On October 27, 2022 Aadi Bioscience, Inc. (NASDAQ: AADI), a commercial-stage biopharmaceutical company focused on developing and commercializing precision therapies for genetically-defined cancers with alterations in mTOR pathway genes, reported that preclinical combination data of KRAS inhibitors and nab-sirolimus at the 34th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium (Press release, Aadi Bioscience, OCT 27, 2022, View Source [SID1234622534]). Nab-sirolimus is a novel albumin-bound nanoparticle form of the mTOR inhibitor sirolimus and is approved for the treatment of locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).

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Sotorasib (AMG510) is approved for the treatment of KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), and adagrasib (MRTX 849) is under review by the FDA for the treatment of KRASG12C-mutated NSCLC. The mTOR pathway is often activated in patients with the KRAS mutation and contributes to adaptive resistance to KRAS inhibitors. This study investigated the preclinical antitumor activity of mTOR inhibitors nab-sirolimus or everolimus in combination with sotorasib or adagrasib in KRASG12C-mutated cancer xenografts.

"We are excited to present these compelling combination data at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium, which laid the foundation for our recent partnership with Mirati on combination strategies to treat NSCLC and solid tumor cancers," said Neil Desai, Ph.D., Founder and Chief Executive Officer of Aadi Bioscience. "These preclinical results demonstrate that nab-sirolimus has the potential to significantly improve the antitumor activity of adagrasib or sotorasib, two of the most promising KRAS inhibitors today. We are actively collaborating to initiate an open label Phase 1/2 study that will evaluate adagrasib and nab-sirolimus in the clinic, with the goal of mitigating resistance and improving clinical outcomes."

Results of these studies showed that combining nab-sirolimus with either sotorasib and adagrasib showed supra-additive or synergistic antitumor activity with significantly greater tumor growth inhibition and meaningful tumor regressions than the single agents. In contrast, everolimus in combination with the KRAS inhibitors was not as effective. We believe that these results strongly suggest that nab-sirolimus is the preferred mTOR inhibitor for combination treatment and should be further explored as a potential combination treatment option with adagrasib or sotorasib in the clinic.

The details of the poster presentation are below:

Title: "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"
Abstract Number: 163
Session Title/Code: Combination Therapies/PP08
Date/Time: Thursday, October 27, 2022, 10am – 5pm
Authors: Shihe Hou, PhD, Jorge Nieva, MD, and Neil Desai, PhD

About nab-sirolimus

Nab-sirolimus is a novel albumin-bound nanoparticle form of the mTOR inhibitor sirolimus and is currently being evaluated in a tumor-agnostic registration-directed trial in mTOR inhibitor-naïve malignant solid tumors harboring TSC1 or TSC2 inactivating alterations. In November 2021, nab-sirolimus was approved by the U.S. Food and Drug Administration (FDA) as FYARRO for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).