Jose A. Karam’s research while affiliated with University of Texas MD Anderson Cancer Center and other places

Background Current treatment for frontline ccRCC focuses on systemic therapy doublets. Although effective, such combinations exhibit substantial toxicities and healthcare costs. An underutilized option is MRWS, which may facilitate a prolonged systemic therapy-free interval in select patients. Unfortunately, no reliable prognostic markers exist to select patients for MRWS. Although ctDNA assays may guide patient selection, implementation in ccRCC has proven challenging due to limited ctDNA shedding. Therefore, advanced sequencing and bioinformatic pipelines are needed to enhance ctDNA reliability in ccRCC. Methods This phase 2 single-arm trial (NCT03575611) enrolled patients with oligometastatic ccRCC and up to 5 metastases. All patients had either never received systemic therapy or ceased >1 month earlier. Patients were treated with MRWS, consisting of predominately stereotactic radiation therapy to all sites of disease. Subsequent rounds of MRWS were administered if limited progression was observed. The co-primary endpoints were progression free survival (PFS) and systemic therapy free survival (STFS). For the latter, a median STFS of >24 months (mo) was prespecified as the threshold for success. Individualized ctDNA panels (Myriad Genetics) were created from tumor whole genome sequencing and applied to serial plasma samples. Molecular residual disease (MRD) status was determined based on whether ctDNA was detected (MRD+) or not (MRD-). Results Between July 2018 to May 2023, 121 oligometastatic ccRCC patients were enrolled. Median follow up was 36 mo (range 13-68 mo). Most patients (72%) had 1 site of metastatic disease and had never received systemic therapy (70%). The median PFS was 18 mo (95% CI: 15-22 mo) and STFS was 34 mo (95% CI: 28-54 mo). The lower bounds of 95% CI of the median STFS exceeded the prespecified 24 mo threshold for success. Two-year PFS and STFS were 40% and 75%, respectively. Median OS was not reached, and 2- and 3-year OS were 94% and 87%, respectively. Eight (7%) patients experienced grade 3+ toxicities at least possibly attributed to MRWS. There were no grade 5 toxicities.MRD+ was detected in 56% of patients at baseline and associated with significantly shorter STFS (HR 2.9, 95% CI 1.4-6.1, P=0.003). Patients who were MRD+ and MRD- at baseline exhibited 27 vs. 54 mo median STFS, respectively. Three months after MRWS, 31% of MRD + patients converted to MRD-. Positive MRD status at 3 month follow up was strongly associated with shorter STFS (HR 4.3, 95% CI 2.0-9.0, P<0.001). Conclusions MRWS exhibited excellent tolerability and facilitated prolonged time off systemic therapy without compromising OS. Our ctDNA approach appears to be a promising baseline prognostic biomarker for STFS and a dynamic marker of MRWS response. Citation Format Chad Tang, Alexander Sherry, Aaron Seo, Kieko Hara, Haesun Choi, Suyu Liu, Xiaowen Sun, Anya Montoya, Ethan Ludmir, Amishi Y. Shah, Eric Jonasch, Amado J. Zurita, Craig Kovitz, Christopher J. Battey, Sarah Ratzel, Giannicola Genovese, Kanishka Sircar, Jose Karam, Nizar Tannir, Pavlos Msaouel. Phase 2 trial of metastasis directed radiotherapy without systemic therapy (MRWS) for oligometastatic clear cell renal cell carcinoma (ccRCC) and investigation of circulating tumor DNA (ctDNA) as a personalized biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT132.

Surgical removal of primary tumors reverses tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT), is not understood. We report the first prospective, pilot, non-comparative clinical trial (NCT02210117) to evaluate the feasibility, clinical benefits, and immunologic changes of combining three different ICT-containing strategies with cytoreductive surgery or biopsy for patients with metastatic clear cell renal cell carcinoma. Primary safety endpoint of this trial has been met, with 43 patients completing cytoreductive surgery, 36 patients undergoing post-ICT biopsy, and 25 patients without either procedure due to progressive disease or toxicities or withdrawal of consent (total N = 104). Patients receiving ICT with cytoreductive surgery or biopsy, did not experience additional ICT- or procedure-related toxicities. The median overall survival was 54.7 months for patients who received ICT plus cytoreductive surgery. Immune-monitoring studies demonstrated that cytoreductive surgery increased antigen-presenting dendritic cell population and decreased KDM6B-expressing immune-suppressive myeloid cells in the peripheral blood. This study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated the potential enhancement of immune responses following ICT plus cytoreductive surgery.

447 Background: The evolving treatment landscape in mRCC since the advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has rendered the role of CN unclear. We sought to quantify CN utilization in the US over the past two decades and assess factors that affect equitable access to CN. Methods: We performed an analysis of the National Inpatient Sample database, using ICD-9 and ICD-10 diagnostic and procedure codes to identify mRCC patients undergoing CN from 2006 to 2021. We calculated annual CN utilization rates, stratified by demographic and socioeconomic factors. We then performed univariable and directed acyclic graph-guided multivariable logistic regression analyses to determine the effect of demographic, socioeconomic, and clinical factors on CN utilization rates. Results: There has been a significant decrease in CN utilization in 2021 compared to 2006 (8.7% vs. 15.8%; OR 0.51, 95% CI 0.42-0.61), consistent across all demographic and socioeconomic groups. Factors associated with decreased CN utilization include Black race (OR 0.70, 95% CI 0.64-0.76), Hispanic race (OR 0.87, 95% CI 0.80-0.95), female gender (OR 0.94, 95% CI 0.90-0.98), being a Medicare (aOR 0.69, 95% CI 0.64-0.73) or Medicaid beneficiary (aOR 0.59, 95% CI 0.54-0.64), lowest income quartile (aOR 0.84, 95% CI 0.78-0.90), Southern US location (aOR 0.83, 95% CI, 0.74-0.93), and treatment in small-sized (aOR 0.57, 95% CI 0.51-0.63) or rural hospitals (aOR 0.33, 95% CI 0.27-0.40). CN utilization has significantly decreased during the ICI era compared to the TKI era (OR 0.69, 95% CI 0.64-0.75). Conclusions: CN utilization has steadily declined across the US over the past two decades, reflecting the uncertainty surrounding its role in mRCC management as new systemic therapies emerge. Access to CN is marked by significant demographic and socioeconomic disparities. Defining the evolving role of CN in the current mRCC treatment era and addressing these disparities is crucial to optimize patient outcomes. Characteristic Univariable analysis(OR [95% CI]) p -value Multivariable analysis(aOR [95% CI]) p -value Black race (ref. White) 0.70 (0.64-0.76) <0.001 - - Hispanic race (ref. White) 0.87 (0.80-0.95) 0.001 - - Female gender (ref. male) 0.94 (0.90-0.98) 0.008 - - 1 st quartile income (ref. 4 th quartile) 0.79 (0.73-0.85) <0.001 0.84 (0.78-0.90) <0.001 Medicare (ref. private insurance) 0.55 (0.53-0.58) <0.001 0.69 (0.64-0.73) <0.001 Medicaid (ref. private insurance) 0.58 (0.54-0.63) <0.001 0.59 (0.54-0.64) <0.001 Southern US (ref. Northeastern US) 0.82 (0.73-0.92) 0.001 0.83 (0.74-0.93) 0.002 Small hospital (ref. large hospital) 0.56 (0.50-0.62) <0.001 0.57 (0.51-0.63) <0.001 Rural hospital (ref. urban teaching hospital) 0.32 (0.27-0.38) <0.001 0.33 (0.27-0.40) <0.001

Immune checkpoint inhibitors can lead to ‘exceptional’, durable responses in a subset of persons. However, the molecular basis of exceptional response (ER) to immunotherapy in metastatic clear cell renal cell carcinoma (mccRCC) has not been well characterized. Here we analyzed pretherapy genomic and transcriptomic data in treatment-naive persons with mccRCC treated with standard-of-care immunotherapies: (1) combination of programmed cell death protein and ligand 1 (PD1/PDL1) and cytotoxic T lymphocyte-associated protein 4 inhibitors (IO/IO) or (2) combination of PD1/PDL1 and vascular endothelial growth factor (VEGF) receptor inhibitors (IO/VEGF). In the IO/IO cohort, clonal neoantigen load was significantly higher in persons with ER. In the IO/VEGF cohort, ER participants displayed strong enrichment of B cell receptor signaling-related pathways, tertiary lymphoid structure (TLS) signatures and evidence of increased metabolic activity. Our results suggest that ER may be related to clonal neoantigen-driven cytotoxic T cell responses and TLS formation in tumor microenvironments. Therapeutic combinations that elicit both T cell-directed and B cell-directed antitumor immunity may be important to achieve exceptional benefit to IO-based treatment in ccRCC.

Background Kidney cancer is amongst the deadliest genitourinary malignancies. Neoadjuvant systemic therapy has the potential to improve survival and overall outcomes in select patients. Enrolling patients in trials of neoadjuvant treatment for kidney cancer is challenging, which limits neoadjuvant treatment development. Objective This study aims to develop a better understanding of the barriers patients face in kidney cancer clinical trial participation, with a particular focus on neoadjuvant trials for renal cell carcinoma. Methods From 2022–2023, we recruited participants with a history of kidney cancer through a Qualtrics survey that was sent to the Kidney Cancer Association (KCA) and Kidney Cancer Cure (KCCure) mailing lists and social media pages. Patient responses on demographics, clinical information, and perspectives were evaluated. Results Ninety-four individuals completed the survey. Eighty-one percent of respondents reported not participating in clinical trials due to not being informed about potential applicable trials. Importantly, many (76%) respondents reported that prevention of cancer return was a highly important reason to participate in clinical trials. Most respondents reported a willingness to undergo a kidney biopsy (59%), and/or additional appointments (58%) and surgery delays. Conclusions Increased patient awareness about clinical trials with the potential to delay cancer recurrence may increase patient participation in clinical trials. Clinical trial design, including additional appointments or interventions and/or minor surgery delays are not major barriers to trial participation.