- Preclinical data demonstrated enhanced anti-tumor activity and tumor regression with FMC-242 in combination with multiple KRAS/RAS inhibitors in KRAS-mutant models, including those insensitive to KRAS inhibitor monotherapy
- FMC-242 is designed with Frontier's AI-powered CovalentAI Platform to selectively disrupt the PI3Ka-RAS interaction while sparing normal metabolic function, potentially addressing key limitations of existing PI3Ka inhibitors
- Frontier has received FDA allowance to proceed to human clinical trials under an Investigational New Drug (IND) application for FMC-242 for the treatment of select advanced solid tumors
- Phase 1/2 clinical trial of FMC-242 expected to begin dosing in the coming months; starting dose is at the high end of the predicted therapeutic dose range, reflecting the CovalentAI Platform's ability to generate highly selective medicines, potentially resulting in expedited drug development
Frontier Medicines Corporation (Frontier), a clinical-stage, AI-powered precision medicines company that discovers and develops covalent medicines for previously undruggable and hard-to-drug disease-causing targets, starting with cancer, today announced that it will present preclinical data from its FMC-242 program at the 38th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, taking place in Barcelona, Spain, from November 18-20. FMC-242 is a novel, orally bioavailable, covalent allosteric breaker of the PI3Ka-RAS interaction designed using Frontier's proprietary, AI-powered CovalentAI Platform. PI3Ka is the second most frequently mutated oncogene in human cancer and plays an essential role in both PI3Ka and RAS-driven cancers.
"These preclinical findings highlight the potential of FMC-242 to address key limitations of existing targeted therapies, including drug resistance and tolerability challenges," said Kevin Webster, Ph.D., Chief Scientific Officer of Frontier Medicines. "By selectively disrupting the PI3Ka-RAS interaction while sparing normal metabolic function, we believe FMC-242 represents a differentiated approach to cancer treatment. We are particularly encouraged by the enhanced anti-tumor activity observed in combination with multiple KRAS/RAS inhibitors in KRAS-mutant models, including those insensitive to KRAS inhibitor monotherapy. These results underscore the power of our AI-powered CovalentAI Platform to develop differentiated precision medicines and support FMC-242's potential as both a monotherapy and combination treatment. We are eager to share these results at the Triple Meeting."
Poster presentation details and summary of the findings to be presented are as follows:
- Title: Combination of FMC-242, a first-in-class, covalent allosteric breaker of the PI3Ka-RAS interaction, with KRAS inhibitors drives enhanced anti-tumor activity including regression in CDX/PDX models harboring KRAS mutations
- Abstract Number: 295
- Poster Number: PB-087
- Session Date Time: Friday,November 20, 2026, 9:00 a.m. 3:00 p.m. CET
- Location: Exhibition Hall
- Presenter: Kevin Webster, Ph.D., Chief Scientific Officer of Frontier Medicines
- Summary of Findings: Preclinical data demonstrated that FMC-242 exhibited potent anti-tumor activity as a monotherapy in xenograft models harboring HER2 amplification and/or KRAS mutations. In KRAS G12C-mutant xenograft models, FMC-242 demonstrated enhanced anti-tumor activity and tumor regression in combination with multiple KRAS/RAS inhibitors (Frontier's FMC-376, an investigational equipotent ON+OFF KRAS G12C inhibitor, as well as divarasib, olomorasib and daraxonrasib), including in models insensitive to single-agent KRAS inhibitors. Additionally, the combination of FMC-242 and daraxonrasib demonstrated robust anti-tumor activity across multiple KRAS G12X patient-derived xenograft models spanning different tumor types. FMC-242 was well tolerated in preclinical models without impacting insulin signaling or blood glucose levels, supporting its potential as a differentiated monotherapy and combination treatment approach.
The presentation follows Frontier's recent announcement that the U.S. Food and Drug Administration (FDA) has allowed Frontier to proceed to human clinical trials under an Investigational New Drug (IND) application for FMC-242 for the treatment of select advanced solid tumors.
"Following the recent IND allowance for FMC-242, we are excited to advance this differentiated program into the clinic with a starting dose at the high end of the predicted therapeutic dose range," said Aaron Weitzman, M.D., Chief Medical Officer of Frontier Medicines. "This reflects the selectivity we have been able to achieve through our CovalentAI Platform and enables us to begin clinical development at doses predicted to have therapeutic activity. As we prepare to begin patient enrollment in the coming months, we look forward to evaluating FMC-242 as both a monotherapy and in combination with targeted therapies across select advanced solid tumors."
About FMC-242
FMC-242 is a novel allosteric breaker of the PI3Ka-RAS interaction that breaks the interaction between PI3Ka and RAS to inhibit downstream signaling in tumors and is designed to do so without impacting normal PI3Ka functions such as glucose homeostasis. The mechanism of action is designed to inhibit RAS-driven PI3Ka-AKT signaling in tumors while sparing PI3Ka catalytic domain function, and in preclinical studies FMC-242 did not affect insulin signaling or blood glucose levels. FMC-242 was identified through application of our CovalentAI Platform, which enabled chemoproteomic and AI-guided discovery of a covalent drug that selectively engages cysteine 242 within the PI3Ka RAS-binding domain (RBD). In preclinical models, FMC-242 has shown potent anti-tumor activity demonstrating the potential to impact patients with lung, colorectal, breast and other cancers that are driven by RTK activation, RAS mutation and PI3Ka mutation/amplification either as a single agent or in combination with other therapies, including HER2-directed therapies, ER antagonists and KRAS inhibitors.
About Frontier Medicines
Frontier Medicines is a clinical-stage precision medicines company pioneering groundbreaking medicines to transform treatment for genetically defined patient populations, starting with oncology and immunology. Our proprietary chemoproteomics-powered drug discovery engine, the CovalentAI Platform, leverages covalent chemistry and artificial intelligence to unlock difficult-to-drug, disease-causing proteins for drug development. Today, we are advancing a diversified pipeline of wholly owned precision medicines against the most critical drivers of cancer and high-value immunology programs. For more information, please visit www.frontiermeds.com. Follow Frontier on LinkedIn.
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