Abstract LB288: Biomarker analysis from AMPECT correlating response to nab-sirolimus with TSC1 and TSC2 inactivating alterations
Authors: Cranmer Lee D. , Wagner Andrew J. , Ravi Vinod , Riedel Richard F. , Ganjoo Kristen N. , Van Tine Brian A. , Chugh Rashmi , Gordon Erlinda M. , Kwiatkowski David J. , Hornick Jason L. , Du Heng , Ding Li , Schmid Anita N. , Navarro Willis H. , Itri Loretta M. , Dickson Mark A. 
Published: April 2023

Abstract
nab-Sirolimus is an mTOR inhibitor (mTORi) approved in the US for the treatment of adult patients with locally advanced, unresectable, or metastatic malignant perivascular epithelioid cell tumor (PEComa) based on clinical efficacy and safety data from the phase 2, multicenter, open-label AMPECT trial (NCT02494570). TSC1 and TSC2 are tumor suppressor genes and key upstream regulators of mTOR complex 1 (mTORC1); inactivating alterations (loss-of-function mutations or deletions) in these genes lead to mTORC1 hyperactivation, which may contribute to tumor formation. Phosphorylation of S6 ribosomal protein (pS6) is a reliable surrogate for mTORC1 activity. Here we present the results of an exploratory biomarker analysis performed on samples from patients enrolled in the AMPECT study. Targeted exome next-generation sequencing (NGS) using a 500-gene OncoPanel test (Center for Advanced Molecular Diagnostics, Brigham and Women’s Hospital, Boston, MA) assessed mutations, copy number changes, and translocation events. pS6 was assessed by immunohistochemistry (IHC). Twenty-five patients had tissue sufficient for NGS, 56% (14/25) had either TSC1 (N=5, 20%) or TSC2 (N=9, 36%) mutations: TSC1, 1 frameshift, 2 splice site, 1 missense, and 1 nonsense mutation; TSC2, 1 nonsense, 7 frameshift, and 1 homozygous deletion. In this dataset, TSC1 and TSC2 inactivating alterations were mutually exclusive. Patients with TSC1 or TSC2 inactivating alterations achieved a clinically meaningful benefit: 64.3% (9/14) objective overall responses (including complete and partial responses) and median (95% CI) duration of response (DOR) of 45.7 (5.6, not reached [NR]) months, progression-free survival (PFS) of 41.2 (5.5, NR) months, and overall survival (OS) of NR (31.6, NR) months. Mutations in TP53, RB1, and ATRX were also common (48%, 24%, and 20%, respectively).
Of tissue samples evaluable for IHC (N=25), responses occurred in 58.8% (10 of 17) of patients with pS6 positive tumors versus 0% (0 of 8) with pS6 negative tumors; absent pS6 staining was negatively associated with response to nab-sirolimus (P=0.008, Fisher’s exact). Median DOR for pS6 positive responders was 39.7 (5.6, NR) months. In pS6 positive vs pS6 negative patients, the median PFS was 24.4 (2.8, 53.1) vs 5.5 (2.8, NR) months, and OS was 53.1 (18.0, NR) vs 37.0 (16.6, NR) months. A variety of pathogenic inactivating alterations were observed in TSC1 and TSC2 genes, though TSC2 mutations were most commonly frameshift mutations; no recurring mutations were observed. A tumor-agnostic study (PRECISION 1: NCT05103358) is now recruiting patients with pathogenic inactivating TSC1 or TSC2 alterations to further examine these biomarker findings.
Citation Format: Lee D. Cranmer, Andrew J. Wagner, Vinod Ravi, Richard F. Riedel, Kristen N. Ganjoo, Brian A. Van Tine, Rashmi Chugh, Erlinda M. Gordon, David J. Kwiatkowski, Jason L. Hornick, Heng Du, Li Ding, Anita N. Schmid, Willis H. Navarro, Loretta M. Itri, Mark A. Dickson. Biomarker analysis from AMPECT correlating response to nab-sirolimus with TSC1 and TSC2 inactivating alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB288.