Association of clinical characterization of renal cell carcinoma (RCC) with merlin protein deficiency and biallelic loss of NF2 .

• DOI: 10.1200/jco.2025.43.5_suppl.506
• Publication Date: 2025-02-18T14:38:27Z
• Authors: Emre Yekeduz; Marc Machaalani; Stephanie E. Sieg...; Eddy Saad; Razane El Hajj Ch...; Clara Steiner; Stephanie A. Berg; Bradley Alexander...; Charlene Mantia; Praful Ravi; Wenxin Xu; Michelle S. Hirsch; Toni K. Choueiri; Michael Thomas Se...
• Keywords: Merlin (protein)

506 Background: Neurofibromin-2 (NF2) is a tumor suppressor gene that encodes the scaffolding protein merlin and commonly mutated in rare RCC subtypes: unclassified (uRCC), papillary (pRCC), collecting duct carcinoma (CDCA), emerging entity, biphasic hyalinizing psammomatous (BHP-RCC). Merlin loss/deficiency by immunohistochemistry (IHC) was recently demonstrated as reliable surrogate marker of NF2 genomic alterations (GAs). We report first clinical outcomes patients (pts) with merlin-deficiency/biallelic loss NF2, treated immune checkpoint inhibitor (ICI) vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKI) therapies. Methods: In our single institutional cohort, we identified 27 pts high-grade morphology suggestive BHP-RCC or unclear subtype. All had deficiency (by IHC) 12/16 data were found to have also biallelic next-generation sequencing). Overall survival (OS), progression-free (PFS), objective response rate (ORR) evaluated. Survival curves generated using Kaplan-Meier method. Results: overall cohort (N=27), histologic subtypes included (N=19), uRCC (N=6), pRCC (N=1), CDCA (N=1). The median age at diagnosis 56 74.1% (N=20) metastatic disease. Seventeen received systemic treatment 76.5% (N=13) ICI-based regimens (Table). PFS OS 4.9 24.5 months, respectively. ORR 28.6% treatment, 18.2% 66.7% (p=0.18) those ICI non-ICI, Pts non-ICI similar (p=0.44), (p=0.14). “classic” BPH-RCC who (N=10), 25% while did not reach median. other merlin-deficient (N=7), 33.3%, 6.6 No statistically significant differences (p=1.00), (p=0.93) (p=0.60) observed between subtypes. Conclusions: IHC has emerged for GAs, which are associated aggressive including BHP-RCC. Despite exposure standard VEGFR TKI therapies, few deficient derived benefit prognosis remains poor. Systemic disease (n=17). ICINivolumab+IpilimumabNivolumab+Ipilimumab+CabozantinibNivolumab+CabozantinibPembrolizumab+AxitinibAtezolizumab+BevacizumabAtezolizumabNon-ICICabozantinibEverolimusChemotherapy 13 (76.5) 6 (35.2)3 (17.6)1 (5.8)1 (5.8) 4 (23.5) 2 (11.7)1