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

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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

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