KRAS G12C Inhibitor

MRTX849

Scientific Basis for Advancement of Potent KRAS Inhibitors

The human body is a complex system with cells that are constantly signaling, sending each other millions of messages every second—including critical messages on how to best grow and spread. The genes responsible for ensuring these messages are accurate include the RAS family: KRAS, NRAS, and HRAS. Together, as part of the MAPK/ERK signaling pathway, the RAS family is responsible for controlling cell growth.

Known as oncogenes, when a gene in the RAS family becomes mutated, cells can grow and spread out of control, leading to cancer. The KRAS mutation was one of the first oncogenes discovered more than 30 years ago and is the most commonly mutated oncogene. Cancers stemming from RAS mutations account for nearly a quarter of all human cancers and contribute to 1 million deaths per year worldwide. Among the RAS family of oncogenes, KRAS gene mutations are the most common, making up to 85% of all RAS mutations.

Targeting mutations in oncogenes, like KRAS, has been valuable for researchers and drug developers. These types of mutations are not inherited—that is, they are created by mistakes during normal cell division—and drive the uncontrolled cell division and growth that eventually becomes cancer. Accordingly, these mutations are known as driver mutations because by themselves they cause cancer (Source: NIH).

Targeted treatment options have been developed and approved for several of the main driver mutations, with the exception of KRAS. Yet because KRAS mutations rarely co-occur with these other, more treatable oncogenic mutations, there are hundreds of thousands of KRAS G12C mutation positive patients are currently without a targeted treatment option. Mirati has developed MRTX849, as a potential treatment option for those patients.

Program Summary

  • Targets

    KRAS G12C mutations

  • Indications

    KRAS G12C mutation-positive cancers with an initial focus on Non-Small Cell Lung Cancer (NSCLC) and Colorectal Cancer (CRC)

  • Status

    Phase I/II

Watch the video above to learn more about the MRTX849 mechanism of action

Scientists have long thought KRAS inhibitors may be a “holy grail” of cancer treatments—and the quest to create one has been going on for over three decades. Yet no KRAS inhibitors had gone beyond pre-clinical testing, making KRAS mutations the most common oncogene mutations with no targeted treatment option. This landscape changed in 2018, when the first investigational new drug (IND) applications for drugs that target KRAS were submitted to the U.S. Food and Drug Administration (FDA), including one for MRTX849.

Patient Populations for KRAS Inhibitors

KRAS mutations are the initial, driving genetic factor for the growth and development of some of the deadliest cancers (Source: NIH).  Patients exhibiting this mutation typically have a poor prognosis and resistance to standard of care treatment, representing an extraordinary unmet need. KRAS G12C, a specific sub-mutation, is the most frequent individual KRAS mutation in non-small cell lung cancer adenocarcinomas, accounting for 14%, (~14,000 new US cases annually), 4% of colorectal adenocarcinomas (~ 5,000 new US cases annually) and 2% of pancreatic cancers (~1,000 new US cancers annually). Collectively, KRAS G12C mutations comprise a patient population with a worldwide annual incidence of greater than 100,000 individuals.

KRAS G12C Mutation Frequency

KRAS mutation frequency

Preclinical & Clinical Development

Mirati’s investigational drug candidate MRTX849, an optimized KRAS G12C inhibitor, is designed to stop some of the most complex and aggressive cancers in their tracks. MRTX849 is a potent, highly selective, oral therapy, that maximizes inhibition by irreversibly locking the KRAS molecule in its inactive state, thereby preventing tumor cell growth which results in tumor cell death. When KRAS signaling is blocked, the cancer cell becomes primed for rapid and uncontrolled cell proliferation as soon as it’s turned back on, therefore total lockdown of KRAS for the entire dosing interval is crucial to prevent tumor cell re-growth. In initial pre-clinical studies, MRTX849 exhibited significantly improved half-life and penetration into the tumor, shutting down KRAS signaling for the entire dosing interval, and showing a higher degree of antitumor activity than previous KRAS mutant-selective inhibitors:

The U.S. Food and Drug Administration (FDA) approved the IND application for MRTX849 clinical development, which began when the first patient was dosed with MRTX849 in January 2019. Initial Phase 1 clinical data showing efficacy and safety from this ongoing study was presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on October 28, 2019. These early data demonstrated the potential of MRTX849 as a potent and effective KRAS therapy. Stay updated >

The MRTX849 clinical program is exploring single-agent activity but is also proactively researching combinations with other anticancer drugs in order to optimize efficacy and prevent treatment resistance, ensuring this breakthrough continues to benefit patients throughout the course of their treatment journey. Mirati has done extensive pre-clinical studies looking at combinations of MRTX849 with PD-1 inhibitors, SHP2 inhibitors, Pan-EGFR inhibitors and CDK 4/6 inhibitors. Mirati will also conduct signal-finding Phase clinical 1/2 trials in 2020 to enable selection of the most efficacious combinations to advance into pivotal trials.

In July 2019, Mirati and Novartis entered into a clinical collaboration where the combination of MRTX849 and TNO155, Novartis’ investigational SHP2 inhibitor, will be evaluated in patients with advanced solid tumors that harbor KRAS G12C mutations. In pre-clinical studies, the combination of MRTX849 with a SHP2 inhibitor demonstrated a greater inhibition of KRAS signaling and resulted in a significant increase in anti-tumor activity in some tumors. Stay updated >

MRTX849 Combination Therapy

KRAS MOA

Select Background Reading

  1. White Paper: Direct targeting of KRAS mutant cancers with a KRAS G12C mutant-selective inhibitor. Jan, 2019. Mirati Therapeutics, Inc.
  2. Ostrem, Jonathan M., Shokat, Kevan M. “Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design.” Nat Rev Drug Discov 15.11 (2016): 771-785.
  3. Ledford, Heidi. “Cancer: The Ras renaissance.” Nature 520.7547 (2015): 278-280.
  4. Matikas, Alexios et al. “Targeting KRAS mutated non-small cell lung cancer: A history of failures and a future of hope for a diverse entity.” Crit Rev Oncol Hematol 110 (2017): 1-12.
  5. Papke Bjoern, Der Channing J. “Drugging RAS: Know the enemy.” Science 355.6330 (2017): 1158-1163.
  6. Lito, Piro et al. “Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism.” Science 351.6273 (2016): 604–608.