• FMC-376 demonstrated robust anti-tumor activity across preclinical models and led to deeper inhibition of KRAS downstream pathways compared to sotorasib –
• FMC-220 potently and selectively restored p53 tumor suppressor function and delivered tumor regressions, including complete responses in p53 Y220C mutant preclinical models –
• FMC-242, a covalent PI3Kα/RAS breaker, shows potent anti-tumor activity, including tumor regressions in CDX and PDX models, and enhanced efficacy in combination with other therapies –

BOSTON and SOUTH SAN FRANCISCO, Calif. (October 22, 2025) – Frontier Medicines Corporation, a clinical-stage precision medicines company unlocking the proteome to develop small molecule oncology and immunology drugs against previously undruggable disease-causing targets, today announced it will present preclinical data from three of its pipeline programs at the 37th AACR-NCI-EORTC International Conference on Molecular Targets, taking place in Boston, MA, from October 22 to 26.

“Our data presented at the Triple Meeting this year is a testament to our ability to execute across programs and to the power of the Frontier^TM Platform. Our lead program, FMC-376, directly blocks both the ON and OFF states of the G12C mutant KRAS protein, leading to a complete and durable blockade of downstream signaling. In preclinical models, this translated to robust anti-tumor activity as a single agent, and synergistic activity when combined with cetuximab,” said Kevin Webster, Ph.D., chief scientific officer of Frontier Medicines. “FMC-220 also showed significant promise, demonstrating tumor regressions in preclinical models as a single agent, and efficacy when combined with other therapeutics, including MDM2 inhibitors or DNA-damaging agents. Finally, FMC-242 demonstrated deep inhibition of the PI3Ka-RAS interaction and potent anti-tumor activity, including tumor regressions, in preclinical models. When combined with KRAS or EGFR inhibitors, FMC-242 demonstrated enhanced efficacy.”

Summary of findings:

“FMC-376, a dual inhibitor of ON+OFF states of KRAS G12C, is active in sotorasib-resistant PDX models.”

Poster Session B – Oct. 24, 12:30-4 p.m. ET

• FMC-376 demonstrated robust anti-tumor activity across a panel of KRAS G12C-mutant, patient-derived xenograft (PDX) models of non-small-cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC).
• FMC-376, as a single agent, inhibits the growth of tumors derived from sotorasib-resistant patients. Complete tumor growth inhibition was demonstrated when FMC-376 was combined with cetuximab.
• FMC-376 led to deeper inhibition of KRAS downstream pathways, including cholesterol homeostasis, EMT, and glycolysis, than sotorasib. Combination with cetuximab demonstrated more profound inhibition of multiple pathways, including mTOR signaling and MYC target genes.
• The Phase 1/2 PROSPER clinical trial (NCT06244771) is currently recruiting to evaluate FMC-376 in participants with KRAS G12C cancers, regardless of prior KRAS G12C (OFF) inhibitor therapy.

“FMC-220, a highly potent and selective covalent activator of p53 Y220C, is broadly active in p53 Y220C-containing PDX models across cancer indications.”

Poster Session B – Oct. 24, 12:30-4 p.m. ET

• FMC-220, a potential first-in-class covalent activator of p53 Y220C, is highly potent and selective in restoring p53 tumor suppressor function, delivering far more durable activation and persistent engagement of target gene promoters than noncovalent strategies.
• FMC-220 inhibits tumor cell viability across a panel of Y220C mutant cell lines and delivers tumor regression, including complete responses in p53 Y220C mutant CDX and PDX models, regardless of histology or co-mutations. (The p53 Y220C mutation is common, occurring in ~1% of cancers).
• FMC-220 combines effectively with other therapeutics, including MDM2 inhibitors or DNA-damaging agents.

“FMC-242, a highly potent and selective covalent breaker of the PI3Kα-RAS interaction, demonstrates improved efficacy and tolerability as monotherapy and in combination with targeted therapies in preclinical models.”

Poster Session C – Oct. 25, 12:30-4 p.m. ET

• In CDX and PDX cell line models, inhibition of the PI3Ka-RAS interaction with FMC-242 results in potent anti-tumor activity, including tumor regressions.
• FMC-242, when combined with KRAS or EGFR inhibitors, results in enhanced efficacy and tumor regressions in vivo.
• Inhibition of the PI3Ka-RAS interaction did not affect insulin signaling or blood glucose levels and was well-tolerated in vivo.
• In vitro, covalent engagement of PI3Ka resulted in inhibition of AKT activation and tumor cell viability.
• FMC-242 is designed to be a potent, selective, orally bioavailable covalent inhibitor of the PI3Ka-RAS family interactions that can disrupt oncogenic RAS and receptor tyrosine kinase (RTK) signaling.

About FMC-376, KRAS G12C ON+OFF Inhibitor

Frontier’s lead program, FMC-376, directly targets both the ON+OFF forms of KRAS G12C with exquisite selectivity. This differentiated mechanism of action of FMC-376 offers the potential to overcome the resistance and lack of response seen with current KRAS G12C single-acting treatments. This KRAS mutation is most prevalent in people with non-small cell lung cancer (NSCLC), colorectal carcinoma (CRC), and pancreatic ductal adenocarcinoma (PDAC). While it has been a target of interest for many years, only recently are meaningful advances being made.

About FMC-220, p53 Y220C Activator

FMC-220 is a highly selective, covalent small molecule activator of the Y220C mutated tumor suppressor p53. It is designed to provide prolonged target residence time and persistent pharmacodynamic effects. These properties deliver tumor regression by driving senescence and tumor cell death. p53 is often referred to as the “guardian of the genome” due to its critical role in maintaining genomic stability, but it can be altered in cancer with mutations such as Y220C. The Y220C mutation destabilizes the p53 protein, impairing its tumor-suppressive functions and contributing to cancer progression. It is estimated to occur in approximately 1-2% of all cancers, with a significant presence in solid tumors such as lung, breast, and colorectal cancers, as well as other cancer types.

About FMC-242, PI3Kα/RAS Breaker
PI3Ka is the second most commonly mutated oncogene and plays an essential role in both KRAS- and RTK-driven cancers, such as colorectal, lung, and breast cancers, among others. Traditionally, PI3K inhibitors aim to block the PI3K/AKT/mTOR pathway, which can slow or stop cancer cell growth. FMC-242 is a covalent allosteric inhibitor that breaks the interaction between PI3Ka and RAS to inhibit downstream effector signaling in tumors without impacting normal functions. The mechanism of action inhibits PI3Kα/AKT effector signaling in tumors while minimizing the toxicities commonly associated with the broader class of inhibitors.

About Frontier Medicines
Frontier Medicines is a clinical-stage precision medicine 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 Frontier™ Platform, leverages covalent chemistry and machine learning 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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