomy (CN) in metastatic nccRCC is contentious. Limited data exist on the role of CN in metastatic nccRCC under current standard of care. This retrospective study focused on the impact of upfront CN on metastatic nccRCC outcomes with first-line immune checkpoint inhibitor (IO) combinations or tyrosine kinase inhibitor (TKI) monotherapy. The study included 221 patients with nccRCC and synchronous metastatic disease, treated with IO combinations or TKI monotherapy in the first line. Baseline clinical characteristics, systemic therapy, and treatment outcomes were analyzed. The primary objective was to assess clinical outcomes, including progression-free survival (PFS)and overall survival(OS). Statistical analysis involved the Fisher exact test, Pearson's correlation coefficient, analysis of variance, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. Median OS for patients undergoing upfront CN was 36.8 (95% confidence interval [CI] 24.9-71.3) versus 20.8 (95% CI 12.6-24.8) months for those without CN (p = 0.005). Upfront CN was significantly associated with OS in the multivariate Cox regression analysis (hazard ratio 0.47 [95% CI 0.31-0.72], p < 0.001). In patients without CN, the median OS and PFS was 24.5 (95% CI 18.1-40.5) and 13.0 months (95% CI 6.6-23.5) for patients treated with IO+TKI versus 7.5 (95% CI 4.3-22.4) and 4.9 months (95% CI 3.0-8.1) for those receiving the IO+IO combination (p = 0.059 and p = 0.032, respectively). Our study demonstrates the survival benefits of upfront CN compared with systemic therapy without CN. The study suggests that the use of IO+TKI combination or, eventually, TKI monotherapy might be a better choice than IO+IO combination for patients who are not candidates for CN regardless of IO eligibility. Prospective trials are needed to validate these findings and refine the role of CN in current mRCC management.

Patient's self-reported quality of life as a prognostic factor in metastatic renal cell carcinoma initially treated with TKI: nomogram proposal.

Numerous prognostic factors have been described for metastatic renal cell carcinoma (mRCC). There are nomograms to assist in clinical decision-making and inform patients of their disease progression. However, they have a limited capacity and moderate concordance rates. Performance status (PS) is one of the most widely used prognostic factors and most closely related to overall survival (OS), but this is a subjective assessment based solely on the clinician's opinion. Patients must be at the center of care. Patient-reported outcomes (PROs) have shown benefits but are not widespread in daily clinical practice. We analyzed 78 consecutive patients diagnosed with mRCC who initiated treatment at our institution between September 2012 and September 2019. We performed a descriptive analysis of the sample's baseline characteristics and the NCCN FKSI 19 questionnaire. We also conducted a survival analysis. The baseline FKSI 19 score demonstrates its prognostic potential, HR of 0.94 (95% CI 0.92-0.97). Our prognostic model would include: FKSI < 58 (HR 3.61 95% CI 1.97-6.61), anemia, thrombocytosis, non-clear cell histology, and metastatic hepatic involvement. AUC 0.86 (95%CI 0.77-0.95). Although it would need external validation, the proposed nomogram could be an alternative to other previously described models. The NCCN FKSI 19 baseline score could replace the clinician's subjective determination of PS. Not applicable.

Cystic Features in Renal Epithelial Neoplasms and Their Increasing Clinical and Pathologic Significance.

Most cystic renal tumors after resection (Boniak IIF to IV cysts) have an indolent course despite the significantly higher proportion of malignant [ie, renal cell carcinoma (RCC)] diagnosis. Most cystic renal tumors have clear cell histology that include cystic clear cell RCC and multilocular cystic renal neoplasm of low malignant potential (MCNLMP). There is growing evidence to suggest that MCNLMP, cystic clear cell RCC, and noncystic clear cell RCC form a cystic-to-solid biological spectrum with MCNLMP representing the most indolent form and with cystic clear cell RCC behaving better than noncystic (solid) clear cell RCC. Extensively (>75%) cystic clear cell RCC also has an excellent outcome similar to MCNLMP stressing the need to reevaluate the histologic criteria that separate these 2 cystic clear cell tumors. Other tumors with clear cells that can be extensively cystic such as the recently reclassified noncancerous clear cell papillary renal tumor and the newly described MED15::TFE3 RCC also have indolent course and may mimic MCNLMP. Cystic features occur also in renal tumors with nonclear cell histology including tumors capable of metastasis such as acquired cystic disease-associated, tubulocystic, fumarate hydratase-deficient, and eosinophilic solid and cystic RCCs. Cystic imaging presentation of some renal tumors such as papillary RCC can be attributed in part to pseudocystic necrosis and hemorrhage. It is important to know that tubulocystic RCC may have a lower Bosniak class presentation that overlaps with benign renal cysts (Bosniak I to IIF) that are managed conservatively. This review highlights the cystic renal tumors with clear cell and nonclear cell morphologies including some novel RCC subtypes that may have cystic features. The presence of cystic features and their extent may aid in the classification and prognostication of renal neoplasms underscoring its increasing importance in the pathologic diagnosis and reporting of renal neoplasia.

Real world evidence from a retrospective multi-center analysis on first-line therapy for metastatic renal cell carcinoma with non-clear cell and/or sarcomatoid histologies.

392 Background: Papillary (pRCC), chromophob (chRCC) and predominantly sarcomatoid renal cell carcinoma (sRCC) as well as RCC with sarcomatoid features are rare cancers. We evaluated real-world treatment outcomes of 1st line treatment in these cohorts in Germany. Methods: We retrospectively analyzed patients with non-clear cell RCC treated at 17 German tertiary cancer centres. Adverse events (AE) were reported according to CTCAE 5.0, objective response rate (ORR) according to RECIST 1.1. Progression free survival (PFS) and overall survival (OS) were calculated from start of treatment to progression or death, respectively and determined by KM plots. Results: We included 189 patients with a median age of 63 years (IQR 54-72). Of these, 49% were pRCC, 12% chRCC, 12% sRCC. 17% of all RCC had a sarcomatoid features. 87% had an ECOG PS of 0/1. IMDC risk was favorable/intermediate/poor in 15/54/31%. 74% received prior nephrectomy. Lymphatic (63%) and pulmonary (51%) metastases were the most common metastatic sites. 72% patients received first-line IO-combinations (IO-IO: 36%, TKI-IO: 64%) and 28% patients TKI-monotherapy, predominantly sunitinib. AE of all grades occurred in 86% and 72% during IO-based therapy or TKI monotherapy, and CTCAE grade ≥ 3 in 46% or 36%, of which led to discontinuation of treatment in 42% or 29% of patients, respectively. ORR and survival outcomes with median follow-up of 17 months (IQR 9-30) are described in the table. Conclusions: IO-combinations are frequently applied in pRCC, chRCC and sRCC. Our data suggests that first-line IO-combinations yields higher ORR compared to single agent TKI in sRCC, but not in chRCC. However, the retrospective nature and small sample size are major limitations of our analysis. Additional analyses to tailor treatment strategies in patients with metastatic nccRCC or sRCC is warranted. [Table: see text]

The role of cytoreductive nephrectomy (CN) in the immune checkpoint inhibitor (ICI) era of metastatic renal cell carcinoma (mRCC): A systematic review and individual patient data (IPD) meta-analysis of 2319 patients.

425 Background: The combination of CN and systemic therapy has been established as one of the mainstay treatments for mRCC during the targeted therapy era. However, the role of CN in the ICI era remains unclear. Methods: We performed a systematic search of the MEDLINE, EMBASE, and Web of Science databases until August 26th, 2023, for studies comparing the combination of CN + ICI vs. ICI alone in mRCC. Using published Kaplan-Meier overall survival (OS) curves, we reconstructed IPD and then performed one-stage and two-stage meta-analyses with both parametric and non-parametric effect estimates. To account for immortal time bias, we performed 6-month and 12-month landmark analyses. We also performed a subgroup analysis according to ICI line of treatment. The risk of bias was assessed using the ROBINS-I tool. Results: We identified eight retrospective cohort studies fulfilling our inclusion criteria. Only two out of eight studies adjusted for immortal time bias and none of them adequately adjusted for all predetermined confounding factors. A total of 2319 (1264 CN + ICI and 1055 ICI only) patients were included in our analysis. Patients in CN + ICI group were younger (median age 58.2 vs. 62.8), had lower proportions of non-clear cell histology (8.8% vs. 15.2%), ≥2 metastatic sites (60.0% vs. 68.5%), liver metastases (9.0% vs. 21.9%), and poor IMDC risk score (21.7% vs. 43.9%), but had higher proportions of sarcomatoid histology (15.6% vs. 10.6%) and ≥2nd line treatment (38.1% vs. 17.1%). The combination of CN + ICI was associated with superior OS in the one stage (HR: 0.45, 95% CI 0.38–0.52), 6-month landmark (HR: 0.45, 95% CI 0.37–0.54), 12-month landmark (HR: 0.50, 95% CI 0.31–0.50) and two-stage (HR: 0.38, 95% CI 0.29–0.49) meta-analyses. Similarly, the combination of CN + ICI was associated with superior OS in the subgroup of patients receiving first-line ICI (HR 0.39, 95% CI: 0.30–0.48). Conclusions: The combination of CN + ICI for mRCC may be associated with superior OS compared to ICI alone, but currently available data are subject to selection bias. More studies, including well-designed randomized controlled trials, are needed to determine the role of CN in the ICI era. [Table: see text]

Clinico-Pathological Features Influencing the Prognostic Role of Body Mass Index in Patients With Advanced Renal Cell Carcinoma Treated by Immuno-Oncology Combinations (ARON-1).

Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by dual immuno-oncology agents (IO+IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first-line therapy for metastatic renal cell carcinoma (mRCC). Medical records of patients with documented mRCC treated by immuno-oncology combinations were reviewed at 47 institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (OS), and overall clinical benefit (OCB), defined as the sum of the rate of partial/complete responses and stable disease. Univariate and multivariate analyses were used to explore the association of variables of interest with survival. A total of 675 patients were included; BMI was >25 kg/m2 in 345 patients (51%) and was associated with improved OS (55.7 vs. 28.4 months, P < .001). The OCB of patients with BMI >25 kg/m2 versus those with BMI ≤25 kg/m2 was significantly higher only in patients with nonclear cell histology (81% vs. 65%, P = .011), and patients with liver metastases (76% vs. 58%, P = .007), Neutrophil to lymphocyte ratio >4 (77% vs 62%, P = .022) or treated by nivolumab plus ipilimumab (77% vs. 64%, P=.044). In the BMI ≤25 kg/m2 subgroup, significant differences were found between patients with NLR >4 versus ≤4 (62% vs. 82%, P = .002) and patients treated by IO+IO versus IO+TKIs combinations (64% vs. 83%, P = .002). Our study suggests that the prognostic significance and the association of BMI with treatment outcome varies across clinico-pathological mRCC subgroups.

Systemic Treatment for Advanced and Metastatic Non-Clear Cell Renal Cell Carcinoma: Examining Modern Therapeutic Strategies for a Notoriously Challenging Malignancy.

Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group of malignancies that represents 25% of renal cell carcinoma (RCC) cases. Treatment for non-clear cell histologies is mostly based on evidence from small phase II clinical trials or extrapolated from successful therapies in clear cell RCC because of the low incidence of non-clear cell pathology. Advances in genomic profiling have improved clinicians' understanding of molecular targets for nccRCC, such as altered mesenchymal epithelial transition (MET) gene status and fumarate hydratase (FH) gene inactivation, but patient outcomes remain poor and optimal management of this disease remains unclear. This review assesses outcomes by histologic subtype from 27 prospective and 13 ongoing clinical trials to identify therapeutic strategies for advanced or metastatic nccRCC. Vascular endothelial growth factor tyrosine kinase inhibitors (TKI), such as sunitinib, and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, have demonstrated efficacy and remain viable treatment options, with a preference for sunitinib. However, everolimus is preferred in patients with chromophobe RCC because folliculin (FLCN) gene mutations upregulate the mTOR pathway. Novel TKIs, such as cabozantinib, show improved outcomes in patients with papillary RCC because of targeted MET inhibition. Platinum-based chemotherapy continues to be the recommended treatment strategy for collecting duct and medullary RCC. Clinically meaningful antitumor activity has been observed across all non-clear cell histologies for immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and ipilimumab. Ongoing trials are evaluating novel tyrosine kinase inhibitor and immunotherapy combination regimens, with an emphasis on the promising MET-inhibitor cabozantinib and pembrolizumab plus lenvatinib.

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.

Localised non-metastatic sarcomatoid renal cell carcinoma: a 31-year externally verified study.

To evaluate post-nephrectomy outcomes and predictors of cancer-specific survival (CSS) between patients with localised sarcomatoid renal cell carcinoma (sRCC) and those with Grade 4 RCC (non-sRCC), as most sRCC research focuses on advanced or metastatic disease with limited studies analysing outcomes of patients with localised non-metastatic sRCC. A total of 564 patients with localised RCC underwent partial or radical nephrectomy between June 1988 to March 2019 for sRCC (n = 204) or World Health Organization/International Society of Urological Pathology Grade 4 non-sRCC (n = 360). The CSS at every stage between groups was assessed. Phase III ASSURE clinical trial data were used to externally validate the CSS findings. The Mann-Whitney U-test and chi-squared test compared outcomes and the Kaplan-Meier method evaluated CSS, overall survival (OS) and recurrence-free survival. Clinicopathological features associated with RCC death were evaluated using Cox proportional hazards regression. The median follow-up was 31.5 months. The median OS and CSS between the sRCC and Grade 4 non-sRCC groups was 45 vs 102 months and 49 vs 152 months, respectively (P < 0.001). At every stage, sRCC had worse CSS compared to Grade 4 non-sRCC. Notably, pT1 sRCC had worse CSS than pT3 Grade 4 non-sRCC. Negative predictors of CSS were sarcomatoid features, non-clear cell histology, positive margins, higher stage (pT3/pT4), and use of minimally invasive surgery (MIS). ASSURE external verification showed worse CSS in patients with sRCC (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.12-2.36; P = 0.01), but not worse outcomes in MIS surgery (HR 1.39, 95% CI 0.75-2.56; P = 0.30). Localised sRCC had worse CSS compared to Grade 4 non-sRCC at every stage. Negative survival predictors included positive margins, higher pathological stage, use of MIS, and non-clear cell histology. sRCC is an aggressive variant even at low stages requiring vigilant surveillance and possible inclusion in adjuvant therapy trials.

Impact of Time to Metastasis (Synchronous vs. Metachronous) on Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with First Line Immune-Checkpoint Inhibitors (ICI)-based Combinations

Abstract Background Metastatic renal cell carcinoma (RCC) can present as synchronous metastatic disease, where primary metastases are detected at the time of diagnosis, or metachronous disease, where metastases appear during follow-up after initial RCC diagnosis. The effect of time to metastasis on patient outcomes is not well characterized in the era of immune checkpoint inhibitor (ICI)-based combinations. Herein, we assess the differences in clinical outcomes between patients with synchronous and metachronous mRCC. Methods Data for mRCC patients treated with first line ICI-based combination therapies between 2014 and 2023 were retrospectively collected from two NCI-designated comprehensive cancer centers. Patients were categorized as having synchronous or metachronous disease based on the time of presentation of metastases. Synchronous disease was defined as the presence of metastases at the time of RCC diagnosis or within 3 months thereafter. The study endpoints were time to treatment failure (TTF), overall survival (OS), and disease control rate (DCR). TTF and OS were estimated by Kaplan-Meier method and compared based on the time of presentation of metastases using log-rank tests. Univariable and multivariable Cox proportional hazard models and logistic regression models were used to examine the impact of sex, IMDC risk score, histology, and age at treatment start on TTF, OS and DCR. Results A total of 223 patients (126 synchronous and 97 metachronous) diagnosed with mRCC were included in the analysis. No significant difference was seen in gender distribution or age at first line treatment between these two groups. Although not statistically significant, the synchronous group had a higher proportion of patients with non-clear cell histology compared to those with metachronous disease (21% vs. 11%, P = 0.057). The median TTF was shorter in patients with synchronous disease but did not reach statistical significance (9 vs. 19.8 months for synchronous and metachronous, respectively, HR 1.37, 95% CI [0.98, 1.92], P = 0.064). Median OS was significantly shorter in patients with synchronous disease (28.0 vs. 50.9 months, adjusted HR 2.23, 95% CI [1.36, 3.65], P = 0.001). Similarly, patients with synchronous mRCC had a lower DCR than patients with metachronous (58.7% vs 78.4%, adjusted odds ratio (OR) 0.29, 95% CI [0.13, 0.64], P = 0.002). In the multivariable analysis, synchronous disease remained an independent factor associated with worse OS and DCR. Conclusions Patients with metastatic disease at the time of RCC diagnosis who were treated with first line ICI-based combinations have a poorer OS, and worse DCR than those who develop metastatic disease during follow-up. Although further validation is needed, these findings could be valuable in designing clinical trials and selecting patients for treatment escalation and closer clinical follow-up. CDMRP DOD Funding: no

Abstract B013: T cell clonotype expansion is common in advanced renal cell carcinoma but is not associated with altered response to PD-1 blockade

Abstract The diversity of T cell receptors (TCRs) becomes increasingly restricted with advancing stage in renal cell carcinoma (RCC), with individual T cell clones becoming dramatically expanded. Further, prior studies have suggested that TCR clonality (i.e. less diversity) could be associated with improved clinical response to anti-PD-1 treatment. To further interrogate the TCR landscape of advanced RCC and its relation to both T cell phenotype and clinical outcomes, single-cell TCR sequencing (scTCR-seq) was performed in parallel with single-cell RNA sequencing (scRNA-seq) for eligible patients with clear cell or non-clear cell metastatic RCC both pre- (baseline) or post- (progression) treatment with front-line nivolumab monotherapy as part of the HCRN GU16-260 trial (NCT03117309). Clonotype assignments and diversity metrics for 19 tumor samples were determined using VDJdive (R/Bioconductor). Overall, the top 10 clonotypes accounted for 12.3% of all T cells (range by sample: 4.2-34.6%). Of note, 5 of 16 (31%) samples with at least 100 T cells displayed substantial clonotype expansion, with the top 10 clonotypes accounting for at least 20% of tumor-infiltrating T cells. Average TCR diversity (normalized Shannon entropy) was 0.55 (range: 0.38-0.91) for all 19 samples. There were no significant differences in T cell diversity both between baseline (n=10) and post-treatment (n=9) samples (p= 0.66) or between clear cell (n=14) and non-clear cell (n=5) histologies (p= 0.75). To assess the relationship between T cell specificity and phenotypic state, we investigated the distribution of the most expanded clonotypes along a trajectory of T cells. Previous trajectory analysis of T cell populations revealed a bifurcating structure with naïve T cells at the root and lineages terminating in either terminally exhausted CD8+ T cells or SLAMF7+ CD8+ T cells (Braun, ASCO GU, 2023). Of the top 20 most expanded clonotypes across all T cells, 95% were distributed almost exclusively in the terminally exhausted lineage. The TCR diversity decreased along each lineage, from naïve T cell cluster at the root (TCR diversity = 0.61) to either the terminally exhausted CD8+ T cell cluster (0.42) or the SLAMF7+ CD8+ T cell cluster (0.56). There were no significant differences in TCR diversity between patients with progressive disease (n=6) versus complete/partial response (n= 6), (p= 0.96). Similarly, there was no association between TCR diversity and either progression-free (p= 0.41) or overall (p=0.39) survival. Altogether, these data reaffirm the presence of clonal expansion in advanced RCC, with the degree varying by sample. The localization of most expanded clonotypes to a single T cell lineage suggests a low degree of phenotypic plasticity. Enrichment of these clonotypes along an exhausted lineage is consistent with prior findings of lower TCR diversity in terminally exhausted CD8+ T cells. Future directions will focus on inferring the tumor specificity of infiltrating T cells along the diverging lineages. Citation Format: Miya B. Hugaboom, Neil Ruthen, Opeyemi Jegede, Nicholas R. Schindler, Lena Wirth, Sasha Kyrysyuk, David F. McDermott, Elizabeth R. Plimack, Jeffrey A. Sosman, Naomi B. Haas, Michael E. Hurwitz, Hans J. Hammers, Sabina Signoretti, Michael B. Atkins, Catherine J. Wu, David A. Braun, Kelly Street. T cell clonotype expansion is common in advanced renal cell carcinoma but is not associated with altered response to PD-1 blockade [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B013.

Renal cell carcinoma with non-clear cell histologies: all the same peas in one pod?

Renal cell carcinoma with non-clear cell histologies: all the same peas in one pod?

Global circulating free DNA methylation and fragmentome deconvolution in patients with metastatic renal cell carcinoma treated with immunotherapy (GOLDEN).

4544 Background: Metastatic renal cell carcinoma (mRCC) lacks molecular biomarkers. Cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) is a new, non-invasive approach to the detection of RCC-derived DNA in the circulation. In the GOLDEN study (NCT03702309), we explored the role of cfMeDIP-seq and fragmentomic dynamics as a biomarker, during immune checkpoint inhibition (ICI)-based treatment in mRCC patients (pts). Methods: Blood samples from mRCC pts were collected before and during treatment. Response to treatment was defined by the treating oncologist as: response, any degree of radiological tumor regression; stable disease (SD), no radiological change; or progressive disease (PD), radiological/clinical progression. More than 10ng of plasma cfDNA was subject to cfMeDIP-seq. A prognostic pan-cancer methylation signature previously generated using TCGA tissue methylation arrays was applied to cfMeDIP-seq output and cancer-signal methylation (CSM) score was calculated. An RCC-specific methylation signature, previously generated by identifying differentially methylated regions between RCC pts and controls, was applied ( Nuzzo et al, Nat Med 2020). Genome-wide fragmentation profiles were generated using DELFI. Using medians as cut off, log-rank test was performed to assess overall survival (OS) and progression-free survival (PFS). Results: Thirty-five patients were enrolled and n=33 received systemic treatment. 31/35 pts (89%) had clear cell and 4/35 (11%) non-clear cell histology. Median age was 61 (30-81) years and the M:F ratio was 6:1. Patients’ IMDC prognostic risk score was favorable n=6/35 (17%), intermediate n=23/35 (65%) and poor n=6/35 (17%). 20/33 (61%) patients received ipilimumab/nivolumab, 10/33 (30%) nivolumab and n=3/33 (9%) pembrolizumab/axitinib. There were n=14/33 (42%) responders, n=4/33 (12%) pts with SD and 15/33 (45%) pts with PD. Patients with high pan-cancer CSM score at baseline trended towards worse OS (HR 3.86, p = 0.079). Fragmentomics signature, consisting of increased proportion of short cfDNA fragments, showed a trend for worse PFS (HR = 3.04, p = 0.075) in on-treatment samples. Using the RCC-specific methylation signature, we found that those with an increase in signature score from baseline to on-treatment had better PFS (HR=2.4x10-10, p=0.002, n=10) and a trend towards better OS (HR=0.17, p=0.074, n=10). We hypothesize that RCC tissue-specific cell death early during ICI treatment could underpin this increase in the methylation score. Conclusions: This small study is the first report on the role of cfMeDIPseq-derived methylation and fragmentomic signatures in patients with mRCC undergoing ICI-based treatment. We found several trends and one significant association between these signatures and pt outcomes, which support further validation in larger cohorts. Clinical trial information: NCT03702309 .

Genetic testing outcomes and pathogenic germline mutation prevalence in renal cell carcinoma.

10601 Background: Germline mutations have been observed in renal cell carcinoma (RCC) with varying frequencies reported from 5% to 18% of patients. Due to the prevalence of germline mutations, current guidelines by the National Comprehensive Cancer Network (NCCN) recommend genetic testing for patients with RCC and high-risk factors such as young age, bilateral or multifocal tumors, family history of RCC, as well as certain RCC histologies. However, the germline mutational landscape in RCC has not been fully characterized. Here, we report the genetic testing results and clinicopathologic factors of patients with RCC who were referred for germline testing. Methods: All patients with a diagnosis code of kidney cancer and referred to the Cancer Genetics clinic at the University of Michigan between 2004 and 2022 were identified. Patients were excluded if they had erroneous RCC diagnosis codes, no history of RCC diagnosis, known familial/hereditary mutation or syndrome, or did not undergo germline testing. Genetic testing outcomes, germline mutation frequency, and clinical factors were obtained through chart review and analyzed using descriptive statistics. Results: A total of 322 patients with a history of RCC and referred for genetic testing were identified. The median age at diagnosis in all patients was 47 (interquartile range: 38-58). Males accounted for 56.8% of the cohort. Most patients (62.4%) had clear cell histology at initial diagnosis, whereas 30.7% had non-clear cell histology. The majority of patients (61.5%) were diagnosed at stage 1. Bilateral and multifocal tumors at diagnosis accounted for 18.9% and 12.7%, respectively. Pathogenic or likely pathogenic variants (P/LP) were identified in 43 patients (13.4%); 225 patients had negative germline testing (69.9%); 54 patients (16.8%) had a variant of unknown significance (VUS). The most frequently mutated RCC-associated genes were FLCN (n=10, 3.1%), SDHA/B/D (n=7, 2.2%), VHL (n=4, 1.2%), MLH1 (n=3, 0.9%), and FH (n=2, 0.6%). Common mutations in other cancer-related genes were CHEK2 (n=4, 1.2%), ATM (n=2, 0.6%), and RAD50 (n=2, 0.6%). Most patients (81.4%) with a P/LP test result had at least 1 of the following: diagnosis age ≤ 46 years, bilateral or multifocal tumors, or at least 1 first-degree relative with RCC. Out of the patients with a P/LP result, 18 patients (39.1%) had a potentially actionable mutation. Conclusions: Among patients with RCC who were unselected for a known familial/hereditary predisposition, P/LP variants were present in 13.4% which is consistent with previous studies. The prevalence of FLCN mutations was higher in our cohort (3.1%) compared to prior observations. Most patients with a P/LP variant met the NCCN criteria for genetic testing. Future studies should optimize the current genetic testing criteria to identify a broader group of patients who may have germline mutations given potential cascade testing and therapeutic implications.

Nivolumab usage patterns combined with TKI for mRCC: Financial toxicity and clinical outcomes from self-paying patients in India—Is low dose an option when access is limited?

e16544 Background: Nivolumab with cabozantinib is an accepted treatment option for metastatic RCC (mRCC). Generic TKI access has improved, although nivolumab at currently licensed doses remains unaffordable in India. Immunotherapy is not reimbursable through national health insurance schemes, therefore patients pay out-of-pocket. We evaluated the practice patterns and clinical outcomes with low dose nivolumab combined with TKI in a tertiary academic hospital in India. Methods: We reviewed and abstracted clinical records of mRCC patients treated with nivolumab and TKIs between December 2019 and January 2022. Due to variations in nivolumab dosing frequencies, a metric of dose/Kg/28 days was used for comparative analysis. Patients also had treatment de-escalation in the form of decrease in dose or frequency of nivolumab. Those treated with such de-escalation strategies were noted along with reasons for de-escalation. PFS, OS were calculated as per standard definitions and adverse events graded as per CTCAE4.1. Results: We identified 53 patients who received nivolumab and TKI with 33(62.2%) IMDC intermediate and 12(22.6%) poor prognoses. The mean age was 54.9±8.5 years, predominantly male (83%), non-clear cell histology in 12(22.6%) and clear cell in the remaining. Site of metastases were: pulmonary 43 (81%), CNS 6 (11.3%), liver 16(30%), non-regional nodes 24(45%) and bone 18 (33.9%). Forty-three (81.1%) received no prior systemic therapy. The TKIs used were Lenvatinib (47.2%), cabozantinib(34%) and Axitinib (2%). Fourteen (26.4%) had a flat starting nivolumab dose of 40mg and the median dose of the cohort was 140mg (IQR, 40-240) every 21 days (IQR, 21-28) resulting in a median adjusted weight-based dosing of 2.2mg/kg/28days (IQR, 1.1- 4). Treatment de-escalation was undertaken in 36 (67.9%) due to financial toxicity 24(45.3%) or drug toxicity 10 (18.9%). Interval nephrectomy was performed in 9 (17%). At the median dose (2.2mg/kg/28days) 26 patients with low dose (LD) and 27 high dose (HD) nivolumab were compared. The median PFS of LD and HD groups were 17 (95% CI,10.8-23.1) months and 21 (95% CI,5.7-36.2) months respectively (P=0.75). The median OS of the LD and HD was NR and 21 (4.9-37) months respectively (P=0.017). The grade 3&amp;4 adverse events were palmoplantar dysesthesia 7 (13.2%), hypertension 7(13.2%), arthritis in 3 (5.7%). One patient had Fournier’s gangrene and another had a pulmonary embolism. Primary hypothyroidism 28(52.8%) was the commonest grade 2 adverse event. Cost of 28 days of treatment was ₹ 87,280 ($1055.11 USD). Conclusions: Using LD nivolumab with TKI did not result in inferior survival and is less expensive than the currently approved dose. Treatment de-escalation due to financial toxicity was common and reflects reality in LMICs. Low dose strategies in mRCC warrant evaluation in prospective clinical trials.

Adjuvant everolimus in patients (Pts) with localized non-clear cell renal cell carcinoma (RCC): Subgroup analysis from the Everest trial (SWOG S0931).

4546 Background: In S0931, adjuvant treatment with the mTOR inhibitor everolimus respectively yielded disease-free survival (DFS) and overall survival (OS) hazard ratios (HR) of 0.85 (95% CI 0.71-1.00) and 0.90 (95% CI 0.71-1.13) in pts with resected, localized RCC. Previously, everolimus had been shown to be active in chromophobe RCC (chRCC; Tannir et al Eur Urol 2016) and papillary RCC (papRCC; Escudier et al Eur J Cancer 2016). We sought to evaluate the efficacy of everolimus within these non-clear cell subsets of EVEREST. Methods: 1545 adult pts with treatment-naïve, non-metastatic, fully-resected RCC at intermediate high- (pT1 G3-4 N0 to pT3a G1-2 N0) or very high-risk (pT3a G3-4 to pT4 G-any or N+) for recurrence were randomized 1:1 to 54 weeks of everolimus 10 mg PO daily or placebo within 12 weeks of radical or partial nephrectomy. Exploratory analyses of RFS and OS chromophobe and papillary subgroups were performed. Results: A total of 99 eligible pts had chRCC; 109 had papRCC (16 type I; 37 type II; 56 NOS). Median follow-up is 6.3 years. Pt characteristics were balanced between the 2 arms in each histological group. Thirty-four (34%) pts in the chRCC subgroup and 50 (46%) pts in the papRCC subgroup had very high-risk disease. Fewer pts completed all 54 weeks of everolimus in each subgroup compared to placebo (49% vs. 74% in the ChRCC subgroup and 46% vs. 71% in the papillary subgroup). DFS and OS for each subgroup are shown. Conclusions: Non-clear cell histology accounted for a considerable proportion (~13%) of S0931 pts. The estimated everolimus HRs for DFS and OS in the chRCC subset are consistent with the overall trial result, but those same modest HRs were not seen in papRCC, in contrast to prior reports of mTOR inhibitor activity in this subtype. Although inferences are limited by sample size and wide CIs, this is the largest experience in chRCC or papRCC among any adjuvant trials presented to date. Clinical trial information: NCT01120249 . [Table: see text]

Real-life use of cabozantinib as front-line therapy in metastatic renal cell carcinoma: The CabFRONT (Meet-URO 24) study.

e16539 Background: Cabozantinib is approved as first-line therapy for patients with intermediate-poor risk metastatic renal cell carcinoma (mRCC); however translating results from pivotal trials to an unselected real-world population remains a concern. Methods: CabFRONT is a retrospective observational multicentre Italian Network for Research in Urologic-Oncology (Meet-URO) study of a real-life population of treatment-naïve patients with intermediate-poor mRCC treated with cabozantinib as per clinical practice between September 2019 and September 2022. Results: 209 patients were enrolled. Median age was 65 years (36 - 85). 158 patients (76%) started with a dose of 60 mg, while 51 (24%) started with a dose of 40 mg. 140 patients (67%) were classified as intermediate and 69 (33%) as poor risk according to IMDC risk model. Clear-cell represented the most common histotype (172/209), followed by papillary (19/209), chromophobe (6/209) and NOS (4/209). Sarcomatoid features were present in 29 patients (14%). Lungs were the most frequent metastatic site, [137 (65%) patients], followed by lymph nodes [115 (55%)], and bones [72 (35%)]. 33 (16%) patients presented brain metastases. At a follow-up of 23 months (mo), the median progression-free survival (mPFS) was 9.6 mo (95% CI, 7.63-10.9 mo) and the median overall-survival was 21 mo (95% CI, 14-30 mo). As best overall response, 7 patients achieved a complete response, 73 a partial response and 77 stable disease for an objective response rate (ORR) of 38% and a disease control rate (DCR) of 75%. ORR for intermediate and poor population was respectively 29% and 10%, DCR was 56% for intermediate risk and 20% for poor risk population. mPFS for intermediate and poor population was respectively 12.73 and 5.27 mo (p &lt; 0.0001). mPFS for intermediate with 1 risk factor was 17.2 and for intermediate with 2 risk factors was 9.7 mo (p 0.0033). Subsequent antineoplastic treatments were received by 41% (86/209) of patients. Subsequent nivolumab was received by 87% of patients. 191 patients (91%) reported at least 1 grade (G) 1 to 2 adverse event (AE). The most common G1 to G2 AEs were fatigue (113 [60%]), mucositis (100 [52%]), hand-foot syndrome (HFS) (91 [47%]), diarrhoea (79 [41%]), hypertension (67 [35%]), and hypothyroidism (60 [31%]). 78 G3 AEs ere reported: the most common were fatigue (19 [24%]) and diarrhoea (18 [23%]). Permanent discontinuations from the study owing to AEs was observed in 7 patients: three for G3 diarrhea, one of which manifested also G3 renal injury, two for G3 asthenia, one for G3 HFS and one for G3 mucositis. At least 131 patients (63%) required a dose reduction and 86 (41%) required a transitory interruption to manage toxic effects. Conclusions: Our data confirmed that front-line Cabozantinib is effective and safe in an unselected real-life population of patients with intermediate-poor mRCC, including non-clear cell histologies.

Cancer-specific mortality free survival rates in non-metastatic non-clear cell renal carcinoma patients at intermediate/high risk of recurrence.

To date, five trials testing the effect of adjuvant systemic therapy in surgically treated non-metastatic renal cell carcinoma included patients with non-clear cell histology. We tested the effect of papillary vs. chromophobe histological subtype, stage, and grade on 10-year cancer-specific survival, in patients eligible for ≥1 such trial. We identified patients meeting ASSURE, SORCE, EVEREST, PROSPER, or RAMPART trial inclusion criteria in the SEER (2000-2018) database. Kaplan-Meier analyses estimated 10-year survival rates and multivariable Cox regression models tested for the independent predictor status of histological subtype, stage, and grade. We identified 5465 (68%) papillary and 2562 (32%) chromophobe renal cell carcinoma patients. Cancer-specific survival rates at 10 years were 77% in papillary vs. 90% in chromophobe. In multivariable Cox regression models applied to papillary patients, cancer-specific mortality independent predictor status was reached for T3G3-4 (HR 2.9), T4Gany (HR 3.4), TanyN1G1-2 (HR 3.1), and TanyN1G3-4 (HR 8.0, P<0.001), relative to T1/2Gany. In multivariable Cox regression models applied to chromophobe patients, mortality independent predictor status was reached for T3G3-4 (HR 3.6), T4Gany (HR 14.0), TanyN1G1-2 (HR 5.7), and TanyN1G3-4 (HR 15.0, P<0.001), relative to T1/2Gany. In surgically treated non-metastatic intermediate/high-risk renal cell carcinoma patients, papillary histologic subtype exhibited worse cancer-specific survival than chromophobe histologic subtype. Although stage and grade represented independent predictors in both histological subtype groups, the magnitude of their effect was invariably worse in chromophobe than in papillary patients. In consequence, papillary and chromophobe patients should be considered separate entities instead of being combined under the non-clear cell designation.