Lilly Seeks First-Line KRAS Treatment with AACR Data Release

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Eli Lilly presented the first clinical data on its KRAS G12 inhibitor at the American Association for Cancer Research (AACR) meeting in Orlando on Monday. Lilly investigators said they hoped to differentiate their Phase I candidate from the competitive KRAS space by making it the first to gain approval as a first-line treatment.

Currently approved competitors work as a second-line treatment.

KRAS G12 is a specific genetic mutation in the KRAS oncogene. The KRAS gene produces a protein called K-Ras, which helps to regulate cell growth and division. A mutation in the KRAS gene can lead to the production of a faulty K-Ras protein that is always active, causing cells to grow and divide uncontrollably, resulting in cancer.

The KRAS G12 mutation refers explicitly to a change in the genetic code of the KRAS gene at position 12, where the amino acid glycine is replaced with another amino acid, most commonly aspartic acid or valine. This mutation is commonly found in various types of cancer, including lung, colorectal and pancreatic cancer.

Lilly enters a space already occupied by Amgen’s Lumakras (sotorasib) and Mirati’s Krazati (adagrasib), both approved as second-line treatments for lung cancer. Nevertheless, David Hyman, chief medical officer at Loxo Oncology, told BioSpace the field is “wide open.”

Although Lumakras and Krazati are approved as second-line treatments for lung cancer, along with other investigational agents, Hyman said the field is having challenges advancing into first-line treatment.

Lilly’s Data

Lilly’s 84-patient study tested LY3537982 alone, and also included 16 patients who were treated with a combination of the drug and Keytruda; 20 patients were a combination of the Lilly drug and cetuximab. The therapy showed preliminary efficacy across all doses of several tumor types, including NSCLC, colorectal cancer and pancreatic cancer, according to a slide presentation at AACR.

Hyman said the efficacy results of the monotherapy arm were similar to those of other KRAS inhibitors' monotherapy efficacy measures. 

In the eight non-small cell lung cancer (NSCLC) patients who had not previously received a KRAS inhibitor, LY3537982 elicited an overall response rate (ORR) of 38% and a disease control rate (DCR) of 88%. In the 14 patients who had previously received a KRAS inhibitor, the results showed an ORR of 7% and DCR of 64%.

In the 20 colorectal cancer patients, the ORR was 10%; DCR 90%. For pancreatic cancer, the ORR was 42%; DCR, 92%. Finally, in “other” (including ovarian and head and neck cancer patients), the ORR was 52%; DCR, 95%.

Hyman also touted LY3537982’s safety profile. Researchers didn’t find the side effects (e.g., diarrhea, liver toxicity) with Lilly’s drug that they have struggled with in competitor assets.

Hyman said that other approved drugs, such as Krazati, are often billed as tolerable, but in reality, that’s not always the case.

“The overall toxicity burden we hear from prescribers, and actually from patients, is such that the regimen is technically tolerable, but not in a way where there’s actually any enthusiasm to use it in that setting, and that matters,” he said.

David Meek, CEO at Mirati, disagreed.

“We believe Krazati is a differentiated product that will become the market-leading treatment for patients with KRAS G12C-mutated cancers based on overall efficacy, tolerability, and its clinically demonstrated CNS activity and combinability with other agents,” he wrote in an email statement to BioSpace.

KRAS Competitors

Mirati and Amgen have attempted first-line trials with mixed results.

Mirati’s drug, combined with Keytruda, shrank tumors in 49% of 53 patients with newly diagnosed KRAS G12C-mutated NSCLC during a Phase II trial published last year. This study examined Krazati as a first-line treatment.

Meanwhile, Amgen’s Lumakras is also approved for KRAS G12C-mutated NSCLC after at least one prior systemic therapy. In June 2022, Amgen touted positive early data from a Phase II trial of Lumakras as a potential first-line treatment for people with KRAS G12 advanced NSCLC, BioSpace reported.

Sumita Bhatta, vice president and global medical therapeutic area head of oncology at Amgen, told BioSpace that making side-by-side comparisons is problematic.

“Cross-trial comparisons cannot be made between KRAS G12 inhibitors,” she said via email.

“As the leaders who brought the first KRASG12C inhibitor, Amgen has several competitive advantages in this market.”

Lumakras is the first and only KRAS G12 inhibitor with once-daily dosing and a proven track record showing its capability to treat KRAS G12-mutated NSCLC in the clinic and the real world, she said. The drug is approved for second-line treatment.

Nonetheless, Lilly still seeks to make first-line status with its research.

“If we’re going to compete to be part of that backbone of therapy, we need to meet the same benefit-risk bar [as chemotherapy], Hyman said. “The idea here is that second-line agents are important advances but not a paradigm shift.”

Lisa Munger is a senior editor at BioSpace. You can reach her at lisa.munger@biospace.com. Follow her on LinkedIn.