A new mTORC1-selective cancer drug controls disease in 64% of patients with little hyperglycemia

The PI3K/mTOR pathway controls cell growth, survival, and protein synthesis, and it is hyperactive in many cancers. Genomic alterations in this pathway occur in roughly 38% of tumors, and PTEN protein loss is seen in about 30% of solid tumors even though PTEN mutations are found in only 6% to 9%. Existing drugs have fallen short. Rapalogs such as everolimus and temsirolimus inhibit 4EBP1 incompletely and cause mucositis. ATP-competitive pan-mTOR inhibitors like sapanisertib block mTORC2 and Akt, causing frequent hyperglycemia, which still reached 33% when metformin was added.

RMC-5552 is the first clinical example of a third-generation, bi-steric mTOR inhibitor. It links rapamycin to an ATP-site inhibitor so that it engages both the allosteric and active sites of mTORC1. It potently suppresses phosphorylation of both 4EBP1 and S6 kinase and is about 40-fold selective for mTORC1 over mTORC2 in cell-based assays. The goal is strong antitumor activity without the insulin-resistance effects tied to mTORC2 inhibition, along with less receptor tyrosine kinase feedback.

This was an open-label, multicenter, first-in-human dose-escalation study (NCT04774952) in adults with advanced solid tumors. Fifty-seven patients received RMC-5552 as a weekly intravenous infusion at 1.6 to 16 mg. The researchers assessed safety, tolerability, pharmacokinetics, and preliminary antitumor activity. They also tested tacrolimus mouthwash (TM) as mucositis prophylaxis and tracked circulating tumor DNA (ctDNA) for changes in PI3K/mTOR pathway variants.

The most common treatment-related adverse events were mucositis (49%), nausea (44%), and fatigue (42%). Treatment-related hyperglycemia occurred in only 4% of patients and was not dose limiting. This contrasts with the high hyperglycemia rates reported for pan-mTOR inhibitors and supports the idea that sparing mTORC2 preserves glucose regulation at clinically active doses.

TM was tested because tacrolimus competes for FKBP12 binding and was predicted to block the drug's mechanism locally in the mouth. Between 8 and 12 mg, mucositis occurred in 65% of patients without TM and 31% with TM. This is consistent with an on-mechanism effect. The text available to me does not detail how patients were assigned to TM, so this should be viewed as promising but preliminary.

For efficacy, the disease control rate was 64%. One patient with PTEN- and PIK3CA-altered endometrial cancer had a complete response, still ongoing at more than six months as of the June 2024 data cut. ctDNA showed clearance of selected PI3K/mTOR pathway variants, which also fits selective on-target activity. Important caveats apply. This is a single-arm phase 1 study with a heterogeneous population and no control group, and disease control rate is a modest efficacy measure. Revolution Medicines sponsored the trial, and several authors are company employees. The findings support further testing, alone or in combinations, in PI3K/mTOR-driven cancers, but they do not establish survival benefit.