Metastatic Clear Renal Cell Carcinoma Research Articles

[Update of the German S3 guideline on renal cell carcinoma].

Renal cell carcinoma is the third most common tumor among urological tumors. In Germany more than 14,000 people are affected every year. The sex ratio is 2/3men and 1/3women. The S3guideline is intended to provide all disciplines dealing with renal cell carcinoma with the current status of diagnostics, therapy and follow-up care of the patients with this tumor. The first version of the German guideline on renal cell carcinoma was published in 2015. The development was carried out at S3level, which means that astructured, evidence-based literature search was carried out, recommendations and statements were developed in topic-related working groups and were approved by an interdisciplinary group of officials elected by the different medical societies. The chapters were gradually revised in 2017, 2020 and 2021 to reflect new aspects. This article provides information about the most important innovations of the most recent update from 2023. In the epidemiology subsection, the substance trichlorethene has been added as arisk factor for the development of renal cell carcinoma. While there were no new data on neoadjuvant therapy, the checkpoint inhibitor pembrolizumab was the first substance to demonstrate improved disease-specific and overall survival in the adjuvant situation. The combination nivolumab plus cabozantinib and lenvatinib plus pembrolizumab were included in the chapter on systemic therapy for metastatic clear cell renal cell carcinoma. New are the chapters on non-clear cell renal cell carcinoma and hereditary tumors. The S3guideline provides astructured, evidence-based overview of all aspects of renal cell carcinoma.

Sunitinib for adenocarcinoma of the rete testis: a case report

BackgroundAdenocarcinoma of the rete testis (AORT) is an extremely rare and aggressive tumor with a poor prognosis. Its etiology and pathological characteristics have not been extensively studied, making accurate diagnosis and appropriate management challenging. AORT, an invasive testicular tumor with a mortality rate of 46%, treatment typically involves radical orchiectomy, retroperitoneal pelvic lymph node dissection (RPLND), adjuvant chemotherapy, and/or ongoing monitoring, but the response to conventional radiation and chemotherapy is limited. At present, no effective targeted therapy for AORT has been found.Case descriptionIn this case report, we present the clinical scenario of a 50-year-old male patient initially diagnosed with a right testicular hydrocele, who subsequently underwent eversion of the parietal tunica vaginalis. Postoperative pathological analysis revealed metastatic clear cell renal cell carcinoma (ccRCC). PET/CT demonstrated findings suggestive of left renal upper pole carcinoma with involvement of the right scrotum, para-aortic region, bilateral iliac vessels, bilateral inguinal region, and multiple metastases. Sunitinib, a tyrosine kinase inhibitor, is commonly employed in the treatment of ccRCC. The patient underwent treatment with sunitinib for a duration of 20 months, resulting in the inactivation of multiple metastases. Following this, a radical orchiectomy was performed, and the postoperative pathology confirmed the presence of AORT. This article provides a comprehensive account of the patient's medical history, diagnostic process, treatment modalities, and subsequent follow-up observations.ConclusionsThis case report highlights the successful use of targeted therapy with sunitinib in a patient with AORT. The patient showed a positive response to targeted therapy. This study not only provides a novel foundation for the treatment of AORT, but also offers valuable insights for future treatment strategies in managing this particular form of testicular cancer.

Cabozantinib with immune checkpoint inhibitorversus cabozantinib monotherapy in patients with metastatic clear cell renal cell carcinoma progressing after prior immune checkpoint inhibitor.

Rechallenge with antibodies targeting programmed cell death protein-1 or its ligand (PD-1/L1) after discontinuation or disease progression in solid tumors following a prior PD-1/L1 treatment is often practiced in clinic. This study aimed to investigate if adding PD-1/L1 inhibitors to cabozantinib, the most used second-line treatment in real-world patients with metastatic clear cell renal cell carcinoma (mccRCC), offers additional benefits. Using de-identified patient-level data from a large real-world US-based database, patients diagnosed with mccRCC, who received any PD-1/L1-based combination in first-line (1L) setting, followed by second-line (2L) therapy with either cabozantinib alone or in combination with PD-1/L1 inhibitors were included. Patients given a cabozantinib-containing regimen in 1L were excluded. The study end points were real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) by 2L. Of 12,285 patients with metastatic renal cell carcinoma in the data set, 348 patients met eligibility and were included in the analysis. After propensity score matching weighting, cabozantinib with PD-1/L1 inhibitors versus cabozantinib (ref.) had similar rwTTNT and rwOS in the 2L setting. Hazard ratios and 95% confidence interval (CI) for rwTTNT and rwOS are 0.74 (95% CI, 0.49-1.12) and 1.15 (95% CI, 0.73-1.79), respectively. In this study, the results align with the phase 3 CONTACT-03 trial results, which showed no additional benefit of adding PD-L1 inhibitor to cabozantinib compared to cabozantinib alone in 2L following PD-1/L1-based therapies in 1L. These results from real-world patients strengthen the evidence regarding the futility of rechallenge with PD-1/L1 inhibitors.

Comparison of Cabozantinib and Axitinib as Second-line Therapy After Nivolumab Plus Ipilimumab in Patients With Metastatic Clear Cell Renal Cell Carcinoma: A Comparative Analysis of Retrospective Real-world Data

BackgroundTo date, no studies have compared the treatment outcomes of second-line therapies in patients with metastatic clear cell renal cell carcinoma (ccRCC). This study retrospectively evaluated the efficacy of cabozantinib and axitinib as second-line treatments in patients with metastatic ccRCC who previously received immune-oncology combination therapy. Patients and MethodsPatients with metastatic ccRCC treated with cabozantinib and axitinib as second-line therapy after nivolumab-ipilimumab treatment were identified among 243 patients with RCC treated between August 1, 2018 and January 31, 2022 at 34 institutions belonging to the Japanese Urological Oncology Group. Patients were assessed for treatment outcomes, including progression-free survival (PFS), overall survival, objective response rate (ORR), and incidence rate of treatment-related adverse events (AEs). ResultsForty-eight patients treated with cabozantinib and 60 treated with axitinib as second-line therapy after nivolumab-ipilimumab treatment for metastatic ccRCC were identified. The median PFS (95% confidence interval) was 11.0 months (9.0–16.0) with cabozantinib and 9.5 months (6.0–13.0) with axitinib. The ORRs were 37.5% (cabozantinib) and 38.3% (axitinib). The rates of any-grade AEs and grade ≥3 AEs were 79.2% (cabozantinib) versus 63.3% (axitinib; P=0.091) and 35.4% (cabozantinib) versus 23.3% (axitinib; P=0.202), respectively. In the poor-risk group, PFS was longer in the cabozantinib group than in the axitinib group (P=0.033). ConclusionThe efficacy and safety of cabozantinib and axitinib were comparable. In the poor-risk group, cabozantinib was more effective than axitinib. These findings provide valuable insights into the selection of second-line treatment options after nivolumab-ipilimumab treatment in patients with metastatic ccRCC. MicroAbstractThe treatment outcomes of the second-line therapies, cabozantinib and axitinib, following nivolumab and ipilimumab in 108 patients with metastatic clear cell renal cell carcinoma (ccRCC) were retrospectively compared. Comparable efficacy and safety were observed. In the poor-risk group, cabozantinib demonstrated superior progression-free survival over axitinib, offering valuable insights for second-line therapy selection after nivolumab-ipilimumab in patients with metastatic ccRCC.

The Pancreas as a Target of Metastasis from Renal Cell Carcinoma: Is Surgery Feasible and Safe? A Single-Center Experience in a High-Volume and Certified Pancreatic Surgery Center in Germany.

Background: Secondary malignant tumors of the pancreas are rare, representing 2-5% of all pancreatic malignancies. Nevertheless, the pancreas is one of the target organs in cases of metastatic clear cell renal cell carcinoma (CCRCC). Additionally, recurrent metastasis may occur. Surgical resection remains the best and prognostically most favorable therapeutic option in cases of solitary pancreatic metastasis. Aim: To review retrospectively the clinical tumor registry of the University Hospital of Magdeburg, Germany, for this rare entity, performing a clinical systematic single-center observational study (design). Methods: A retrospective cohort analysis of consecutive patients who had undergone pancreatic resection for metastatic CCRC was performed in a single high-volume certified center for pancreatic surgery in Germany from 2010 to 2022. Results: All patients (n = 17) included in this study had a metachronous metastasis from a CCRCC. Surgery was performed at a median time interval of 12 (range, 9-16) years after primary resection for CCRCC. All 17 patients were asymptomatic at the time of diagnosis. Three of those patients (17.6%) presented with recurrent metastasis in a different part of the pancreas during follow-up. In a total of 17 patients, including those with recurrent disease, a surgical resection was performed; Pancreatoduodenectomy was performed in 6 patients (35%); left pancreatectomy with splenectomy was performed in 7 patients (41%). The rest of the patients underwent either a spleen-preserving pancreatic tail resection, local resection of the tumor lesion or a total pancreatectomy. The postoperative mortality rate was 6%. Concerning histopathological findings, seven patients (41%) had multifocal metastasis. An R0 resection could be achieved in all cases. The overall survival at one, three and five years was 85%, 85% and 72%, respectively, during a median follow-up of 43 months. Conclusions: CCRC pancreatic metastases can occur many years after the initial treatment of the primary tumor. Surgery for such a malignancy seems feasible and safe; it offers very good short- and long-term outcomes, as indicated. A repeated pancreatic resection can also be safely performed.

Abstract 928: Real-world comparison of first-line treatments for metastatic clear cell renal cell carcinoma (mccRCC)

Abstract Multiple regimens are available for management of mccRCC including either immuno-oncology doublet (IO/IO) or combinations of IO and tyrosine kinase inhibitors (TKI). Clinical trials have compared these regimens to sunitinib, with no direct comparison between them. As such, there is ambiguity among physicians about preferred first-line for mccRCC. We performed a single-institution retrospective study of adults treated in first-line for mccRCC between 1/1/2017 and 1/1/2023. Regimens included IO/IO (ipilimumab/nivolumab [I/N]) or IO/TKI (pembrolizumab/axitinib [P/A], nivolumab/cabozantinib [N/C], or pembrolizumab/lenvatinib [P/L]). We compared efficacy and toxicity endpoints, using Kruskal-Wallis test for medians and Chi-square for categorical variables. 42 patients with median age of 61 (range: 36-95) were included. Patient distribution in IO/IO vs IO/TKI group was 20.0% vs 30.8% in International Metastatic Database Consortium (IMDC) favorable risk, 46.7% vs 38.5% in intermediate-risk, and 33.3% vs 30.8% in poor-risk group. 78.6% vs 66.6% of patients had WHO grade 3/4 ccRCC, 18.8% vs 15.4% had sarcomatoid features in the IO/IO vs IO/TKI, respectively. 38% (16/42) received I/N, 7% (3/42) N/C, 52% (22/42) P/A, and 2% (1/42) P/L. Median follow-up was 109 weeks. Table-1 compares the efficacy of IO/IO vs IO/TKI. IO-related toxicity, TKI-related toxicity, treatment interruptions, dose reductions, and need for steroids were not significantly different between IO/IO and IO/TKI (p= 0.240, p=0.372, p=0.923, p=1.00, and p=0.248, respectively). Genomic characteristics will be reported in poster. Despite small sample size, our real-world data showed that patients treated with IO/IO had significantly worse outcomes compared to those treated with IO/TKI. While this difference may stem from a more aggressive disease in IO/IO group but further insights needs to be obtained through future prospective studies comparing IO/IO and IO/TKI regimens. Variable IO/IO IO/TKI p-value Median treatment duration (weeks) 8.3 59.4 <0.001 Disease control rate (complete response + partial response + stable disease) (%) 50.0 91.7 0.024 Time from 1st line to 2nd line therapy (weeks) 14.6 57.1 0.001 Median overall survival (weeks) 63.6 Not reached 0.001 Citation Format: Omid Yazdanpanah, Sami Dwabe, Garrett Harada, Steven Seyedin, Nataliya Mar. Real-world comparison of first-line treatments for metastatic clear cell renal cell carcinoma (mccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 928.

Humoral complementomics – exploration of noninvasive complement biomarkers as predictors of renal cancer progression

ABSTRACT Despite the progress of anti-cancer treatment, the prognosis of many patients with solid tumors is still dismal. Reliable noninvasive biomarkers are needed to predict patient survival and therapy response. Here, we propose a Humoral Complementomics approach: a work-up of assays to comprehensively evaluate complement proteins, activation fragments, and autoantibodies targeting complement proteins in plasma, which we correlated with the intratumoral complement activation, and/or local production, focusing on localized and metastatic clear cell renal cell carcinoma (ccRCC). In two prospective ccRCC cohorts, plasma C2, C5, Factor D and properdin were elevated compared to healthy controls, reflecting an inflammatory phenotype that correlated with plasma calprotectin levels but did not associate with CRP or with patient prognosis. Conversely, autoantibodies against the complement C3 and the reduced form of FH (a tumor neo-epitope reported in lung cancer) correlated with a favorable outcome. Our findings pointed to a specific group of patients with elevated plasma C4d and C1s-C1INH complexes, indicating the initiation of the classical pathway, along with elevated Ba and Bb, indicating alternative pathway activation. Boostrapped Lasso regularized Cox regression revealed that the most predictive complement biomarkers were elevated plasma C4d and Bb levels at the time of surgery, which correlated with poor prognosis. In conclusion, we propose Humoral Complementomics as an unbiased approach to study the global state of the complement system in any pathological plasma sample and disease context. Its implementation for ccRCC revealed that elevated C4d and Bb in plasma are promising prognostic biomarkers, correlating with shorter progression-free survival.

The Survival Outcomes of the Metastatic Nonclear Cell Renal Cell Carcinoma in the Immunotherapy Era: Princess Margaret Cancer Centre Experience.

Immunotherapy (IO) with or without targeted therapy (TT) is the standard treatment for patients with metastatic clear cell renal cell carcinoma (RCC). The evidence supporting their use in metastatic nonclear cell renal cell carcinoma (nccRCC) subtypes is based on small prospective trials and retrospective analyses. Here, we report survival outcomes for patients with metastatic nccRCC treated with IO and/or TT at the Princess Margaret Cancer Centre, Toronto, ON, Canada. Demographics, disease characteristics, and survival outcomes were collected retrospectively. Overall (OS), progression-free survival (PFS), and objective response rates (ORR) were calculated. We identified 69 patients with metastatic nccRCC treated with IO and/or TT as the first-line treatment, and 36 (52.1%) patients as the second-line treatment. Median OS of the first line IO recipients (n = 12) and non-IO recipients (n = 57) was not reached (NR) and 17.2 months (95% confidence interval (95% CI): 7.3-27.0; P = 0.23), respectively. Median PFS of first-line IO recipients and non-IO recipients was NR and 4.7 months (95% CI: 3.7-5.6; P = 0.019), respectively. The ORR of IO recipients versus non-IO recipients was 50% versus 12.3% (P = 0.007). Median OS of the second-line IO recipients (n = 8) and non-IO recipients (n = 28) was NR and 6.3 months (95% CI: 3.2-9.3; P = 0.003), respectively. Median PFS of second-line IO recipients and non-IO recipients was 4.8 months (95% CI: 2.7-6.8) and 2.8 months (95% CI: 1.8-3.7; P = 0.014), respectively. ORR of IO recipients and non-IO recipients was 37.5% and 3.5%, respectively; P = 0.028. While the number of patients included in our retrospective review was small, our analysis suggested that patients with nccRCC have improved survival outcomes with IO treatment. Validation of prospective dataset is required before widespread clinical utilization.

Integrated genomic and proteomic analyses identify PYGL as a novel experimental therapeutic target for clear cell renal cell carcinoma

Sunitinib, the first-line targeted therapy for metastatic clear cell renal cell carcinoma (ccRCC), faces a significant challenge as most patients develop acquired resistance. Integrated genomic and proteomic analyses identified PYGL as a novel therapeutic target for ccRCC. PYGL knockdown inhibited cell proliferation, cloning capacity, migration, invasion, and tumorigenesis in ccRCC cell lines. PYGL expression was increased in sunitinib-resistant ccRCC cell lines, and CP-91149 targeting the PYGL could restore drug sensitivity in these cell lines. Moreover, chromatin immune-precipitation assays revealed that PYGL upregulation is induced by the transcription factor, hypoxia-inducible factor 1α. Overall, PYGL was identified as a novel diagnostic biomarker by combining genomic and proteomic approaches in ccRCC, and sunitinib resistance to ccRCC may be overcome by targeting PYGL.

NLR Outperforms Low Hemoglobin and High Platelet Count as Predictive and Prognostic Biomarker in Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors

BackgroundReliable biomarkers in renal cell carcinoma (RCC) remain elusive. While several markers have been shown to be associated with prognosis, and may aid in risk assessment, predictive biomarkers of response to immune checkpoint inhibitors (ICIs) have not been established. Previous studies have shown that a high pretreatment neutrophil-lymphocyte ratio (NLR) is a negative prognostic factor in RCC. However, a clinically useful cut-off for the predictive and prognostic value of NLR has not been well defined. MethodsWe conducted a retrospective analysis of 132 patients with previously untreated metastatic clear cell RCC (ccRCC) who received first line ICI-based therapy. ICI-based therapy included anti-PD-1/PD-L1 alone or in combination with anti-CTLA-4 or VEGF-TKI. Platelet, haemoglobin, neutrophil and lymphocyte counts were collected prior to treatment and at 12-weeks after treatment initiation. Radiologic response at 12-weeks and overall survival (OS) data was also collected. ResultsLow haemoglobin, high platelet count, and NLR ≥3 were statistically significant negative predictive biomarkers when assessed at 12-weeks, but not at baseline. Median OS was shorter in patients with low haemoglobin (20.3 months vs. 51.6 months, P = .009), high platelet count (14.3 months vs. 43.8 months, P = .003), and NLR ≥ 3 (17.5 months vs. 40.3 months, P < .001) at 12-weeks. In an IMDC-risk adjusted analysis, only NLR ≥3 at 12-weeks remained statistically significant (OR of 2.11, P = .003) A dynamic change towards lower absolute NLR overtime was associated with longer OS. In patients who had baseline NLR ≥ 3, those who achieved NLR < 3 at 12-weeks demonstrated significant longer median OS compared to those whose NLR remained persistently ≥ 3 (40.3 months vs. 14.7 months, P = .004). ConclusionNLR ≥3, low haemoglobin and elevated platelet count after 12-weeks of ICI-based first line therapy were negatively prognostic and predictive in patients with metastatic RCC. Normalization of NLR in patients with baseline elevation was associated with longer median OS and response to therapy. These results suggest that monitoring of routine haematologic biomarkers during therapy may provide important predictive and prognostic information, beyond what is available with baseline risk assessment scoring systems.

Survival pattern of metastatic renal cell carcinoma patients according to WHO/ISUP grade: a long-term multi-institutional study

The World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading of renal cell carcinoma (RCC) is classified from grade 1–4, regardless of subtype. The National Comprehensive Cancer Network (NCCN) guidelines (2022) state that if there is an adverse pathological feature, such as grade 3 or higher RCC in stage 1 patients, more rigorous follow-up imaging is recommended. However, the RCC guidelines do not provide specific treatment or follow-up policies by tumor grade. Therefore, this study attempted to find out whether tumor grade affects survival rates in patients with metastatic RCC. The Korean Renal Cancer Study Group (KRoCS) database includes 3108 patients diagnosed with metastatic RCC between September 1992 and February 2017, with treatment methods, progression, and survival data collected from 11 tertiary hospitals. To obtain information on survival rates or causes of death, we utilized the Korea National Statistical Office database and institutional medical records. Data were accessed for research purpose on June, 2023. We then reviewed these sources to gather comprehensive and reliable data on the outcomes of our study cohort. This database was retrospectively analyzed, and out of 3108 metastatic RCC patients, 911 had been identified as WHO/ISUP grade. Grades were classified into either a low-grade (WHO/ISUP grade 1–2) or a high-grade group (WHO/ISUP grade 3–4). The patients were then analyzed related to progression and overall survival (OS). In metastatic clear cell RCC patients, the 1-year OS rate was 69.4% and the median OS was 17.0 months (15.5–18.5) followed up to 203.6 months. When comparing the patient groups, 119 low-grade and 873 high-grade cases were identified. No baseline difference was observed between the two groups, except that the high-grade group had a higher ECOG 1 ratio of 50.4% compared with 34.5% for the low-grade group (p = 0.009). There was a significant difference in OS between high-grade and low-grade groups. OS was 16.0 months (14.6–17.4) in the high-grade group and 28.0 months (21.1–34.9) in the low-grade group (p < 0.001). However, there was no difference in progression-free survival (PFS) rates with 9.0 months (8.0–10.0) for the high-grade group and 10.0 months (6.8–13.2) for the low-grade group (p = 0.377) in first-line treatment. In multivariable analysis, WHO/ISUP grade was a risk factor (HR = 1.511[1.135–2.013], p = 0.005) that influenced the OS. In conclusion, WHO/ISUP grade is a major data source that can be used as a ubiquitous marker of metastatic RCC in pre-IO era. Depending on whether the RCC is high or low grade, the follow-up schedule will need to be tailored according to grade, with higher-grade patients needing more active treatment as it can not only affect the OS in the previously known localized/locoregional recurrence but also the metastatic RCC patient.

Metastasis of Clear Cell Renal Cell Carcinoma to Uterine Leiomyoma: First Case Report and Review of Literature.

Metastasis of clear cell renal cell carcinoma (clear cell RCC) to the gynecologic tract is infrequent, and involvement of the uterus is extremely rare. A review of the literature identified a total of 12 reported examples with metastasis to the uterine serosa (1), endometrium (5), cervix (5) and only one with metastasis to the myometrium. This report represents the first case of tumor-to-tumor metastasis involving a clear cell RCC with metastasis to a uterine leiomyoma. The patient was a 50-year-old woman status post-radical nephrectomy for newly diagnosed unilateral clear cell RCC (stage pT3a) with negative margins, who subsequently underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy for the incidental finding of multiple uterine masses measuring up to 14.5 cm suggestive of fibroid on pelvic ultrasound. The pathologic exam of the specimen was consistent with metastatic clear cell RCC (1.2 cm) to uterine leiomyoma, confirmed with keratin, vimentin, CD10, CA9, and PAX8 immunohistochemistry. The patient's postoperative course was uneventful, and no new lesions were identified at follow-up during the past 6 months.

Combination of Anti-Angiogenics and Immunotherapies in Renal Cell Carcinoma Show Their Limits: Targeting Fibrosis to Break through the Glass Ceiling?

This review explores treating metastatic clear cell renal cell carcinoma (ccRCC) through current therapeutic modalities-anti-angiogenic therapies and immunotherapies. While these approaches represent the forefront, their limitations and variable patient responses highlight the need to comprehend underlying resistance mechanisms. We specifically investigate the role of fibrosis, prevalent in chronic kidney disease, influencing tumour growth and treatment resistance. Our focus extends to unravelling the intricate interplay between fibrosis, immunotherapy resistance, and the tumour microenvironment for effective therapy development. The analysis centres on connective tissue growth factor (CTGF), revealing its multifaceted role in ccRCC-promoting fibrosis, angiogenesis, and cancer progression. We discuss the potential of targeting CTGF to address the problem of fibrosis in ccRCC. Emphasising the crucial relationship between fibrosis and the immune system in ccRCC, we propose that targeting CTGF holds promise for overcoming obstacles to cancer treatment. However, we recognise that an in-depth understanding of the mechanisms and potential limitations is imperative and, therefore, advocate for further research. This is an essential prerequisite for the successful integration of CTGF-targeted therapies into the clinical landscape.

Safety and efficacy of nivolumab in elderly patients with metastatic clear cell renal cell carcinoma: Analysis of the NIVOREN GETUG-AFU 26 study

IntroductionImmune checkpoint inhibitors are standard of care in metastatic renal cell carcinoma but their activity and safety in elderly patients is insufficiently explored. We evaluated outcomes of elderly patients with mRCC treated with nivolumab in the GETUG-AFU 26 NIVOREN phase 2 trial (NCT03013335) and conducted exploratory circulating biomarker analyses. MethodsPatients with mRCC were treated with nivolumab after at least one antiangiogenic therapy. The main endpoint of this analysis was safety in patients ≥ 70 years old (y.o), as per the rate of treatment-related grade 3–5 events (TRAE). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival. Exploration of candidate biomarkers associated with aging included baseline circulating cytokines involved in inflammation, adhesion, immune checkpoints, angiogenesis (IL6, IL7, IL8, BAFF, CXCL13, VCAM-1, 4–1BB, VEGF). ResultsOf 720 patients, 515 were < 70 y.o and 205 ≥ 70 y.o. Patients ≥ 70 y.o exhibited numerically less IMDC poor risk disease (21.0% vs 26.9%), sarcomatoid component (4.9% vs 9.8%) or brain metastases (5.9% vs. 14.7%), but more previous treatment lines (≥ 2 in 54.1% vs 48.5%). TRAE were higher in patients ≥ 70 y.o (24.9% vs. 17.9%, p = 0.033). Respective ORR (19.2% vs. 22.1%) and median PFS (4.5 versus 3.0 months, HR 0.97 [95%CI 0.81–1.15]) were similar. Overall survival was shorter in patients ≥ 70 y.o (19.3 versus 26.9 months, HR 1.26 [95%CI 1.04–1.51]), but not significantly in a competitive risk model. Only V-CAM1 and 4–1BB were found to be increased in patients ≥ 70 y.o. ConclusionsNivolumab displayed higher grade 3/4 TRAE but manageable toxicity in elderly patients, with sustained activity. Elderly patients did not display specific inflammatory or angiogenic circulating profiles.

A multicentric, single arm, open-label, phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer (PRadR)

BackgroundDespite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer.MethodsThis is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS).DiscussionOur prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients.Trial registrationClinicalTrials.gov: NCT06059014.

Multiomics approach for patient stratification and novel target identification in metastatic clear cell renal carcinoma (Meet-URO 31).

TPS498 Background: The choice of the best treatment in first line metastatic clear-cell renal cell carcinoma (mccRCC) patients is becoming an issue, since no biomarkers are available to guide the treatment allocation strategy. Recently there has been a great deal of interest in Artificial Intelligence (AI) systems and their ability to process heterogeneous data for both classification and prediction purposes. An additional fields of interest in genitourinary oncology are also liquid biopsy and radiomics. Non-invasive liquid biopsy methods are able to detect and characterize circulating cell-free DNA (cfDNA), extracellular vesicles (EV) associated RNAs and circulating tumor cells (CTCs) and to allow longitudinal evaluation of tumor evolution whereas radiomics may provide a novel approach to develop predictive tools by correlating imaging features to tumor characteristics including histology, tumor grade, genetic patterns and molecular phenotypes, as well as clinical outcomes. We hypothesize that AI can be used to integrate data obtained from radiomics, genomic and transcriptomic analysis of CT scan, neoplastic tissues and circulating cell-free DNA or microvescicle-associated RNA with the purpose of defining an optimal allocation strategy for patients with mccRCC undergoing first-line therapy and identifying novel targets in mccRCC. Methods: This is a multicenter Italian prospective translational study evaluating transriptomic, genomics and radiomics in treatment-naïve advanced ccRCC patients. Subjects will be screened to identify a total of 100 patients eligible for the study, candidate to receive first-line treatment as per investigator’s choice according to clinical practice. Tumoral tissue, plasma samples and radiological exams will be collected at baseline, at 3 months, at the time of first radiological evaluation and at disease progression (PD) to provide a comprehensive molecular profile and radiomic features extrapolation, respectively. AI systems will be used to build a genomic-radiomic profile of patients to correlate to treatment response. The planned sample size of 100 patients will allow an exploratory analysis of the prognostic and predictive performance of the "multiomic" classifier, to be subsequently validated in a larger expansion cohort of patients. Through the above research we are confident to provide proof of concept that AI is able to combine the information from genomics, transcriptomic and radiomics to provide an opportunity for a molecularly driven patients' stratification, aiming to choose the ideal first-line systemic treatment for each patient. Enrollment has already begun and the trial has enrolled 15 of the planned 100 patients. Clinical trial information: NCT05782400 .

A phase I/II, open label, single arm study on safety, tolerability and anti-tumour effiacy of orellanine treatment in patients with metastatic clear-cell or papillary renal cell carcinoma.

A phase I/II, open label, single arm study on safety, tolerability and anti-tumour effiacy of orellanine treatment in patients with metastatic clear-cell or papillary renal cell carcinoma.

Final results of a phase I trial of HERV-E TCR transduced T cells for the treatment of HLA-A*11 patients with metastatic clear cell renal cell carcinoma (mccRCC).

435 Background: Human endogenous retrovirus type E (HERV-E) is specifically expressed in ccRCC providing a safe target for T cell-based therapies. We investigated T cells transduced with a TCR targeting HERV-E (HERV-E T cells) for the treatment of mccRCC. Methods: This first-in-human study assessed the safety &amp; efficacy of escalating doses of HERV-E T cells and manufacturing/clinical endpoints correlative analysis. HLA-A*11+ mccRCC patients (pts) were treated with a conditioning regimen, infusion of HERV-E T cells &amp; IL-2. (NCT03354390). Results: Nineteen of185 pts tested were found to express HLA-A*11. 17 HLA-A*11 + pts enrolled on the study: 3 pts on each DL1-3 &amp; 6 pts on DL4. 2 pts did not receive HERV-E T cells given disease progression during manufacturing period. Median age was 57 years. 86% received ≥ 3 prior systemic treatment (range 1-8). The manufacturing failure rate after first apheresis was 12% (n=2); both met target dose after second apheresis and repeat in vitro expansion. All HERV-E T cell products met release criteria for infusion including INF-γ production in response to HERV-E/HLA-A11-expressing tumor cells. Median HERV-E vector copy number (VCN) was 1.9. No dose-limiting toxicities (DLT), off-target toxicities or treatment-related deaths occurred. Pt#17 is on DLT monitoring period. 7 pts completed the planned 14 doses of IL-2 and all received at least 8 doses. Reasons for IL-2 discontinuation: hemodynamic (57%), cardiovascular (28%), pulmonary (28%), renal (14%) criteria &amp; pts decision (14%). The best response was partial response in 7% &amp; stable disease at least 8 weeks in 29% pts. HERV-E mRNA expression was detected in 5 primary &amp; 9 metastatic specimens. HERV-E T cells were measurable in circulation post-dosing, with peak concentrations in the peripheral blood mononuclear compartment on day(D)+7. [DL1: 0.3 %, DL2: 1.2%, DL3: 0.5%, DL4: 12.3%]. Median HERV-E T cell VCN showed no correlation with HERV-E T cells peak concentration on D+4 &amp; D+7. Conclusions: Proof of concept that HERV-T cells can induce tumor regression without evidence of causing off-target toxicities has been established by this trial. Infused HERV-E T cells were detectable transiently in vivo and induce effector cytokine production. Our initial results support the further development of HERV-E-directed therapies that focus on methods to improve in vivo persistence of TCR engineered T-cells and to target HERV-E antigens expressed on more commonly expressed HLA alleles.[Table: see text]

Comparing molecular variations and outcomes in Hispanic and non-Hispanic patients with metastatic clear cell renal cell carcinoma (ccRCC).

372 Background: Hispanic patients with renal cell carcinoma (RCC) have worse clinical outcomes than non-Hispanic White (NHW) patients. It is unclear if this disparity is related to biological differences or social determinants of health (SDOH). There is limited knowledge about potential genetic variations in RCC between these ethnic populations. Methods: Patients with metastatic ccRCC evaluated at UCSD were retrospectively identified from chart review or a single institutional database. Patients with genomic sequencing on tissue samples from primary kidney and/or metastatic sites were included for analysis. Patients were categorized as non-Black Hispanic or NHW based on self-identification. Logistic regression was applied for the presence of divergent frequencies of somatic mutations. Cox regression models evaluated the effect of additional factors on overall mortality, with correction for multiple tests using Benjamini-Hochberg method. Results: The analysis included 103 patients with metastatic ccRCC, of whom 46% were Hispanic. We did not observe statistically significant differences in median age at diagnosis (61 vs 62 years), BMI (28 in both), proportion of males (74% vs 73%), never smokers (47% vs 56%), sarcomatoid component (24% vs 17%), receipt of systemic therapy (92% vs 96%) or treatment initiated after 2017 (57% vs 56%) between Hispanic and NHWs. There were also no differences in the number or locations of metastases between ethnic groups. Hispanics were more likely to have public health insurance (34% vs 9%, p&lt;0.01) and IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) intermediate/poor risk disease (81% vs 55%, p&lt;0.01). Hispanics had a higher frequency of BAP1 mutations (28% vs 7%, p=0.01) compared to NHWs, whereas NHWs had more frequent TP53 (24% vs 4%, p=0.01) and SETD2 alterations (29% vs 4%, p&lt;0.01). VHL (80% vs 74%, p=0.51) and PBRM1 (26% vs 36%, p=0.34) mutations were comparable between Hispanic and NHWs. First-line treatment regimens were similar between the two groups: tyrosine kinase inhibitor (TKI) monotherapy (45% vs 42%), immunotherapy (IO/IO) doublet (23% vs 27%) and combined IO/TKI (15% vs 11%). On multivariable analysis, there was a significant difference in OS between Hispanic and NHWs (HR 3.60, 95%CI 1.49-8.67, adjusted p= 0.04) after correcting for age, sex, smoking, insurance, IMDC risk group, number of metastatic sites, sarcomatoid feature, therapy regimen and VHL, PBRM1, SETD2, TP53 and BAP1 mutations. Conclusions: We demonstrated a marked association in survival outcomes and differences in the mutational landscape of ccRCC between Hispanic and NHW patients. These findings underscore the interplay between genetic variations and social determinants, especially given the observed insurance disparities. Our study emphasizes the need for further research in ccRCC across diverse ethnicities.

Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T.

LBA360 Background: NIVO IV has improved outcomes in multiple tumor types. Evolving treatment paradigms have created a need for administration options that address treatment burden and improve efficiencies of healthcare systems. SC delivery of antibodies for various cancer indications has proved safe and effective. CheckMate 67T (NCT04810078) is a multicenter, randomized, open-label, phase 3 study that evaluated PK and objective response rate (ORR) noninferiority of NIVO SC vs IV in patients (pts) with locally advanced or metastatic ccRCC. Methods: Enrolled pts had measurable disease that progressed during or after 1–2 prior systemic regimens, no prior immuno-oncology treatment, and a Karnofsky performance score ≥ 70. Pts were randomized 1:1 to receive NIVO SC 1200 mg + recombinant human hyaluronidase PH20 Q4W or NIVO IV 3 mg/kg Q2W until disease progression, unacceptable toxicity, withdrawal of consent, completion of 2 years’ treatment, or death. The co-primary PK endpoints for noninferiority testing were time-averaged serum concentration over the first 28 days (Cavgd28) and minimum serum concentration at steady state (Cminss) determined by a population PK analysis. ORR by blinded independent central review (BICR) was a key powered secondary endpoint for noninferiority testing. Other secondary objectives included additional PK exposure measures, safety, efficacy, and immunogenicity. Results: A total of 495 pts were randomized to NIVO SC (n = 248) or NIVO IV (n = 247). The median age was 64/66 years in the SC/IV arms. Most pts were male. Average injection time with NIVO SC was &lt; 5 minutes. Noninferiority for the co-primary PK and key powered secondary ORR endpoints was met (see table). Incidence of NIVO SC local injection-site reactions was 8.1%; reactions were low grade and transient. Most deaths were due to disease progression; study drug toxicity led to 3/1 deaths with NIVO SC/IV. Conclusions: The co-primary PK and key powered secondary ORR endpoints were met, supporting the use of NIVO SC as a new option to improve healthcare efficiency. The safety profile for NIVO SC was consistent with NIVO IV. Clinical trial information: NCT04810078 .[Table: see text]