ESMO 2019 - Amgen’s KRAS drug finds colorectal cancer a challenge

Amgen’s KRAS inhibitor AMG 510 has shown little effect in colorectal cancer patients, according to new data reported at the ESMO congress in Barcelona.

The highly-anticipated drug went into ESMO on a wave of enthusiasm driven by positive results in non-small cell lung cancer (NSCLC) reported at the ASCO conference in the US earlier this year.

AMG 510 was however able to achieve just one partial response out of 12 colorectal cancer patients who had received the 960 mg target dose in the ESMO update on the phase 1 study, which is being conducted in multiple solid tumour types expressing the KRAS G12C biomarker.

Amgen pointed to the fact that 10 of the patients had stable disease, which translates to a 92% disease control rate, but the results give the first indication that KRAS may not be broadly effective against KRAS-positive cancers, at least as a monotherapy.

Amgen reprised data in NSCLC which were more promising, with seven partial responses out of 13 patients (54%) and stable disease in the remaining six. And it also provided details of one partial response seen in two patients with appendiceal cancer, with the other patient showing disease stabilisation.

The main objective of the phase 1 trial was to show safety, and on that score Amgen’s drug performed pretty well, and the company was quick to point out that the colorectal cancer population under test was heavily pre-treated with a very poor prognosis.

One of the investigators in the trial – Marwan Fakih of City of Hope Hospital in Duarte, California – noted that the patients would be expected to have a median progression-free survival of just over two months “so to see patients still on treatment at the target dose after more than three months is very encouraging.”

"We are encouraged by these early results, particularly since these patients have progressed after receiving a median of four prior therapies, and in some cases as many as 10,” said Amgen’s head of R&D Davide Reese.

“The data suggest there are relevant molecular differences between tumour types. We are initiating combination studies to further explore the potential of AMG 510 in lung and colorectal tumours."

For years researchers have been trying to develop inhibitors for KRAS but have been unsuccessful given the structure of the molecule – it has limited pockets where a drug agent could bind.

Amgen solved that issue when it discovered that the G12C mutation – which occurs in around 13% of NSCLC cases and up to 5% of colorectal cancers – could be targeted and made to irreversibly force KRAS into an inactive state.

Its success has sparked renewed interest in the KRAS field, and other companies including Mirati, Novartis and Boehringer Ingelheim are now pursuing the target, once considered “undruggable”.

For now Amgen is well in the lead, with AMG 510 the only KRAS drug to have clinical data available at ESMO. Mirati has said it should have first results with its MRTX849 candidate in the next two to three months.