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PURPOSE Both immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for advanced renal cell carcinoma treatment and can cause cardiovascular events (CVs); thus, combination therapy could lead to major adverse CV events (MACE). Cardiac serum biomarker assessment and imaging, including left ventricular ejection fraction (LVEF) monitoring, can be used to evaluate MACE. METHODS To our knowledge, the JAVELIN Renal 101 trial, assessing avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma, is the first randomized study of ICI plus VEGFR inhibitor treatment to include prospective serial cardiac monitoring of LVEF and serum cardiac biomarkers. RESULTS MACE (defined as grade ≥ 3 CV AEs) occurred in 31 patients (7.1%) in the combination arm and 17 patients (3.9%) in the sunitinib arm. Patients in the combination arm who had high baseline troponin T values were at higher risk of MACE versus patients with low values (MACE in 6/35 v 7/135, respectively; relative risk, 3.31; 95% CI, 1.19 to 9.22). This association was not observed in patients treated with sunitinib. Other CV baseline risk factors and serum cardiac biomarkers were not significantly predictive for MACE, although a trend toward an association with dyslipidemia was seen in the combination arm. No clinical value of on-treatment routine monitoring of LVEF in relation to MACE was observed. Although LVEF decline was significantly more frequent in the combination arm, most patients recovered, and decline was not associated with other significant cardiac events or symptoms. CONCLUSION Patients with high baseline troponin T levels receiving ICI and VEGFR combinations may need to be monitored more closely for MACE. Routine monitoring of LVEF in asymptomatic patients is not recommended.

PURPOSE Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti–PD-1 pathway–targeted therapy. PATIENTS AND METHODS Patients with metastatic RCC who received prior anti–PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed. RESULTS Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients. CONCLUSION Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

671 Background: There has been interest in adjuvant immune checkpoint inhibition (ICI) following surgical resection in patients with high-risk renal cell carcinoma (RCC) given high recurrence rates and approvals of ICI in metastatic RCC. The primary objective of this analysis was to synthesize available data regarding the disease-free survival (DFS) benefit of adjuvant ICIs for patients with RCC. Methods: This systematic review was performed according to the PRISMA guidelines. The protocol was registered in PROSPERO (CRD42022361599). We searched PubMed, EMBASE, and relevant conference proceedings to identify phase III randomized controlled trials (RCTs) comparing adjuvant ICI versus placebo/observation. The primary outcome of interest was DFS. Results: Among the four included studies, one demonstrated a significant DFS benefit. There was considerable clinical and statistical heterogeneity (I2=64%) due to differences in inclusion criteria and interventions. While pooled results across the four studies did not demonstrate a significant benefit in DFS overall (HR 0.85, 95% CI 0.69-1.04), there was significant benefit among patients with positive PD-L1 expression (HR 0.72, 95% CI 0.55-0.94) or sarcomatoid features (HR 0.59, 95% CI 0.38-0.91). Conclusions: The evidence base to date regarding ICI as adjuvant therapy in RCC is mixed – conclusions are limited by considerable heterogeneity between studies. However, pooled analyses suggest that patients with positive PDL1 expression or sarcomatoid features are most likely to benefit from adjuvant immunotherapy.

670 Background: Analyses from the phase 3 JAVELIN Renal 101 trial (NCT02684006) suggested that CRP levels at baseline (BL) and early after treatment may predict outcomes with A + Ax in patients with aRCC. In addition, many patients with International Metastatic RCC Database Consortium (IMDC) poor risk who had prolonged progression-free survival (PFS) and overall survival (OS) were observed at the third interim analysis of OS. We analyzed the association between CRP levels and prolonged PFS/OS with A + Ax in patients with IMDC poor risk. Methods: CRP levels were assessed at screening and on day 1 of each 6-week cycle. Patients in the A + Ax arm with 3 or 4-6 IMDC risk factors were categorized into subgroups with CRP normal (BL CRP

672 Background: The combination of ipilimumab and nivolumab (Ipi/Nivo) is approved for patients (pts) with treatment-naïve, intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), but duration of therapy and safety/efficacy of re-induction at progression is unknown. A phase II trial of intermittent Ipi/Nivo with re-induction at progression was conducted (NCT03126331). Methods: Patients with treatment-naïve mRCC were treated with induction Ipi/Nivo followed by up to 24 weeks (+/- 8 weeks) of maintenance Nivo. Pts who achieved a complete response (CR) or partial response (PR) were eligible for inclusion and entered a treatment-free observation period. Pts were restaged every 12 weeks. Pts with no disease progression (PD) remained off therapy. Upon PD, pts were re-challenged with 2 doses of Ipi/Nivo every 3 weeks, with 1 or 2 more doses at physician discretion. The study objectives were to estimate success rate of observation in pts who achieve a CR/PR (defined by 50% of CR/PR pts sustaining a treatment-free interval of at least 9 months), and to assess toxicity in pts undergoing re-induction. The study was closed early given poor accrual in the rapidly changing mRCC treatment landscape. Results: Nine pts were included; 89% male, median age 57, 78% prior nephrectomy, 67% clear-cell histology, all had KPS ≥ 80%, and 78% were intermediate-risk by IMDC criteria. All pts had 4 doses of induction Ipi/Nivo. Response to Ipi/Nivo and Nivo maintenance prior to enrollment was 33% CR and 67% PR. Most (78%) pts patients have remained off therapy, with a median treatment-free interval (TFI) of 34.3 months (range, 8.7-41.8). The success rate of 0.78 (95% CI: 0.40-0.97) exceeded the pre-specified threshold of 50%. Two pts had PD off therapy (3 and 8 months after therapy cessation; both with best initial response of PR). Both received 2 cycles of re-induction Ipi/Nivo. No grade 3 or greater toxicities occurred with re-induction, but both pts developed PD at their first scans after re-induction. Conclusions: This pilot prospective study demonstrates that patients with a radiographic response to Ipi/Nivo can have prolonged treatment-free intervals. Further studies of de-escalation strategies are warranted. Correlative investigations for this trial are ongoing. Clinical trial information: NCT03126331 .

TPS742 Background: The first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC) includes an immuno-oncology (IO) based combination. The current standard regimens include a PD-1 inhibitor plus either (1) an anti-CTLA-4 inhibitor (IO/IO), or (2) an anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) (IO/TKI). Currently, there is no level 1 evidence to guide physician’s choice between an IO/IO versus IO/TKI combination. The phase III IMmotion 151 trial performed RNA-seq from 823 ccRCC tumors and established seven biologically distinct gene expression clusters of ccRCC (Motzer and Rini et al., Cancer Cell 2020). The seven clusters showed differential responses to immune checkpoint inhibitor and may serve as a predictive biomarker to select frontline treatment. Methods: This trial is a phase II, multicenter study using the established biologic clusters to assign patients with mccRCC to either an IO/IO (ipilimumab/nivolumab) or an IO/TKI (nivolumab/cabozantinib) regimen. Patients diagnosed with mccRCC without prior systemic therapy (including in the neoadjuvant or adjuvant setting) and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. RNA-seq will be performed on metastatic tumor specimens and used to assign tumor clusters. Patients with cluster 1/2 tumors will be assigned to the nivolumab/cabozantinib arm; patients with cluster 4/5 tumors will be assigned to the ipilimumab/nivolumab arm. Cluster 3/6/7 will be excluded. The primary endpoint is overall response rate (ORR) per RECIST 1.1. The hypothesis is that use of tumor clusters to assign front-line therapy to either nivolumab/cabozantinib or ipilimumab/nivolumab will lead to a 20% greater ORR compared to unselected historical controls in CheckMate 9ER (ORR: 55%) or CheckMate 214 (ORR: 40%). This trial adopts Simon’s MiniMax two-stage design (power: 80%, one-sided α: 0.1). For the nivolumab/cabozantinib arm, stage I will enroll 12 eligible patients. If there are 7 or more responders in the first 12 patients, the trial will continue for stage II to enroll additional 14 patients (total n=26). The primary endpoint will be met if there are 18 or more responders (ORR ≥75%). For the ipilimumab/nivolumab arm, stage I will enroll 16 eligible patients. If there are 7 or more responders in the first 16 patients, the trial will continue for stage II to enroll additional 12 patients (total n=28). The primary endpoint will be met if there are 15 or more responders (ORR ≥60%). Key secondary endpoints include progression-free survival (PFS), depth of response>80%, and rate of immune-related adverse events (irAEs). This trial is funded by the Department of Defense Kidney Cancer Research Program Clinical Trial Award (W81XWH-22-1-1033) (NCT05361720). Clinical trial information: NCT05361720 .

683 Background: In renal cell carcinoma (RCC), partial nephrectomy (PN) is indicated for patients with solitary kidney, chronic kidney disease, or bilateral tumors. A subset of these patients, however, may have large and complex renal masses not initially suitable for PN. Neoadjuvant Tyrosine Kinase Inhibitor therapy has shown promising results in cytoreducing renal tumors and may permit PN in circumstances not otherwise feasible. Methods: This was a single arm phase II clinical trial of neoadjuvant axitinib in patients with complex (RENAL nephrometry score 10-12 and cT1b-cT3M0) biopsy-proven clear cell RCC with strong indications for partial nephrectomy (PN), and in whom radical nephrectomy may result in dialysis dependence. Axitinib 5 mg was administered orally twice daily for 8 weeks prior to surgery. Primary outcome was reduction in longest tumor diameter; secondary outcomes included tumor response (RECIST), change in RENAL score, feasibility of PN, change in estimated glomerular filtration rate (DeGFR), and post-surgical complications. Results: 26 patients were enrolled. 19 (73.1%) patients had ≥ clinical T3a staged tumors. Post therapy, 17 (65.4%) patients had ≥T3a staged tumors. Axitinib resulted in reductions in tumor size (7.7 vs. 6.3 cm, p

TPS4618 Background: ABACUS and PURE-01 trials demonstrated the activity of single agent atezolizumab and pembrolizumab respectively as neoadjuvant therapy for muscle invasive bladder carcinoma (MIBC). However, downstaging to non-muscle invasive disease was noted in only 50 percent of patients. Resistance to programmed death (PD)- 1/L1 antibodies is likely to include factors such as impaired dendritic cell maturation/function, infiltration of T-Regs and myeloid derived suppressor cells, impaired T-cell priming and T-cell trafficking in tumors. Cabozantinib is a tyrosine kinase inhibitor which targets MET, AXL, MER, Tyro3 and VEGFR2. Cabozantinib has a unique immunomodulatory profile and has demonstrated clinical activity as monotherapy and in combination with PD-1/L1 antibodies in various solid tumors including urothelial cancer (UC), renal cell, castrate- resistant prostate and non-small cell lung cancer. We hypothesize that the combination of cabozantinib and atezolizumab as neoadjuvant therapy for MIBC would improve rates of pathologic downstaging compared to single-agent checkpoint inhibitors. Methods: ABATE is an open-label, single arm, multi-center study to assess the efficacy and safety of cabozantinib with atezolizumab as neoadjuvant therapy for cT2-T4aN0/xM0 MIBC. An estimated 42 patients will be enrolled to obtain 38 evaluable patients, and the study will have over 80% power to declare the investigational combination to be successful using a Bayesian evaluation at 90% posterior probability cutoff, if the response probability is 59%, i.e., 20% higher than the 39% response rate with the single agent atezolizumab. Eligible patients will receive cabozantinib 40 mg PO daily with atezolizumab 1200mg every 3 weeks for a total duration of 9 weeks (3 cycles) followed by radical cystectomy. Adults (≥18 years) with resectable MIBC who are either cisplatin-ineligible or decline cisplatin-based chemotherapy are eligible. Patients are required to have an ECOG PS of 0-2 and provide tumor tissue for PD-L1 expression analysis. UC should be predominant component (≥ 50%). Previous systemic anticancer therapies for MIBC are not permitted. CT/MRI will be performed before investigational therapy and cystectomy. Primary endpoint is pathologic response rate defined as the absence of residual muscle-invasive cancer in the surgical specimen (< pT2). Secondary endpoints are safety and toxicity, pathologic complete response rate and event-free survival. Exploratory end points include patient-reported outcomes and outcome associations with biomarkers. Accrual began May 2020. Clinical trial information: NCT04289779.

3035 Background: The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) multi-arm phase II clinical trial tested tumor tissue from 5,954 patients with advanced refractory cancer to assign treatment based on the molecular profile. Molecular profiling was successful for 93% of patients. For 267 of the patients who were not enrolled because molecular profiling was not successful, plasma cfDNA was evaluated to provide insight into the potential utility of blood-based testing in a broad spectrum of histologies when tissue is not evaluable. Methods: Cell-free DNA was extracted from plasma collected from Streck blood tubes and quantitated. Libraries were constructed using ³ 15 ng cfDNA into the Illumina TruSight Oncology 500 ctDNA RUO Assay, including unique molecular identifiers and duplex barcodes for error correction. Libraries were sequenced on the NovaSeq 6000 with S4 XP flow cells. Results: Of the 267 samples, 250 samples (94%) were evaluable, representing 72 histologies, including colorectal cancer (N = 36), lung adenocarcinoma (N = 15), pancreatic adenocarcinoma (N = 14), and invasive breast carcinoma (N = 12). Of these, 231 (92%) had ³ 1 OncoKB annotated mutation, with 208 patients (83%) having putative somatic mutations detected in genes not commonly associated with clonal hematopoiesis. The most common somatic mutations were in TP53, KRAS, APC, and PIK3CA, reported in 51%, 20%, 12%, and 12% of patients respectively. A total of 109 patients (44%) had ³ 1 actionable mutation of interest (aMOI) reported that could have been used for treatment assignment in the NCI-MATCH clinical trial. After applying histology and molecular exclusions, 75 patients (30%) had ³ 1 aMOI. The most common assignable treatment arms were Z1B/Z1BX1 (palbociclib with CCND1/2/3, N = 13), Z1F (copanlisib with PIK3CA Mutations, N = 13), S1/S1X1 (trametinib with NF1 mutation, N = 12), and Z1C/Z1CX1 (palbociclib with CDK4/CDK6 Amplification and Rb Expression by IHC, N = 10). Mutations in genes commonly associated with clonal hematopoiesis (CH) were prevalent in this population. Along with the expected high frequency of DNMT3A (21% of patients) and TET2 (11%) mutations, PPM1D mutations were the highest amongst CH genes, with 61 patients (24%) having ³ 1 PPM1D mutation, likely due to the heavily pre-treated nature of these patients. Conclusions: Variants observed in the blood are consistent with what is reported in the tissue. Using liquid biopsy when tissue is not evaluable can expand the ability of patients to obtain mutation information that can inform treatment compared to using tumor tissue only. Cell-free DNA provided valuable mutation information for these patients and could have resulted in up to an additional 75 patients being eligible for treatment selection based on their mutation profile. These results indicate that blood-based screening could be a tool for future NCI-sponsored clinical studies.

3002 Background: Cadherin 6 (CDH6) is part of the cadherin family, which is involved with cell-cell adhesion, organ development, and epithelial-mesenchymal transition. CDH6 is found to be overexpressed in various cancers, particularly RCC and OVC. DS-6000a is an antibody-drug conjugate, comprised of an humanized anti-CDH6 IgG1 monoclonal antibody attached to a topoisomerase I (TOP1) inhibitor payload via a cleavable linker. DS-6000a specifically binds to CDH6 on the surface of tumor cells and is internalized upon binding. The payload is then released, resulting in target cell apoptosis. In preclinical studies, DS-6000a inhibited tumor growth and induced tumor regression in CDH6-expressing RCC and OVC. Here, we report initial results from a phase I trial of DS-6000a in patients (pts) with advanced RCC and OVC (NCT04707248). Methods: This dose-escalation (Part A) and expansion (Part B) study will recruit pts with advanced RCC and OVC. DS-6000a is administered IV as monotherapy on Day 1 of 21-day cycles. Part A assesses safety, tolerability, and maximum tolerated dose or recommended dose for expansion (RDE) using Bayesian optimal interval design; additional pts are enrolled to examine safety and efficacy. The starting dose of DS-6000a is 1.6 mg/kg followed by 3.2, 4.8, 6.4, 8, and 9.6 mg/kg. Part B will assess safety, tolerability and efficacy at the RDE. Results: Part A interim results are presented. At data cutoff (19 NOV 2021), 22 pts had enrolled (7 RCC, 15 OVC). All RCC pts had received an immune checkpoint inhibitor and the majority of OVC had platinum resistant (Pt-R) disease; median age was 63.5 years (range, 41-78); median of 4 (range, 1-12) prior lines of therapy were administered; and median treatment duration was 8.0 wks (range, 3-33.14). Fifteen pts (68.2%) were ongoing at the cutoff date. Treatment-emergent adverse events (TEAEs) occurred in 19 pts (86.4%). Related TEAEs occurred in 17 pts (77.3%). The most common related TEAEs (>20%) were fatigue and nausea (45.5% each), and vomiting (27.3%). Grade ≥3 related TEAEs occurred in 4 pts (18.2%); the most common was neutropenia (13.6%). One patient (4.5%) had a Grade 3 febrile neutropenia. One dose-limiting toxicity of Grade 4 thrombocytopenia (9.6 mg/kg) occurred. There was no study drug discontinuation due to a TEAE. Among 15 evaluable pts, 2 partial responses (PRs; 1 confirmed in RCC and 1 unconfirmed PR in Pt-R OVC) were observed; 9 pts had stable disease. Moreover, 5 out of 11 OVC evaluable pts showed CA-125 responses using GCIG criteria and all CA-125 responders had Pt-R disease. Conclusions: The interim data from dose-escalation of this FIH study showed acceptable tolerability with early signals of efficacy in heavily pretreated pts with advanced RCC and Pt-R OVC, which support further clinical evaluation of DS-6000a in the planned dose-expansion cohorts in advanced RCC and OVC. Clinical trial information: NCT04707248.

12039 Background: ICIs have changed the treatment paradigm in many cancer histologies. Population-level data regarding the impact of ICIs on the contemporary US cancer patients is scarce. In addition, elderly patients were underrepresented in the landmark trials. Methods: Metastatic cancers (melanoma, lung cancer, kidney cancer, head and neck cancer, Hodgkin’s lymphoma, and urothelial cancer) diagnosed between 2004-2018 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. The year of the first FDA approved ICI in each cancer site was considered the commencement of the ICI era. The impact of metastatic cancers diagnosed in the ICI era was assessed in each age group (

4531 Background: Vascular endothelial growth factor (VEGF) and immune checkpoint inhibitors (IO) combinations are a standard in mRCC. Molecular clusters of patients have been identified and correlated with outcomes in the phase 3 IMmotion151 (IM151) trial of atezolizumab + bevacizumab (IO+VEGF) vs. sunitinib (Sun) (Motzer, Cancer Cell 2020 & JAMA Oncol 2021). Avelumab+axitinib (AA) is an approved IO+VEGF combination in mRCC. This work aims to evaluate these clusters in patients from the phase 3 JAVELIN Renal 101 (JR101; NCT02684006 ) trial of AA vs. Sun. Methods: Bulk RNA-sequencing of primary and metastatic samples and clinical data (data cutoff: 28 January 2019) from JR101 were obtained. A random forest model designed to predict molecular clusters based on transcriptomic data was trained on the IM151 dataset. Using this model, patients from JR101 study were categorized into previously defined molecular subgroups. We then evaluated treatment outcomes including progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) from JR101 in relation to molecular subgroups. Results: The proportion of patients in each molecular subtype and across MSKCC risk groups were largely comparable between the 2 trials (accuracy: 81.6%; p=0.2). AA was generally superior to Sun. for PFS and ORR across all molecular subsets, including angiogenic and immune-based clusters (Table). Combining immune and/or cell cycle-enriched clusters 4+5 resulted in improved PFS (HR: 0.65; 95% CI: 0.44-0.97) for AA vs. Sun. Conclusions: We were able to largely validate the molecular clusters classification and some of the associations with survival outcomes from IM151 in the JR101 clinical trial cohort. Biomarkers of specific VEGF+IO combinations in mRCC should be prospectively validated in randomized trials. [Table: see text]

e17053 Background: 18F-DCFPyL (piflufolastat F 18) is a PSMA-targeted agent FDA-approved for PET imaging in men with prostate cancer. Given the recent availability for clinical use, we sought to evaluate the impact and potential changes in management after the incorporation of 18F-DCFPyL (PyL) PET/CT at an academic medical center. Methods: We reviewed the first 100 PyL PET/CT scans performed at the Vanderbilt-Ingram Cancer Center for men with prostate adenocarcinoma. Patient demographics, treatment history, and prior imaging results were recorded, along with PyL PET results, most recent PSA, and clinical management plans. Management changes were designated as change in systemic therapy, radiation, or surgery and were determined by two independent reviewers with a third reviewer for any discordant cases. Results: There were 100 men included with PyL PET scans dating from 9/1/21 to 12/31/21. The median age was 69 years, 76% of patients were white and 13% were black. The median Gleason sum at diagnosis was 7 (4+3), 55% of men had prior prostatectomy, and 38% had prior radiation to the prostate/pelvis. The median PSA prior to PyL PET scan was 1.86 (IQR 0.53-9.95 ng/mL), 32% of men had previous ADT exposure, and 15% were on ADT at the time of PyL PET scan. The clinical setting prior to PyL PET scan was initial staging 22%, biochemical recurrence 59%, m1HSPC 14%, m0CRPC 2%, and m1CRPC 3%. There were 16 patients who had a prior 18F-fluciclovine within six months of PyL PET; of these 69% (11/16) had additional disease on PyL PET not previously identified. Activity in lymph nodes was observed in 48%, bone 37%, visceral sites 3%, prostate/prostate bed 46%, and 15% had no PSMA-avid disease. Clinical staging was altered after the PyL PET scan in 55% of patients, with the most common change being from BCR to m1HSPC (40/55). Clinical management was altered in 59% of cases: systemic therapy 38%, radiation planning 46%, and surgical planning 6% (Table). Conclusions: Clinical management was affected in 59% of cases after implementation of PyL PET in this retrospective, single center review. Given the rapid adoption of PSMA-targeted PET imaging agents, further studies are needed to evaluate the clinical impact of subsequent changes to management planning, as well as to develop multidisciplinary consensus statements and protocols to guide management.[Table: see text]

4538 Background: The Lung Immune Prognostic Index (LIPI), defined by lactate dehydrogenase (LDH) and derived neutrophil to lymphocyte ratio (dNLR), has been shown to correlate with outcomes of immune checkpoint inhibitor therapy in patients (pts) with lung and other cancers, including pts with previously treated aRCC receiving nivolumab in the phase 2 NIVOREN GETUG-AFU 26 trial. We report an analysis of LIPI in pts with previously untreated aRCC receiving N+I or SUN in the randomized phase 3 CheckMate 214 trial with 5 years minimum follow-up. Methods: Data were used from CheckMate 214 comparing N+I (N 3 mg/kg + I 1 mg/kg) vs SUN (50 mg) for untreated aRCC (N = 1096). Pts with available LIPI data were categorized into 3 LIPI groups (good [LG], dNLR ≤ 3 and LDH ≤ upper limit of normal [ULN]); intermediate [LI], dNLR > 3 or LDH > ULN; and poor [LP], dNLR > 3 and LDH > ULN). This analysis focused on the prognostic value of LIPI using overall survival (OS) outcomes. Univariable analyses (UVAs) were conducted to evaluate LIPI groups alongside known risk factors including age, sex, IMDC risk, baseline PD-L1 status, prior nephrectomy, and baseline tumor burden. Variables that were statistically significant in UVAs ( P < 0.1) were included in the full multivariable analyses (MVAs), from which a reduced model was generated. Results: A total of 1085 pts were evaluable for LIPI (N+I, n = 542; SUN, n = 543). Pts were distributed evenly between treatment arms for all 3 LIPI groups, but distribution between LIPI groups was unbalanced, with most pts grouped as LG (Table). OS outcomes were improved with N+I over SUN across all LIPI groups. Moreover, pts in the LG group had better OS outcomes vs pts in the LI or LP groups regardless of treatment, but with more distinct differences between LIPI groups in the SUN arm (Table). Final MVA results showed the LIPI correlated with OS for LI vs LG in the N+I arm and for LI vs LG and LP vs LG in the SUN arm (Table). Conclusions: These results from CheckMate 214 indicate the potential prognostic value of the LIPI in pts with untreated aRCC receiving N+I or SUN. Additional analyses are ongoing to further investigate the prognostic value of LIPI in this pt population and its impact on other clinical outcomes. Clinical trial information: NCT02231749. [Table: see text]

4529 Background: Immune checkpoint blockade has revolutionized mRCC Tx, but primary and acquired resistance continues to result in poor patient outcomes. OX40 (CD-134) mediates IO resistance. Co-stimulatory OX40 (CD-134) activates exhausted T-cells. OX40 activation in dendritic cells increases the proliferation, effector function, and survival of T cells. PFOX is an agonist for OX40. We hypothesized that PFOX + the VEGFR inhibitor Axi would improve outcomes vs. Axi in patients (pts) with mRCC after IO Tx. Methods: Pts with predominantly clear cell mRCC were stratified for MSKCC risk groups then randomized 1:1 to Axi 5mg po bid plus PFOX 0.3mg/kg iv (Arm 1) or placebo (PL) iv (Arm 2) on Day 1 of a 2-week cycle. The primary endpoint was progression free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR) per RECIST v1.1, and safety/tolerability. A prespecified interim analysis (IA) tested PFS at a 1-sided P < 0.02 when ≥ 33 events were observed. Results: Between February 2018 and October 2021 a total of 59 pts were randomly assigned and treated with Axi+PFOX (N = 29) or Axi+PL (N = 30). Pt and disease characteristics are summarized in the table. As of October 2021, 38 PFS events had occurred, 19 on each arm. The IA rejected the hypothesis of added efficacy for PFOX with a p of 0.0089. Subsequently the study was closed to new accrual. At a median follow up of 13.4 mo, median PFS was 13.1 (6-15.8) months (mo) for Arm 1 and 8.5 (5.5-11) mo for Arm 2 (HR = 0.85 [95% CI: 0.45-1.60] p = 0.61). After adjusting by MSKCC risk group and prior lines of Tx, HR = 0.74 [95% CI: 0.38-1.46] p = 0.39. Median OS was not reached (adjusted HR = 0.71 [95% CI: 0.24-2.12] p = 0.54). ORR Arm 1: 31% PR, 52% SD, 14% PD, and Arm 2: 37% PR, 50% SD, 13% PD. Median DOR 9.1 (3.3-23.9) mo for Arm 1, and 7.5 (1.8-32.7) mo. for Arm 2. Rates of any grade Tx related adverse events (TRAEs; 93% vs 100%), including grade 3 or 4 TRAEs (66% vs 47%), in Arm 1 and Arm 2, respectively. 4 pts discontinued Tx due to TRAE, 3 in Arm 1 (1 grade 3 hypertension, 1 grade 2 stroke, 1 grade 3 bullous dermatitis) and 1 in Arm 2 (grade 4 ALT elevation). The most common TRAEs were diarrhea 52%, hypertension 52%, fatigue 41%, nausea 41% for Arm 1 and hypertension 67%, diarrhea 53%, fatigue 50% for Arm 2. Conclusions: In IO-pretreated mRCC pts, Axi + PFOX did not improve outcomes compared to Axi alone. Clinical trial information: NCT03092856. [Table: see text]