Radiologic, Pathologic, and Deep Learning Predictors of Response to Immune Checkpoint Blockade in Renal Cell Carcinoma Patients Undergoing Post-Treatment Nephrectomy

AbstractO_ST_ABSBackgroundC_ST_ABSResponse assessment of primary kidney tumors in the consolidation cytoreductive and neoadjuvant settings offers a unique opportunity to inform postoperative adaptive treatment strategies. Yet, systematic analyses evaluating radiology, pathology, and machine learning are lacking. MethodsWe retrospectively identified consecutive renal cell carcinoma (RCC) patients with locoregionally advanced or metastatic RCC who received at least one cycle of ICI-containing doublet therapy prior to nephrectomy at the UTSW Kidney Cancer Program (2017-2024). Radiologic and pathologic features were centrally reviewed and correlated with clinical outcomes: freedom from start of next systemic therapy (FFNT) in cytoreductive patients and metastasis-free survival (MFS) in neoadjuvant patients. Pathologic response to ICI results in tumor cell death and fibrosis creating hypocellular areas and increased immune infiltrate, features we utilized to build Deep learning (DL) models. We leveraged DL models to validate pathologist-assessed regression objectively and quantitate immune infiltrate. ResultsAmong 99 patients (cytoreductive nephrectomy {CN}, n=66; neoadjuvant nephrectomy {NaN}, n=33), radiologic tumor shrinkage [≥]30% (p=0.0036) and the extent of ICI-induced pathologic regression as assessed by central review (HR 0.97; CI 0.95-0.99; p=0.0023) and by DL (HR 0.96; CI 0.93-0.99; p=0.0041), but not coagulative necrosis, were significantly associated with prolonged FFNT, with similar trends in neoadjuvant cohort. Multivariable Cox regression analyses showed pathologic regression, DL-derived extent of immune infiltrate and tumor largest dimension at nephrectomy to be independent predictors of FFNT. ConclusionsThis study provides, for the first time, an integrated, quantitative framework of post-ICI response in RCC. Our data suggests that immune-mediated pathologic regression changes differ from coagulative necrosis, an indicator of poor prognosis. Our findings provide a blueprint for complementary role of radiology and pathology evaluation of post ICI-nephrectomy specimens that if validated prospectively, could guide adaptive approaches and clinical trial design for ICI-based therapies in kidney cancer and beyond.