Clinical outcomes in NF2-mutated RCC treated with contemporary immunotherapy regimens

Abstract Background: Neurofibromin-2 (NF2) encodes the cell scaffolding protein merlin, which is involved in the Hippo tumor suppressor pathway. Somatic loss of function NF2 alterations in renal cell carcinoma (RCC) are associated with poor prognosis and can also molecularly define a subset of unclassified renal cell carcinomas without a standard of care treatment. While immuno-oncology (IO) combination regimens such as ipilimumab/nivolumab (IO/IO) or PD-1 inhibitor with a VEGFR-targeted therapy (IO/VEGFR) are the standard of care for clear cell RCC, efficacy of IO-based regimens for NF2 mutated RCC remains unknown. We report the first comparison of clinical responses to IO/IO, IO/VEGFR, or other systemic therapies for NF2-mutated RCC. Methods: NF2-mutated RCC patients receiving systemic therapy at Memorial Sloan Kettering Cancer Center were retrospectively identified by screening of our targeted exome sequencing (MSK-IMPACT) database. Groups are defined by 1st line systemic therapy regimens: IO/IO, IO/VEGFR, and other (VEGFR-targeted monotherapy, IO monotherapy, everolimus/bevacizumab, and chemotherapy). PFS-2 is defined as time from start of 1st line to progression on next therapy, or death. ORR, PFS, and PFS-2 were measured by an independent RECIST radiologist (CD). PFS, PFS-2, and OS are estimated using the Kaplan-Meier method. Results: Histologic subtypes in the overall cohort were unclassified (N=25), clear cell (N=7), and papillary (N=3). ORR of IO containing regimens in any line of treatment (N=29) was 57% (95% CI 37, 75). In the 1st line setting, 8 patients received IO/IO, 12 received IO/VEGFR, and 15 received other regimens with an ORR of 38% (95% CI 9, 76), 75% (95% CI 43, 95), and 23% (95% CI 5, 54), respectively. Thirty-three patients were included for PFS and PFS-2 analysis and 34 for OS with a median duration of follow-up of 40 months. Median PFS is 11 months (95% CI 4, 19; 26 events), median PFS-2 is 14 months (95% CI 9, 25; 25 events) and median OS is 27 months (95% CI 13, 65; 21 events). PFS, PFS2, and OS did not differ by 1st line treatment group. Among patients who received any IO exposure in the 1st line versus patients who received non-IO-based therapy, there was no significant difference in median PFS (12 (95% CI 5, 22) vs 5 (95% CI 2,21) months, p=0.39), PFS2 (17 (95% CI 9, 28) vs 13 (95% CI 3, 25) months, p=0.49), or OS (27 (95% CI 13, 73) vs 26 (95% CI 4, NE), p=0.90). OS did not differ by tumor histologic subtype; however, sample size limits power to detect differences. Conclusion: In comparison to clear cell RCC, prognosis for patients with NF2-mutated RCC remains poor. IO-based therapy has activity in treating NF2-mutated RCC; patients may derive benefit even if first exposure to IO occurs ≥2nd treatment line. There was no significant difference in PFS, PFS2, or OS based on 1st line regimen for patients with NF2-mutated RCC. Further investigation of inhibitors specifically targeting downstream effectors of the Hippo pathway are warranted. Citation Format: Kelly N. Fitzgerald, Cihan Duzgol, Andrea Knezevic, Rachel Jacobi, Ritesh R. Kotecha, David H. Aggen, Maria I. Carlo, Neil J. Shah, Martin H. Voss, Darren R. Feldman, Robert J. Motzer, Chung-Han Lee. Clinical outcomes in NF2-mutated RCC treated with contemporary immunotherapy regimens [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B022.