AMG 510: A novel molecule targeting KRAS G12C mutant solid tumours

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Published: 4 Oct 2019
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Prof Marwan Fakih - City of Hope National Medical Center, Duarte, USA

Prof Marwan Fakih speaks to ecancer at ESMO 2019 in Barcelona about the phase I study of AMG 510, which a novel agent that targets solid tumours with a KRAS G12C mutation. 

He presents the updated safety data in patients with predominately non-small-cell lung cancer (NSCLC) and colorectal cancer.

Prof Fakih also reports that approximately half of the NSCLC patients had an objective response and 79 percent of colorectal cancer patients had disease control.

He emphasises that this agent displays clear activity and is robust in NSCLC. Combinations with AMG 510 are now being explored, including immunotherapy and MEK inhibitors.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

At this meeting we presented a poster on an update on the AMG 510 in patients with KRAS G12C mutation. This is based on the cut-off on July ’17 and at this point we presented safety data on 76 patients with a variety of tumours, predominantly non-small cell lung cancer and colorectal cancer.

On this study we’ve shown that there is now some maturity on the response rate data, specifically we have seen that approximately half the patients with non-small cell lung cancer have an objective response. The majority of patients with KRAS G12C, whether it’s non-small cell lung cancer or colorectal cancer, have disease control. In colon cancer 29 patients were evaluable for response and in that setting we have seen that 79% of patients had disease control, either stable disease or response. The response rate in colorectal cancer was lower than in non-small cell lung cancer.

How does this agent work?

AMG 510 is a small molecule and it binds specifically to the cysteine moiety on the KRAS G12C. By binding to the cysteine moiety it basically blocks the KRAS G12C from being activated by blocking it from binding to the GDP which makes it active, therefore completely deactivating G12C.

Can you explain the update of the safety profile?

We basically presented safety data on 76 patients and the nice thing about this agent is because it’s very, very specific to KRAS G12C it doesn’t really have that much of an off-target inhibition and most of the toxicities were grade 1, grade 2 toxicities. Very few grade 3 toxicities were noted, they were diarrhoea and anaemia.

What’s next?

We’re really waiting for the data to mature further as far as the progression free survival and overall survival of these patients. Clearly there is activity, I think it’s robust in non-small cell lung cancer. There are several studies now looking at AMG 510 in combination with other agents, specifically there is a study launching combining AMG 510 in combination with immunotherapy as well as another study looking at AMG 510 or an arm looking at AMG 510 plus a MEK inhibitor. We believe the combinations may result in better activity, specifically we want to interrogate those in colorectal cancer to see if the responses will be better.

We have interrogated AMG 510 as well in non-colorectal cancer and non-small cell lung cancer. KRAS G12C is quite rare in non-colorectal and non-lung cancer. In non-small cell lung cancer it’s about 13-14% of patients, in colorectal cancer 3%. But when you look across other solid tumours it’s only about 1% but we have seen activity with disease stability as well as response rate noted in patients with appendiceal cancer. There’s a patient also with small bowel cancer that has also had stable disease on the study.