KRAS G12C mutated NSCLC and bladder cancer xenografts treated with sotorasib and adagrasib in combination with mTOR inhibitors show improved antitumor activity of nab-sirolimus vs everolimus

Background: KRAS is frequently mutated in non-small cell lung cancer (NSCLC) and other tumor types, with G12C mutation representing ∼9% of NSCLC patients. mTOR pathway often activated patients contributes to adaptive resistance inhibitors. A combination inhibitors may mitigate resistance. nab-Sirolimus a novel albumin-bound nanoparticle form inhibitor sirolimus approved for the treatment locally advanced unresectable or metastatic malignant perivascular epithelioid (PEComa). Previous nonclinical studies have shown superior antitumor activity nab-sirolimus vs everolimus as single agent PTEN-null bladder TSC2-deficient hepatocellular carcinoma models. Sotorasib (AMG510) G12C-mutated NSCLC, adagrasib (MRTX 849) under review NSCLC. This study investigated sotorasib xenografts. Material methods: Athymic mice bearing subcutaneous STK11-mutated xenografts NCI-H2030 NCI-H2122 UMUC3 were treated saline, (in H2122) at clinically relevant equal weekly dose 15 mg/kg/wk, NCI-H2122) 30 mg/kg/day (∼16% ∼13% respective clinical dose), alone combination. Tumors harvested analysis downstream markers inhibition. Results: In (n = 6 tumors/group), both demonstrated growth inhibition (TGI: 68% 22%, P ns). When combined sotorasib, there was greater than nab-sirolimus+sotorasib 109% everolimus+sotorasib 53%, 0.0008). Combining showed significantly TGI (109%) compared (68%, 0.0102) (20%, 0.0002). Similar results seen lines. Conclusions: improves response against tumors vivo. potency preferred further development using this strategy. Conflict interest: Ownership: JN: Epic Sciences, Quantgene, Indee Bio ND: yes Advisory Board: Aadi Bioscience, Naveris, BMS, Fujirebio, Astra Zeneca, Mindmed, G1 Therapeutics Board Directors: Bioscience Corporate-sponsored Research: Genentech, Merck Other Substantive Relationships: SH: Full-time employee shareholder Patent licensing – Cansera AADI