Priya Rao

Supplementary Figures and Tables

Purpose: SMARCB1-deficient renal medullary carcinoma (RMC) is an ultrarare, lethal malignancy refractory to therapies approved for other renal cell carcinomas, and its rarity makes randomized trials logistically unfeasible. We investigated whether wild-type (WT) epidermal growth factor receptor (EGFR) is a therapeutically actionable dependency in RMC and translated this insight into a deployable clinical regimen. Experimental Design: EGFR expression was assessed by Clinical Laboratory Improvement Amendments–certified immunohistochemistry in RMC tumors and by integrated RNA and chromatin immunoprecipitation sequencing of primary tumors and adjacent kidney. Panitumumab was compared with erlotinib in patient- and cell line–derived xenografts, and its mechanism defined by immunoblotting, confocal co-localization, cell-cycle and apoptosis assays, and natural killer (NK) cell coculture. Panitumumab-based therapy was then evaluated prospectively in 26 patients with RMC across 10 centers on two continents. Results: RMC showed uniformly high membranous EGFR (median H-score 300), with enhancer and promoter reprogramming at the EGFR locus and a ligand switch from EGF to epiregulin and amphiregulin. EGFR expression was uncoupled from SMARCB1 status in vitro. Panitumumab outperformed erlotinib in RMC xenografts, suppressed AKT and ERK1/2 signaling, and routed EGFR to LAMP1-positive lysosomes in vitro; its effect was predominantly cytostatic, with minimal NK cell–mediated cytotoxicity. Clinically, panitumumab-based therapy achieved a 53.9% objective response rate, including 15.4% complete responses, with median progression-free and overall survival rates of 5.8 and 9.5 months, respectively. Conclusions: WT EGFR is a foundational dependency in RMC that is effectively targeted by panitumumab-based therapy. These findings, derived from a nonrandomized registry, provide a biological and clinical rationale for further prospective validation.

Overall survival from treatment initiation with ixazomib plus gemcitabine plus doxorubicin.

Single-cell landscape of TME and epithelial cells from longitudinally collected tumor samples at baseline and during trial therapy.

Cell–cell communication between malignant and TME populations through BMP and WNT signaling.

Probability density functions for the two co-primary endpoints in trial and historical control cohorts.

Treatment emergent adverse events at least possibly related to study therapy.

Treatment emergent adverse events regardless of attribution.

Number of tumor cells in scRNA-seq analysis from the 11 patients with RMC.