Lilly rejoins KRAS race with swipe at Amgen and Mirati, plans 2021 clinical trial 

Lilly
Eli Lilly said other KRAS-G12C inhibitors “have relatively modest activity." (Eli Lilly/LinkedIn)

Eli Lilly has rejoined the KRAS race months after toxicity forced it to dump its first candidate. The Big Pharma is set to enter phase 1 later this year with a new drug it compared favorably to rival assets developed by Amgen and Mirati Therapeutics.

Late in 2019, Lilly began a phase 1 clinical trial of LY3499446 in advanced solid tumor patients with the KRAS-G12C mutation. The trial gave Lilly a spot in the race to develop a drug against one of the hottest targets in oncology. However, Lilly stopped the trial last year after seeing unexpected toxicity. The study enrolled five patients before Lilly pulled the plug.

Now, Lilly has shared details of another KRAS candidate, LY3537982. Lilly disclosed details of the new inhibitor of KRAS-G12C in an abstract released ahead of this year’s annual meeting of the American Association for Cancer Research. 

The candidate hits the same target as Amgen’s AMG 510 and Mirati’s MRTX849. In the abstract, Lilly said KRAS-G12C inhibitors currently in clinical trials “have relatively modest activity compared to other approved therapies targeting other classic oncogenic drivers.” 

As Lilly sees it, near complete target engagement may be needed to maximize clinical benefit in patients with the KRAS-G12C mutation. That thinking suggests Lilly has a shot at coming from behind to capture a piece of the market.

In a KRAS-G12C mutant lung cancer cell line, AMG 510 and MRTX849 had IC50 values of 47.9 nM and 89.9 nM, respectively, according to Lilly. LY3537982, in contrast, had an IC50 value of 3.35 nM. Tests in another cell line also revealed a gulf between the IC50 values. 

The comparisons suggest LY3537982 is a more potent inhibitor of KRAS-G12C than the molecules in development at Amgen and Mirati. If Lilly is right, that additional potency may translate into a more effective treatment for patients with KRAS-G12C mutations. In animal models, Lilly saw outcomes ranging from complete regression to significant tumor growth inhibition. 

Buoyed by the data, Lilly plans to start a phase 1 clinical trial of the KRAS inhibitor later this year. As was the case with the now-abandoned LY3499446, combinations look set to be central to Lilly’s plans for its latest KRAS inhibitor. Lilly has generated early evidence that LY3537982 works synergistically with AurA inhibitor LY3295668 and EGFR inhibitor Erbitux.