Trial to Evaluate Adagrasib Plus Nab-sirolimus in Patients with Advanced Non-Small Cell Lung Cancer, Other Solid Tumors with KRAS Mutation

A clinical collaboration from Mirati Therapeutics and Aadi Bioscience Inc will evaluate the combination of adagrasib (MRTX849), a KRAS^G12C selective inhibitor, and nab-sirolimus, a small molecule mTOR inhibitor complexed with human albumin in KRAS^G12C mutant non-small cell lung cancer (NSCLC) and other solid tumors.

The objective of the open-label phase 1/2 trial is to determine the optimal dose and recommended phase 2 dose for the combination of adagrasib and nab-sirolimus in patients with KRAS^G12C mutant solid tumors. Additionally, the study will evaluate the safety, tolerability, and efficacy of the in combination in patients both with and without prior exposure to a KRAS^G12C inhibitor.

The KRAS gene is a member of the RAS/MAPK pathway and plays key part in cell division, differentiation, and apoptosis.Approximately 35% of patients with NSCLC carry KRAS mutations, which frequently leads to poor responses to chemotherapy and overall prognoses.1

The KRAS protein converts GTP into GDP molecules. Binding to GTP has been found to cause downstream intracellular signal transduction. Approximately 14% of patients with NSCLC harbor KRAS^G12C mutations.

Adagrasib is an investigational, highly selective, KRAS^G12C inhibitor that is optimized to sustain target inhibition. Previous studies of adagrasib have shown that the drug has a long half-life, extensive tissue distribution, and is well tolerated.

In February 2022, the FDA accepted a new drug application (NDA) for the use of adagrasib for patients with NSCLC harboring KRAS^G12C mutation who have previously received at least 1 systemic therapy. The FDA accepted the adagrasib NDA based on the phase 2 registration-enabling cohort of the KRYSTAL-1 study.

In the phase 2 KRYSTAL cohort A, 113 patients (97.4%) experienced treatment-related adverse effects (TRAEs) with grade 1 or 2 in 52.6%, and grade 3 or higher in 44.8% of patients. Approximately 6.9% of patients discontinued adagrasib due to TRAEs. The most common TRAEs were diarrhea (62.9%), nausea (62.1%), vomiting (47.4%), and fatigue (40.5%).

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.

The trial will be based on preclinical data showing enhanced anti-tumor efficacy with the combination of adagrasib and nab-sirolimus relative to either agent alone.

"We are pleased to collaborate with Aadi on this clinical study of adagrasib and nab-sirolimus.Our collaborative preclinical work has demonstrated that combinatorial mTOR and KRAS inhibition addresses key bypass and feedback pathways associated with either drug target and also results in enhanced efficacy in tumor models harboring KRAS^G12C mutations. We believe the data from this trial may improve patient outcomes," said Charles Baum, MD, PhD, president, founder and head of research and development, Mirati Therapeutics, Inc, in a press release. "This clinical collaboration is an example of how Mirati is aggressively advancing the study of adagrasib both as a monotherapy and in rational combinations as part of our expanding development portfolio to benefit people living with difficult-to-treat cancers."

REFERENCE

Mirati Therapeutics and Aadi Bioscience Partner to Evaluate the Combination of Adagrasib with Nab-sirolimus in Patients with Advanced Non-Small Cell Lung Cancer and Other Solid Tumors with a KRAS[G12C] Mutation. Mirati Therapeutics. October 12, 2022. Accessed October 14, 2022. https://ir.mirati.com/press-releases/press-release-details/2022/Mirati-Therapeutics-and-Aadi-Bioscience-Partner-to-Evaluate-the-Combination-of-Adagrasib-with-Nab-sirolimus-in-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer-and-Other-Solid-Tumors-with-a-KRASG12C-Mutation/default.aspx