Baghdadi, Tareq Al

PURPOSE Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223 ) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% ( P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

4500 Background: BM occur in ~30% of RCC pts and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, prolongs survival in advanced prostate cancer. A pilot study of radium-223 with VEGF tyrosine kinase inhibitors (TKI) in RCC with BM showed safety and early efficacy (McKay, CCR, 2018). Cabozantinib is a TKI that showed efficacy in BM. RADICAL (NCT04071223) was designed to investigate cabozantinib ± radium-223 in RCC with BM. Methods: This open label multicenter study enrolled RCC pts with ≥1 symptomatic BM not previously irradiated and Karnofsky performance status ≥60%. Prior therapies were allowed; non-clear cell population was limited to 20%. Randomization was 1:1 to cabozantinib with (Arm A) or without (Arm B) radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, baseline opioid use, and IMDC risk. In Arm A, cabozantinib was 40 mg daily cycle 1, 60 mg thereafter if tolerated; radium-223 was 1.49 microcurie/kg IV every 28 days for 6 doses. In Arm B, cabozantinib was 60 mg daily. The primary endpoint was SSE-free survival (SSE-FS). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). The study was designed with 85% power to detect improvement in 6-month SSE-FS from 65% to 78% (one-sided α=0.05), with planned interim futility analysis at 50% of expected events. Results: From 12/2019 to 9/2025, 90 pts were enrolled and evaluable for the interim analysis. Median age was 63 years; 74.4% male, 90.0% White, 83.3% clear cell histology. 11.1% were treatment naïve, 80.0% received OTT, 51.1% had baseline opioid use. IMDC risk was 16.7% favorable, 68.9% intermediate, 14.4% poor. Median cabozantinib dose was 31.4 mg (Arm A) and 40.0 mg (Arm B); median radium-223 cycles was 6. Median follow-up was 13.1 (range 0.1-49.4) months with 50 events, 17 SSEs (Arm A: 10; Arm B: 7) and 33 deaths (Arm A: 13; Arm B: 20). Outcomes are in Table. 71 pts were evaluable for response. ORR was 22.2% (Arm A), 22.9% (Arm B). Any grade treatment-related adverse events were 97.7% (Arm A), 93.2% (Arm B); grade ≥3 were 65.9% (Arm A), 56.8% (Arm B). The trial closed after interim analysis as SSE-FS did not meet the prespecified futility boundary (HR≤1). Conclusions: Radium-223 did not improve the primary endpoint of SSE-FS when added to cabozantinib but a numerical prolongation in OS was observed. Combination treatment was safe. Alternative radiotherapeutics warrant investigation in RCC. Clinical trial information: NCT04071223 . Interim efficacy analysis. Arm Median(95% CI) HR (95% CI) Stratified SSE-FS A 17.9 (15.0-NE) 1.24 (0.62-2.48) B 17.6 (10.9-NE) Unstratified SSE-FS A 17.9 (15.0-NE) 0.90 (0.51-1.59) B 17.6 (10.9-NE) OS A 32.2 (17.9-NE) 0.77 (0.42-1.41) B 21.3 (12.3-NE) Stratified PFS A 11.0 (5.8-17.4) 1.39 (0.72-2.66) B 11.2 (9.0-18.5)

ABSTRACT The epidemiology of myelodysplastic syndromes/neoplasms (MDS) is challenging to define due to inconsistent reporting, complex diagnostic procedures, and evolving diagnostic criteria. Using the National MDS Natural History Study—a prospective cohort with centrally adjudicated histopathology and genetic variant review—we characterized the landscape of MDS across the United States and identified differences across demographics. Among 2115 participants, 64% (1346) had an MDS spectrum condition, including MDS (24%), MDS/myeloproliferative neoplasm (5%) and precursor conditions—clonal cytopenia of undetermined significance (22%) and idiopathic cytopenia/dysplasia of undetermined significance (13%). The median age was 74 years, and participants were predominantly male (66%), White (91%), and Non‐Hispanic (92%). Myeloid‐associated variants were detected in 68% of participants, most commonly in TET2, DNMT3A, ASXL1, SF3B1, and SRSF2 . Black, compared to White, participants were younger at diagnosis (69 vs. 74 years, p = 0.01), had equal or increased prevalence of higher‐risk MDS, lower hemoglobin, and higher peripheral blood blasts, yet were less likely to receive MDS‐directed therapy (14% vs. 42%, p = 0.008). Black and Hispanic participants had fewer detectable gene mutations than White participants. Females had lower variant allele frequencies and fewer RNA splicing gene mutations than males. After multivariable adjustment, TP53 mutations, MDS diagnosis, and higher‐risk disease were associated with worse progression‐free and overall survival; age was also associated with overall survival. Black race trended toward improved progression‐free survival. These findings highlight the need for enhanced understanding of MDS pathogenesis across patient groups and refined prognostic tools to improve personalized management of MDS spectrum conditions. Trial Registration: ClinicalTrials.gov identifier: NCT02775383

PURPOSE The primary objective of this randomized, double-blind, placebo-controlled, multicenter phase II study (Alliance A221805) was to screen two doses of duloxetine for preventing sensory oxaliplatin-induced peripheral neuropathy (OIPN). METHODS Participants were randomly assigned 1:1:1 to receive once daily 30 mg duloxetine, 60 mg duloxetine, or placebo. Eligible participants had stage II to III colorectal cancer and no baseline neuropathy, had Eastern Cooperative Oncology Group performance status 0-2, were age 25 years and older, and received oxaliplatin via one of the following doses and schedules: 85 mg/m 2 every 2 weeks (6 or 12 doses) or 130 mg/m 2 every 3 weeks (4 doses). Duloxetine/placebo was taken once daily beginning day 1 of cycle 1 and continued for 17 weeks. The primary end point, a composite response reflecting sensory OIPN symptom severity and onset, was measured in weeks 19-21 using a validated participant-reported outcome survey assessing extremity numbness, tingling, and pain. Response was defined as a participant-reported highest score of ≤2 (ie, 1 = not at all; 2 = a little) on survey items. To be evaluable for the response end point, eligible participants must have initiated oxaliplatin and submitted ≥1 postbaseline OIPN survey. RESULTS Of the 199 participants (n = 66, 30 mg duloxetine; n = 66, 60 mg duloxetine; n = 67, placebo), 46, 47, and 50 (N = 143, 71.8%), respectively, were evaluable for primary end point analysis based on modified intention-to-treat criteria. Participant mean age was 55.1 years (standard deviation = 10.4). Most were White (n = 113, 80.7%) and male (n = 82, 58.6%). The proportion of responders among those receiving placebo (68.0%) was similar to those receiving duloxetine 30 mg (65.2%) or 60 mg (66.0%). Duloxetine adherence rates, measured via pill counts—30 mg (54%), 60 mg (57%), and placebo (59%) groups—were low (<75%). CONCLUSION Duloxetine is not more promising than placebo for preventing sensory OIPN.

Abstract Patients at risk for progression from myeloid precursor states (idiopathic cytopenia of undetermined significance [ICUS] and clonal cytopenia of undetermined significance [CCUS]) to myelodysplastic syndrome (MDS) are not well defined. Epidemiologic risk factors, clonal changes for MDS development, and evolution from one MDS state to another were available in the MDS Natural History Study (NHS), a prospective cohort enrolled at diverse US sites. Extensive clinical data and biospecimens were collected at baseline and follow-up. A total of 1177 (56%) individuals with MDS or MDS-related precursor conditions (ICUS/idiopathic dysplasia of undetermined significance [IDUS], CCUS, and MDS/myeloproliferative neoplasm overlap) were enrolled and diagnosed in the MDS NHS. The median age was 74 years, with 89% aged ≥60 years, and most were male patients. Median follow-up time was 1.6 years and was similar among ICUS/IDUS, CCUS, and MDS. During follow-up period, 68% of participants terminated the study, 35% died, and 38% had disease progression. Using a refined clinical definition of progression, the greatest proportion of progression was observed among higher-risk-MDS (116 [73%]), followed by lower-risk-MDS (170 [52%]); fewer progression events were observed among participants with CCUS (65 [22%]) and ICUS/IDUS (46 [17%]). Predictors of progression are delineated, including female sex, higher quantity of mutations, the presence of TP53 mutation, and poor/very poor cytogenetic score. Based on these prospective data, guidelines for clinical management including monitoring and surveillance are outlined. The MDS NHS provides real-world data to illustrate how clinical and genotypic differences inform the classification, disease course, and approach to therapy, with informed monitoring guidelines for patients. This trial was registered at www.ClinicalTrials.gov as NCT02775383.

Abstract Introduction Defining the epidemiology of myelodysplastic syndromes/neoplasms (MDS) and precursor conditions, such as clonal cytopenia of undetermined significance (CCUS), is challenging due to inconsistent reporting, complex diagnostics, and evolving criteria. The National MDS Natural History Study (NHS) overcomes these challenges through central pathology review, prospective follow-up, and a nationally representative cohort enrolled at the time of suspected MDS, enabling robust analysis across the myeloid disease spectrum. We analyzed clinical, genetic, and pathologic features in NHS participants by race, ethnicity, and sex to characterize disease variation across populations. Methods The NHS (NCT02775383) enrolled individuals undergoing evaluation for suspected MDS from June 2016–July 2024 at 102 US sites. Participants underwent bone marrow assessment with centralized, adjudicated histopathology review. Those meeting WHO 2016 criteria for MDS, MDS/myeloproliferative neoplasm (MPN), CCUS, idiopathic cytopenia/dysplasia of undetermined significance (ICUS/IDUS), or oligoblastic AML were followed longitudinally. Demographics, comorbidities, exposures, and clinical data were collected at baseline and every 6 months. Deep DNA sequencing was performed on baseline marrow, with pathogenic variants manually curated (53 genes). Statistical analyses assessed associations using chi-squared, Fisher's exact, Kruskal-Wallis, logistic regression, and Cox models. A p-value &lt;0.05 was considered significant. Results Among 2,021 participants, 1,174 (58%) were diagnosed with MDS or precursor conditions. Median age was 74 years (yrs) and 66% were male. Most identified as Non-Hispanic White (NHW, 92%), with 4% Black and 4% Hispanic. The most common diagnoses were MDS (42%) and CCUS (37%). Pathogenic somatic mutations were identified in 84% (774/918) of MDS/CCUS, with TET2 (26% of 918), DNMT3A (21%), and ASXL1 (16%) most frequent. Median follow-up was 1.8yrs and consistent across race, ethnicity, and sex (p≥0.6). Black, compared to NHW, participants were younger (69 vs 74 yrs, p=0.006) and trended toward more females (47% vs 34%, p=0.09) and more MDS diagnoses (51% vs 41%, p=0.07). Black participants showed more advanced disease (e.g., lower hemoglobin, higher peripheral blood blasts, higher variant allele frequencies (VAFs) of pathogenic mutations), yet received less MDS-directed treatment (14% vs 41%, p=0.01). Black, compared to NHW, participants had more mutations in RUNX1, TP53, BCOR, and DNMT3A, but fewer in TET2 and ASXL1. Hispanic, compared to Non-Hispanic, participants had fewer known pathogenic mutations, leading to more ICUS (19% vs 5%, p=0.02). Females, compared to males, were younger at diagnosis (72 vs 75yrs, p&lt;0.001), had more ICUS/IDUS (20% vs 10%, p&lt;0.001), fewer pathogenic mutations, especially in splicing/chromatin modifier genes (U2AF1, SRSF2, ASXL1, ZRSR2), more DNMT3A mutations, and lower VAFs (0.27 vs 0.33, p&lt;0.001). Median overall survival (OS) was 6.4yrs, and shorter in MDS (4.2yrs) than CCUS (not reached). Worse OS was associated with age (adjusted hazard ratio (aHR) 1.06), MDS (vs CCUS; aHR 1.89), higher-risk disease by IPSS-R/CCRS (aHR 2.15), and TP53 mutations (aHR 2.17) (all p&lt;0.001). A trend toward improved OS in Black participants was attenuated after adjustment (aHR 0.79, p=0.6). Progression (e.g., worsening of disease, increase in transfusion dependency, death) occurred in 53% of participants. Worse progression-free survival (PFS) was associated with MDS diagnosis (aHR 2.59), higher-risk disease by IPSS-R/CCRS (aHR 2.17), and TP53 mutations (aHR 1.86) (all p&lt;0.001). Despite more advanced disease and less MDS therapy, Black participants trended toward improved PFS (aHR 0.62, p=0.14), while age was borderline significant (aHR 1.01, p=0.05). Conclusions For the first time, we show that among individuals evaluated for suspected MDS at sites across the US, 58% had MDS or precursor conditions. Differences across demographics underscore the heterogeneity of MDS. Black participants presented with more advanced MDS, received less treatment, but trended toward improved outcomes, particularly PFS, even after adjustment, suggesting biological rather than access-to-care differences driving disparities. These findings highlight the complex interplay of sex, race, and genetics in shaping MDS outcomes and reinforce the need for diverse, large-scale studies to improve risk stratification and personalized care.

Abstract Background Myelodysplastic syndromes (MDS) develop from the acquisition of somatic mutations over years or decades. While some mutations are random stochastic events, others derive from extrinsic agents that promote genomic instability, including environmental exposures. Agent Orange (AO) is a phenoxy herbicide used by the U.S. military as a defoliant during the Vietnam War (1962-71), often diluted with gasoline to promote aerosolization, contaminated with the carcinogen dioxin during the manufacturing process, and linked to various cancers. We studied AO as a risk factor for MDS. Methods The prospective National Heart, Lung, and Blood Institute National MDS Natural History Study includes patients (pts) with suspected or recently diagnosed MDS enrolled from 6/2016-6/2024. Bone marrow samples underwent central pathology review, resulting in diagnoses including MDS, MDS/myeloproliferative neoplasm overlap (MDS/MPN), or clonal cytopenia of undetermined significance (CCUS). Pts completed detailed assessment for AO exposure and other risk factors for MDS development. Associations between AO exposure, mutation prevalence, and key covariates (demographics, diagnosis, military service, clinical history, cytogenetics and smoking) were assessed using univariate tests of association, multivariable regression and Cox regression models for survival and progression. Results Among 2115 enrolled pts, 1191 (56%) had a myeloid malignancy or precursor condition and 130 (6.1%) reported AO exposure, the majority (96%) male. Compared to unexposed pts, AO exposed pts were more likely to derive from the 1945-54 birth cohort (p&lt;.001), of age to serve in Vietnam, and to have an ultimate diagnosis of MDS or CCUS vs. a non-clonal diagnosis (57% vs. 44%, p=.046). AO exposure was more common among Blacks (12% vs 6%, p=.02), specifically Black males (21% vs 9%, p=.006). AO exposure was marginally associated with International Prognostic Scoring System (IPSS)-R poor-risk cytogenetics (p=.066) and lower baseline platelet count (p=.072). In multiple regression analyses, risk of AO exposure was significantly higher for the 1945-1954 birth cohort (OR [95% CI]=10.3 [4.4-30.6], p&lt;.001), among those with military service (OR=24.1 [11.9-55.8], p&lt;.0001), and for Blacks vs Whites (OR=2.6 [1.2-5.5], p=.017). The crude risk of AO exposure trended higher for patients with MDS compared to idiopathic cytopenia of undetermined significance (ICUS; OR=2.1 [0.9-6.0],p=.13), but not in multivariable analysis (OR=1.3 [0.5-4.4, p=.60]). AO exposure trended toward an association with younger age at MDS diagnosis (p=.06) and toward having a prior primary malignancy (49% vs. 41%, p=.09): Compared to non-AO exposed pts, AO exposed pts had higher rates of prior prostate cancer (16% vs. 8%), notable given its documented association with AO exposure. AO exposure was not associated with a history of or intensity of cigarette smoking (p=.67). After accounting for age, diagnosis, sex, and military service, AO exposure was significantly associated with increased numbers of pathogenic variants in 53 genes (OR=1.2 [1.0-1.4], p=.02) and with having Very Poor/Poor risk IPSS-R cytogenetics (OR=3.7 [1.2-11.1], p=.02). AO exposed and non-exposed pts had similar overall survival (HR=1.1 [0.8-1.7], p=.50), but those exposed to AO had a higher risk of disease progression in the first two years following diagnosis (HR =1.9 [1.2-2.8], p=.004). AO exposed pts appeared more likely to have del (5q) (15% vs. 8%) and del (20q) (13% vs. 5%) karyotypic abnormalities, and TP53 (7.7% vs. 4.5%), STAG2 (5.1% vs. 2.8%), and NRAS mutations (3.4% vs. 1.7%), although sample sizes were small. Focusing on gene pathways, AO exposed pts appeared more likely to have abnormalities in RAS signaling (10.3% vs. 5.7%), cell cycle (7.7% vs. 4.5%), and cohesion complex pathways (6.0% vs. 3.1%), but less likely to have abnormalities in cytokine receptor pathways (0% vs. 4.5%). ConclusionsIn our representative national cohort of pts with at least one cytopenia, and for the first time, we demonstrated that AO exposure is associated with younger age at MDS diagnosis, ultimate MDS diagnosis, genetic complexity of MDS, increased risk of disease progression, and with Black race, despite Black individuals comprising just 16% of men who served in the Vietnam War and being less likely to have MDS than white individuals. AO should formally be recognized as a risk factor for the development of MDS.

TPS3650 Background: A total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone in those with locally advanced rectal cancer. Recent data indicate that optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to improve complete response rates. The use of FOLFIRINOX has shown to improve response and outcomes compared to CRT and surgery alone. Data have also shown that patients with clinical complete response (cCR) after TNT may be managed with a watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to improve cCR rates has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. We designed this NCI-sponsored study of chemotherapy intensification to address this and to increase cCR rates, provide opportunity for organ preservation, and survival outcomes. Methods: In this multigroup randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N+) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0–4; 4–8; 8–12 cm). Patients will be randomized to receive neoadjuvant long-course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX (control arm)) or triplet chemotherapy (FOLFIRINOX (experimental arm)) for 3–4 months. LCRT in both arms involve 4500 cGy in 25 fractions over 5 weeks +900 cGy boost in 5 fractions with a fluoropyrimidine. Patients will undergo assessment 8–12 (±4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 312 patients (156 per arm) will provide statistical power of 90.5% to detect a 17% increase in cCR rate, at a one-sided alpha = 0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include overall survival, organ preservation time, time to distant metastasis, and adverse event rates. This study has accrued 587 patients as of January 2025, and is investigating exploratory correlatives (e.g., ctDNA). Support: U10CA180821, U10CA180882, U24 CA196171. https://acknowledgments.alliancefound.org. Clinicaltrials.gov ID: NCT05610163. Clinical trial information: NCT05610163 .

TPS4616 Background: Osseous metastases (OM) occur in approximately 30% patients with advanced RCC. Despite therapeutic advances, OM are associated with poor survival and risk of symptomatic skeletal events (SSEs). Cabozantinib targets multiple tyrosine kinases, including vascular endothelial growth factor (VEGF) receptors and MET (Mesenchymal-Epithelial Transition factor), which are overexpressed in OM, contributing to cabozantinib’s enhanced bone activity. Radium-223, an alpha-emitting bone-seeking radioisotope, prolongs survival in men with metastatic castration-resistant prostate cancer to the bone. Building on this therapeutic approach targeting OM, our pilot study of radium-223 with VEGF inhibition in RCC with OM has also shown safety, improvement in circulating bone turnover markers, and early efficacy (McKay et al, CCR 2018). To address the unmet need to improve SSE rates and outcomes in RCC and OM, we designed a study investigating cabozantinib with or without radium-223 in patients with RCC with OM (NCT04071223). Methods: This is an open-label, multicenter randomized phase-2 study. Key inclusion criteria include metastatic RCC of any histology with ≥1 OM, at least 1 OM without prior radiation, any number of prior therapies, and Karnofsky performance status ≥ 60%. Use of a bone protecting agent is required unless contraindicated. Patients are randomized 1:1 to cabozantinib with (Arm A) or without (Arm B) radium-223. The starting dose of cabozantinib for Arm A is 40 mg by mouth daily to be escalated to 60 mg daily after cycle 1 (1 cycle = 28 days) if no persistent grade 2 or grade ≥3 toxicity. Radium-223 is administered at a fixed dose of 1.49 microcurie/kg IV every 28 days x 6 doses. The starting dose for cabozantinib in Arm B is 60 mg daily. The primary endpoint is SSE-free survival. Secondary endpoints include safety, progression-free survival, overall survival, time to first SSE, objective response rate, time to subsequent anti-cancer therapies, quality of life (QoL) measures, and correlative analyses including liquid biopsy and tumor tissue analysis. The study is designed to have 85% power to detect an improvement in 6-month SSE-free survival rate from 65% to 78% with one-sided α = 0.05 significance. To ensure 124 evaluable patients, target accrual is 134 (67 per arm). The group-sequential design includes a safety run-in and an interim analysis for futility when 50% of the expected number of events have been observed. The safety run-in, performed in the first 12 patients randomized to combination therapy, did not demonstrate dose limiting toxicities. Final data analysis will occur when 99 events have been observed. The study was activated in July 2020 and accrual is ongoing throughout the National Clinical Trials Network (NCTN). Continued site participation and enrollment are essential to evaluate this therapeutic strategy. Clinical trial information: NCT04071223 .