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So far so good for Amgen's much-anticipated KRAS inhibitor

Promise to hit previously 'undruggable' target


Amgen has the first clinical data for its inhibitor of KRAS, a cancer target long though to be almost undruggable despite its promise.

The phase 1 data is due to be reported at this year’s ASCO conference in Chicago, and according to the abstract of the trial released this week, there are no safety issues to prevent the drug advancing into later-stage development, as well as some preliminary signs of efficacy.

The abstract covers 22 patients with KRAS G12C-mutated solid tumours, mainly non-small cell lung cancer (NSCLC) and colorectal cancer, who were enrolled before the data cut-off in the trial.

At that point nine patients had reached the tumour assessment stage, and of these there was one partial response, six subjects with stabilised disease, and two whose cancer progressed despite the drug. KRAS has been a target for drug developers for years, but the protein has a featureless, almost spherical structure that has made it very difficult to make a compound that can bind and inhibit its activity. It is an oncogene that acts as an on/off switch in cell signalling, and plays a key role in proliferation.

The KRAS G12C mutation is present in approximately 14% of non-small cell lung adenocarcinomas and 5% of colorectal cancers, with a 1%-3% rate in other solid tumours. A drug that effectively and safely inhibits it could be an important therapy for a sizeable number of patients, based on tumour genetics instead of tumour type or location. Preclinical results have also shown that AMG 510 seems to work particularly well when given alongside checkpoint inhibitors in mouse models of colon cancer.

As the phase 1 trial was a dose-ranging trial, and the maximum-tolerated dose hasn’t yet been encountered, it’s far too early to make a judgment on AMG 150’s clinical potential but analysts at William Blair reckon the signs are good. “Given the abstract only includes efficacy data for highly pre-treated patients treated at low dosage levels, we believe the results are encouraging,” they said in a research note.

Amgen will be presenting the data at ASCO on 3 June. Amgen is in a race with Mirati Therapeutics to bring a KRAS G12C inhibitor through development. Mirati isn’t due to report any clinical results for its MRTX849 candidate at ASCO, but is presenting a poster on the design of its proposed phase 1/2 trial.

At the moment Mirati’s drug is in the latter stages of preclinical development. Amgen will also present data on a clutch of bispecific T-cell engager (BiTE) antibodies at ASCO, as it tries to build a pipeline behind its approved bispecific Blincyto (blinatumomab) for relapsed/refractory acute lymphoblastic leukaemia (ALL).

Clinical data will be available on two new BiTEs, an anti-BCMA and CD3 candidate AMG 420 for relapsed/refractory multiple myeloma – which was a highlight of the ASH programme last December – and pasotuxizumab, a PSMA and CD3-targeting BiTE for metastatic castration-resistant prostate cancer.

Article by
Phil Taylor

17th May 2019

From: Research



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