- FMC-242 is designed to selectively disrupt the PI3Kα-RAS interaction while sparing normal metabolic function, potentially addressing key limitations of existing PI3Kα inhibitors
- Phase 1/2 trial to evaluate FMC-242 as monotherapy and in combination with standard of care targeted therapies in patients with HER2-altered, HR+/HER2-negative, PI3Kα-altered and RAS-mutant solid tumors
- Phase 1/2 trial will also evaluate FMC-242 in combination with FMC-376, Frontier’s investigational equipotent ON+OFF KRAS G12C inhibitor, in patients with KRAS G12C-mutant colorectal cancer or non-small cell lung cancer (NSCLC)
BOSTON and SOUTH SAN FRANCISCO, Calif. (October 28, 2026) – 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 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. FMC-242 is a novel, orally bioavailable, covalent allosteric breaker of the PI3Kα-RAS interaction designed using Frontier’s proprietary, AI-powered CovalentAI™ platform. The allowance enables Frontier to initiate a Phase 1/2 clinical trial evaluating FMC-242 as monotherapy and in combination with other targeted therapies in patients with advanced or metastatic solid tumors.
“FDA allowance of our IND for FMC-242 represents an important milestone as we advance FMC-242, a differentiated medicine discovered through our AI-powered CovalentAI™ platform, into clinical development,” said Chris Varma, Ph.D., Co-founder and Chief Executive Officer of Frontier Medicines. “PI3Kα is the second most frequently mutated oncogene in human cancer and plays an essential role in both PI3Kα and RAS-driven cancers. We rationally designed FMC-242 to selectively disrupt the interaction between PI3Kα and RAS, a critical driver of oncogenic signaling, while leaving normal metabolic signaling intact. By potentially addressing the dose-limiting toxicities and resistance mechanisms associated with existing PI3Kα inhibitors, we believe FMC-242 could offer a differentiated treatment approach both as monotherapy and in combination with other targeted agents. Moreover, FMC-242’s starting dose is at the high end of the predicted therapeutic dose range, reflecting the CovalentAI™ platform’s ability to generate highly selective medicines resulting in expedited drug development. We look forward to beginning patient enrollment in the monotherapy dose-escalation cohorts in the coming months.”
The Phase 1/2 trial is designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of FMC-242 as a monotherapy and in combination with other targeted therapies. Dose-escalation cohorts will enroll patients with select HER2-, PI3Kα- and RAS-driven solid tumors, with combination cohorts evaluating FMC-242 alongside therapies targeting complementary pathways. The Phase 2 portion will include disease-specific expansion cohorts evaluating FMC-242 at the recommended Phase 2 dose as a monotherapy and in combination.
At the American Association for Cancer Research (AACR) Annual Meeting 2026, Frontier presented preclinical findings demonstrating that in cell line- and patient-derived xenograft models with HER2 amplification and/or KRAS mutations, FMC-242 led to potent anti-tumor activity with favorable tolerability and no effect on insulin signaling or blood glucose levels. In combination with EGFR inhibitors, HER2-directed therapies, ER antagonists and KRAS G12C inhibitors (including Frontier’s FMC-376), and pan-RAS/KRAS agents, FMC-242 further enhanced anti-tumor activity, supporting its potential as a differentiated monotherapy and combination approach.
About FMC-242
FMC-242 is a novel allosteric breaker of the PI3Kα-RAS interaction that breaks the interaction between PI3Kα 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 PI3Kα-AKT signaling in tumors while sparing PI3Kα 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 PI3Kα 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 PI3Kα 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.
Media Contacts
Frontier Medicines:
Ashlea Kosikowski (1AB)
(704) 488-7369