-Pre-clinical results demonstrate the combination of FMC-376 with PD-1 immunotherapy increases survival and response rates compared to PD-1 alone 

-FMC-376 is broadly active in KRASG12C mutant containing PDX models derived from patients with solid tumors, including from heavily pretreated patients, across innate and acquired resistance and in models of brain metastases 

-The Phase 1/2 PROSPER clinical trial is currently evaluating FMC-376 in patients with KRASG12C cancers, regardless of prior KRAS inhibitor therapy 

BOSTON and SOUTH SAN FRANCISCO, Calif.  – Frontier Medicines Corporation, a clinical-stage precision medicine company seeking to unlock the proteome to advance transformational therapies against otherwise undruggable disease-causing targets, today presented new preclinical data on its KRASG12C inhibitor, FMC-376, at the American Association for Cancer Research (AACR) Annual Meeting 2024 in San Diego, California. The new findings demonstrate FMC-376’s potential to overcome known mechanisms of innate and acquired resistance and in a CNS model of metastasis as a monotherapy and increase the efficacy of PD-1 immunotherapy in combination.  

“We really pushed FMC-376 pre-clinically to better understand its ability to overcome common resistance mechanisms that have plagued single-acting KRAS inhibitors and limited their ability to provide meaningful and durable benefits to people with KRAS G12C cancers,” said Andrew Krivoshik, M.D., Ph.D., chief medical officer, Frontier. “These data demonstrate FMC-376’s unmatched potential to overcome over 90 percent of known resistance mechanisms, including those cancers that have become refractory to approved KRAS inhibitors. We look forward to proving FMC-376’s best-in-class potential to help even the hardest-to-treat cancers in our ongoing PROSPER clinical trial.”

FMC-376 was discovered by applying the Frontier™ Platform to directly engage both ON+OFF KRASG12C with exquisite selectivity. The differentiated dual direct mechanism of action of FMC-376 offers the potential to overcome the resistance and lack of response seen with current KRASG12C single-acting treatments.

“From the start, we designed FMC-376 to deliver dual inhibition of ON+OFF state KRASG12C with a highly selective profile that is eminently suitable to provide benefit to patients both as a monotherapy and in combination use,” said Kevin Webster, Ph.D., Frontier’s chief scientific officer. “These exciting preclinical data demonstrate FMC-376’s broad activity regardless of resistance mechanism, the addition of FMC-376 to an immune checkpoint inhibitor may lead to improved response and survival rates in patients with lung cancer, compared to a PD-1 inhibitor alone and demonstrate FMC-376’s ability to overcome CNS metastases, which are known to lead to worse treatment outcomes.”

FMC-376 a dual inhibitor of ON and OFF states of KRASG12C is broadly active in PDX models of resistance (Abstract #5948)

In preclinical results, FMC-376 is shown to be highly active in models of G12C inhibitor resistance where ON state KRAS G12C is upregulated. FMC-376 is efficacious in KRASG12C mutant containing patient-derived xenograft (PDX) models derived from patients with colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and pancreatic cancer, including tumors derived from heavily-treated patients. These results reinforce that FMC-376 has the potential to overcome limitations of single-acting KRASG12C inhibitors. 

The clinical dual KRASG12C inhibitor FMC-376 has demonstrated potential as both a monotherapy and in combination for the treatment of patients with KRASG12C mutation positive NSCLC (Abstract #5949)

These preclinical data demonstrate FMC-376 overcomes drivers of innate and acquired clinical resistance to OFF state inhibitors of KRASG12C, as demonstrated by robust anti-tumor activity across a broad panel of NSCLC PDX models. The combination of FMC-376 with an immune checkpoint inhibitor also leads to an increased response and survival in preclinical models. In addition, 27-42% of patients with KRASG12C positive NSCLC present with central nervous system CNS metastasis, and FMC-376 is highly active in an intracranial NSCLC model of CNS-metastasis, resulting in tumor regression.

About the PROSPER Trial

FMC-376 is currently being evaluated in the Phase 1/2 PROSPER clinical trial (NCT06244771), an open-label, multi-center dose escalation and expansion study designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of FMC-376 in participants with locally advanced unresectable or metastatic solid tumors which harbor the KRASG12C mutation. For more information on the PROSPER trial, please visit clinicaltrials.gov.

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 hard-to-treat disease causing proteins for drug development. Today, we are advancing a diversified pipeline of wholly-owned precision medicines against the most important drivers of cancer and high-value immunology programs. Our lead candidate, FMC-376, is a dual inhibitor of ON+OFF KRASG12C. FMC-376 is a potential best-in-class therapy designed to completely block both forms of the KRAS mutation to overcome the lack of response and resistance seen with single-acting KRASG12C inhibitors. For more information, please visit www.frontiermeds.com. Follow Frontier on LinkedIn.