Prospective clinical activity and preclinical basis of panitumumab-based EGFR blockade in SMARCB1-deficient renal medullary carcinoma (RMC): A collaborative multi-institutional study.

4520 Background: RMC is a rare, exceptionally aggressive malignancy that predominantly affects young individuals of African descent with sickle cell trait. RMC is typically refractory to standard kidney cancer therapies, including anti-angiogenic agents and immune checkpoint inhibitors. While cytotoxic chemotherapy is the current standard, objective response rates (ORR) remain low (~29%), with a median progression-free survival (PFS) of ≤ 4 months in the first-line setting. This study explores wild-type EGFR as a therapeutic dependency in RMC. Methods: We characterized EGFR expression and mutation status in primary RMC tumors using whole exome sequencing (WES), CLIA-certified IHC and integrated bulk RNA and histone ChIP-sequencing. Preclinical efficacy was compared between the EGFR antibody panitumumab and the kinase inhibitor erlotinib across two RMC xenograft models. Subsequently, a prospective multi-national registry (N=26) evaluated panitumumab-based therapy (monotherapy or combined with nab-paclitaxel ± carboplatin) in heavily pretreated patients with RMC. Results: No EGFR mutations were detected on WES. RMC tumors demonstrated uniformly high wild-type EGFR protein expression and enhancer-associated activation. In vivo, panitumumab induced profound tumor regressions in both RMC xenograft models, significantly outperforming erlotinib (p < 0.005). Mechanistically, panitumumab triggered definitive lysosomal receptor degradation and suppressed AKT and ERK1/2 signaling. The prospective clinical registry (N=26) included 20 (76.9%) males and 6 (23.1%) females, with a median age of 33.5 years (range, 17–67). At treatment initiation, patients had a median of 4 metastatic disease sites (range, 2–6). The cohort was heavily pretreated with a median of 2 prior systemic therapies (range, 0–4); 96.2% had progressed on prior platinum-based chemotherapy. We observed an ORR of 53.9% (14/26 patients), including 4 (15.4%) complete responses. Median PFS was 5.8 months (95% CI: 4.0–8.2) and median OS was 9.5 months (95% CI: 7.6–NE). Treatment was well-tolerated, with manageable grade 1-2 acneiform rash (80.8%), no grade 3+ rash cases observed, and no treatment-related deaths. Conclusions: These data establish wild-type EGFR dependency as a foundational vulnerability in RMC. Panitumumab-based therapy yields unprecedented responses in heavily pretreated patients and represents a transformative new systemic standard of care for this lethal disease. Clinical outcomes. Total (N=26) Best overall response, n (%) Complete response 4 (15.4%) Partial response 10 (38.5%) Stable disease 7 (26.9%) Progressive disease 5 (19.2%) Depth of response % Median (IQR) -30.9 (-58.9, +3.1)