We Have a Winner! Amgen Grabs First FDA Nod in the Race for Undruggable KRAS

On May 28th, Amgen announced the FDA approval of Lumakras (sotorasib) to treat patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a KRAS G12C mutation. With this, Lumakras becomes the first and only therapy against the previously “undruggable” target of KRAS. After the news, Amgen’s stock rose 1.12%. In comparison, the NASDAQ composite rose 0.09% in the same session.

KRAS is a major cancer driver mutated in approximately 90% of pancreatic cancers, 30%-40% of colon cancers, and 15%-20% of lung cancers. Developing inhibitors for KRAS has been a challenge and has led to several high-profile failures, including Eli Lilly’s LY3499446, which was dropped from the pipeline after unexpected toxicity in 2020.

The two main reasons for the KRAS protein to remain “undruggable” were:

• The high levels of similarity between all members of the RAS family, i.e., HRAS, NRAS, and KRAS. As hitting more than one can lead to unacceptable levels of toxicity.
• Its structure is very complex. Its G domain has a dynamic structure with no deep pockets described often described as a “squishy tennis ball.”

A Landmark Approval

The FDA approval is based on data from the Phase 1/2 CodeBreaK 100 clinical trial. In the Phase 2 trial, 124 patients with KRAS G12C were treated orally with 960 mg of Lumakras once daily. Around 81% of patients achieved disease control, with a median duration of response of 10 months. Importantly, 36% of patients had a significant reduction (≥30%) in tumor size.

The FDA approval is contingent upon verification of benefits and efficacy in subsequent clinical trials. Including a randomized active-controlled Phase 3 clinical trial comparing Lumakras to docetaxel in patients with KRAS G12C-mutated NSCLS.

Lumakras could prove to be a blockbuster drug for Amgen, and they have plans to test its efficacy as a monotherapy or as a combination therapy in various solid tumors. Their next approval could be for colorectal cancer as their Phase 2 clinical trial has completed enrollment, and results are expected before the end of 2021.

“The FDA approval of Lumakras is a breakthrough moment for patients with KRAS G12C-mutated non-small cell lung cancer because there is now a targeted therapy for this common, but previously elusive, mutation,” said David M. Reese, M.D., Executive Vice President of Research and Development at Amgen.

“KRAS has challenged cancer researchers for more than 40 years, with many deeming it as ‘undruggable.’ The Lumakras development program was a race against cancer for Amgen’s scientists and clinical trial investigators who together have now successfully delivered this new medicine to patients in less than three years—from first patient dosed to U.S. regulatory approval.”

LUMAKRAS™, a once-daily oral therapy, Image courtesy: Amgen, Inc.

Amgen has partnered with Guardant Health and QIAGEN to develop blood- and tissue-based companion diagnostics, respectively, for Lumakras. The company said the drug would have a US list price of $17,900 per month.

KRAS Showdown on the Cards

The approval of Lumakras has important implications for other companies developing KRAS inhibitors. Its main competitor, Mirati Therapeutics, has completed Phase 2 clinical trials for their selective KRAS inhibitors, MRTX849. Mirati’s stock rose almost 3.4% after the news of the approval. A showdown to determine which therapy becomes the standard of care is underway, as both inhibitors target the same mutation and both aim to treat solid tumors. After the failure of its first candidate, Eli Lilly has re-entered the race two months back with another KRAS candidate, LY3537982.

Related Article: Targeting KRAS Mutants: Advances in Drugging the “Undruggable”

Author

Daniel Ojeda