Amgen has achieved something which has eluded many other drugmakers, bringing a drug that inhibits the oncogene KRAS to the clinic and showing preliminary activity.
For three decades, mutations in the KRAS pathway have been recognised as an important factor in oncology, seen in around a third of all human cancers, and intensely studied as a potential drug target with such little success that it came to be considered as an “undruggable” target.
Amgen seems to have succeeded where others have failed, reporting safety, tolerability and preliminary anti-tumour activity in a phase 1 trial of its AMG 510 candidate – which targets a KRAS mutation known as G12C– at the ASCO congress in Chicago.
The study in 35 patients found no dose-limiting toxicities at the tested dose levels, and revealed a 50% partial response rate among a subgroup of 10 patients with KRAS-positive non-small cell lung cancer (NSCLC).
Another four NSCLC patients had stabilised disease, giving the drug a disease control rate of 90%, according to Amgen, and one patient went onto achieve a complete response to the drug. In addition, 13 of 18 evaluable patients with colorectal cancer saw their disease stabilise.
It is estimated that around 14% of NSCLC adenocarcinoma patients and roughly 5% of colorectal cancer patients have the KRAS G12C mutation.
It is known that a glycine to cysteine mutation at position 12 causes RAS protein activation, driving cellular mechanisms that promote an array of mechanisms that affect the tumour microenvironment as well as stimulating chemokines, cytokines and growth factors that drive cell growth.
KRAS was long thought to be undruggable because the protein lacked traditional small molecule binding pockets, according to David Reese, Amgen’s executive vice president of R&D.
David Reese
“AMG 510 seeks to crack the KRAS code by exploiting a previously hidden groove on the protein surface,” he said. “By irreversibly binding to cysteine 12 on the mutated KRAS protein, AMG 510 is designed to lock it into an inactive state.”
The KRAS G12C mutation has emerged as a clear front-runner among the various targets for pharmacological intervention. However, while Amgen can claim to be first to the clinic there are a number of other compounds on its heels in preclinical development, including candidates from AstraZeneca, Mirati, Johnson & Johnson/Wellspring and Merck/Moderna.
Amgen now intends to move quickly ahead with additional studies of the drug, both alone and in combination with other targeted and immune therapies and in a broader range of tumour types.
The company also reported encouraging early stage data from candidates based on its novel bispecific T cell engager (BiTE) platform at ASCO, including its AMG 420 candidate for patients with relapsed and/or refractory multiple myeloma.