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Nab-sirolimus added to KRAS inhibitor treatment demonstrated significantly greater antitumor activity and tumor regressions compared to the KRAS inhibitors alone
The KRAS inhibitor combinations with nab-sirolimus were significantly more active than the corresponding everolimus combinations
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 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
Authors: Shihe Hou, PhD,
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
About Aadi Bioscience, Inc.
Aadi is a commercial-stage biopharmaceutical company focused on precision therapies for genetically defined cancers to bring transformational therapies to cancer patients with mTOR pathway driver alterations. Aadi received FDA approval in November of 2021 and in February of 2022 commercialized FYARRO® for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).
Aadi has also initiated PRECISION 1, a Phase 2 tumor-agnostic registration-intended trial in mTOR inhibitor-naïve malignant solid tumors harboring TSC1 or TSC2 inactivating alterations. More information on the Company's development pipeline is available on the Aadi website at www.aadibio.com and connect with us on Twitter and LinkedIn.
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