Abstract 5484: Synergistic antitumor activity of nab-sirolimus in combination with KRAS inhibitors (KRASis) sotorasib and adagrasib in KRAS G12C NSCLC and bladder cancer xenografts

Abstract

Abstract KRAS is frequently mutated in non-small cell lung cancer (NSCLC) and other tumor types, with KRAS G12C mutation representing ~12% of patients with NSCLC. Sotorasib (sot) is approved and adagrasib (ada) is under review for the treatment of KRAS G12C NSCLC. Mutations in KRAS may lead to mTORC1 activation, and mTOR may contribute to adaptive resistance to KRASis. nab-Sirolimus (nab-S) is a novel albumin-bound nanoparticle form of the mTOR inhibitor sirolimus approved for the treatment of locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumors. This study investigated the antitumor activity of nab-s in combination with KRASis in KRAS G12C NSCLC and bladder xenograft models. Athymic mice bearing subcutaneous KRAS G12C- and STK11-mutant NCI-H2030 and NCI-H2122 NSCLC and KRAS G12C and PTEN-null UMUC3 bladder cancer were treated for 6 weeks with nab-s IV at 15 mg/kg/wk, sot or ada (for NCI-H2122 and UMUC3) orally at 30 mg/kg/d alone or in combination. Tumor samples were harvested for analysis of tumor drug levels and biomarkers. In all 3 models tested, single-agent (SA) nab-s or KRASis overall showed modest tumor growth suppression. In contrast, nab-s in combination with either sot or ada showed greater tumor growth inhibition and a higher meaningful tumor regression rate vs SA (Table). There was no significant difference in antitumor activity between combinations of nab-s with either sot or ada. High trough intertumoral sirolimus levels were observed in groups treated with nab-s alone or in combination with KRASis, indicating sustained presence of sirolimus in the tumor. nab-S in combination with either sot or ada showed synergistic antitumor activity compared to the SA. A multicenter, single-arm, open-label Phase 1/2 clinical study is planned to determine the recommended Phase 2 dose, safety, tolerability, and efficacy for the combination of ada and nab-s in patients with KRAS G12C tumors. Changes in TGI and Tumor Regression Tumor Model Combination Treatment TGI vs Single Agent (%) P Value vs Single Agent for Tumor Growth Curve (ANOVA) Tumor Regression Over 30% P Value vs Single Agents for Rate of Tumor Regression Over 30% (Chi-Square) vs nab-S vs KRASi vs nab-S vs KRASi NCI-H2030 nab-S + Sotorasib 129 111 0.01 0.001 3/6 0.03 NCI-H2122 nab-S + Sotorasib 112 106 0.001 <0.001 8/10 <0.001 nab-S + Adagrasib 101 100 0.001 <0.001 4/10 0.03 UMUC3 nab-S + Sotorasib 107 105 <0.001 <0.001 6/6 <0.001 nab-S + Adagrasib 107 107 <0.001 0.04 6/6 0.001 ANOVA, analysis of variance; KRASi, KRAS inhibitor; nab-s, nab-sirolimus; TGI, tumor growth inhibition. Citation Format: Shihe Hou, Andrew Kwon, Jorge Nieva, Neil Desai. Synergistic antitumor activity of nab-sirolimus in combination with KRAS inhibitors (KRASis) sotorasib and adagrasib in KRAS G12C NSCLC and bladder cancer xenografts. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5484.