Advanced Clear Cell Renal Carcinoma Research Articles

A spatial architecture-embedding HLA signature to predict clinical response to immunotherapy in renal cell carcinoma.

An important challenge in the real-world management of patients with advanced clear-cell renal cell carcinoma (aRCC) is determining who might benefit from immune checkpoint blockade (ICB). Here we performed a comprehensive multiomics mapping of aRCC in the context of ICB treatment, involving discovery analyses in a real-world data cohort followed by validation in independent cohorts. We cross-connected bulk-tumor transcriptomes across >1,000 patients with validations at single-cell and spatial resolutions, revealing a patient-specific crosstalk between proinflammatory tumor-associated macrophages and (pre-)exhausted CD8+ T cells that was distinguished by a human leukocyte antigen repertoire with higher preference for tumoral neoantigens. A cross-omics machine learning pipeline helped derive a new tumor transcriptomic footprint of neoantigen-favoring human leukocyte antigen alleles. This machine learning signature correlated with positive outcome following ICB treatment in both real-world data and independent clinical cohorts. In experiments using the RENCA-tumor mouse model, CD40 agonism combined with PD1 blockade potentiated both proinflammatory tumor-associated macrophages and CD8+ T cells, thereby achieving maximal antitumor efficacy relative to other tested regimens. Thus, we present a new multiomics and spatial map of the immune-community architecture that drives ICB response in patients with aRCC.

Acetylation- and ubiquitination-regulated SFMBT2 acts as a tumor suppressor in clear cell renal cell carcinoma

BackgroundClear cell renal cell carcinoma (RCC) is the most common kidney tumor. The analysis from medical database showed that Scm-like with four MBT domains protein 2 (SFMBT2) was decreased in advanced clear cell RCC cases, and its downregulation was associated with the poor prognosis. This study aims to investigate the role of SFMBT2 in clear cell RCC.MethodsThe expression of SFMBT2 in clear cell RCC specimens were determined by immunohistochemistry staining and western blot. The overexpression and knockdown of SFMBT2 was realized by infection of lentivirus loaded with SFMBT2 coding sequence or silencing fragment in 786-O and 769-P cells, and its effects on proliferation and metastasis were assessed by MTT, colony formation, flow cytometry, wound healing, transwell assay, xenograft and metastasis experiments in nude mice. The interaction of SFMBT2 with histone deacetylase 3 (HDAC3) and seven in absentia homolog 1 (SIAH1) was confirmed by co-immunoprecipitation.ResultsIn our study, SFMBT2 exhibited lower expression in clear cell RCC specimens with advanced stages than those with early stages. Overexpression of SFMBT2 inhibited the growth and metastasis of clear cell RCC cells, 786-O and 769-P, in vitro and in vivo, and its silencing displayed opposites effects. HDAC3 led to deacetylation of SFMBT2, and the HDAC3 inhibitor-induced acetylation prevented SFMBT2 from SIAH1-mediated ubiquitination modification and proteasome degradation. K687 in SFMBT2 protein molecule may be the key site for acetylation and ubiquitination.ConclusionsSFMBT2 exerted an anti-tumor role in clear cell RCC cells, and HDAC3-mediated deacetylation promoted SIAH1-controlled ubiquitination of SFMBT2. SFMBT2 may be considered as a novel clinical diagnostic marker and/or therapeutic target of clear cell RCC, and crosstalk between its post-translational modifications may provide novel insights for agent development.

A three-gene expression score for predicting clinical benefit to anti-PD-1 blockade in advanced renal cell carcinoma.

In the advanced renal cell carcinoma (RCC) scenario, there are no consistent biomarkers to predict the clinical benefit patients derived from immune checkpoint blockade (ICB). Taking this into consideration, herein, we conducted a retrospective study in order to develop and validate a gene expression score for predicting clinical benefit to the anti-PD-1 antibody nivolumab in the context of patients diagnosed with advanced clear cell RCC enrolled in the CheckMate-009, CheckMate-010, and CheckMate-025 clinical trials. First, a three-gene expression score (3GES) with prognostic value for overall survival integrating HMGA1, NUP62, and ARHGAP42 transcripts was developed in a cohort of patients treated with nivolumab. Its prognostic value was then validated in the TCGA-KIRC cohort. Second, the predictive value for nivolumab was confirmed in a set of patients from the CheckMate-025 phase 3 clinical trial. Lastly, we explored the correlation of our 3GES with different clinical, molecular, and immune tumor characteristics. If the results of this study are definitively validated in other retrospective and large-scale, prospective studies, the 3GES will represent a valuable tool for guiding the design of ICB-based clinical trials in the aRCC scenario in the near future.

Efficacy, Safety, and Tolerability of Tivozanib in Heavily Pretreated Patients With Advanced Clear Cell Renal Cell Carcinoma.

Tivozanib has been approved as a third-line or later therapy for advanced renal cell carcinoma based on the TIVO-3 trial, which was conducted before immune checkpoint therapies (ICT), cabozantinib, and lenvatinib/everolimus became incorporated in the current sequential treatment paradigm for advanced clear cell RCC (ccRCC). We performed a retrospective study of patients with advanced ccRCC treated with tivozanib at MD Anderson Cancer Center during 6/2021-7/2023. A blinded radiologist assessed tumor response by RECIST v1.1. We assessed overall response rate (ORR), clinical benefit rate (CBR) [percentage of all treated patients who achieved radiologic response or stable disease (SD) for ≥ 6 months], progression-free survival (PFS), overall survival (OS), and safety. Of 30 analyzed patients, 23% had performance status ≥ 2; 47% had International Metastatic RCC Database Consortium (IMDC) poor-risk disease. Median number of prior therapies was 4 (range 1-8). All patients received prior ICT, 87% cabozantinib and 60% lenvatinib ± everolimus. Of 26 evaluable patients, 2 patients had confirmed partial response (ORR 7.7%); 5 patients had SD for ≥ 6 months (CBR 23.3%). Median PFS was 3.8 months (range 0.7-13.9); median OS was 14.1 months (range 0.3-28.5). Fifteen patients (50%) had ≥ 1 treatment-related adverse event (TRAE). There were 6 grade ≥ 3 TRAEs [hypertension, congestive heart failure (3), mucositis, and GI perforation (grade 5)]. In this cohort of heavily pretreated patients with advanced ccRCC, tivozanib yielded a modest clinical benefit in a minority of patients who received prior ICT, cabozantinib, and lenvatinib ± everolimus. TRAEs were consistent with previously published reports.

Efficacy, safety, and tolerability of tivozanib (TIVO) in heavily pretreated patients (pts) with advanced clear-cell renal cell carcinoma (ccRCC).

419 Background: TIVO, a potent tyrosine kinase inhibitor that predominantly targets vascular endothelial growth factor receptors, is approved as a third or later line therapy for advanced RCC based on improved progression-free survival (PFS) compared with sorafenib in the TIVO-3 trial. However, TIVO-3 was conducted before immune checkpoint-based therapies (ICT), cabozantinib (CABO), and lenvatinib/everolimus (LEN/EVE) became fully incorporated in the sequential treatment paradigm for advanced ccRCC. Hence, an appraisal of the role of TIVO in the current RCC treatment landscape is warranted. Methods: We performed a retrospective study of pts with advanced ccRCC treated with TIVO at MD Anderson Cancer Center during 6/2021-7/2023. Demographic and clinical data were abstracted from the electronic medical records. A blinded radiologist assessed tumor response by RECIST v1.1. We assessed objective response rate (ORR), clinical benefit rate [percentage of all treated pts who achieved a complete or partial response (PR) or had stable disease (SD) for ≥6 months (mo)], time on treatment (TOT), PFS, overall survival (OS), and safety. Results: 30 pts (23 males, 7 females; median age 66 years, range 43-80) were included in this analysis. Median follow-up was 10.8 mo. At initiation of TIVO, 77% of pts had ECOG PS 0/1, 23% had PS ≥2; 53% had intermediate-risk and 47% had poor-risk disease by IMDC; 83% had ≥3 metastatic sites; 80% had prior nephrectomy. Median number of prior therapies was 4 (range, 1-8). All pts received prior ICT (30% nivolumab/ipilimumab), 40% received prior axitinib, 87% CABO and 60% LEN +/- EVE. 23 pts (76.7%) started TIVO at full-dose (1.34 mg/day, 3 weeks on, 1 week off) and 7 pts (23.3%) at 0.89 mg/day, 3 weeks on, 1 week off. Of 26 pts with evaluable radiographic response, 2 pts had a confirmed PR (ORR 7.7%) and 5 pts had SD for ≥6 mo (clinical benefit rate 23.3%). Median TOT was 3.2 mo (range, 0.1-13.5), median PFS 3.7 mo (range, 0.7-13.5); median OS has not been reached (13 pts had died at time of analysis). 7 pts (23.3%; 5 pts who started at 1.34 mg/d and 2 pts who started at 0.89 mg/d) required dose-reduction due to treatment related adverse events (TRAEs). 15 pts (50%) had ≥1 any grade TRAE; 4 pts (13.3%) had any grade hypertension. There were 6 Grade ≥3 TRAEs [congestive heart failure (3), hypertension, mucositis, GI perforation]. 5 pts (16.6%) were continuing treatment with TIVO at time of analysis; 20 pts (66.7%) discontinued TIVO due to progressive disease, 3 pts (10%) for TRAEs, and 2 pts for other reasons (infection, worsening of prior ICT-mediated neuropathy). 1 pt died of TIVO-related GI perforation. Conclusions: In this cohort of heavily pretreated pts with advanced ccRCC, TIVO yielded a modest clinical benefit in a minority of pts who received prior ICT, CABO, and LEN +/- EVE. TRAEs observed with TIVO were consistent with previously published reports.

Phase 1b/2 study of combination 177Lu girentuximab plus cabozantinib and nivolumab in treatment naive patients with advanced clear cell RCC.

Phase 1b/2 study of combination ¹⁷⁷Lu girentuximab plus cabozantinib and nivolumab in treatment naive patients with advanced clear cell RCC.

A Pooled Analysis of 3 Phase II Trials of Salvage Nivolumab/Ipilimumab After Nivolumab in Renal Cell Carcinoma.

Nivolumab plus ipilimumab has demonstrated improved survival for treatment-naïve advanced clear cell renal cell carcinoma (RCC). A series of clinical trials evaluated the effect of salvage nivolumab plus ipilimumab in patients without an objective response to nivolumab. Given the size and heterogeneity of these studies, we performed a pooled analysis to better inform the activity of nivolumab plus ipilimumab after nivolumab. Eligible patients included those with advanced clear cell RCC having received no prior immunotherapy. The primary objective was confirmed objective response rate (ORR) by investigator-assessment. Secondary objectives included progression-free survival (PFS) and overall survival (OS). The analysis included 410 patients with clear cell RCC, of whom 340 (82.9%) had IMDC intermediate/poor risk disease, and 137 (33.4%) had prior treatment. The 16-18-week ORR to nivolumab prior to nivolumab plus ipilimumab was 22.7% (n = 93), and best ORR to nivolumab was 25.1% (n = 103). Two hundred and thirty (56.1%) patients treated with nivolumab received nivolumab plus ipilimumab at a median of 16 weeks (IQR 9-19) after initiation of nivolumab [27.0% (n = 62) with stable disease and 73.0% (n = 168) with progressive disease to nivolumab]. The ORR to nivolumab plus ipilimumab was 12.6% (n = 29). Six-month PFS on nivolumab plus ipilimumab was 37% (95% CI, 27-47). Median follow-up was 34.3 months and 3-year OS was 59% (95% CI, 53-64) from nivolumab start. A small subset of patients lacking a response to nivolumab derive benefit from salvage nivolumab plus ipilimumab. When possible, both drugs should be given in concomitantly, rather in an adaptive fashion.

Expanding "Practice-Changing" Belzutifan's Reach in RCC.

In the LITESPARK-005 and -003 trials, the HIF-2α inhibitor looks effective in advanced clear-cell renal cell carcinoma, both as monotherapy and in combination with VEGFR tyrosine kinase inhibitors. The results favor expanding belzutifan's use beyond von Hippel-Lindau disease-associated cancers, its only current indication.

Real-World Treatment Patterns and Clinical Outcomes Among Patients With Advanced Renal Cell Carcinoma

BackgroundNearly 30% of new renal cell carcinoma (RCC) cases are diagnosed at an advanced or metastatic stage. Recent approvals of immunotherapies (IO) have significantly impacted patient care, but real-world outcomes of these treatments have not been widely evaluated. MethodsEligible physicians abstracted demographic and clinical data from patient medical records for patients with advanced clear and non-clear cell RCC (aRCC) who initiated treatment between January 1, 2018, and December 31, 2020. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. A multivariate Cox regression model was developed to assess the impact of treatment category on clinical outcomes while controlling for International Metastatic RCC Database Consortium (IMDC) risk category, histology, and other patient characteristics. ResultsA total of 498 patients were included (201 from US, 62 from Canada, 58 from UK, 59 from France, 58 from Germany, 60 from Spain). Of these, 250 received tyrosine kinase inhibitor (TKI) monotherapy, 197 received immunotherapy (IO) combination (119 IO+TKI, 78 IO+IO), and 32 received IO monotherapy as first-line treatment for aRCC; 19 patients received various other regimens. 16% of patients had a favorable IMDC risk score. Based on results of multivariable Cox regression, PFS (hazard ratio [HR] [95% confidence interval (CI)]: 0.50 [0.36-0.72]) (P < .001) and time to next treatment (TTNT) were significantly longer (HR [95% CI]: 0.54 [0.39-0.73]) (P < .001) for patients treated with IO combination versus TKI monotherapy. IO combination had a numerically reduced, but statistically insignificant, risk of death versus TKI monotherapy (HR: 0.66; P = .114). IO+TKI combination was associated with significantly longer PFS and reduced risk of progression (HR: 0.52; P = .04) versus IO+IO combination; similar results were observed for TTNT (HR: 0.57; P = .03). ConclusionOur evaluation of real-world treatment outcomes in aRCC revealed that IO + TKI combination is associated with improved PFS and prolonged TTNT compared with TKI monotherapy and IO+IO combination.

STARLITE 1: Phase 1b/2 study of combination 177Lu girentuximab plus cabozantinib and nivolumab in treatment naïve patients with advanced clear cell RCC

Abstract Background Complete response (CR) is still a rare event in patients with advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently approved for the first-line treatment of ccRCC based on the CheckMate 9ER phase 3 study demonstrating improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, the CR rate was only 9%. Since the anti-tumor effects of immune checkpoint inhibitors are dependent on the presence of activated tumor-infiltrating T cells, drugs that could synergize with T cells’ anti-tumor activity can allow us to improve CR rates. Activation of the cGAS-STING pathway, the master regulator of anti-tumor immunity which is induced by radiation-induced DNA damage, is one promising mechanism that has been investigated. Many studies have shown that radiation treatment augments immune checkpoint inhibition. However, it is not always possible to radiate all metastatic lesions. Therefore, targeted peptide receptor radionuclide therapies (PRRT), have been developed by conjugating radioisotopes to receptor binding analogs targeting specific cancer cell surface proteins, thereby delivering targeted radiation to cancer cells in the body with minimal damage to surrounding healthy cells. 177Lu girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase IX-expressing cells, which includes &amp;gt;90% of ccRCC. It has been tested in metastatic ccRCC as a single agent and shown to be safe and effective in stabilizing disease in 57% of pts. In this study, we hypothesize that 177Lu girentuximab-induced DNA damage will potentiate the STING pathway, and this activation will synergize with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells to tumors and achieve higher CR rates. Methods Up to 100 patients with treatment naïve, biopsy-proven ccRCC with adequate organ/marrow function with ≥1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety, and futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate (primary endpoint) of 18% as better than 9% using a beta(0.09, 0.91) prior. Secondary endpoints are objective response, PFS by RECIST 1.1, and overall survival. 177Lu-girentuximab 1480 MBq/m2 (61% of single agent MTD) will be administered every 12 weeks for up to 3 treatment cycles. Starting with the second cycle, nivolumab and cabozantinib will be added at standard dose. To explore the effects of the combination therapy on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with [18F]F-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics and proteomics studies. This is an investigator initiated trial. Telix Pharmaceuticals provided drug and funding support. Also supported by DOD grant W81XWH-22-1-0456 CDMRP DOD Funding: yes

Phase 1b/2 trial of Ipilimumab, Nivolumab, and Ciforadenant (INC) (adenosine A2a receptor antagonist) in first-line advanced renal cell carcinoma

Abstract Background Ciforadenant is an investigational immunotherapeutic small molecule that selectively and reversibly binds adenosine2A receptors (A2ARs) on T lymphocytes and other cells of the immune system. RCC metabolism is known to be highly glycolytic with a need to export adenosine triphosphate (ATP) to allow for continued proliferation of cancer cells. In the tumor microenvironment (TME) ATP is hydrolyzed to adenosine by CD39/CD73. Adenosine has immune suppressive effects on the TME through the A2 adenosine receptor (A2AR) including decreased T cell activation and proliferation (Ohta et al., 2009). Blocking A2AR on tumor associated myeloid cells such as macrophages, dendritic cells, and myeloid derived suppressor cells in preclinical mouse models have shown enhanced tumor killing (Cekic et al 2014). Preclinical studies show that the addition of ciforadenant to CTLA4 and PD1 blockade shows enhanced efficacy and in some cases elimination of the established tumors (Willingham et al., 2018). Recently, in a first in human study, the A2AR antagonist ciforadenant was found to be safe and showed activity as monotherapy in RCC patients with refractory disease following multiple lines of therapy showing a median progression free survival (mPFS) of 4.1 months (Fong et al., 2019). In the same study, the addition of ciforadenant to PD-L1 blockade with atezolizumab was shown to be safe and demonstrate activity with mPFS of 5.8 months and OS probability at 25 months of 90%. We hypothesize that the addition of the A2aR antagonist, ciforadenant, to the combination of ipilimumab and nivolumab will favorably modulate metabolic adenosine signaling and the myeloid compartment to enhance patient response by reducing immunosuppression. Methods INC is a Phase 1b/2 single-arm, multicenter study to assess safety and efficacy of the combination of ipilimumab, nivolumab, and ciforadenant in the frontline treatment of patients with advance clear cell renal cell carcinoma. This study is being conducted through the Kidney Cancer Clinical Trial Consortium. Eligibility criteria include untreated advanced clear cell RCC, ECOG PS 0 or 1, measurable disease by RECIST 1.1 and adequate organ function and excludes patients who have previously received immunotherapy. The study will include a lead-in safety phase 1b portion with enrollment of four to eight patients treated with ciforadenant 100 mg BID, nivolumab 3 mg/kg and ipilimumab 1 mg/kg (IV) q3 weeks. If the rate of patients with a dose limiting toxicity is more than 45% another four patients will be enrolled at reduced dose of ciforadenant 50 mg BID, nivolumab 3 mg/kg and ipilimumab 1 mg/kg IV q3 weeks. If continuing on trial, patients will receive nivolumab 480 mg infusion and ciforadenant beginning Cycle 2, Day 1 q4 weeks. In the Phase 2 dose-expansion portion of the study, 42 additional patients (total 50) patients consisting of untreated advanced clear cell renal cell carcinoma will be treated at the RCD determined in the Phase 1b portion of the study. The primary objective is to determine the safety and tolerability and to assess the depth of response (&amp;gt;50% by RECIST 1.1 Eisenhaur, 2009) based on a Bayesian design in patients with advanced RCC treated with ipilimumab, nivolumab, and ciforadenant. Secondary objectives will estimate the objective response rate (ORR), duration of response (DOR) progression free survival (PFS), progressive disease (PD) rate, and irAE rate of ipilimumab, nivolumab, and ciforadenant combination in untreated advanced RCC. Exploratory objectives include assessing gene expression signatures and pharmacodynamic parameters with outcome. This study is open to enrollment with six patients on trial anticipating lead-in safety analysis to be completed shortly for identification of randomized phase 2 dosing and opening the expansion cohorts. The trial will be open through the Kidney Cancer Research Consortium at MD Anderson, Vanderbilt University Medical Center, Duke University, and University of Pennsylvania. CDMRP DOD Funding: yes

ExPert ConsEnsus on the management of Advanced clear-cell RenaL celL carcinoma: INDIAn Perspective (PEARL-INDIA)

In advanced Renal Cell Carcinoma (aRCC), systemic therapy is the mainstay of treatment, with no or little role for surgery in these patients. Tyrosine kinase inhibitors (TKIs) and immune-oncological (IOs) therapies, either alone or in combination, are recommended in these patients depending on patient and tumour factors. The sequencing of therapies is critical in RCC because the choice of subsequent line therapy is heavily dependent on the response and duration of the previous treatment. There are additional barriers to RCC treatment in India. Immunotherapy is the cornerstone of treatment in ccRCC, but it is prohibitively expensive and not always reimbursed, effectively putting it out of reach for the vast majority of eligible patients in India. Furthermore, in advanced RCC (particularly the clear cell variety), Indian oncologists consider the disease burden of the patients, which is particularly dependent on the quantum of the disease load, clinical symptoms, and performance status of the patient, before deciding on treatment. There are no India-specific guidelines for clear cell RCC (ccRCC) treatment or the positioning and sequencing of molecules in the management of advanced ccRCC that take these country-specific issues into account. The current consensus article provides expert recommendations and treatment algorithms based on existing clinical evidence, which will be useful to specialists managing advanced ccRCC.

Clinical factors for tumor response, progression, and survival in nivolumab for advanced renal cell carcinoma in the SNiP-RCC study.

This study is part of the SNPs in Nivolumab PD-1 inhibitor for RCC (SNiP-RCC). Here we aimed to reveal clinical factors for tumor response, progression, and survival in nivolumab for advanced clear cell renal cell carcinoma (RCC) in Japanese patients. We included patients from 23 institutions in Japan. We evaluated the objective response, radiographic progression-free survival (PFS), overall survival (OS), and treatment-related grade ≥ 3 (serious adverse events [SAEs]). We included 222 patients. The median age was 69 years (interquartile range 62-74 years), and 71% of the patients were male. Pancreas metastasis, lung metastases, prior cytokine therapy, and SAEs, were associated with objective response. The median PFS was 18 months. Liver metastases (hazard ratio [HR], 1.61), age ≥ 75 (HR, 0.48), previous resection of primary sites (HR, 0.47), and SAEs (HR, 0.47) were independent prognostic factors for PFS. Karnofsky Performance Status <70 (HR, 2.90), high platelets (HR, 4.48), previous resection of primary sites (HR, 0.23), and pathological grade (HR, 0.19 for grade 2 and HR, 0.12 for grade 3) were independent prognostic factors for OS. SAEs were reported in 45 (20.3%) cases. In the group of patients with prior nephrectomy, SAEs were associated with objective response, PFS, and OS. The SNiP-RCC study identified clinical parameters correlated with treatment outcomes in Japanese patients with priorly treated advanced clear cell RCC undergoing nivolumab monotherapy.

Cost-effectiveness and budget impact of pembrolizumab+axitinib versus sunitinib in patients with advanced clear-cell renal cell carcinoma in the Netherlands.

The phase 3 clinical trial KEYNOTE-426 suggested a higher efficacy regarding overall survival (OS) and progression-free survival (PFS) of pembrolizumab+axitinib compared to sunitinib as a first-line treatment for patients with advanced renal cell carcinoma. In this analysis, the potential cost-effectiveness of this combination treatment versus sunitinib for patients with advanced clear-cell renal cell carcinoma (accRCC) was examined from the societal perspective in the Netherlands. For this analysis, a partitioned survival model was constructed. Clinical data were obtained from the published KEYNOTE-426 trial reports; data on costs and (dis-)utilities were derived from published literature. Costs outside of the healthcare sector included treatment-related travel, informal care and productivity loss. Next to a probabilistic scenario analysis, various scenario analyses were performed that aimed at survival extrapolation, different utility values, treatment duration and drug pricing, as well as restricting the cohort to patients with an intermediate or poor prognosis. Further, a budget impact analysis over three years was conducted, in which a sensitivity analysis concerning ranges in costs and the number of patients was applied. Moreover, a scenario concerning increasing market penetration of pembrolizumab+axitinib up to a market share of 80% in the third year was analyzed. The incremental cost-effectiveness ratio (ICER) of pembrolizumab+axitinib was estimated at €368,396/quality-adjusted life year (QALY) gained, with an incremental QALY gain of 0.55 over sunitinib. The probability of cost-effectiveness at a willingness-to-pay threshold of €80,000/QALY was estimated at 0%, a 50% probability was estimated at €340,000/QALY. Cost-effectiveness was not achieved in any of the applied scenarios. The budget impact over three years amounted to €417.3 million upon instantaneous and full replacement of sunitinib, and to €214.9 million with increasing market penetration. Pembrolizumab+axitinib was not estimated to be cost-effective compared to sunitinib as a first-line treatment for patients with accRCC in the Netherlands from a societal perspective. In none of the analyzed scenarios, cost-effectiveness was achieved. However, price reductions and shorter treatment durations might lead to a more favorable ICER.

Fruquintinib plus sintilimab in patients with either treatment-naive or previously first line treated metastatic clear-cell renal cell carcinoma (ccRCC): Results from a multicenter, single-arm phase 2 study.

e16514 Background: Antiangiogenic therapy combined with immunotherapy significantly improved the progression-free survival (PFS) and preliminary survival benefit for advanced clear-cell renal cell carcinoma (ccRCC). However, no combined immune therapies are currently approved for ccRCC in China. Fruquintinib (F, a highly selective VEGFR inhibitor) combined with sintilimab (S, an anti-PD-1 monoclonal antibody) showed encouraging antitumor activity in multiple solid tumors. Here, we reported the results of F plus S in metastatic ccRCC cohort from an open-label, single-arm phase 2 study (NCT03903705). Methods: Patients (pts) with pathologically confirmed metastatic ccRCC who were treatment-naive or had failed previously first-line treatment were eligible. They received F (5 mg, 2 weeks on/1 week off, orally, QD) plus S (200 mg, IV, Q3W) in 21-day cycles until disease progression or unacceptable toxicity; treatment of S was allowed for up to 24 months. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Results: As of cutoff (November 30, 2022), a total of 42 pts (22 treatment-naïve pts, and 20 previously first-line treated pts) were enrolled and received the combination treatment. Median (range) age was 59.0 (34.2-72.4) years; 34 (81.0%) pts were male. Among previously treated pts, 19 (19/20, 95.0%) pts had received VEGFR therapy as prior first-line treatment, including sunitinib (3/20, 15.0%), pazopanib (7/20, 35.0%), axitinib (2/20, 10.0%) and others (7/20, 35.0%). International Metastatic RCC Database Consortium (IMDC) risk included: favorable in 15 (35.7%) pts, intermediate in 22 (52.4%) pts, and poor in 5 (11.9%) pts. The median follow-up duration was 14.8 months (m) and 23.3 m for treatment-naive and previously treated pts, respectively. All pts had at least 1 post-baseline tumor assessment. Confirmed ORR was 68.2% and 60.0%, median duration of response was not reached (NR) and 13.9 m, and disease control rate was 95.5% and 85.0% for treatment-naive and previously treated pts, respectively. Median PFS (mPFS) was NR and 12m-PFS rate was 64.8% in treatment-naive pts; mPFS was 15.9 m in previously treated pts. The median treatment duration of F and S was both 14.7 m. All pts experienced at least 1 treatment-emergent adverse event (TEAE). Common (≥5%) grade ≥3 TEAEs were hypertension (21.4%), hypertriglyceridaemia (9.5%), amylase increased (7.1%), cerebral infarction (7.1%) and proteinuria (7.1%). No new safety signals were observed. Conclusions: F plus S demonstrated a favorable efficacy with manageable toxicity for treatment-naive and previously first-line treated metastatic ccRCC. A phase 2/3 study is being conducted to confirm this combination efficacy in the second-line treatment of ccRCC (NCT05522231). Clinical trial information: NCT03903705 .

Phase 1b/2 study of combination 177Lu girentuximab plus cabozantinib and nivolumab in treatment naïve patients with advanced clear cell RCC.

TPS4605 Background: Complete response (CR) is still a rare event in patients with advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently approved for the first-line treatment of ccRCC based on the CheckMate 9ER phase III study demonstrating improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, the CR rate was only 9%. Since the anti-tumor effects of immune checkpoint inhibitors are dependent on the presence of activated tumor-infiltrating T cells, drugs that could synergize with T cells’ anti-tumor activity can allow us to improve CR rates. Activation of the cGAS-STING pathway, the master regulator of anti-tumor immunity which is induced by radiation-induced DNA damage, is one promising mechanism that has been investigated. Many studies have shown that radiation treatment augments immune checkpoint inhibition. However, it is not always possible to radiate all metastatic lesions. Therefore, targeted peptide receptor radionuclide therapies (PRRT), have been developed by conjugating radioisotopes to receptor binding analogs targeting specific cancer cell surface proteins, thereby delivering targeted radiation to cancer cells in the body with minimal damage to surrounding healthy cells. 177Lu girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase IX-expressing cells, which includes &gt; 90% of ccRCC. It has been tested in metastatic ccRCC as a single agent and shown to be safe and effective in stabilizing disease in 57% of pts. In this study, we hypothesize that 177Lu girentuximab-induced DNA damage will potentiate the STING pathway, and this activation will synergize with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells to tumors and achieve higher CR rates. Methods: Up to 100 patients with treatment naïve, biopsy-proven ccRCC with adequate organ/marrow function with ≥1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety, and futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate of 18% as better than 9% using a beta(0.09, 0.91) prior. Secondary endpoints are objective response, PFS by RECIST 1.1, and overall survival. 177Lu-girentuximab 1480 MBq/m2 (61% of single agent MTD) will be administered every 12 weeks for up to 3 treatment cycles. After the first cycle, nivolumab and cabozantinib will be added starting with the second cycle at standard dose. To explore the effects of the combination therapy on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with [18F]F-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics and proteomics studies.

LITESPARK-024: Randomized phase 1/2 study of belzutifan with or without palbociclib for treatment of advanced renal cell carcinoma (RCC).

TPS4603 Background: Immunotherapy is a standard-of-care first-line treatment for advanced clear cell RCC (ccRCC). However, many patients (pts) will develop resistance to first-line therapy, and effective second- and later-line treatment options are therefore needed. The von Hippel-Lindau ( VHL) gene is inactivated in approximately 90% of ccRCC cases and results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α), a key oncogenic driver in RCC. Belzutifan, a first-in-class HIF-2α inhibitor, has demonstrated antitumor activity with manageable safety in previously treated pts with advanced ccRCC. The cyclin-dependent kinase (CDK) pathway is also associated with poor clinical outcomes in ccRCC. In RCC cell lines, the CDK 4/6 inhibitor palbociclib inhibited cell growth. CDK 4/6 inhibition has shown synergistic antiproliferative effects with HIF-2α inhibition in HIF-2α–dependent VHL -/- RCC cell lines. Palbociclib could therefore potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: LITESPARK-024 is a 2-part, open-label, multicenter, phase 1/2 randomized study (NCT05468697). Part 1 is intended to establish the recommended phase 2 dose (RP2D) of belzutifan + palbociclib using a modified toxicity probability interval design. After the RP2D is established, part 2 will directly compare the safety and efficacy of belzutifan monotherapy with belzutifan + palbociclib in pts with advanced ccRCC. In both parts, pts with measurable disease per RECIST v1.1, a KPS score of ≥70%, and histologically confirmed unresectable stage IV RCC with a clear cell component with disease progressing on or after receiving at least 2 systemic treatments (both an anti–PD-1/L1 monoclonal antibody and a VEGF receptor–targeted tyrosine kinase inhibitor, in sequence or in combination) will be enrolled. Up to 30 pts will be enrolled into 3 dose groups in part 1 and will receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events and to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are CBR, DOR, and PFS per RECIST v1.1 by investigator assessment, OS, and safety and tolerability. Enrollment began in July 2022. Clinical trial information: NCT05468697 .

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma

BackgroundThe efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown.MethodsIn this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization.ResultsOverall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P=0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing.ConclusionsAmong patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219.)

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

Understanding the Tumor Immune Microenvironment in Renal Cell Carcinoma.

Scientific understanding of how the immune microenvironment interacts with renal cell carcinoma (RCC) has substantially increased over the last decade as a result of research investigations and applying immunotherapies, which modulate how the immune system targets and eliminates RCC tumor cells. Clinically, immune checkpoint inhibitor therapy (ICI) has revolutionized the treatment of advanced clear cell RCC because of improved outcomes compared to targeted molecular therapies. From an immunologic perspective, RCC is particularly interesting because tumors are known to be highly inflamed, but the mechanisms underlying the inflammation of the tumor immune microenvironment are atypical and not well described. While technological advances in gene sequencing and cellular imaging have enabled precise characterization of RCC immune cell phenotypes, multiple theories have been suggested regarding the functional significance of immune infiltration in RCC progression. The purpose of this review is to describe the general concepts of the anti-tumor immune response and to provide a detailed summary of the current understanding of the immune response to RCC tumor development and progression. This article describes immune cell phenotypes that have been reported in the RCC microenvironment and discusses the application of RCC immunophenotyping to predict response to ICI therapy and patient survival.