Merck Launches Phase III Study for KRAS Hopeful, Eyes Challenge to Amgen and BMS

Merck research laboratories_iStock, hapabapa

Pictured: Office of Merck Research Laboratories in South San Francisco, California/iStock, hapabapa

Merck on Thursday launched a Phase III trial that will evaluate its oral KRAS inhibitor candidate MK-1084 in non-small cell lung cancer patients carrying the G12C mutation in the KRAS gene.

The late-stage study will combine MK-1084 with the blockbuster PD-1 inhibitor Keytruda (pembrolizumab), and will test the regimen in patients who also test positive for the PD-L1 protein and have a tumor proportion score of at least 50%. The trial has an enrollment target of 600 participants and is set to initially wrap up in February 2029.

Merck will primarily assess the combination regimen based on progression-free survival (PFS) and overall (OS). Key secondary outcome measures include objective response rate, duration of response and quality of life. The study will also assess MK-1084’s safety when used with Keytruda in non-small cell lung cancer (NSCLC).

The decision to push MK-1084 into late-stage studies was driven by “early evidence” showing that its combination with Keytruda had a “manageable safety profile and promising anti-tumor activity,” Marjorie Green, head of oncology, global clinical development at Merck Research Laboratories, said in a statement.

MK-1084, which Merck is developing under a January 2020 collaboration with Ostuka subsidiaries Taiho and Astex, is a potent and specific covalent inhibitor of the G12C-mutated KRAS gene. KRAS is a gene that encodes for a protein, which in turn forms part of a signaling cascade that tells the cell to grow and divide. The G12C mutation keeps the protein activated, giving rise to the uncontrollable cell proliferation in cancers.

In NSCLC, the KRAS G12C mutation is the most common genetic anomaly, present in around 14% of cases.

KRAS is notoriously a difficult target in the cancer space, and for years has been considered undruggable. Amgen in June 2021 won the first-ever regulatory clearance for a targeted KRAS G12C therapy for Lumakras (sotorasib). The drug was approved under the FDA’s accelerated pathway, and to keep it on the market, Amgen ran the Phase III CodeBreaK 200 trial as a confirmatory study.

However, in October 2023, the FDA’s Oncologic Drugs Advisory Committee flagged issues with the trial. In a 10–2 vote, the panel of external experts agreed that CodeBreaK 200 could not be reliably interpreted, especially due to its high number of dropouts, small sample size and potentially biased behavior of its investigators.

The FDA denied full approval for Lumakras in December 2023.

Late last month, BMS emerged as the frontrunner in the KRAS race after its own oral candidate Krazati (adagrasib) aced a confirmatory Phase III KRYSTAL-12 study, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival versus standard-of-care chemotherapy in patients with locally advanced or metastatic NSCLC with KRAS G12C mutations.

Krazati, a covalent blocker of KRAS G12C, was originally developed by Mirati Therapeutics and joined the BMS fold after the pharma’s $4.8 billion acquisition deal in October 2023.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Back to news