Citations

e20011 Background: The therapeutic landscape of lung cancer is rapidly evolving, presenting oncologists with the challenge of staying updated amidst an overwhelming influx of data. Clinical decision support (CDS) tools, including artificial intelligence (AI) and large language models (LLMs), may help bridge this gap. Evaluating the accuracy of LLMs in complex, real-world oncology scenarios is crucial to understanding their potential. Methods: Twenty-five de-identified lung cancer cases from the fellows’ clinic at Karmanos Cancer Institute, Detroit, MI, were analyzed. Two LLMs, GPT-4 (OpenAI) and Claude Opus (Anthropic), were assessed using advanced prompting techniques like persona-based and chain-of-thought prompting. Five board-certified lung cancer oncologists from NCI-designated centers evaluated LLM-generated responses based on accuracy, treatment recommendation comprehensiveness, and supportive care planning, using a 1–5 scale. Novel insights, the presence of fabricated information, and harmful recommendations were flagged as binary outcomes. Oncologists were blinded to the LLM source and actual treatment decisions. Results: Table 1 presents patient characteristics. GPT-4 achieved an average accuracy score of 4.2 (95% CI, 3.9–4.4), with 3.7 for comprehensiveness of medical/surgical treatment recommendations and 3.7 for supportive care planning. Six responses (32%) were flagged as potentially harmful, and two (8%) contained inaccuracies. Sixteen GPT-4 responses (64%) were rated trustworthy as a CDS tool. Claude Opus had an average accuracy score of 3.6 (95% CI, 3.1–4.1), scoring 3.6 for treatment recommendation comprehensiveness and 3.5 for supportive care planning. Nine responses (36%) were flagged for potential harm, and five (20%) included inaccuracies. Eleven Claude responses (44%) were deemed trustworthy. Significant differences were observed in accuracy (p=0.04) and trustworthiness (p=0.03) between models using McNemar's test. Other factors showed no statistical significance. Conclusions: GPT-4 outperformed Claude Opus in accuracy and trustworthiness, but both models demonstrated limitations, including harmful recommendations and inaccuracies. These findings highlight the need for improved LLM refinement before routine use as CDS tools in lung cancer treatment. Patient demographics and clinical characteristics. Category subcategory Number Median Age (range)- Yr 65 (26-78) Female 7 Male 18 Histology Adenocarcinoma 10 Squamous Cell Carcinoma (SCC) 7 Small Cell Carcinoma 6 Poorly Differentiated 2 Total 25 Stage NSCLC Stage 3 7 NSCLC Stage 4 13 Small Cell limited stage 3 Small Cell Extensive Stage 2

e19008 Background: Cytokine release syndrome (CRS) is typically reversible in CAR-T therapy, while hyperinflammatory syndromes like macrophage activation-like syndrome (MAS-L) and high-grade immune effector cell-associated hemophagocytic syndrome (IEC-HS) are associated with significant morbidity and mortality. Early interventions are critical for improving outcomes. We aim to analyze clinical cytokine assays and cellular phenotypes early in hyperinflammatory syndromes to identify profiles for severe cases to inform management decisions. Methods: This study included 113 CAR-T patients (pt) (September 2019-March 2024) with cytokine profiles (CP) performed at the second tocilizumab dose or with suspected hyperinflammatory states (CP1), followed by assessments at 24 hours (CP24) and 48 hours (CP48). 52 pts consented to blood (PB) and bone marrow (BM) cell immune phenotyping at pre-treatment (pre-LD) and day 1 for PB. Results: Among the 113 pts, CRS pts (N=74), when compared to MAS-L(N=19) & IEC-HS (N=20) at CP1, had lower levels of TNF (median in pg/mL; 31, 62.9, 47.7) , IL-18 (794, 1353, 2011), and MCP-1 (689, 2722, 2485.5). While MAS-L and IEC-HS had similar CP1 profiles, CP24 and CP48 differed between them: TNF & MCP-1 levels decreased in MAS-L but remained elevated or increased in IEC-HS. IL-18 was stable in MAS-L but increased steadily daily in IEC-HS. Infections were more frequent in IEC-HS (CRS: 43%; MAS-L: 58%; IEC-HS: 85%; p=0.002). Notably, patients who died with persistent E. faecium bacteremia had higher IL-18 in CP48. In the 52 pts with cell phenotypes available by flow, 33 had CRS, 18 MAS-L and 8 IEC-HS. The correlation between cell phenotypes and cytokine levels showed that elevated TNF at CP1 correlated with increased non-classical monocytes in pre-LD BM and higher NK and NK-T cells in pre-LD PB. Similarly, elevated IL-18 CP48 levels correlated with increased CD8 T-cells, NK-T cells, and intermediate monocytes in pre-LD PB, as well as increased NK cells at both pre-LD and day 1 (Table). Conclusions: We report distinct cytokine profiles in IEC-HS early in the inflammatory course post-CAR-T therapy. These elevated cytokines correlate with specific immune cell subsets, including BM-resident monocytes, intermediate monocytes with heightened cytokine trafficking and inflammatory capacity. This study demonstrates the feasibility for identifying potential biomarkers for early risk stratification and targeted interventions. Cytokine Sample source Immune cells R P value TNF CP1 BM pre-LD Non-classical monocytes (CD14loCD16+) 0.38 0.025 PB pre-LD Monocytes (All) 0.47 0.022 NK cells (CD56+CD16+) 0.34 0.024 NK-T cells (CD3+CD56+CD16-) 0.29 0.04 IL-18 CP48 PB pre-LD CD8+ T-cells 0.59 0.0093 NK-T cells (CD3+CD56+CD16-) 0.53 0.023 Intermediate monocytes (CD14+CD16+) 0.58 0.012 PB pre-LD NK cells (CD56+CD16+) 0.56 0.49 0.015 0.024

TPS3171 Background: Genetic alterations in fibroblast growth factor receptors 2 and 3 ( FGFR2/3 ) occur in nearly all cancer types. FGFR2 fusions and rearrangements occur in up to 10-15% of intrahepatic cholangiocarcinomas (iCCA) and alterations in FGFR3 occur in 15-30% of urothelial cancers. The clinical benefit from currently approved FGFR inhibitors (FGFRi) is often curtailed by development of acquired resistance, which may arise through on-target mutations in the FGFR2/3 kinase domain. Additionally, off-tumor effects on FGFR1 by pan-FGFRi can lead to hyperphosphatemia and consequently to dose reductions or dose holds. Thus, there is an unmet clinical need for a selective FGFR2/3 inhibitor that has clinical efficacy against activating alterations and resistance mutations without causing FGFR1-mediated hyperphosphatemia. CGT4859 is an orally bioavailable, ATP-competitive, reversible inhibitor of FGFR2/3, with potency against clinically relevant FGFR2/3 kinase domain mutations. In addition, CGT4859 demonstrates >140 fold selectivity over FGFR1, and shows robust efficacy in target altered in vivo tumor models without increases in serum phosphorus. Nonclinical pharmacokinetics (PK) and safety data support evaluating CGT4859 in a first-in-human, open-label, dose-escalation and signal-seeking Phase I/II study (NCT06777316). Safety, tolerability, PK, pharmacodynamics, and antitumor activity of CGT4859 will be assessed in adults with histologically confirmed unresectable or metastatic iCCA or other solid tumors with FGFR2/3 alterations. Methods: CGT4859 will be administered orally continuously in 28-day cycles to patients (N=~50) at a starting dose of 1 mg QD, and dose escalation will not exceed 40 mg QD as determined using a Bayesian optimal interval design with backfill (BF-BOIN). This approach will be used to guide dose escalation and establish the maximum tolerated dose (MTD) and recommended Phase 2 Dose (RP2D). BF-BOIN enables backfilling of participants to doses that are cleared for safety during the dose escalation, generating additional data on safety and tolerability below the MTD. Objective response rate (ORR) and disease control rate will be determined based on investigator assessment using RECIST v1.1. Phase II will enroll up to 4 cohorts, each enrolling ~15 patients. Proposed cohorts will include participants who have iCCA and are either FGFRi-naïve or FGFRi-exposed. Two additional cohorts with other advanced solid tumors harboring FGFR2/3 alterations may be included based on signals detected in dose escalation. The primary efficacy endpoint for Phase II is ORR per RECIST v1.1. The preclinical data support the study of CGT4859 in this patient population with solid tumors harboring FGFR2 and/or FGFR3 genetic alterations. The phase I dose escalation study is currently enrolling at sites in the United States. Clinical trial information: NCT06777316 .

e19033 Background: CLL tends to affect older individuals, and older patients often endure greater health disparities and treatment burdens that may impact their access to healthcare resources, adherence to treatment regimens and treatment outcomes (UN, Health Inequalities in Old Age). This study aimed to assess treatment utilization patterns, discontinuation, and healthcare resource utilization (HCRU) of 1L use of BTKi in CLL, focusing on older patients ≥65 years (yrs). Methods: A retrospective observational study using the Symphony Integrated Dataverse was conducted to identify adult CLL patients initiating a 1L BTKi (zanubrutinib [ZANU], acalabrutinib [ACA] or ibrutinib [IBR]) treatment regimen from 02/2022 and 09/2024 (index period). Patients were required to have ≥30 days of continuous enrollment in the pre- and post-index periods. Patients initiating a BTKi were further categorized by age at index date. Patient sociodemographic, clinical characteristics, and outcomes were reported in overall and older (≥65 yrs) CLL patients by each BTKi group. Treatment discontinuation rate was examined at 60, 90, 120, 150, 180, and 360 days, and by median time to discontinuation (TTD), estimated using the Kaplan-Meier method, censoring patients at the end of follow-up. HCRU (outpatient, inpatient, and other services) was evaluated during time on treatment and over the follow-up period and reported as per-patient-per-year (PPPY). Results: A total of 6,846 patients initiated a 1L BTKi (ZANU: n=1,853; ACA: 3,519; IBR: 1,474) for CLL during the index period. Patients receiving ZANU were older (mean age: 70.9 yrs; 78% ≥65 yrs) than those receiving ACA (69.4 yrs; 71% ≥65 yrs) and IBR (69.6 yrs; 73% ≥65 yrs). Payer type and geography were significantly different across each BTKi group ( p <.001). There were no significant differences across the BTKis regarding baseline comorbidities. ZANU patients had the longest estimated median TTD overall (ZANU: 18.9 months [m], ACA: 17.8 m, IBR: 14.5 m; p <.001) and in patients ≥65 yrs (ZANU: 17.2 m, ACA: 15.2 m, IBR: 12.6 m; p <.001). ZANU patients also had the lowest estimated discontinuation rates at 60- , 90-, 120-, 150-, 180-, and 360-days post BTKi initiation in the overall and ≥65 yrs groups. There were significant differences across the BTKi group for inpatient visits PPPY in all patients and ≥65 yrs with ZANU having the lowest visits of the BTKis (ZANU: 2.6, ACA: 3.6, IBR: 4.6; p =.029 and ZANU: 2.5, ACA: 4.3, IBR: 5.3; p =.004, respectively). Conclusions: This real-world study demonstrated that CLL patients treated with ZANU had longer TTD, lower discontinuation rates, and less HCRU than ACA and IBR across all patients and specifically in older patients ≥65 yrs. Further studies on long-term and clinical outcomes are warranted.

e19025 Background: Recent studies suggest that patients with CLL/SLL (herein, CLL) relapsed/refractory (R/R) to both cBTKi and BCL2i (double R/R [DR]) may have poorer outcomes than the broader group of double-exposed (DE) patients. This study evaluated real-world response (rwR) and time-to-event (TTE) outcomes of a CLL DE cohort and DR subcohort in the US. Methods: This retrospective study used the nationwide Flatiron Health electronic health record-derived deidentified database to include patients with CLL treated with sequential or combination cBTKi and BCL2i in any line of therapy (LOT) on or after January 1, 2011, and a subsequent LOT (ie, index LOT) on or before November 30, 2022 (DE cohort). A subset with DR CLL (DR subcohort) was analyzed separately. Descriptive statistics were generated for demographic and clinical characteristics. Outcomes included clinician-confirmed rwR rate (rwRR) and median TTE outcomes (real-world duration of response [rwDOR], progression-free survival [rwPFS], time to next treatment [rwTTNT], and overall survival [rwOS]; Kaplan Meier, follow-up to May 31, 2023). Results: The DE cohort included 264 patients, 107 of whom were in the DR subcohort. Patients were mostly male (64%), White (75%), aged ≥65 years at first index LOT (72%) after prior cBTKi and BCL2i treatment, and treated in the community setting (71%). Approximately one-third of patients received a subsequent treatment after each index LOT. Most patients were re-treated with a cBTKi and/or BCL2i in the first index LOT (69% DE; 54% DR), and the percentage treated with chemotherapy increased with each subsequent index LOT. Confirmed rwRR was similar between DE and DR for all index LOTs (Table). More relevant are the median TTE outcomes, which were shorter for DR than DE, especially for the first index LOT, and shorter in subsequent index LOTs for both groups. Conclusions: The high percentage of patients re-treated with cBTKi and BCL2i therapies and increasing use of chemotherapy regimens with each subsequent index LOT indicate a lack of standard of care and options. Our results suggest a high unmet need in the DE CLL population, particularly in patients DR to cBTKi and BCL2i therapy, who have worse outcomes. Efficacious and durable therapy options are needed to address this unmet need. Double Exposed Index LOT Double R/R Index LOT 1st 2nd 3rd 1st 2nd 3rd N 264 90 35 107 41 12 rwRR, % (95% CI) 39(33-45) 42(32-53) 40(24-58) 36(27-45) 34(21-51) 42(16-71) Median TTE outcomes, months (95% CI) rwDOR 20.3 (13.5-32.6) 6.0(5.5-NR) 3.1(2.7-NR) 11.5 (7.9-23.5) 6.0(3.6-NR) 2.9(2.7-NR) rwPFS 8.8(7.5-10.6) 5.1(4.0-7.3) 4.3(2.9-6.3) 5.0 (4.0-7.3) 3.6(2.6-5.7) 4.7(2.7-NR) rwTTNT 13.8 (10.3-18.3) 7.9(5.7-11.3) 5.7(4.2-14.6) 8.0 (6.2-11.5) 5.9(4.4-11.4) 5.0(4.2-NR) rwOS 25.2 (22.1-37.1) 15.2(11.4-22.6) 6.6(5.7-NR) 14.7 (12.3-22.6) 11.4(5.9-NR) 6.6(5.0-NR)

e19022 Background: Chronic lymphocytic leukemia (CLL) is a common adult leukemia that originates by dysfunctional development of the lymphocytes. Acalabrutinib, a second-generation Bruton’s tyrosine kinase (BTK) inhibitor, has demonstrated promising outcomes as a targeted therapy alternative to chemoimmunotherapy for treating CLL. The objective of this retrospective analysis was to compare the safety profiles of acalabrutinib and chemoimmunotherapy in patients with CLL and to evaluate the potential of acalabrutinib as an alternative therapeutic option. Methods: We conducted a retrospective cohort analysis using the TriNetX platform analyzing data of patients diagnosed with CLL from January, 2000 to January, 2025. Data was classified into cohorts on the basis of treatment with either acalabrutinib or chemoimmunotherapy. Propensity score matching analysis was carried out to balance their demographic and clinical characteristics. Demographic factors included age (≥18 years), sex, race, and ethnicity. Outcomes assessed included all cause death, atrial fibrillation, hypertension, acute heart failure, ventricular arrythmias, and bleeding. Kaplan-Meier survival analysis was employed. Results: A total of 4,006 patients were included in the analysis, 847 received acalabrutinib and 3,172 underwent chemoimmunotherapy, with a mean age of 70±11 and 69±14 years respectively. Participants were mostly male, with the majority of the patients being non-Hispanic Whites. Median period of follow up was 578 and 925 days respectively, incidence and risk of mortality and adverse events were assessed. A lower risk of mortality was noted with acalabrutinib (RR: 0.407; 95%CI: 0.32, 0.51; p<0.0001). Additionally, atrial fibrillation developed in fewer than 10 patients on use of acalabrutinib, thus carrying significantly lower odds (odds ratio (OR):0.3; 95%CI: 0.16, 0.58; p=0.001) than chemoimmunotherapy, which reported atrial fibrillation in 120 patients. Similarly, significantly lesser incidence of hypertension was noted on use of acalabrutinib, implying safer drug profile. Bleeding risk was also reduced in the acalabrutinib cohort and was statistically significant (OR:0.36, 95%CI: 0.24, 0.52; p<0.0001). The odds of acute heart failure (OR:1.25, 95%CI: 0.61, 2.57; p=0.54) and ventricular arrhythmia (OR:1.5, 95%CI: 0.72, 3.14; p=0.2) were statistically nonsignificant. Conclusions: The use of acalabrutinib in patients with CLL was associated with statistically significant better safety profile, with lesser risk of mortality, bleeding events and atrial fibrillation. Clinicians may consider using acalabrutinib as a superior treatment modality in the treatment of CLL. Further research maybe required to optimize treatment protocols in the best interest of patients.

4568 Background: The 2IR immune response score was initially developed using bulk RNA sequencing of pre-treatment tissue from ImVigor 210 and CheckMate 275 trials, however these trials enrolled patients (pts) with pure urothelial carcinoma (pUC) histology. Patients with hsUC often exhibit worse response to immune checkpoint inibitors (ICI) than patients with pUC. Here, we evaluated the 2IR score as a prognostic or predictive biomarker in real-world pts with hsUC. Methods: Specimens from pts with pUC (n = 1677) and hsUC (n = 417) were profiled at Caris Life Sciences (Phoenix, AZ) using next generation sequencing (NGS) of DNA and RNA. HsUC histologies included majority ( > 50%) squamous (n = 340), sarcomatoid (n = 51), neuroendocrine (n = 20), and micropapillary (n = 6) component. 2IR was calculated by comparative RNA expression of 10 adaptive immune genes and 39 pro-tumorigenic genes. Tumors were classified as 2IR-Low (2IR ≤ -0.5), -Mid (-0.5 < 2IR < 0), and -High (2IR ≥ 0), as previously described (Wang et al., 2022). Spearman correlation analysis was utilized to compare 2IR with tumor mutation burden (TMB), interferon score (IFN) and the tumor microenvironment (TME) cell fractions estimated using quanTIseq. Clinical outcomes included real-world overall survival (rwOS) from ICI start to last contact and time on treatment (ToT) with pembrolizumab, obtained via matched insurance claims data and calculated using Kaplan-Meier methods, while Hazard ratio (HR) was calculated by Cox proportional model. Results: For patients with hsUC, distribution of 2IR score was High 5.76%, Mid 33.3%, and Low 60.9%. Median 2IR score was significantly lower in squamous (-0.60, p < 0.0001) and sarcomatoid UC (-0.82, p < 0.0001) compared to pUC (-0.41) and significantly higher in neuroendocrine UC (-0.15, p = 0.003). Among patients with hsUC, median rwOS was significantly longer for patients with high/mid 2IR score compared to low 2IR score (25.3 [10.9-39.3] months vs. 8.7 [6.2-11.3] months; HR 0.52, 95% CI 0.34 – 0.78, p = 0.0017). ToT with pembrolizumab was also significantly longer for high/mid 2IR score compared to low 2IR score (3.0 [1.4-5.5] months vs. 2.1 [1.4-3.3] months; HR 0.68, 95% CI 0.46-1.00, p = 0.0471). Similar to pUC, 2IR score in patients with squamous UC was positively associated with CD8 T cell infiltration (r = 0.39; p < 0.0001), IFN score (r = 0.41, p < 0.0001), and TMB (r = 0.20, p < 0.001) and negatively associated with M1 macrophage infiltration (r = -0.25, p < 0.0001). 2IR scores in hsUC correlated positively but not significantly with mutations in TP53 (Median: -0.59 vs -0.62, p = 0.067) and PIK3CA (Median: -0.56 vs -0.61, p = 0.172) and negatively with mutations in CDKN2A (Median: -0.67 vs -0.59, p = 0.052). Conclusions: In a real-world cohort of patients with hsUC, we show the 2IR score may be prognostic for rwOS and predictive for pembrolizumab ToT. Prospective studies are needed to further validate this biomarker for use in this population.

e20041 Background: Paraneoplastic syndromes (PNS) are caused by underlying malignancy but not due to metastasis, or treatment related side effects. Studies are lacking which target PNS seen in non small cell lung cancer (NSCLC) Methods: Systematic search of PubMed & Scopus was conducted to include all case reports & case series of adult NSCLC patients with PNS, published globally from inception upto July 7, 2024. Patient demographics, geographical distribution, NSCLC histology, clinical manifestations, diagnosis, treatment was extracted. Quality was assessed by JBI's critical appraisal checklist. Results: 138 publications (136 case reports, 2 case series) describing 142 patients published in 30 countries were included. Majority patients were male (69.7%) with mean age 57 years. Top publishing countries were USA (28.2%), Japan (13%), China (6.5%), Germany (5%), with publications (n=16) peak seen in 2020. Histological type of NSCLC with PNS was adenocarcinoma (39.8%), SCC (26.8%), unspecified histology (13%) & large cell (8.6%). Most common PNS seen in NSCLC were hypertrophic osteoarthropathy (7.2%), bilateral diffuse uveal melanocytic proliferation (5.7%), leukemoid reaction (4.3%) & limbic encephalitis (4.3%). Conclusions: Study provides bird’s eye view of all PNS found in NSCLC, aiding in timely diagnosis & treatment of NSCLC. Organ system PNS Cases Neurology Limbic encephalitisOpsoclonus myoclonus syndromeGBSSensorimotor peripheral neuropathyCerebellar degenerationEncephalomyelitisPerson in barrel syndromeMyoclonusPandysautonomiaNeuromyelitis opticaOpsoclonusAntiHu Ab neuropathyMononeuritis multiplexMorvan syndrome 63221111111111 Cardiology & haematology Leukemoid reactionLeukocytoclastic vasculitisHSPDICITPMyelofibrosisAcral vascular cyanosisHyper eosinophiliaHeart blockTrousseau syndromeHaemophilia ASVC syndromeChurg Strauss syndrome 6332211111111 Endocrinology SIADHCushing syndromeHypercalcemia of malignancyGynaecomastiaβ HCG secretionErectile dysfunction 433221 Rheumatology Hypertrophic osteoarthropathyPolyarthritisPolymyositisDermatomyositisMyasthenia gravisLambert Eaton syndromePolymyalgia rheumaticaSclerodermaRaynaud phenomenonAnti synthetase syndrome 10433311111 Dermatology Bazex syndromeBullous pemphigoidErythema gyratumLeser Trélat Tripe palmsErythrodermaIchthyosisAcanthosis nigricansRhinophymaGranuloma annularePityriasis rubria pilarisEczemaErythema induratumHyperhidrosis 42212111111111 Ophthalmology Bilateral diffuse uveal melanocytic proliferationCancer associated retinopathyCicatrizing conjunctivitisRetinal detachmentOrbital inflammationOcular flutterProptosis 8311111 Nephrology Nephrotic syndrome 3 Gastroenterology Pseudo achalasiaVerner Morrison syndromeGranulomatous visceral neuronopathy 111 Musculoskeletal Necrotizing myopathy 2

4558 Background: In the past 7 years, 4 immuno-oncology (IO) based combinations have been approved for mRCC. However, QOL data on these combinations are limited to trials in which collection and reporting was not standardized, which further limits cross trial comparisons. Real-world QOL data with multiple treatment regimens are needed to understand how these regimens are tolerated in practice. Methods: ODYSSEY is a multi-site, prospective observational study of 500 US pts with mRCC. Pts must have mRCC (any histology), no prior ST, and follow up at a PCORnet study site. Exclusion criteria include treatment for cancer except mRCC. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Minimally important differences (MID) are 3 points for FKSI-19 total score, 1 point for the FKSI-Disease Related Symptoms (DRS) subscale and 7 points for FACT-G. Results: As of 1/6/25, 392 pts were enrolled of whom 299 were managed with ST. Of pts on ST, 114 were treated with IO-IO, 108 with IO-TKI, 33 with IO alone, 27 with Other, and 18 with TKI alone. Median follow up for all pts is 8.8 months (IQR 2.9, 16.2). IO-IO pts are median age 64 yrs, 81% male, 84% white, 56% prior nephrectomy, 84% clear cell; IO-TKI pts median age 66 yrs, 76% male, 92% white, 43% prior nephrectomy, 66% clear cell; IMDC risk profiles are similar. IO-IO pts are more likely to be KPS 100; whereas, IO-TKI pts have a higher median number of metastatic sites and are more likely to have bone or liver metastasis. With median follow-up of 6.0 (IQR 1.8, 14.9) and 8.8 months (4.5, 17.8) in the IO-IO and IO-TKI cohorts, 17 (15%) and 21 (19%) pts had died with a median time to death of 5.4 (2.5, 6.4) and 5.7 months (4.4, 12.8), respectively. 20 (18%) and 16 (15%) pts on IO-IO and IO-TKI had discontinued therapy at a median of 3.0 (IQR 2.0, 4.0) and 6.4 months (2.4, 13.0), respectively. Rates of discontinuation for disease progression and toxicity are similar. Baseline PROs for pts on ST are shown in the Table (higher score indicates better QOL), with RCT data for reference (NA, not assessed). Conclusions: In our prospective multi-center ODYSSEY study, we demonstrate that real world pts treated with contemporary ST have worse baseline QOL than those enrolled on pivotal RCTs. One-third of IO-IO and IO-TKI pts died or discontinued therapy within 6 months of initiation. Our data on real world vs RCT differences in baseline QOL may partially explain the limitations of current IO combination regimens in practice and support development of alternative treatment approaches. Instrument, Mean (SD) ODYSSEYIO-IO(N=114) CheckMate214(N=425) ODYSSEYIO-TKI(N=108) KEYNOTE426(N=402) CheckMate9ER(N=323) CLEAR(N=351) FKSI-19 total 56.0 (12.5) 60.1 (9.8) 53.8 (11.8) NA 58.7 (10.6) NA FKSI-DRS 27.5 (6.3) 30.7 (4.5) 27.0 (5.8) 32 (4.2) 30.2 (5.2) 31.3 (4.4) FACT-G 82.4 (16.7) 82.6 (15.0) 78.5 (16.0) NA NA NA

4553 Background: AS is a recognized strategy in select pts with mRCC to maximize QOL and delay potential toxicity of systemic therapy (ST); however, only 2 prospective studies of AS in mRCC have been published: only 1 with patient-reported outcomes (PRO) and none in the IO-TKI era. Methods: ODYSSEY is a prospective observational study of 500 US pts with mRCC. Eligible pts must have mRCC (any histology), no prior ST, age ≥19. Pts were excluded if treated for non-mRCC cancers or if not followed at a PCORnet study site. Pts completed QOL surveys at baseline, by phone every 3 months for 2 years and then every 6 months until end of follow up. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Minimally important differences (MID) are 3 points for FKSI-19 total score, 1 point for the FKSI-Disease Related Symptoms (DRS) subscale and 7 points for FACT-G. Here we report baseline pt characteristics in AS pts compared to ST pts, and baseline QOL differences between these cohorts. Results: As of 1/6/25, 392 pts were enrolled of whom 299 were managed with ST, and 93 pts deferred ST; of these, 53 pts (57%) were classified as AS. Pts on AS are median age 68 yrs, 66% male, 94% white, 81% clear cell, 50% favorable risk, 44% intermediate risk. Compared with ST pts, AS pts were more likely to have undergone nephrectomy (91% vs 53%), favorable risk profile (50% vs 15%), pancreatic metastasis (15% vs 5%), and longer time since RCC diagnosis (median 58 vs 3.3 months); and less likely to have bone, brain, or liver metastasis. After median 8.8 months follow-up (IQR 2.9, 16.2), 2 pts (4%) on AS had died compared with 45 pts (15%) on ST. One pt (2%) on AS started first-line therapy and 45 pts (15%) discontinued ST. Mean baseline QOL (FKSI-19 total, DRS and FACT-G) for AS and ST ODYSSEY pts is shown in the Table (higher score indicates better QOL), with RCT data for reference (NA, not assessed). ODYSSEY pts on AS had higher QOL for all measures compared with ODYSSEY pts on ST. FSKI-DRS was the same or lower for pts on AS compared to the pivotal trials, while ODYSSEY pts on ST had both lower FKSI-19 total and DRS. Conclusions: In our large prospective cohort from ODYSSEY, pts on AS had higher median QOL scores than pts on ST, but similar to those included in RCTs. These results suggest that some RCT pts could have benefitted from AS. Further follow up is needed to determine long term outcomes in pts on AS and how they respond to deferred ST. Clinical trial information: NCT04919122 . Instrument, Mean (SD) ODYSSEY AS (N=53) ODYSSEY ST (N=299) ODYSSEY Difference, AS vs ST (95% CI) CheckMate 214 (N=425) KEYNOTE 426 (N=402) CheckMate 9ER (N=323) CLEAR (N=351) FKSI-19 total 63.4 (9.2) 56.3 (12.5) 7.0(4.0, 10.1) 60.1 (9.8) NA 58.7 (10.6) NA FKSI-DRS 30.8 (4.2) 27.9 (6.0) 2.9(1.5, 4.7) 30.7 (4.5) 32 (4.2) 30.2 (5.2) 31.3 (4.4) FACT-G 87.9 (14.0) 82.4 (16.7) 5.6(1.1, 10.0) 82.6 (15.0) NA NA NA