Abstract 5519: Selinexor synergizes with anti-PD-1 antibody and inhibits tumor growth and metastasis in syngeneic mouse models of KRAS mutant colorectal cancer

Abstract

Background: Colorectal cancer (CRC) is the second leading cause of cancer related death. In approximately half of all CRC cases, oncogenic KRAS mutations underlie poor prognosis and drug resistance. A previous multi-genomic analysis of 4,725 biological processes with 106 human non-small-cell lung cancer cells identified nuclear transport machinery as the sole process selectively required for the survival of KRAS mutant cells. Selinexor is a clinically approved oral inhibitor of nuclear export protein Exportin 1 (XPO1/CRM1). In preclinical studies, selinexor demonstrated robust synthetical lethality with native or engineered oncogenic KRAS both in vitro and in vivo. Clinical activity of selinexor monotherapy was observed in CRC patients with various KRAS oncogenic mutations (Razak 2016 JCO). We performed preclinical studies to evaluate the effectiveness of selinexor and the anti-PD-1 antibody RMP1-14 in syngeneic mouse models of KRAS mutant CRC. Methods: Two syngeneic CT-26 KRAS mutant CRC mouse models were tested: 1) metastasis model with intra-hepatically injected CT-26 cells expressing luciferase (8 mice per group); and 2) subcutaneous model with CT-26 injected into the left flank (10 mice per group). Mice were allocated to four groups: vehicle control, selinexor (15 mg/kg, PO, once weekly), RMP1-14 (300 µg/mouse, IP, once weekly), or the combination of selinexor and RMP1-14. Tumor progression and body weight of test mice were monitored throughout the experiment. Tumor samples and plasma were collected at the end of the study for further analysis. Results: Both selinexor and RMP1-14 demonstrated single agent activity against KRAS mutant CRC in the two mouse models relative to controls. In the metastasis model, tumor growth inhibition (TGI) at Day 21 was 63.5% (p=0.0001) for selinexor and 68.9% (p<0.0001) for RMP1-14. The combination of selinexor and RMP1-14 significantly inhibited tumor growth and metastasis with a TGI of 98.9% (p<0.0001). No tumors were detected in two mice from the combination group at the end of the study. A similar trend was observed in the subcutaneous xenograft models, at Day 17, TGIs for selinexor, RMP1-14 and combination treatment were 17.6% (p=0.0921), 26.9% (p=0.0059) and 70.4% (p<0.0001), respectively. Conclusions: Synergistic anti-cancer activity of selinexor and anti-PD-1 antibody in KRAS mutant CRC mouse models warrants further clinical investigation. Citation Format: Hua Chang, Leah Henegar, Christopher J. Walker, Trinayan Kashyap, Marie Maloof, Feng Wang, Kathleen Martyn, Shira Orr, Michael G. Kauffman, Sharon Shacham, Yosef Landesman. Selinexor synergizes with anti-PD-1 antibody and inhibits tumor growth and metastasis in syngeneic mouse models of KRAS mutant colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5519.

Safety, tolerability, and clinical activity of selinexor in combination with pembrolizumab in treatment of metastatic non–small cell lung cancer

“…17 Preclinical studies reported an increased antitumor activity in animal models, when a combination of selinexor and anti-PD-1 antibody administered concurrently compared with the monotherapy by altering the local immune environment, notably by increasing the relative number of T cells and NKT cells with a concomitant reduction in Gr1+ and CD11b+ myeloid cells and Foxp3+ regulatory T cells. 18,19 Selinexor has been investigated in hematologic and solid malignancies as monotherapy and in combination with chemotherapy in different therapy doses. The U.S. Food and Drug Administration approved selinexor for the treatment of previously treated relapsed or refractory diffuse large B-cell lymphoma and multiple myeloma.…”

“…Immunogenic activities of selinexor had been described in preclinical models, where it increased PDCD1 and CTLA4 gene expression in leukocytes and induced CD274 gene expression in human melanoma cell lines 17 . Preclinical studies reported an increased antitumor activity in animal models, when a combination of selinexor and anti–PD‐1 antibody administered concurrently compared with the monotherapy by altering the local immune environment, notably by increasing the relative number of T cells and NKT cells with a concomitant reduction in Gr1+ and CD11b+ myeloid cells and Foxp3+ regulatory T cells 18,19 …”