Advanced Clear Cell Research Articles

P168 Transcriptomic profiling of primary and secondary lesions identified a potential crosstalk between MARCO+ macrophages and deregulated cancer-cell proliferation in mediating progression and therapy response of advanced clear cell renal cell carcinoma

P168 Transcriptomic profiling of primary and secondary lesions identified a potential crosstalk between MARCO+ macrophages and deregulated cancer-cell proliferation in mediating progression and therapy response of advanced clear cell renal cell carcinoma

Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.

Copper (Cu) is a cofactor of cytochrome c oxidase (CuCOX), indispensable for aerobic mitochondrial respiration. This study reveals that advanced clear cell renal cell carcinomas (ccRCCs) accumulate Cu, allocating it to CuCOX. Using a range of orthogonal approaches, including metabolomics, lipidomics, isotope-labeled glucose and glutamine flux analysis, and transcriptomics across tumor samples, cell lines, xenografts, and PDX models, combined with genetic and pharmacological interventions, we explored Cu's role in ccRCC. Elevated Cu levels stimulate CuCOX biogenesis, providing bioenergetic and biosynthetic benefits that promote tumor growth. This effect is complemented by glucose-dependent glutathione production, which facilitates detoxification and mitigates Cu-H2O2 toxicity. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics reveal increased oxidative metabolism, altered glutathione and Cu metabolism, and diminished HIF activity during ccRCC progression. Thus, Cu drives an integrated oncogenic remodeling of bioenergetics, biosynthesis, and redox homeostasis, fueling ccRCC growth, which can be targeted for new therapeutic approaches.

Emerging innovative treatment strategies for advanced clear cell renal cell carcinoma.

Dramatic advances in biological discoveries, since the 1990s, have continued to reshape the treatment paradigm of metastatic renal cell carcinoma (RCC). Von Hippel Lindau (VHL) gene alterations are associated with pro-angiogenic activity and are central to the pathogenesis of clear cell RCC (ccRCC), the most predominant histologic subtype of RCC. Antiangiogenic strategies revolving around this VHL/HIF/VEGF axis have been shown to improve survival in metastatic ccRCC. The discovery of immune checkpoints and agents that target their inhibition introduced a new treatment paradigm for patients with RCC. While initially approved as monotherapy, studies investigating immune checkpoint inhibitor combinations have led to their approval as the new standard of care, providing durable responses and unprecedented improvements in clinical outcome. Despite these advances, the projected 14390 deaths in 2024 from RCC underscore the need to continue efforts in expanding and optimizing treatment options for patients with metastatic RCC. This article reviews key findings that have transformed the way we understand and treat metastatic RCC, in addition to highlighting novel treatment strategies that are currently under development.

Retrospective study assessing the role of theandrogen receptor in clear cell renal cell cancer patients treated with VEGFR inhibitors in monotherapy.

Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading tothe question ofwhether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions. We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis. Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC. AR-overexpression and its association with other genes could favor a transcriptomic signature set to aidin identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.

Chinese expert consensus on the systemic treatment of advanced clear cell renal cell carcinoma (2024 edition)

Renal cell carcinoma (RCC) accounts for approximately 2% to 3% of malignant tumors in adults, with a male-to-female ratio of approximately 1.5∶1 worldwide. It can occur in all age groups, with a peak incidence in the 60-70 age range, and the median age is approximately 64 years. The current causes of kidney cancer are still unclear, but smoking, obesity, hypertension, and some genetic factors are considered risk factors for kidney cancer development. Conducive to the gradual popularization of physical examination and screening, more and more patients with kidney cancer are being detected and treated in the early stages. However, nearly 30% of patients still have locally advanced or metastatic kidney cancer at the time of initial diagnosis. Traditional chemotherapy drugs are generally ineffective for advanced RCC, and currently, advanced RCC is mainly treated with anti-vascular and immunotherapy. At present, first-line treatment is mostly stratified based on clinical characteristics such as International mRCC Database Consortium (IMDC) prognosis risk, and there are multiple options available, including anti vascular therapy, anti-vascular combined immunotherapy, and dual immunotherapy. Subsequently, first-line treatment often selects drugs based on the composition, effectiveness, and safety of first-line treatment plans. In recent years, research has found that the molecular typing and metastasis characteristics of RCC also affect the prognosis of patients, leading to many controversies in the treatment of advanced RCC. This consensus is guided by the controversial clinical issues in the management of advanced RCC. After discussion and voting by multidisciplinary clinical experts, a consensus of 10 clinical issues has been reached. At the same time, experts recommend domestic clinical and research institutions to lead or participate in more large-scale clinical trials, providing more basis for clinical decision-making and the selection of the best beneficiaries.

Randomized phase II dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma

Belzutifan is a first-in-class hypoxia-inducible factor subunit 2α (HIF-2α) inhibitor approved at a dose of 120 mg once daily for certain adults with VHL disease and adults with advanced renal cell carcinoma (RCC) following therapy with a programmed cell death protein 1 (PD-1) [or programmed death ligand 1 (PD-L1)] inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. However, whether the belzutifan dose could be optimized is unclear. The phase II LITESPARK-013 study (NCT04489771) enrolled patients with advanced clear cell RCC whose disease progressed after one to three prior systemic therapies, including an anti-PD-(L)1 regimen. Patients were randomly assigned 1 : 1 to receive belzutifan 120 or 200 mg once daily. The primary endpoint was the objective response rate (ORR) per RECIST version 1.1. The secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 154 patients were enrolled (120 mg: n= 76; 200 mg: n= 78). The median follow-up was 20.1 months (range 14.8-28.4). The ORR was 23.7% versus 23.1% for the 120 mg and 200 mg groups, respectively [P= 0.5312;-0.5%, 95% confidence interval (CI)-14.0% to 12.9%]. The median DOR was not reached for the 120 mg arm and was 16.1 months (2.1+ to 23.5+) for the 200 mg arm. No between-group differences were observed for PFS [hazard ratio (HR) 0.94, 95% CI 0.63-1.40] or OS (medians not reached; HR 1.11, 95% CI 0.65-1.90). Grade 3 or 4 treatment-related adverse events were observed in 35 patients (46.1%) in the 120 mg group and 36 patients (46.2%) in the 200 mg group. The efficacy of belzutifan was similar between the 120 mg dose and the 200 mg dose for previously treated clear cell RCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg once daily as the preferred dose for belzutifan.

LBA74 Final analysis of the phase III LITESPARK-005 study of belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC)

LBA74 Final analysis of the phase III LITESPARK-005 study of belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC)

42 Belzutifan versus everolimus for previously treated advanced clear cell renal cell carcinoma: Subgroup analysis of the phase 3 LITESPARK-005 study

Abstract Background Belzutifan monotherapy is approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a PD-(L)1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) based on the results of the phase 3 LITESPARK-005 study (NCT04195750). In LITESPARK-005, belzutifan improved progression-free survival (PFS; HR 0.75; 95% CI, 0.63-0.90; P < 0.001) and objective response rate (ORR; 21.9% vs 3.5%; P < 0.00001) versus everolimus at first interim analysis (IA1); overall survival (OS) did not reach statistical significance at IA2 (HR 0.88; 95% CI, 0.73-1.07; P = 0.1). We present efficacy outcomes by prespecified subgroups from IA2. Methods Patients with clear cell RCC whose disease progressed after anti–PD-(L)1 and VEGF-targeted therapies and who had 1-3 prior systemic regimens were randomly assigned 1:1 to belzutifan 120 mg by mouth once daily or everolimus 10 mg by mouth once daily until progression or intolerable toxicity. The dual primary end points of PFS by central review per RECIST v1.1 and OS and the key secondary end point of ORR were evaluated by prespecified baseline characteristic subgroups: IMDC risk (favorable vs intermediate/poor), prior VEGF-TKIs (1 vs 2-3), and number of prior lines of therapy (1 vs 2 vs 3). These analyses were not controlled for multiplicity and no formal statistical testing occurred. The database cutoff date was June 13, 2023. Results Overall, 746 patients were assigned to belzutifan (n = 374) or everolimus (n = 372). Baseline characteristics were balanced between groups. Median follow-up was 25.7 months (range, 16.8-39.1). Across analyzed subgroups, PFS and OS results were consistent with the primary analysis (Table). ORR favored belzutifan over everolimus for all subgroups: IMDC favorable risk (22.8% vs 6.0%), IMDC intermediate/poor risk (22.7% vs 2.8%), 1 prior VEGF-TKI (19.7% vs 3.7%), 2 prior VEGF-TKIs (25.7% vs 3.3%), 1 prior line of therapy (28.3% vs 5.8%), 2 prior lines (19.1% vs 2.4%), and 3 prior lines (24.6% vs 3.9%). Conclusions Consistent with the intention-to-treat population of LITESPARK-005, PFS and ORR favored belzutifan over everolimus across prespecified subgroups. These results support belzutifan as a new treatment option for patients with advanced clear cell RCC after prior anti–PD-(L)1 and VEGF-targeted therapies.

39 Safety profile of belzutifan monotherapy in patients with renal cell carcinoma: A pooled analysis of 4 clinical trials

Abstract Background The first-in-class hypoxia-inducible factor-2α inhibitor, belzutifan, is indicated in the United States for the treatment of certain patients with von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery and for patients with advanced RCC previously treated with a PD-(L)1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. Due to its unique mechanism of action, belzutifan has a distinct safety profile. We characterized the safety profile of belzutifan monotherapy in a post hoc pooled analysis of patients with previously treated advanced clear cell RCC in the phase 1 LITESPARK-001 (NCT02974738), phase 3 LITESPARK-005 (NCT04195750), and phase 2 LITESPARK-013 (NCT04489771) studies and patients with RCC associated with VHL disease in the phase 2 LITESPARK-004 study (NCT03401788). Methods All patients who received ≥1 dose of belzutifan 120 mg orally once daily across the 4 studies were included. Severity of adverse events (AEs) were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 or 5.0, and were descriptively summarized. Results A total of 576 patients were included (n = 58 [including 3 patients with advanced solid tumors other than RCC], LITESPARK-001; n = 381, LITESPARK-005; n = 76, LITESPARK-013; and n = 61, LITESPARK-004). Overall, 572 patients (99.3%) had ≥1 all-cause AE and 355 patients (61.6%) had ≥1 grade 3-5 AE. AEs led to dose modification (reduction, interruption, or discontinuation) in 288 patients (50.0%), although treatment discontinuation for AEs occurred in 37 patients (6.4%). The most common all-grade AEs were anemia (including patients with decreased hemoglobin; n = 485 [84.2%]; grade 3 or 4, n = 166 [28.8%]), fatigue (n = 246 [42.7%]; grade 3, n = 16 [2.8%]), nausea (n = 139 [24.1%]; grade 3, n = 5 [0.9%]), and dyspnea (n = 123 [21.4%]; grade 3 or 4, n = 10 [1.7%]). Hypoxia was reported in 94 patients (16.3%); grade 3 or 4 hypoxia occurred in 57 patients (9.9%). Summary and time to first onset of adverse drug reactions (AEs considered associated with belzutifan), including anemia and hypoxia, are reported in the table. Among 485 patients with anemia or decreased hemoglobin, 111 (22.9%) were treated with erythropoiesis-stimulating agent (ESA) only, 85 (17.5%) were treated with blood transfusions only, and 62 (12.8%) were treated with ESA and blood transfusions. Among 94 patients with hypoxia, 66 (70.2%) were treated with oxygen therapy. Treatment-related AEs occurred in 526 patients (91.3%) and 217 (37.7%) experienced a grade 3-5 treatment-related AE. One grade 5 adverse event (multiple organ dysfunction syndrome) was considered related to treatment. Conclusions To date, this is the largest pooled safety dataset for belzutifan monotherapy in patients with RCC. The results provide an in-depth characterization of the safety profile for belzutifan and the associated AE management strategies.

Prognostic significance of inflammatory markers in patients with advanced renal cell carcinoma receiving nivolumab plus ipilimumab.

A useful biomarker for the efficacy of immune checkpoint inhibitors (ICIs) in advanced renal cell carcinoma (RCC) has not yet been established. This study aims to investigate whether inflammatory markers are associated with the efficacy of nivolumab plus ipilimumab therapy before and during treatment. Data from patients with advanced clear cell RCC who received a combination treatment of nivolumab plus ipilimumab were retrospectively analyzed. The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) levels were assessed at baseline and 3, 6, and 9weeks after treatment initiation. The correlation between these inflammatory markers and the patient's prognosis was investigated. Eighty-four patients were identified. The multivariate analysis identified NLR at week 3, CRP at week 6, and NLR and CRP at week 9 as the consistent predictor associated with poor overall survival (OS) at each time point. The survival analysis and receiver operating characteristic (ROC) curve analysis revealed that an NLR of ≥ 2.4 at week 3, CRP of ≥ 1.4mg/dL at week 6, and NLR of ≥ 4.8 and CRP of ≥ 1.0mg/dL at week 9 were associated with worse OS (hazard ratios (HR) = 5.70, P = 0.008, HR = 3.23, P = 0.004, HR = 7.38, P < 0.001 and HR = 3.55, P = 0.002). Both NLR and CRP were considered useful biomarkers for understanding the prognosis during nivolumab plus ipilimumab therapy. Furthermore, an NLR of ≥ 4.8 and CRP of ≥ 1.0mg/dL at week 9 are helpful in reconsidering treatment continuation.

Durability of Response with First-Line Combined Immune Checkpoint Inhibitor Therapy Compared to Checkpoint Inhibitor with VEGFR-TKI in Advanced Clear Cell Renal Cell Carcinoma

Over the past several years, four regimens incorporating immune checkpoint inhibitors have become widely used in the front-line setting to treat metastatic clear cell renal cell carcinoma: nivolumab with ipilimumab, axitinib with pembrolizumab, cabozantinib with nivolumab, and lenvatinib with pembrolizumab. These regimens all demonstrated favorable response rates and survival outcomes compared to sunitinib in phase III trials. As these data have matured, nivolumab with ipilimumab has been most clearly associated with durable long-term disease response and stable survival benefit. Moreover, responses obtained using nivolumab with ipilimumab are more likely to persist after treatment discontinuation compared to regimens containing a VEGFR-TKI. These outcomes underline the value of using nivolumab with ipilimumab to pursue durable response in patients with advanced clear cell renal cell carcinoma.

Identification of tumor-antigen signatures and immune subtypes for messenger RNA vaccine selection in advanced clear cell renal cell carcinoma

BackgroundAdvanced clear cell renal cell carcinoma still lacks reliable diagnostic and prognostic biomarkers. Recently, tumor vaccines targeting specific molecules have been proposed as a promising treatment in mitigating tumor progression, which was rekindled under the background of the COVID-19 pandemic. However, the application of messenger RNA vaccine against advanced clear cell renal cell carcinoma antigens remains stagnant, and no subgroup of patients deemed suitable for vaccination has been extensively studied or validated. Our study aims to explore novel advanced clear cell renal cell carcinoma antigen signatures to select suitable patients for vaccination. MethodsGene expression profiles of advanced clear cell renal cell carcinoma samples and their corresponding clinical data were retrieved from The Cancer Genome Atlas. The least absolute shrinkage and selection operator model was applied to develop signatures to stratify patients with advanced clear cell renal cell carcinoma. Receiver operating characteristic analysis was used to compare the prognostic accuracy of each factor. Tumor Immune Estimation Resource was used to visualize the relationship between the proportion of antigen-presenting cells and the expression of filtered genes. The "CIBERSORT" and "WGCNA" R Packages were employed to ascertain disparities in immune infiltration levels between advanced clear cell renal cell carcinoma subgroups. The Search Tools for the Retrieval of Interacting Genes database and Cytoscape were used to construct the protein-protein interaction network. CCK-8 and colony formation assays were included in the invitro experiment. ResultsIn total, 244 potential tumor antigens were identified. Using the least absolute shrinkage and selection operator Cox regression, 21 tumor antigens were selected for developing a risk evaluation signature. The risk score signature can be a useful tool to predict the outcome of advanced clear cell renal cell carcinoma patients. According to the differential clinical, molecular, and immune-related genes, we divided advanced clear cell renal cell carcinoma patients into the immune “cold” subtype and immune “hot” subtype. By developing a logistic score, the immune subtype signature can better distinguish a patient more likely to be immune “cold” subtype or immune “hot” subtype.Interestingly, patients with high risk scores had a higher proportion of immune “hot” subtype than those with a low risk score. Furthermore, the prognostic value was significantly improved when combining risk score and immune subtype. Distinct immune landscapes and signal pathways were observed between different tumor subtypes. Finally, novel tumor antigens related to oxidative stress were identified. ConclusionThe tumor-antigens–based risk score and immune subtype signatures identified potentially effective neo-antigens for advanced clear cell renal cell carcinoma messenger RNA vaccine development, and patients with low risk scores and immune “cold” subtype tumors are more prone to benefit from messenger RNA vaccination. Furthermore, our study highlights the significant role of oxidative stress in determining the efficacy of the messenger RNA vaccine.

Belzutifan plus lenvatinib (len) for Chinese patients (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): Preliminary results of cohort 1 of the phase 1 LITESPARK-010 study.

4537 Background: Belzutifan, a first-in-class HIF-2α inhibitor, alone or in combination with a VEGFR-TKI, has shown durable antitumor activity in first- and subsequent-line settings of advanced ccRCC. LITESPARK-010 (NCT05030506) is a phase 1, 2-cohort, open-label study of belzutifan + len, with or without pembrolizumab, in Chinese pts with advanced ccRCC. We present preliminary results cohort 1. Methods: Chinese adults with histologically confirmed ccRCC who had 1-3 prior treatment regimens received belzutifan 120 mg PO QD for 3 wk followed by belzutifan 120 mg + len 20 mg PO QD until intolerable toxicity, disease progression, or pt withdrawal. The study included a dose-limiting toxicity (DLT) phase of 21 days after the start of combination treatment. Dual primary end points were safety and PK. Secondary end points included ORR, DOR, and PFS per RECIST v1.1 by investigator assessment and OS. Results: As of August 29, 2023, 24 pts were enrolled in cohort 1 and 23 received combination treatment; 1 pt discontinued in the monotherapy period because of treatment with non-study anti-cancer therapy. Median age was 61 years, 17 pts (71%) were male, and 14 (58%) had intermediate/poor IMDC risk. 14 pts (58%) received 1 prior line of therapy and 10 (42%) received ≥2 prior lines. Five pts (21%) received prior therapy with a PD-(L)1 inhibitor. As of the data cutoff date, 11 pts (46%) remained on treatment. Median follow up was 14.4 mo (range, 1.6-22.1). Ten pts were evaluated in the DLT phase, and 1 experienced a DLT (grade 2 treatment-related transient ischemic attack). All 24 pts (100%) experienced a treatment-related AE (TRAE) of any grade, most commonly anemia (100%) and proteinuria (88%). Grade 3 or 4 TRAEs occurred in 17 pts (71%), most commonly anemia (29%) and hypertension (29%). One pt (4%) experienced grade 3 hypoxia. No pts died (grade 5) due to a TRAE. After a single dose of belzutifan monotherapy, median Tmax was 1.8 h (range, 0.6-8.0), geometric mean AUC0-24 was 22,400 h·ng/mL (90% CI, 19,600-25,500), and geometric mean Cmax was 1640 ng/mL (90% CI, 1490-1820). Steady-state concentration was reached after 14 days of belzutifan monotherapy treatment; the accumulation ratio of AUC0-24 was 1.7 (90% CI, 1.5-1.9). Belzutifan + len treatment had similar PK to belzutifan monotherapy. In all 24 pts, confirmed ORR was 50% (95% CI, 29-71; all PRs). Median DOR was not reached (NR; range, 3.5-20.4+ months); 50% of responders remained in response for ≥12 mo per Kaplan-Meir estimate. Median PFS was 13.7 mo (95% CI, 8-NR) and median OS was NR (95% CI, NR-NR). The 12-mo PFS and OS rates were 57% and 75%, respectively. Conclusions: Preliminary data from the belzutifan + len showed promising antitumor activity in Chinese pts with previously treated ccRCC. The safety of belzutifan 120 mg + len 20 mg was consistent with the safety profiles of the individual drugs. Clinical trial information: NCT05030506 .

EVOLVE-HNSCC: A global phase 3 study of volrustomig as sequential therapy for unresected locally advanced head and neck squamous cell carcinoma (LA-HNSCC) following definitive concurrent chemoradiotherapy (cCRT).

TPS6120 Background: Currently there are no approved maintenance therapies for patients (pts) with unresected LA-HNSCC following definitive cCRT. The PD-1 inhibitors pembrolizumab and nivolumab are licensed for treatment of pts with recurrent or metastatic HNSCC who have progressed on or after a platinum-based therapy. Dual inhibition of CTLA-4 and PD-L1 is approved in solid tumors including renal cell carcinoma (RCC), NSCLC, and melanoma, and has shown a numerical trend towards improved survival in first-line pts with recurrent/metastatic HNSCC whose tumors express PD-L1. Volrustomig (MEDI5752) is a monovalent, PD-1/CTLA-4 bispecific, humanized IgG1 monoclonal antibody engineered to specifically inhibit PD-1, with increased CTLA-4 blockade on PD-1+ activated T cells compared to PD-1– resting peripheral T cells. In a first-in-human phase 1/2 study (NCT03530397), volrustomig monotherapy showed promising efficacy with acceptable tolerability in advanced clear cell RCC and in combination with chemotherapy in advanced NSCLC. The phase 3, randomized, open-label, multicenter, eVOLVE-HNSCC study will evaluate the efficacy and safety of sequential therapy with volrustomig compared with observation in pts with unresected LA-HNSCC who have not progressed after receiving definitive cCRT (NCT06129864). Methods: Key eligibility criteria include histologically or cytologically confirmed, unresected LA-HNSCC with no evidence of metastatic disease, i.e. AJCC 8th edition (TNM staging system) stage IVA/B cancers of the hypopharynx, oral cavity, larynx or HPV-negative oropharynx, or stage III HPV-positive oropharynx cancer; age ≥18 years; WHO/ECOG performance score of 0 or 1; and adequate organ and bone marrow function. Key exclusion criteria include requiring further treatment with curative intent after definitive cCRT, resected LA-HNSCC, recurrent/metastatic disease, and &gt;1 primary tumor. Following initial screening and definitive cCRT (cisplatin or carboplatin + paclitaxel or carboplatin + 5-FU, plus concomitant radiotherapy), approximately 1145 pts whose disease has not progressed within 12 weeks of the last dose of cCRT will be randomized 1:1 to Arm A or B. Arm A will receive volrustomig intravenously every 3 weeks for a maximum of 12 months or 18 cycles, or until RECIST v1.1-defined radiological progressive disease (PD) or unacceptable toxicity. Arm B will undergo observation for a maximum of 12 months or until PD. The primary endpoint is PFS in pts with PD-L1-expressing tumors. Secondary endpoints include PFS in all randomized pts, OS in pts with PD-L1-expressing tumors and in all randomized pts, PFS2, safety, patient-reported outcomes, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses will also be conducted. Enrollment began in December 2023. Clinical trial information: NCT06129864 .

Neoadjuvant toripalimab combined with axitinib in patients with locally advanced clear cell renal cell carcinoma: a single-arm, phase II trial

BackgroundA combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study aims to prospectively evaluate the safety, efficacy,...

Molecular analysis of the HCRN GU16-260-Cohort A phase II study of first-line (1L) nivolumab (nivo) and salvage nivo + ipilimumab (ipi) in patients (pts) with advanced clear cell renal cell carcinoma (accRCC).

4546 Background: Seven molecular subsets of ccRCC have been proposed: 1: Angiogenic/Stromal; 2: Angiogenic; 3: Complement/Ω-oxidation; 4: T-effector/Proliferative; 5: Proliferative; 6: Stromal/Proliferative; and 7: snoRNA (Motzer et al. Can Cell 2020). In an analysis of IMmotion 151, which compared 1L atezolizumab/bevacizumab to sunitinib, combination immune checkpoint blockade (ICB) and anti-VEGF therapy was associated with improved progression-free survival (PFS) and overall survival (OS) in clusters (CLs) 4 and 5, increased PFS in CL 7, and decreased OS in CL 2 (Motzer Can Cell 2020, Motzer JAMA Onc 2022). CL 4 was also associated with higher PFS and objective response rate (ORR) in &gt;1L nivo compared to everolimus in an analysis of CheckMate-025 (Denize CCR 2022). To date, outcomes have not been compared among accRCC subtypes in pts who received 1L pure ICB. Methods: In HCRN GU16-260-Cohort A, pts with accRCC received 1L nivo monotherapy until progressive disease (PD), unacceptable toxicity, or completion of 96 weeks of therapy. Pre-treatment FFPE tumor samples were obtained. A machine learning model (random forest) was trained on annotated transcriptomic data from bulk RNA-seq and used to classify tumors that passed quality control into one of the 7 molecular subtypes. Results: 70 tumor samples contained adequate RNA quality and were classified as outlined in the table. IMDC rates and ORR (40%) for the RNAseq population closely matched those of the whole study (Atkins JCO 2022). No tumors were classified in CL 7 and only 3 in CL 5. Tumors in each IMDC group contained a mix of subtypes. The highest ORR occurred in CL 4 (6/10, 60.0%); CL 4 median PFS was 15.2 months and 1-year PFS was 60%. ORR was also high in CLs 1 and 3 at 52.4% and 40.0%, respectively and lowest in CL 2 (12.5%). PD as best response (5/10, 50.0%) and short PFS (5.1 months) were seen in CL 6. Conclusions: Consistent with prior analyses with combination ICB + anti-VEGF and &gt;1L ICB, CL 4 was associated with robust 1L ICB monotherapy antitumor efficacy. Surprisingly, ORR was also high in CLs 1 and 3. In this small dataset, transcriptomic signatures enriched for but did not fully predict ORR. Future prospective trials are needed to identify more discriminative biomarkers of efficacy for pure ICB therapy.[Table: see text]

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.

Comparison of the Efficacy and Safety of Nivolumab Plus Cabozantinib versus Sunitinib in the Treatment of Elderly Patients with Advanced Clear Cell Renal Cell Carcinoma.

Advanced clear cell renal cell carcinoma (ccRCC) seriously affects the life and health of patients, but effective treatment for this disease is still lacking in clinic. This study investigated the efficacy of nivolumab plus cabozantinib versus sunitinib in the treatment of elderly patients with advanced ccRCC. The clinical data of 216 elderly patients with advanced ccRCC in our hospital from January 2020 to January 2022 were retrospectively analysed. On the basis of different treatment regimens, patients were divided into the cabozantinib group (n = 111, receiving nivolumab and cabozantinib) and the sunitinib group (n = 105, receiving nivolumab and sunitinib). The overall survival time, disease control rates, health status, incidence of adverse events and identification of prognostic risk were compared between the two groups. The cabozantinib group had higher overall survival time, disease control rate and scores in the Functional Assessment of Cancer Therapy-Kidney Symptom Index and EuroQol-Five Dimensions-Three Levels Questionnaire than the sunitinib group. The incidence of adverse events in the cabozantinib group was lower than that in the sunitinib group (p < 0.001). However, no difference existed in the identification of prognostic risk between the two groups (p > 0.05). The effect of nivolumab plus cabozantinib on the treatment of elderly patients with advanced ccRCC is better than that of nivolumab plus sunitinib, with fewer adverse reactions and higher safety. However, the research results require further clinical studies to confirm and promote.

Belzutifan in patients with advanced clear cell renal cellcarcinoma (ccRCC): Subgroup analysis of the phase 2 LITESPARK-013 study.

4534 Background: In the randomized phase 2 LITESPARK-013 study (NCT04489771), the first-in-class HIF-2α inhibitor belzutifan showed comparable antitumor activity in patients with pretreated advanced ccRCC at 200 mg and 120 mg doses (objective response rate [ORR]: 23.1% vs 23.7%; 1-sided P= 0.5312). We present results of a post hoc analysis of the pooled population (200 mg and 120 mg arms) across patient subgroups based on prior therapy and IMDC risk group. Methods: Patients with advanced ccRCC, measurable disease per RECIST v1.1, a Karnofsky Performance Scale score of ≥70%, ≤3 prior systemic regimens for advanced ccRCC (including an anti–PD-(L)1 regimen), and disease progression during or after an anti–PD-(L)1 regimen were randomly assigned 1:1 to receive belzutifan 200 mg or 120 mg QD. End points in the pooled population and subgroups were ORR and duration of response per RECIST v1.1 by blinded independent central review. Data cutoff was February 10, 2023. Results: A total of 154 patients were enrolled (200 mg, n = 78; 120 mg, n = 76). In the pooled population, the median age was 64.0 years, 127 patients (82.5%) had intermediate/poor risk per IMDC criteria, 110 patients (71.4%) received 1-3 prior tyrosine kinase inhibitor (TKI) regimens, and 81 patients (52.6%) received 2 or 3 prior lines of therapy. As of the data cutoff date, 39 patients (25.3%) in the pooled population remained on treatment. Median follow-up was 20.1 months (range, 14.8-28.4). In the pooled population, ORR was 23.4% (95% CI, 16.9-30.9; 4 complete responses [CRs], 32 partial responses [PRs]) and median duration of response (DOR) was 16.1 months (range, 2.1+ to 23.5+). Additional efficacy analyses for subgroups are presented in the table. Conclusions: This post hoc analysis from the LITESPARK-013 study of patients with pretreated advanced ccRCC suggests that belzutifan has antitumor activity regardless of prior lines of therapies and prognostic risk category. These results further support belzutifan as a treatment option for advanced RCC. Clinical trial information: NCT04489771 . [Table: see text]

A phase I/II study of talazoparib and axitinib in patients with advanced clear cell renal cell carcinoma.

4541 Background: Targeting the VEGF pathway is a backbone therapeutic for patients with advanced clear cell renal cell carcinoma (ccRCC). Tumor and tissue hypoxia may also lead to DNA repair suppression and PARPs are key regulators of DNA damage and genomic maintenance which interact with HIF proteins. Pairing a potent VEGFR TKI with a selective PARP inhibitor (PARPi) may lead to improved outcomes in ccRCC patients. Methods: This was a phase I/II, investigator-initiated, single-center, open-label study (NCT04337970) of talazoparib plus axitinib in previously treated ccRCC patients. In the phase Ib dose escalation, patients must have been previously treated with a PD-1/PD-L1 inhibitor with no maximum lines of prior therapy, and those in dose expansion were required to have prior treatment with a PD-1/PD-L1 inhibitor and prior VEGFR TKI, with a maximum of 2 prior lines of therapy. Patients received escalating doses of talazoparib (0.5 mg, 0.75 mg and 1 mg daily) with axitinib (5 mg twice daily) in a 3+3 design, with primary endpoint of safety and tolerability. After establishing the recommended phase II dose (RP2D), a dose expansion cohort enrolled patients in a Simon two-stage design with a primary endpoint of objective response (ORR), and secondary endpoints including progression-free survival (PFS). Results: From 2020-2023, 23 ccRCC patients were enrolled and treated on study. In the dose escalation, 15 patients enrolled across all 3 dose levels and there were 2 observed DLTS (1 in dose levels 2 and 3). Both DLTs was due to a lack of minimum exposure to study drugs during cycle 1 due to treatment-related toxicities. The maximum tolerated dose and RP2D established was 1 mg talazoparib daily with axitinib 5 mg twice daily. In the phase II dose expansion portion, an additional 9 patients were enrolled to evaluate preliminary efficacy. In total, 13/14 patients treated at the RP2D discontinued therapy due to progressive disease. The objective response rate (ORR) was 7% (90% CI 0, 30), with 1 patient achieving a partial response and 12 patients achieving stable disease (86%). With a median follow-up of 13.2 months (R: 6.6 -29), the median PFS was 6.1 months (95% CI 3.5, 8.4) and median overall survival (OS) was 27 months (95% CI 12- NE). Across the study, 13 (56%) patients had at least one treatment-emergent AE of grade 3+, and 9 (39%) patients had at least one treatment-related AE of grade 3+. Most common grade 3+ AEs included diarrhea, nausea, and anemia. Conclusions: This is the first clinical study evaluating combination PARPi and VEGFR TKI in metastatic ccRCC patients. This study established the RP2D and MTD of combination talazoparib and axitinib and demonstrated a tolerable safety profile across all dose escalation cohorts. The study did not meet the pre-defined efficacy threshold for further enrollment per Simon stage two design. Exploratory efforts to evaluate this treatment approach with tissue biomarker data remain ongoing. Clinical trial information: NCT04337970 .