4535 Background: Clear cell renal cell carcinoma (ccRCC), characterized by loss of von Hippel-Lindau (VHL) tumor suppressor function, and constitutive stabilization of hypoxia-inducible factor (HIF) proteins results in activation of genes promoting angiogenesis, metabolic reprogramming including altered lipid metabolism and glycolysis, cell proliferation, and immunosuppressive remodeling of the tumor microenvironment. HC-7366 is a novel, selective GCN2 kinase activator that regulates metabolic stress via the ATF4–driven integrated stress response. Preclinically, GCN2 hyperactivation with HC-7366 enhances belzutifan (BEL) activity, broadly impairing stress adaptation, disrupting tumor metabolism, decreasing HIF expression, inhibiting the cell cycle, and remodeling the tumor immune microenvironment. Methods: In this phase 1b study (NCT06234605), 69 patients with advanced ccRCC received HC-7366 monotherapy (60 mg QD; n=16) or HC-7366 (20 mg, n=7; 40 mg, n=22; 60 mg, n=24) plus BEL (120 mg QD). Blood samples for soluble biomarkers and paired biopsies for IHC were collected per IRB-approved guidelines. Results: Overall, PK analysis (N=69) demonstrated steady state free exposure of HC-7366 at 40-60 mg doses (Cmax = 5.8 ng/mL, AUC = 75 h*ng/mL) that were consistent with exposures providing maximal BEL combination benefit preclinically. Compared with screening biopsies, all on-treatment biopsies at week 3 (8/8) showed induction of the ATF4 pathway biomarker ASNS (asparagine synthetase). Baseline HIF expression analysis by IHC from 52 patients demonstrated that 33 patients (63%) express mid to high levels of HIF1 and HIF2. HIF1α, but not HIF2α, was reduced consistently with treatment across all cohorts (7/8, 66-98% reduction). Reduced cell cycle biomarkers, including pRB and Ki67 (4/4), and increased frequency of CD8 + PD1 + TCF1 + Lag3 - Tim3 - T-cells (3/3), suggesting ICI responsiveness, were observed in the 40-60 mg combination cohorts. Systemic changes were also observed in serum, including deep and sustained inhibition of EPO, decreases in proangiogenic cytokines like VEGF-A and PDGF-BB, and changes in adipokines that counter RCC progression (Table 1). Low baseline serum levels of KIM-1 predicted response to the combination (p=0.005). Conclusions: Early clinical findings suggest HC-7366 + BEL is associated with modulation of angiogenic and immune-related pathways in ccRCC, providing a rationale for the combination with ICIs and/or VEGFR-TKIs. Clinical trial information: NCT06234605 . Avg max change with treatment. Biomarker 60 mg mono 20 mg combo 40 mg combo 60 mg combo EPO (week 2) -43% -82% -81% -84% Chemerin (week 2) -34% -16% -36% -28% Adiponectin (week 5) +64% +35% +46% +36% VEGF-A (week 9) -53% -42% -28% -37% PDGF-BB (week 9) -30% -20% -54% -63%

4534 Background: HC-7366 is a novel, selective, potent activator of general control nonderepressible 2 (GCN2) kinase, regulating metabolic stress via the integrated stress response. Our preclinical studies in RCC demonstrated that prolonged GCN2 activation by HC-7366 resulted in antitumor activity accompanied by inhibition of HIFs and cell cycle progression. Furthermore, combination with belzutifan (BEL) results in superior preclinical efficacy, accompanied by inhibition of HIF signaling and cell-cycle progression, supporting clinical evaluation of the combination in RCC. Methods: Patients with advanced ccRCC previously treated with ≥1 anti-PD/PD-L1 and ≥1 VEGF-TKI were enrolled into HC-7366 monotherapy (60 mg QD) or a dose-escalation/expansion cohort of HC-7366 (20, 40, 60 mg QD) with BEL (120 mg QD). Primary objectives were safety, tolerability, and investigator-assessed ORR per RECIST v1.1. Enrollment in escalation and expansion is complete; second expansion is ongoing. Results: As of the data cutoff 10 Dec 2025, 69 patients received study treatment: 16 monotherapy and 53 combination (7 at 20 mg, 22 at 40 mg, 24 at 60 mg). Median prior therapies were 3 (range 1-5) in monotherapy and 2 (range 1-4) in combination. Most TEAEs were Grade (Gr) 1-2. Gr 3 events were mainly hematological (anemia) and gastrointestinal (nausea and diarrhea), with one DLT (Gr 3 nausea, 40 mg combination). In efficacy-evaluable patients, the 40 mg combination demonstrated the best overall response rate (BORR) of 36.8%, including a confirmed ORR (cORR) of 26.3%, disease control rate (DCR) of 89.5%, and primary progressive disease (PD) rate of 10.5%. The 60 mg combination had a BORR of 31.6%, with a cORR of 31.6%, DCR of 84.2%, and primary PD rate of 15.8%. In monotherapy, BORR of 15.4% and DCR of 61.5% were observed. Early efficacy signals at 40–60 mg align with the preclinical projected maximal efficacious dose range. Conclusions: HC-7366, alone or in combination with BEL, was generally well tolerated. Preliminary efficacy analyses indicate favorable disease control, characterized by a high DCR and low primary PD. Clinical trial information: NCT06234605 . Efficacy and safety data by cohort. Monotherapy60 mgN=13 HC-7366 + BELZ20/120 mgN=7 HC-7366 + BELZ 40/120 mg N=19 HC-7366 + BELZ 60/120 mg N=19 Median follow-up (mo) 16.9 13.4 11.2 8.5 BORR /cORR (%) 2 (15.4) /0* 0 /0 7 (36.8) /5 (26.3)​ 6 (31.6) /6 (31.6) DCR (%) 8 (61.5)​ 5 (71.4)​ 17 (89.5)​ 16 (84.2)​ Primary PD (%) 5 (38.5) 2 (28.6) 2 (10.5) 3 (15.8)​ PFS 6 mo (%) 15.4 42.9 57.9 73.7 Any Gr /Gr 3 AEs 15 (93.8) /9 (56.3) 7 (100) /4 (57.1) 22 (100) /16 (72.7) 24 (100) /17 (70.8) Gr 3 Anemia /Hypoxia 0 /2 (12.5) 2 (28.6) /1 (14.3) 5 (22.7) /2 (9.1) 5 (20.8) /2 (8.3) Gr 3 Nausea /Diarrhea 2 (12.5) /3 (18.8) 0 /1 (14.3) 1 (4.5) /0 2 (8.3) /0 Dose Red /Discont. 6 (37.5) /2 (12.5) 1 (14.3) /0 11 (50.0) /2 (9.1) 7 (29.2) /3 (12.5) *PRs not confirmed due to emergence of brain metastases.

4527 Background: In CLEAR, lenvatinib + pembrolizumab (L+P) significantly improved efficacy vs sunitinib (S) in treatment-naïve patients with advanced renal cell carcinoma (Motzer 2021, Motzer 2024). We summarize efficacy by patterns of progressive disease (PD) for the L+P arm and report survival per a modified PD classification system (based on patients receiving immunotherapy; data cutoff 31 July 2022). Methods: Treatment‐naïve patients (n=1069) who had clear‐cell advanced renal cell carcinoma were randomized (1:1:1) to receive: L 20 mg PO daily + P 200 mg IV Q3W; or L + everolimus; or S 50 mg PO daily (4 wks on/2 wks off). Methods for post-progression survival/OS analyses were previously reported (Grünwald 2025). A modified system of classifying PD (Saal 2025) is used in new analyses of the L+P arm reported here: low risk (progression of existing lesions); intermediate risk (new lesions without progression of existing lesions); high risk (progression of existing lesions + new lesions). The number of patients with PD was determined by independent imaging review at the data cutoff date. Results: At the time of PD, the median tumor burden of target lesions was lower with L+P (−48.1%) vs S (−17.4%). Patients in the L+P arm with larger % decreases in sums of target lesion diameters at PD had longer median post-progression survival (≤-61% [n=59], 35.6 mos [95% CI 28.4−39.2]; >-61%-≤-34% [n=58], 24.4 mos [95% CI 15.5−34.5]; >-34% [n=59], 20.2 mos [95% CI 16.4−26.9]) and OS (Grünwald 2024, 2025). In the L+P arm, most patients had low/intermediate risk PD (Table). Patients with low (HR 0.39; 95% CI 0.22-0.70) or intermediate risk (HR 0.47; 95% CI 0.27-0.81) PD had improved OS vs patients with high risk PD. Patients with low/intermediate risk PD stayed on 1 st subsequent anticancer medication longer than patients with high risk PD (Table). Conclusions: In the L+P arm, PD was mainly characterized by progression of existing lesions or formation of new lesions without progression of existing lesions (low/intermediate risk PD); these patients had improved OS (vs high risk PD) suggesting prognostic/predictive value of patterns of PD. Patients with low/intermediate risk PD stayed on 1 st subsequent anticancer medication longer than patients with high risk PD, implying that 2L therapy can be used effectively upon progression with L+P. These results, together with lower tumor burden seen at PD in the L+P arm (Grünwald 2024), indicate that L+P has robust tumor control, supporting its use as a standard 1L therapy in advanced renal cell carcinoma. Clinical trial information: NCT02811861 . Low risk PD(n=69) Intermediate risk PD(n=91) High risk PD(n=30) Patients with any subsequent systemic anticancer medication during survival follow-up, n (%) 49 (71.0) 58 (63.7) 15 (50.0) Time to discontinuation of 1 st anticancer medication during survival follow-up, median (Q1, Q3) (months) 14.4 (5.6, not estimable) 7.3 (3.1, 20.3) 4.3 (1.5, 13.7) Included data is from the L+P arm.

Understanding how health-related quality of life (HRQOL) concerns vary by disease stage is essential for developing patient-reported outcome measures (PROMs) that reflect the lived experiences of individuals with renal cell carcinoma (RCC). This study aimed to explore differences in the perceived relevance of HRQOL domains between patients with localized and metastatic RCC using a provisionally grouped item set derived from validated instruments. This is a secondary analysis of a prospective international study conducted from August 2022 and October 2024, with participants from the United States, Europe, and Brazil (Bergerot et al., JCO 2025). In Phase 1, a 54-item was developed using the Functional Assessment of Cancer Therapy–Kidney Symptom Index (FKSI-19), the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30), and the EuroQol (EQ-5D). Items were provisionally grouped into four conceptual domains: physical disease-related symptoms (DRS-P), emotional symptoms (DRS-E), treatment side effects (TSE), and function/well-being (FWB). Patients with localized or metastatic RCC rated item relevance. We calculated the mean number of relevant items per domain and conducted ANOVAs to compare groups, reporting partial eta squared (η²) for effect size. A total of 200 patients (localized n = 83; metastatic n = 117) were included. Patients with metastatic RCC reported greater relevance of physical symptoms (DRS-P: M = 39.2, SD = 6.0) compared to those with localized disease (M = 35.3, SD = 6.7; F(1,198)=17.53, P < .001, η²=0.081). Similarly, metastatic patients reported higher treatment side effect burden (TSE: M = 12.2, SD = 2.3 vs. 10.6, SD = 2.5; F(1,198)=19.47, P < .001, η²=0.089). No significant difference was observed in emotional symptoms (DRS-E; P = .260). Conversely, patients with localized RCC more often endorsed concerns related to function and well-being (FWB: M = 17.6, SD = 3.5) than those with metastatic disease (M = 15.5, SD = 2.9; F(1,198)=20.52, P < .001, η²=0.094). Given the differences in trajectory and treatment modalities across localized and metastatic RCC, our findings underscore the evolving nature of HRQOL concerns across the RCC continuum. While physical symptoms and treatment side effects were highly relevant across both groups, their prominence among metastatic patients suggests the burden of advanced disease and systemic therapies. In contrast, patients with localized disease prioritized functional limitations and emotional concerns, potentially linked to surveillance-related anxiety. These insights support the need for stage-specific PROMs and highlight the importance of integrating both physical and emotional dimensions of care in RCC. Validation of such a tool for both localized and metastatic RCC is underway in forthcoming studies.

TPS4614 Background: HC-7366 is a novel, highly selective and potent activator of general control nonderepressible 2 (GCN2) kinase, a core regulator of metabolic stress through activation of the integrated stress response (ISR). Prolonged or hyper-activation of GCN2 suppresses general protein synthesis and induces cell cycle arrest, ultimately leading to apoptosis. HC-7366 decreases HIF expression in tumor and immunosuppressive myeloid cells and inhibits glycolysis, oxidative phosphorylation, and TCA cycle function in tumor cells. In CDX RCC xenografts, HC-7366 combined with belzutifan (BLZ) exhibited tumor regression, and in BLZ-resistant PDX models, HC-7366 demonstrated monotherapy (mono) antitumor activity. These preclinical effects of HC-7366 suggest potential therapeutic benefit in clear cell renal cell carcinoma (ccRCC) and rationale for combinations with HIF2α antagonists. Mechanism of action studies identified biomarkers of pathway engagement which may be predictive of efficacy (Stokes, AACR 2024, Abstract 4615). HC-7366 75 mg was determined to be the maximum tolerated dose (MTD) in a previous phase 1a study in patients (pts) with solid tumors which did not include ccRCC ( data on file with sponsor ). Methods: This is a multicenter, open-label, phase 1b dose escalation and expansion study evaluating safety, tolerability, MTD, recommended phase 2 dose (RP2D) of HC-7366 + BLZ (combo) in pts with advanced / metastatic RCC, predominantly clear cell histology. Additionally, HC-7366 60 mg mono (up to 20 patients) is assessed in parallel. In dose escalation, HC-7366 (20, 40, 60 mg po qd) + BLZ (120 mg po qd) is evaluated using a modified Toxicity Probability Interval design in up to 20 pts. Dose expansion will evaluate two HC-7366 doses selected from escalation + BLZ (15 pts/dose level). Tumor response will be assessed by CT scans every 8 wks (RECIST v1.1). Secondary endpoints include ORR, DOR, TTR, DCR, PFS, and OS. PK data will be profiled, and exploratory objectives include pharmacodynamic marker evaluation in tumor biopsies and peripheral blood samples. Key eligibility criteria include 1-3 prior therapies for the combo cohorts (naïve to BLZ/ HIF-2α inhibitors) and 1-4 prior therapies for the mono cohort (may include BLZ/ HIF-2α inhibitors), >1 measurable lesion, and willingness to provide biopsy or archival tumor samples at two timepoints. Escalation Dose levels 1 and 2 of the combination cohorts have been cleared and enrollment is ongoing for Dose level 3 (60 mg + BLZ), Expansion Dose Level 1 (40 mg + BLZ) and the mono cohort (60 mg HC-7366) at 20 US sites. The trial is sponsored by HiberCell, Inc. in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Sponsor contact: Paulette Mattson pmattson@hibercell.com , 651.312.5831. Clinical trial information: NCT06234605 .

526 Background: Existing HRQOL measures may not fully capture the experiences of patients with localized and advanced RCC. This study aimed to develop a validated, patient-centered HRQOL metric by incorporating insights from patients, advocates, and clinical experts for both localized and advanced RCC. We previously developed a questionnaire for advanced RCC (Bergerot et al., JCO 2024). In this study, we integrate it into the FKSI-19 model and create a new questionnaire. Methods: A four-phase approach was used. Previous work in advanced RCC assessed item relevance from established HRQOL measures (FKSI-19, EORTC QLQ-C30, EQ-5D), refined through patient feedback and expert review. This phase expanded to include localized RCC in the adjuvant setting. In Phase 1, patients with localized RCC rated the the relevance of 54 items from the metastatic cohort. Phase 2 included a panel of 11 expert refining the adjuvant-specific items. Phase 3 gathered feedback from patient advocates, and Phase 4 further refined the items by harmonizing them with the FACT library for consistency across RCC stages. Results: In Phase 1, 6 of 54 items were rated as most relevant by patients with localized RCC. Phase 2 refined these further, excluding redundant items and adding 4 new questions focused on adjuvant therapy. Phase 3 led to minor revisions after advocate review, and Phase 4, the new items were harmonized with validated FACT library questions. The final adjuvant-specific questionnaire comprises 10 items, addressing concerns such as long-term side effects, surveillance anxiety, and post-surgery emotional distress. The advanced-specific version includes 13 items. Both versions deemed to be of utmost importance to patients with localized and advanced disease. These items can be used as standalone scoring options, resulting in the creation of a novel FKSI-23 metric, allowing for customized questionnaires tailored to specific clinical scenarios. Conclusions: Through collective input from patients, advocates and experts, novel items that aid in capturing the experience of RCC patients were identified and existing metrics were refined to generate separate “scoring options” for patients with localized and metastatic disease. Validation of the resulting FKSI-23 tool is underway in forthcoming studies in RCC.

531 Background: L+P significantly improved efficacy vs sunitinib in treatment-naïve pts with aRCC in the CLEAR trial (Motzer 2021). We report data from further analyses on the impact of tumor burden at the time of progression and shifts in IMDC scores in the L+P arm of the CLEAR study. Methods: Study design has been reported (Motzer 2021). Data cutoff for analyses was July 31, 2022 (median follow-up: ~4 years; Motzer 2024). Data herein are limited to the L+P arm of CLEAR. Medians for survival from either progression or randomization (i.e., overall survival) were estimated by Kaplan-Meier method, and 95% CIs were estimated via generalized Brookmeyer and Crowley method. Survival was assessed according to percent changes from baseline in target lesion diameters of pts at progression (on L+P) by tertiles (T1: ≤-61%; T2: >-61%-≤-34%; T3: >-34%-≤51%). Changes in IMDC score from baseline were reported at 6 months to assess treatment impact on prognosis. Results: Pts with a larger percentage decrease in sums of target lesion diameters at progression had longer median survival (months [95% CI]) from time of progression vs pts with smaller percentage decreases in tumor size (T1 [n=59], 35.6 [28.4-39.2]; T2 [n=58], 24.4 [15.5-34.5]; T3 [n=59], 20.2 [16.4-26.9]). Similar trends were observed with overall survival (from randomization; T1, not estimable [49.9-NE]; T2, 43.0 [33.0-NE]; T3, 31.5 [22.4-34.4]). Most pts, irrespective of tumor shrinkage at progression, received subsequent systemic anticancer medication during survival follow-up (T1: 63%; T2: 59%; T3: 71%). Pts received an anti-VEGF therapy (46%; 45%; 59%) as their first subsequent medication more frequently than any other medications. The most frequently used anti-VEGF therapies were cabozantinib (22%; 29%; 29%), sunitinib (12%; 3%; 20%), and axitinib (7%; 3%; 8%). At 6 months, IMDC score stayed the same or decreased from baseline in most pts; ≤10% of pts had increases in IMDC score, regardless of score at baseline (Table). Conclusions: Pts in the L+P arm with lower disease burden at progression showed improved prognosis, highlighting the importance of deep tumor response when considering treatment sequence. IMDC risk scores were typically constant or improved in pts treated with L+P; data are limited by missing pts. Clinical trial information: NCT02811861 . L+P arm IMDC score at 6 months, n (%) Baseline IMDC score a Decreased by ≥1 points Remained constant Increased by 1 point Increased by ≥2 points Missing b 0 (n=110) NA 84 (76) 9 (8) 2 (2) 15 (14) 1 (n=137) 25 (18) 82 (60) 8 (6) 2 (1) 20 (15) 2 (n=72) 34 (47) 18 (25) 5 (7) 1 (1) 14 (19) 3 (n=26) 18 (69) 0 0 0 8 (31) 4 (n=5) 4 (80) 0 0 0 1 (20) 5 (n=1) 1 (100) 0 0 0 0 Total (n=355) 84 (24) 186 (52) 22 (6) 5 (1) 58 (16) a 4 pts had a missing score at baseline. b IMDC prognostic score was derived based on total risk score from 6 prognostic factors at baseline and month 6 (+/- 2 weeks).

BACKGROUND:The phase III TIVO-3 study demonstrated improvement in progression-free survival (PFS) with tivozanib compared with sorafenib in patients with 2-3 prior systemic regimens for metastatic renal cell carcinoma (mRCC). METHODS:The TIVO-3 trial enrolled patients with measurable mRCC who had received 2 or more prior systemic therapies, including a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). Patients were stratified by International Metastatic RCC Database Consortium risk score and type of prior treatment and were randomized 1:1 to receive tivozanib or sorafenib. Efficacy was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 criteria, with PFS as the primary endpoint. Safety was evaluated using Common Terminology Criteria for Adverse Events version v4.03, and statistical analyses included Cox regression for overall survival (OS) and descriptive statistics for duration of response (DOR). The current post-hoc long-term follow-up analysis consists of an assessment of OS in the previously stratified subpopulation of patients with prior CPI exposure. RESULTS:Between May 2016, and August 2017, 350 patients were randomized, of which 26% had prior CPI exposure, with final analysis data cut off on June 21, 2021. In patients previously treated with CPIs (n = 91), the median PFS of tivozanib was 7.3 months versus 5.1 months with sorafenib and hazard ratio (HR) of 0.55 (95% CI, 0.32-0.94). The OS HR in the CPI-treated subset was 0.69 (95% CI, 0.43-1.11, P =.0992) favoring tivozanib, although with a median OS of 18.1 and 20.9 months, for tivozanib and sorafenib, respectively. Tivozanib demonstrated a longer median DOR of 20.3 versus 5.7 months for sorafenib in the subset previously treated with CPIs. The safety profile favored tivozanib, with lower rates of VEGF-TKI class-related grade ≥3 adverse events compared with sorafenib. However, in the subset of patients previously treated with CPIs, the incidence of grade ≥3 adverse events was higher, at 58% for tivozanib and 67% for sorafenib, compared with the ITT population, at 46% and 55%, respectively. CONCLUSIONS:In this long-term post-hoc update of the TIVO-3 trial, we show that in CPI-resistant mRCC, the PFS benefit of tivozanib over sorafenib is accompanied with improved OS data, although not statistically significant, and durable responses.

INTRODUCTION:Allogeneic chimeric antigen receptor (CAR) T-cell therapy is a promising yet underexplored treatment for clear cell renal cell carcinoma (ccRCC), potentially more effective than existing treatment options. This review compares several ongoing preclinical and clinical trials using CAR T-cell therapy. AREAS COVERED:This review discusses the development of CAR T-cell therapy in ccRCC, covering four significant themes: (1) optimizing therapeutic efficacy through combination strategies, (2) the translation pathway from preclinical development to clinical application, (3) safety and toxicity management, and (4) immune response modulation in the tumor microenvironment. Finally, this review highlights opportunities to overcome current limitations and guide future therapeutic approaches. We conducted a structured review of existing research using the PubMed and Google Scholar databases from the past 5 years, compiled relevant studies on CAR T-cell therapies for ccRCC, and categorized them into four key themes, which were then cross-analyzed to identify trends, challenges, and emerging limitations. EXPERT OPINION:Development of universal CAR T-cells may be more affordable, more accessible, and easier to administer in less time with fewer mechanical failures than autologous CAR T-cell therapy. Some challenges persist, including patient toxicities, depletion of CAR T-cells in vivo, and an immunosuppressive tumor microenvironment.

BACKGROUND:In CLEAR, lenvatinib + pembrolizumab (L + P) significantly improved efficacy versus sunitinib in first-line treatment of patients with advanced renal cell carcinoma (aRCC). We report results from CLEAR biomarker analyses. PATIENTS AND METHODS:Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) and next-generation sequencing assays (whole exome sequencing/RNA sequencing) were carried out on archival tumor specimens. For IHC-derived/RNA sequencing analyses, a continuous analysis was carried out adjusting by Karnofsky performance status (KPS) score for: PD-L1 combined positive score (CPS) versus best overall response (BOR)/progression-free survival (PFS); and each gene signature score [T-cell inflamed gene expression profile (TcellinfGEP)/non-TcellinfGEP signatures including proliferation and angiogenesis] versus BOR/PFS. Association between mutation status of RCC driver genes and PFS were analyzed for genes for which ≥20 patients per arm had oncogenic alterations. Association of molecular subtypes with outcome was evaluated with baseline KPS adjustments. The set of biomarkers evaluated and statistical significance criteria for PD-L1 CPS, gene signature scores, and molecular subtypes were prespecified. RESULTS:Within-arm analyses using continuous values showed no association between PD-L1 levels and BOR/PFS for either treatment. PFS hazard ratios between arms were similar regardless of the mutant or wild-type subgroups of RCC driver genes (VHL, PBRM1, SETD2, BAP1, KDM5C). No associations between PFS and gene signature scores were observed for L + P. With sunitinib, high proliferation and MYC signature scores showed shorter PFS; high angiogenesis and microvessel density signature scores showed longer PFS. Six new molecular subtypes were defined. Tumors of patients with favorable/intermediate risk were enriched in angiogenesis and angiogenesis/stromal clusters; those with poor risk were enriched in proliferative and unclassified (low-TcellinfGEP/low-angiogenesis/low-proliferation) clusters. No association between molecular subtypes and PFS for L + P/sunitinib was observed (after adjustment for KPS and gene signatures that were individually associated with PFS). CONCLUSIONS:Improvements in objective response rate and PFS for L + P versus sunitinib in aRCC were observed consistently across a range of biomarker subgroups defined using RCC driver mutations, PD-L1, gene expression signatures, and molecular subtypes.

Abstract Background HC-7366 is a novel, orally administered, highly selective and potent activator of general control nonderepressible 2 (GCN2) kinase, a core regulator of metabolic stress through activation of the integrated stress response (ISR). Activation of GCN2 promotes cell survival, whereas prolonged activation induces apoptosis. GCN2 activation also suppresses general protein synthesis and induces cell cycle arrest, thereby preventing cell growth during nutrient scarcity. Additionally, HC-7366 decreases HIF expression and inhibits glycolysis, oxidative phosphorylation, and TCA cycle function. HC-7366 also inhibits HIF expression in immunosuppressive myeloid cells, including macrophages. These effects of HC-7366 on metabolism, HIF signaling, and immune suppression suggest therapeutic benefit in ccRCC with clear rationale for combinations with HIF2a antagonists and immune checkpoint inhibitors. HC-7366 (0.5-1 mg/kg), combined with belzutifan (1 mg/kg), exhibited combination benefit in HIF-2 dependent A-498 and 786-O RCC xenografts, yielding 90% tumor growth inhibition and a three-fold increase in complete responses, respectively. Additionally, HC-7366 drives significant monotherapy antitumor activity in PDX models that demonstrated belzutifan resistance. Mechanism of action studies have identified several pathway engagement and potential efficacy biomarkers (Stokes, et al., 2024). Trial design/schema This multicenter, open-label phase 1b study will identify the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of HC-7366 in combination with fixed-dose belzutifan, 120 mg po qd, in patients with advanced or metastatic RCC with renal cell histology irrespective of VHL gene mutation. Monotherapy HC-7366 will be evaluated in parallel. The monotherapy arm, HC-7366, 60 mg p.o. qd, includes patients who have relapsed after 1 to 4 prior lines of standard of care that may include belzutifan or another HIF-2α inhibitor. The combination arm includes patients who have received 1 to 3 prior lines of standard of care and are belzutifan or HIF-2α naïve. HC-7366 dose escalation arm evaluates combination fixed dose belzutifan, 120 mg po qd plus HC-7366 at 20, 40, or 60 mg po qd. Enrollment will start with the HC-7366 monotherapy arm. Subsequently, patients will begin to enroll in the combination therapy HC-7366 dose escalation arm, while the monotherapy arm will continue to enroll. Expansion will evaluate the combination of fixed dose belzutifan with two doses of HC-7366 selected from escalation. Assessments include safety, PK, and anti-tumor activity. The study will enroll up to 80 patients at US study sites. Significance and vision Combination HC-7366 plus belzutifan, supported by preclinical evidence, is being studied to assess antitumor activity in the RCC relapsed setting. Determining safety and evaluation of dose are foundational to this study. Reference Stokes M, Tameire F, Wojnarowicz P, et al. HC-7366, a potent GCN2 activator, complements belzutifan, a HIF-2⍺ antagonist, by providing combination benefit in belzutifan-sensitive models and monotherapy activity in belzutifan-resistant models. Meeting of the American Association for Cancer Research; 2024 Apr 5-10; San Diego (CA); AACR; 2024. Abstract 4615. This study is in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA

The majority of metastatic renal cell carcinoma (mRCC) patients receive one or more VEGFR TKI agents, alone or in combination with an immune-oncology (IO) agent or an mTOR inhibitor. To date, the cost of adverse events (AEs) common to VEGFR TKIs has not been quantified. This study estimated the potential impact of differences in VEGFR TKI AE profiles on treatment cost efficiency in the relapsed/refractory (R/R) setting. Patients with documented mRCC who were treated with VEGFR TKI therapies between Jan 2015 and Mar 2021 were identified using EMR. ICD-10 diagnosis codes were used to identify the first occurrence of each class effect AE. Patients were matched to 3rd party insurance claims, and costs associated to TKI AEs within 90 days of index event were captured. Average per patient AE cost data was calculated and applied to published incidence data to estimate regimen-specific AE total cost burden within a hypothetical commercial plan for mRCC patients undergoing treatment in the R/R setting. The highest total cost for AE management was attributed to lenvatinib and everolimus use at 13,303, followed closely by sunitinib at13,092. Tivozanib treatment was associated with the lowest total cost of AE management at 7,523, driven by the relatively lower incidence of certain high-cost AEs. The estimated costs of managing VEGFR TKI class-effect AEs were lowest with tivozanib, and highest with lenvatinib and everolimus, indicating potentially differential healthcare resource burden by TKI regimen. The use of tivozanib in the 3 L + mRCC setting suggests potential costs offsets when compared to other TKI regimens.

Autonomic dysreflexia is a life-threatening medical condition characterized by episodes of uncontrolled hypertension that occur in response to sensory stimuli after spinal cord injury (SCI)[1][1]–[7][2]. The fragmented understanding of the mechanisms underlying autonomic dysreflexia hampers the development of therapeutic strategies to manage this condition, leaving people with SCI at daily risk of heart attack and stroke[8][3]–[18][4]. Here, we expose the complete de novo neuronal architecture that develops after SCI and causes autonomic dysreflexia. In parallel, we uncover a competing, yet overlapping neuronal architecture activated by epidural electrical stimulation of the spinal cord that safely regulates blood pressure after SCI. The discovery that these adversarial neuronal architectures converge onto a single neuronal subpopulation provided a blueprint for the design of a mechanism-based intervention that reversed autonomic dysreflexia in mice, rats, and humans with SCI. These results establish a path for the effective treatment of autonomic dysreflexia in people with SCI.### Competing Interest StatementThe authors declare competing financial interests: G.C., A.A.P., J.W.S, J.B., R.D. and S.P.L. hold various patents in relation with the present work. G.C, A.A.P. and R.D. are consultants of ONWARD medical. G.C., A.A.P., J.B. and S.P.L. are minority shareholders of ONWARD, a company with direct relationships with the presented work. [1]: #ref-1 [2]: #ref-7 [3]: #ref-8 [4]: #ref-18

TPS3190 Background: JZP898 is a conditionally activated prodrug of interferon alpha (IFNα) that can preferentially deliver IFNα to the tumor microenvironment while potentially minimizing systemic IFNα therapy-associated toxicity. Antitumor activity of IFNα is well-established, but concerns regarding systemic toxicity restrict its use in clinical practice. JZP898, in combination with a checkpoint inhibitor such as pembrolizumab, may provide lasting and potent antitumor activity with minimal additive toxicity attributed to conventional or pegylated IFNα. This phase 1 FIH study will determine a maximum tolerated dose (MTD)/recommended dose (RD) and investigate safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of JZP898 monotherapy and JZP898 combined with pembrolizumab in adult patients with advanced or metastatic solid tumors. Methods: This phase 1, FIH, open-label, multicenter study (NCT06108050) is investigating JZP898 intravenous infusion in adult patients (≥18 years old) with histological or cytological diagnosis of advanced or metastatic solid tumors, European Cooperative Oncology Group performance status ≤1, and measurable disease per RECIST v1.1 criteria. The study consists of a dose finding phase (JZP898 as monotherapy and in combination with pembrolizumab; Part A) and a combination dose expansion phase (JZP898 in combination with pembrolizumab; Part B). In Part A (dose finding), the JZP898 MTD and/or monotherapy RD will be determined using Bayesian optimal interval (BOIN) design based on the incidence of dose-limiting toxicities (DLTs) and all available safety and PK data; the combination recommended phase 2 dose (RP2D) will be determined using BOIN criteria and all available safety, PK/PD, immunogenicity, and preliminary signal of antitumor activity data. Patients will be treated until disease progression, death, unacceptable toxicity, or withdrawal from the study. All patients will be followed for survival until 18 months after the last patient starts study intervention. Primary endpoints include: the incidence and nature of DLTs (Part A); investigator-assessed objective response rate (ORR) per RECIST v1.1 (Part B); the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events; changes in laboratory values or vital signs; and the incidence of dose modifications or discontinuations due to TEAEs. Secondary endpoints include: PK parameters; incidence of antidrug antibodies; investigator-assessed duration of response; progression-free survival; disease control rate; investigator-assessed ORR (Part A); and overall survival (Part B). The study is actively enrolling patients with a planned enrollment of up to 177 patients. Clinical trial information: NCT06108050 .

e15118 Background: Tumor cells have been shown to adapt to the endoplasmic reticulum (ER) stress resulting from activated oncogenes, nutrient stress, and hypoxia by activating one of the kinases in the Unfolded Protein Response (UPR) pathway, Protein kinase RNA-like Endoplasmic Reticulum Kinase (PERK). This adaptation enables them to survive these stresses and develop resistance to standard of care. Targeting PERK in cancer cells could disrupt their ability to thrive under adverse conditions, potentially leading to apoptosis. HC-5404 is a novel, highly selective and potent PERK inhibitor that demonstrates bioavailability and target engagement at efficacious doses across preclinical tumor models. Herein, we report clinical data from the Ph1a study evaluating HC-5404 in patients with advanced solid tumors. Methods: In this first-in-human trial, HC-5404 was administered orally in 21-day cycles to patients ≥18 years old with advanced solid tumors. A Bayesian Optimal Interval (BOIN) design was employed to escalate through 7 dose levels (25 mg to 600 mg BID). Dose Limiting Toxicity (DLT) was assessed during the first cycle. The primary objectives were to establish the Maximum Tolerated Dose (MTD) and evaluate the safety and tolerability of HC-5404. The secondary objectives included evaluating PK/PD and antitumor activity (response rate and survival outcomes). Results: 23 patients received HC-5404 across various dose levels. Of these, 47.8% were ≥ 65 years old, 52.2% were male, and 82.6% had received ≥3 prior therapies. Overall, 1 partial response (PR) with a duration of 130 weeks was observed in a renal cell carcinoma (RCC) patient who started at the 25 mg dose and was escalated to 50 mg, while 8 patients had stable disease (SD) as best overall response. Three DLTs were observed, including hyperglycemia (300 mg), increased AST, ALP, GGT (200 mg) and decreased ejection fraction (EF) (100 mg). Hyperglycemia was observed only at higher doses (≥300 mg) above clinically relevant exposures of 25-100 mg. The MTD was not established. Treatment-related adverse events (TRAEs) of any grade occurred in 69.6% of patients with common events (≥ 20%) including nausea, fatigue, diarrhea, and dry mouth. Grade ≥3 TRAEs occurred in 17.4% of patients and included hyperglycemia, acute myocardial infarction, decreased EF, increased troponin, AST, GGT, ALP, and lipase. HC-5404 PK analysis showed rough dose-proportionality across 25-600mg doses and PK/PD analyses demonstrated the human dose range of 25-100 to be functionally equivalent to the pre-clinical efficacious doses. Final analysis of safety and clinical response are ongoing. Conclusions: HC-5404 showed a favorable safety profile and encouraging preliminary efficacy in heavily pretreated patients with advanced solid tumors. Safety and exposure-response analyses support further exploration of the 25-100 mg dose level of HC-5404, as monotherapy and in novel combinations. Clinical trial information: NCT04834778 .

4524 Background: In the primary analysis of the CLEAR trial of patients (pts) with aRCC, L+P significantly improved efficacy vs S (Motzer NEJM 2021). Results were further confirmed at the final prespecified OS analysis (Motzer JCO 2024). Here, we discuss patterns of progression and subsequent therapy in CLEAR. Methods: Treatment-naïve pts (n=1069) who had aRCC with a clear-cell component were randomly assigned (1:1:1) to receive: L 20 mg PO QD + P 200 mg IV Q3W; or L 18 mg + everolimus 5 mg PO QD; or S 50 mg PO QD (4 wks on/2 wks off). Stratification factors were region and MSKCC prognostic risk group. To explore progression pattern within individual organs, time to progression was defined for each organ independently using lesions within each specific organ only, based on Independent Image Review per RECIST v1.1. Medians and quartiles were estimated with Kaplan-Meier (KM) method; 95% CIs were estimated with a generalized Brookmeyer and Crowley method. Hazard ratio (HR) reported is for L+P vs S based on Cox regression model with treatment as factor; HR was stratified by region and MSKCC prognostic groups. The Efron method was used for correction for ties. Results: The HRs (95% CI) of time to progression for L+P vs S across tumors in different organs were: bone, 0.40 (0.25-0.63); CNS, 0.47 (0.19-1.19); kidney, 0.65 (0.37-1.14); liver, 0.52 (0.32-0.84); lung, 0.48 (0.36-0.62); and lymph nodes, 0.63 (0.46-0.85). At overall disease progression, the median sums of diameters of target lesions were lower with L+P vs S (29.8mm vs 42.8mm; Table). In the L+P arm, 181 pts received subsequent anticancer regimens during survival follow-up (43 received axitinib and 101 received cabozantinib). In the S arm, 246 pts received subsequent anticancer regimens (47 received axitinib and 107 received cabozantinib). The median duration of axitinib as the first anticancer regimen (95% CI) after L+P was 23.7 months (5.3-not estimable [NE]), and after S was 12.6 months (6.8-NE). The median duration of cabozantinib as the first anticancer regimen (95% CI) after L+P was 13.2 months (8.2-NE), and after S was 7.1 months (4.1-20.0). Conclusions: Pts in the L+P arm trended to show later progression across tumors in different organs. At overall disease progression, the tumor burden of target lesions was lower with L+P vs S; and pts in the L+P arm stayed on 2L axitinib or cabozantinib longer than pts in the S arm. Together, these results continue to support L+P as a standard-of-care 1L therapy in pts with aRCC. Clinical trial information: NCT02811861 . [Table: see text]

In the phase 3 CLEAR trial, lenvatinib plus pembrolizumab (L + P) showed superior efficacy versus sunitinib in treatment-na & iuml;ve patients with advanced renal cell carcinoma (aRCC). The combination treatment was associated with a robust objective response rate of 71%. Here we report tumor responses for patients in the L + P arm in CLEAR, with median follow-up of 4 yr at the final prespecified overall survival (OS) analysis. Tumor responses were assessed by independent review using Response Evaluation Criteria in Solid Tumors v1.1. Patients with a complete response (CR; n = 65), partial response (PR) with maximum tumor shrinkage >= 75% (near-CR; n = 59), or PR with maximum tumor shrinkage <75% (other PR; n = 129), were characterized in terms of their baseline characteristics. The median duration of response was 43.7 mo (95% confidence interval [CI] 39.2-not estimable) for the CR group, 30.5 mo (95% CI 22.4-not estimable) for the near-CR group, and 17.2 mo (95% CI 12.5-21.4) for the other PR group. The 36-mo OS rates were consistently high in the CR (97%), near-CR (86%), and other PR (62%) groups. Robust objective response rates were observed across International Metastatic RCC Database Consortium favorable-risk (69%, 95% CI 60-78%), intermediate-risk (73%, 95% CI 67-79%), and poor-risk (70%, 95% CI 54-85%) subgroups. The robust response to L + P supports this combination as a standard-of-care first-line treatment for patients with aRCC.

Background Tivozanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) with efficacy in advanced renal cell carcinoma (RCC). Long-term exploratory analyses from the TIVO-3 trial in relapsed/refractory (R/R) RCC including patients (26%) with prior immuno-oncology (IO) therapy are reported.Methods Patients with R/R advanced RCC that progressed with 2 or 3 prior systemic therapies (>= 1 VEGFR TKI) were randomized to tivozanib 1.5 mg QD or sorafenib 400 mg BID, stratified by IMDC risk and previous therapy. Safety, investigator-assessed long-term progression-free survival (LT-PFS), and serial overall survival (OS) were assessed.Results Mean time on treatment was 11.0 months with tivozanib (n = 175) and 6.3 months with sorafenib (n = 175). Fewer grade >= 3 treatment-related adverse events occurred with tivozanib (46%) than sorafenib (55%). Dose modification rates were lower with tivozanib than sorafenib across age/prior IO subgroups; prior IO therapy did not impact dose reductions or discontinuations in either arm. Landmark LT-PFS rates were higher with tivozanib (3 years: 12.3% vs 2.4%; 4 years: 7.6% vs 0%). After 22.8 months mean follow-up, the OS HR was 0.89 (95% CI, 0.70-1.14); when conditioned on 12-month landmark PFS, tivozanib showed significant OS improvement over sorafenib (HR, 0.45; 95% CI, 0.22-0.91; 2-sided P = .0221).Conclusions Tivozanib demonstrated a consistent safety profile and long-term survival benefit in patients with R/R advanced RCC who were alive and progression free at 12 months. These post hoc exploratory analyses of LT-PFS and conditional OS support a clinically meaningful improvement with tivozanib versus sorafenib in this advanced RCC population. Tivozanib is an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor with efficacy in advanced renal cell carcinoma (RCC). Long-term exploratory analyses from the TIVO-3 trial in relapsed/refractory RCC, including patients with prior immuno-oncology therapy, are reported.

TPS4609 Background: Efficacy outcomes for advanced RCC have improved with vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (IO), and CABO has become an established treatment for both front-line and refractory, advanced RCC. However, most patients develop resistance to CABO. With each subsequent line of therapy, efficacy and survival benefits also shorten and treatment options become limited. It is thus important to explore ways to maximize each line of therapy. Methods: Based on previous studies suggesting 1) dose-dependent effect of VEGFR-TKIs with feasibility/efficacy of CABO dose escalation to 80mg and 2) immune-modulatory effects of CABO, we have designed a two-cohort phase 2 trial to salvage CABO response, either by escalating the dose of CABO to 80mg oral (PO) daily (cohort 1) or by combining CABO 40mg PO daily with NIVO 480mg intravenous (IV) every 4 weeks (cohort 2), based on investigator choice. Subjects will be treated until progression or unacceptable toxicity. Main inclusion criteria include progressive advanced RCC after prior CABO monotherapy for at least 6 months, able to tolerate CABO 60mg PO daily (cohort 1) and 40mg PO daily (cohort 2), radiographically measurable disease, ECOG < 2, and adequate end-organ function. Main exclusion criteria include prior treatment with concurrent CABO/NIVO, uncontrolled co-morbidities, uncontrolled HIV, and concurrent malignancy (excepting completely excised skin cancers and organ-confined Gleason 6 prostate cancer). Primary endpoint is progression free survival (PFS) with key secondary endpoints including overall response rate, disease control rate, duration of response, and overall survival. The null hypothesis of median PFS 3 months will be tested against an alternative hypothesis of median PFS 6 months. Assuming a 2-sided significance level of 10% and 80% power, and estimating 10% drop out, 18 patients per cohort (36 patients total) will be enrolled.Pharmacokinetics, circulating biomarkers, and pre-/post-biopsies are planned for tissue-based analyses. The study is open for enrollment (NCT05931393). Clinical trial information: NCT05931393 .