Association of clinical characterization of renal cell carcinoma (RCC) with merlin protein deficiency and biallelic loss of <i>NF2</i> .
Authors: Emre Yekeduz, Marc Machaalani, Stephanie E. Siegmund, Eddy Saad, Razane El Hajj Chehade, Clara Steiner, Stephanie A. Berg, Bradley Alexander McGregor, Charlene Mantia, Praful Ravi, Wenxin Xu, Michelle S. Hirsch, Toni K. Choueiri, Michael Thomas Serzan
Journal: Journal of Clinical Oncology (2025)

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