Drugging the undruggable? KRAS inhibitor shows early promise

Selective inhibition of the KRAS p.G12C mutation is offering some promise for patients with locally advanced and metastatic solid tumours.

A phase 1 trial of sotorasib in 129 patients – including Australians – with mainly non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) has found no dose-limiting toxic effects or treatment-related deaths associated with the drug.

In the international CodeBreaK 100 study, published in the NEJM and presented at the ESMO Virtual Congress, 53% of patients experienced grade 3 or above adverse events including elevated ALT levels, anaemia, vomiting and diarrhoea, abdominal pain and fatigue.

Importantly, “promising anti-cancer activity” was evident with 32% of the lung cancer patients showing an objective response to the treatment and 88% showing disease control.

Responses were seen at daily doses of 180 mg, 360 mg, 720 mg and 960 mg.

The median progression-free survival for the lung cancer sub-group was 6.3 months.

CRC patients didn’t fare as well with only a 7% objective response rate and 74% disease control. Their median PFS was 4.0 months.

“The inconsistency in tumour response between NSCLC and colorectal cancer suggests either that KRASp.G12C is not the dominant oncogenic driver for colorectal cancer or that other pathways, such as Wnt or EGFR pathways, mediate oncogenic signaling beyond KRAS, a hypothesis supported by recently published preclinical evidence,” the study authors said.

Similarly, the smaller sub-group of patients with other tumour types had a 14% objective response rate and 75% disease control.

Speaking in a highlights session at the Congress, lead author Dr David Hong, from the MD Anderson Cancer Center in Houston (US), said about 13% of all NSCLC patients may harbour KRAS p.G12c mutations.

“Overall, I think this is, although the data is preliminary, it is very encouraging to suggest that there may be another drug that we could use to target patients with non-small cell lung cancer,” he said.

An editorial in the NEJM said the tumour responses to sotorasib were much better than those seen with the current standard of care for similar patients.

“Overall, the results of this trial are very encouraging, showing the first step in “drugging the undruggable,” it said.

“Despite these encouraging results, no complete responses were observed, perhaps because tumours harbouring KRAS mutations often have multiple oncogenic drivers,” it said.

“Informed combination strategies may improve the likelihood of achieving complete responses to KRASG12C inhibition.”

“The early development of KRASG12C-targeted agents is just the beginning, lending hope that the ability to target not only other KRAS mutations but also other targets previously thought to be undruggable may be within reach.”

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