Abstract 6486: Correlation of <i>nab</i>-sirolimus tumor drug levels and improved tumor suppression in <i>KRAS G12C</i> non-small cell lung cancer xenografts treated with <i>nab</i>-sirolimus in combination with <i>KRAS</i> inhibitors
Authors: Shihe Hou, Jorge Nieva, Maria Zalath, Neil Desai
Journal: Cancer Research (2024)

Abstract Background: KRAS mutations are found in a variety of tumor types, including non-small cell lung cancer (NSCLC), where KRAS G12C mutation is present in ~12% of NSCLC patients. KRAS G12C inhibitors (KRAS G12Cis), sotorasib and adagrasib, are approved for the treatment of KRAS G12C-mutated, locally advanced or metastatic NSCLC. The mTOR pathway is often activated in patients with KRAS mutations and may contribute to resistance to KRAS G12Cis. nab-Sirolimus is a nanoparticle albumin-bound intravenously (IV) administered form of the mTOR inhibitor (mTORi) sirolimus and is approved for the treatment of patients with advanced malignant perivascular epithelioid cell tumors. This study assessed tumor and blood drug level correlation with antitumor activity of nab-sirolimus or everolimus alone or in combination with KRAS G12Cis. Methods: Athymic mice bearing subcutaneous KRAS G12C- and STK11-mutated NSCLC xenografts (NCI-H2122) were treated with saline, mTORis nab-sirolimus (IV) or everolimus (oral) at clinically relevant and equal weekly dose of 15 mg/kg/wk, or KRAS G12Cis sotorasib (oral) or adagrasib (oral) at 30 mg/kg/day alone or in combination. Tumor volume changes from baseline were assessed; tumor and blood samples were harvested at the end of study (6 wks) for analysis of trough drug levels by LC-MS/MS, and tumor lysates were analyzed for downstream markers for mTOR inhibition by Western blot. Results: In nab-sirolimus plus KRAS G12Ci treated groups, significantly slower tumor growth was observed compared with single agent treated groups and everolimus plus KRAS G12Ci treated groups. Compared with single-agent nab-sirolimus (170.1 ng/g), treatment with nab-sirolimus plus sotorasib resulted in reduced tumor nab-sirolimus drug levels (73.6 ng/g, P=0.0040); while similar tumor nab-sirolimus drug levels were observed for nab-sirolimus plus adagrasib (121.6 ng/g, P=ns). Corresponding to greater antitumor activity, significantly greater tumor trough mTORi drug levels were observed in nab-sirolimus plus either sotorasib or adagrasib treated groups compared with similar everolimus combinations (85-fold, P&amp;lt;0.0001; and 91-fold, P=0.0050, respectively). Correspondingly, stronger mTOR downstream target inhibition of pS6 were observed for nab-sirolimus plus KRAS G12Ci treated groups compared with everolimus plus KRAS G12Ci treated groups. Conclusions: The addition of a KRAS G12Ci to nab-sirolimus significantly reduced tumor volume and increased tumor drug levels, suggesting enhanced tumor targeting compared with everolimus plus KRAS G12Cis and correlating to improved antitumor activity and mTOR target suppression. Clinical dose-finding studies are needed to determine potential drug-drug interactions between nab-sirolimus and KRASis. Citation Format: Shihe Hou, Jorge Nieva, Maria Zalath, Neil Desai. Correlation of nab-sirolimus tumor drug levels and improved tumor suppression in KRAS G12C non-small cell lung cancer xenografts treated with nab-sirolimus in combination with KRAS inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6486.