Reference Detail

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Abstract

PMID

Authors

Howard A. Burris III, Susanna Varkey Ulahannan, Eric B. Haura, Sai-Hong Ignatius Ou, Anna Capasso, Pamela N. Munster, Hidenori Kitai, Zhican Wang, Josie Hayes, Lin Tao, Sofia Wong, Yu Chi Yang, Jingjing Jiang, Bojena Bitman, Mallika Singh, W. Clay Gustafson, Neal Rosen, Alison M. Schram

Title

The bi-steric mTORC1-selective inhibitor RMC-5552 in tumors with activation of mTOR signaling: Preclinical activity in combination with RAS(ON) inhibitors in RAS-addicted tumors, and initial clinical findings from a single agent phase 1/1b study

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of Clinical Oncology	40	16_Suppl	June 2, 2022

URL

https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.3098

Abstract Text

Background: RMC-5552 is a potent bi-steric mTORC1-selective inhibitor that activates the downstream tumor suppressor 4EBP1, thereby inhibiting initiation of protein translation. This novel therapeutic moiety addresses a key limitation of rapalogs, which do not effectively inhibit phosphorylation of 4EBP1. RMC-5552 has previously demonstrated significant anti-tumor activity in preclinical models of human cancers with mTOR pathway activation. Additionally, mTOR signaling plays a key role in therapeutic response and resistance in RAS-addicted cancers, which represent a significant unmet medical need. Methods: We examined the combination of bi-steric mTORC1 inhibitors (RMC-5552 and the research tool compound RMC-6272) with direct inhibitors of active RAS (RAS(ON) inhibitors) in mutant KRAS-driven models. To enable the clinical testing of RMC-5552 as a companion inhibitor for RAS(ON) inhibitors, a Phase 1/1b dose-escalation trial of RMC-5552 monotherapy is currently testing a once-a-week IV schedule. Results: RMC-5552 and RMC-6272 demonstrated marked combinatorial anti-tumor activity with RAS(ON) inhibitors across a series of preclinical models of KRAS mutated non-small cell lung cancer. The combination enhanced tumor apoptosis and resulted in durable tumor regressions as compared to tumor growth inhibition resulting from single agents alone. As of 13 January 2022, a total of 14 patients with solid tumors have been evaluated in an ongoing Phase 1/1b trial over 5 dose levels ranging from 1.6 to 12 mg IV weekly. Median age was 62 years and the majority received ≥3 prior therapies. The most common (> 25%) drug-related adverse events were mucositis/stomatitis (43%) and decreased appetite (29%). The most common grade 3 drug-related adverse events were mucositis/stomatitis observed in 3 patients in dose levels ≥ 10 mg (21%) and were dose-limiting. The dose of 6 mg IV weekly was well tolerated. Plasma exposures of RMC-5552 were dose-proportionate at lower dose levels up to 6 mg but increased above dose proportionality with higher dose levels. Plasma exposures at 6 mg and above were consistent with those resulting in inhibition of tumor p4EBP1 in preclinical models. Of 5 patients evaluable for efficacy at doses of 6 mg and higher, one confirmed PR was observed in a patient with head and neck cancer with a pathogenic mutation in PTEN (ORR 20%) and 3 patients had a best response of SD. Dose-optimization is ongoing. Conclusions: RMC-5552 is clinically active in tumors with mTORC1 signaling activation at a tolerable dose and schedule and has the potential to be a companion inhibitor of choice for RAS(ON) inhibitors in RAS-addicted tumors. Clinical trial information: NCT04774952

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN inact mut	head and neck cancer	predicted - sensitive	RMC-5552	Case Reports/Case Series	Actionable	In a Phase I/Ib trial, RMC-5552 treatment resulted in an objective response rate of 20% (1/5) and 3 stable disease in patients with advanced solid tumors, with 1 partial response observed in a patient with head and neck cancer harboring a pathogenic PTEN mutation (J of Clin Oncol40, no. 16_suppl (June 01, 2022) 3098; NCT04774952).	detail...