Double trouble for Incyte in KRAS

Incyte’s belt-and-braces approach to KRAS G12D – developing two separate inhibitors of this protein – has hit stormy waters: the study of one has gone on clinical hold over a pneumonitis death, it has emerged, while that of the other stopped recruitment having hit just 10% of its enrolment target.

The molecules involved are INCB161734 and INCB186748, the latter thought to be a follow-up version of the former, and the problems were revealed in updates to the two studies’ listings on the EU registry and clinicaltrials.gov. No statement on the status of the projects has been issued by Incyte, which at the time of publishing hadn’t responded to ApexOnco’s request for clarification.

Based on the disclosures, INCB161734, Incyte’s first KRAS G12D inhibitor, appears to be in the greatest difficulty. The EU listing of its phase 1 solid tumour study has revealed that four member states have put the study on clinical hold. The halt is “temporary”, and patients already enrolled can continue receiving INCB161734.

Pneumonitis death

However, an explanatory note discloses that there was “a case of grade 5 pneumonitis in a participant” receiving 1.2g daily. Worryingly, 1.2g is what Incyte previously determined to be the go-forward dose.

As a result of the death the other 300 or so patients enrolled were reviewed, revealing “three additional cases of confirmed or suspected pneumonitis”, all involving the 1.2g dose. Three of the four cases were seen in chemo combo cohorts, while the fourth concerned INCB161734 monotherapy, according to the EU registry.

This comes as a major surprise, given how positive initial data from this trial had seemed when presented at last year’s ESMO conference. In particular, a 34% response rate with the 1.2g dose was called “remarkable” by the discussant, Dr Ignacio Garrido-Laguna of the University of Utah.

And there were at that time no toxicity concerns; among the 67 patients given 1.2g, treatment-related adverse events at grade 3 or higher were limited to single cases of nausea, diarrhoea and decreased appetite, and two cases of increased lipase. No “additional AEs of significance” were noted.

Follow-up?

As for the second molecule, INCB186748, Incyte has so far not disclosed its mechanism, but since its first-in-human trial concerns KRAS G12D-mutated solid tumours it seems a sure bet that INCB186748 is another G12D inhibitor.

That study began a year ago, seeking to enrol 308 patients. However, a few months later its status on clinicaltrials.gov was changed from “recruiting” to “active, not recruiting”, with just 30 subjects having been enrolled.

It might be surmised, if there are structural similarities between INCB161734 and INCB186748, that the premature ending of recruitment into the latter’s study was taken as a precaution. But this doesn’t fit with the chronology: the issue with INCB186748’s trial occurred months before INCB161734 went on clinical hold.

Incyte’s efforts in KRAS G12D inhibition

Note: *assumed follow-up to INCB161734. Source: trial registries & OncologyPipeline.