Aadi Bioscience, Inc. announced new nonclinical data demonstrating the significantly higher intratumoral drug concentration, stronger inhibition of mTOR targets and greater antitumor activity of nab-sirolimus compared to intravenous and oral mTOR inhibitors in a xenograft model. These data will be available as an abstract and published in the Journal of Clinical Oncology supplement to coincide with the American Society of Clinical Oncology (ASCO) Annual Meeting taking place May 31 ? June 4, 2024.

Despite the broad importance of the mTORC1 pathway in cancer cell growth and survival, mTOR inhibitors (mTORis) temsirolimus, sirolimus and everolimus have limited clinical application in the cancer setting. In A549 xenografts, nab-sirolimus resulted in significantly greater suppression of tumor growth compared with IV temsirolimus and oral sirolimus and everolimus. Average intratumoral drug concentrations 24 hours after IV mTORi treatment were significantly higher with nab-sirolimus (420-539 ng/g) compared with temsirolimus (34.9 ng/g) and its active metabolite (13.2 ng/g); similarly, tumor uptake of nab-sirolimus greatly exceeded that of sirolimus and everolimus at steady-state.

these results support further clinical evaluation of nab-sirolimus as a single agent or in combination with other therapeutic agents. In addition, Aadi will present a trials-in-progress poster on its Phase 2 trial in advanced or recurrent endometrioid-type endometrial cancer (EEC), a difficult-to-treat mTOR-driven cancer. Endometrial cancer is the most common cancer of the female reproductive organs and one of the few cancers with increasing mortality.

There are an estimated 10,000 cases of EEC diagnosed annually. This is a Phase 2 open-label, multi-institutional study to evaluate the efficacy and safety of nab-sirolimus and letrozole in patients with advanced or recurrent endometrioid endometrial carcinoma, exploring the potential for this combination to produce additive anti-tumor activity in patients with EEC. Dysregulation of mTOR signaling is implicated in the pathology of EEC, in which >80% harbor PTEN or PI3K/AKT/mTOR pathway alterations.

Prior clinical studies with mTOR inhibitors and letrozole in endometrial cancer patients have yielded promising results. Alternative treatment options for patients with advanced or recurrent EEC remain necessary despite recent pivotal data demonstrating improved outcomes with immunotherapy plus chemotherapy. Aadi is a commercial-stage precision oncology company focused on the development and commercialization of therapies for cancers with alterations in the mTOR pathway, a key regulator of cell growth and cancer progression.

To unlock the full potential of mTOR inhibition, Aadi uniquely combines nanoparticle albumin-bound (nab) technology with the potent mTOR inhibitor, sirolimus. Aadi received FDA approval and commercializes FYARRO® for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa). Aadi is exploring nab-sirolimus in PRECISION1, a Phase 2 tumor-agnostic registration-intended trial in mTOR inhibitor-naïve malignant solid tumors harboring TSC1 or TSC2 inactivating alterations.

Aadi is also exploring nab-sirolimus in two single-indication Phase 2 trials for difficult-to-treat mTOR-driven cancers: neuroendocrine tumors (NETs), and advanced or recurrent endometrioid-type endometrial cancer (EEC) in combination with letrozole.