Blog March 8, 2021

KRAS: Undruggable No More

For 40 years, drug developers considered the KRAS oncogene undruggable. The most frequently mutated oncogene in solid tumors, KRAS plays a key role in signaling pathways regulating cell proliferation and differentiation. It is a small protein with a structure offering few sites where an inhibitor might bind. As a result, past attempts to inhibit KRAS directly have been unsuccessful. In addition, attempts to provide benefits by blocking KRAS’s downstream signaling effects have also been disappointing due to the complexity of those pathways. 

But now, KRAS’s status as a drug target has changed, following the 2013 discovery by scientists at the University of California, San Francisco, of a hidden groove on one mutated form, KRAS G12C, to which a drug might bind. The first KRAS G12C inhibitors should soon reach the market – led by Amgen’s sotorasib, with a second molecule, Mirati Therapeutics’ adagrasib, in a Phase 1/2 trial. Wellspring Bioscience/Janssen, Dicerna, and Roche all have KRAS G12C inhibitors in development, and Mirati has added to its KRAS inhibitor portfolio a new G12D inhibitor, MRTX1133, still in preclinical development. Additionally, Boehringer Ingelheim and BioBridge Pharma are both developing pan-KRAS drugs, inhibiting KRAS regardless of mutations.

KRAS G12C is the most prevalent of three KRAS mutations that can drive disease in non-small cell lung cancer (NSCLC), affecting 10-12% of all NSCLC patients and accounting for half of all KRAS mutations in such tumors. G12C mutations are also found in about 3% of colorectal and pancreatic cancers. While occurring in about 1-3% of other solid tumor types, KRAS G12C mutations are more prevalent than all ALK, ROS, RET, and NTRK mutations combined. Interestingly, KRAS mutations rarely occur alongside other known cancer-driving mutations. As a result, patients bearing the KRAS G12C mutation are unlikely to be eligible for therapies targeting other known driver mutations, contributing to their poor prognosis. 

Results of Amgen’s Phase 2 CodeBreaK 100 trial, presented in late January at the World Conference on Lung Cancer, showed an early, significant, and durable response to daily sotorasib in 126 previously treated NSCLC patients with G12C KRAS mutations. Overall response to treatment was 37.1% after a median follow-up of 12.2 months, with a median duration of response of 10 months. Progression-free survival was 6.8 months. Sotorasib was also associated with a favorable risk-benefit profile, especially when compared to those of docetaxel or gemcitabine, the two drugs often used as salvage therapies in patients with KRAS mutations whose disease has progressed after treatment with immuno-oncology and other chemotherapy drugs. 

Sotorasib received Breakthrough Therapy designation in late 2020 and Priority Review designation in February of this year from the U.S. Food and Drug Administration for use in patients with KRAS G12C-mutated locally advanced or metastatic NSCLC. The China National Medical Products Administration has also awarded the drug Breakthrough status. Amgen filed for approval in December 2020 with FDA and the European Medicines Agency as second-line therapy. Analysts are expecting a quick accelerated approval and product launch by Q3 of this year, which would make sotorasib the first targeted treatment for NSCLC patients with a KRAS G12C mutation. Amgen is now enrolling a Phase 3 trial to compare sotorasib plus docetaxel with docetaxel alone. 

Mirati’s adagrasib has shown similar clinical results as a single agent in a Phase 1/2 trial and the company expects to submit regulatory filings for approval in the second half of this year. Mirati recently announced that it has teamed up with the University of Texas MD Anderson Cancer Center to expand clinical investigation of both adagrasib and its other G12D inhibitor, MRTX1133. 

The fact that only one third of KRAS G12C mutated NSCLC patients respond to treatment suggests that additional tumor drivers may exist. Thus, for many patients, effective treatment may require a combination approach of direct KRAS targeting and indirect targeting of downstream effectors, creating a synthetic lethality that arises when deficiencies in the expression of two or more genes leads to cell death.  Sotorasib is now being tested in 10 different drug combinations with modulators of EGFR, SHP2, MEK, and PD-1 in an adaptive study where successful hits can quickly be advanced to Phase 2 testing. Mirati is planning a similar approach for both adagrasib and MRTX1133 through its MD Anderson collaboration.