Incyte goes pivotal in CDK2

Mixed results with CDK2 inhibitors haven’t stopped companies pressing ahead with this mechanism, and Incyte has become the first group to go pivotal with its project INCB123667, according to a new listing on clinicaltrials.gov.

While overall much CDK2 activity so far has been in breast cancer, Incyte is focused on the less competitive ovarian cancer space. The Maestra-2 trial, slated to start in December, will enrol platinum-resistant patients with cyclin E1 (CCNE1) overexpression, and compare INCB123667 monotherapy versus investigator’s choice of chemo.

It’s somewhat surprising that Incyte hasn’t plumped for a combination, with CDK2 inhibitors generally looking better when used alongside other agents. But the company has said it wants to evaluate INCB123667 combos, so perhaps more details of its plans here will emerge soon.

Take it away, Maestra

In Maestra-2, Incyte will no doubt hope to replicate data seen in an ovarian cancer cohort of a phase 1 solid tumour trial, which were presented at ASCO this year. Patients had CCNE1 amplification or overexpression and had received a median of four prior lines of therapy; many had already been treated with Avastin and PARP inhibitors.

The overall response rate was 31% among 16 patients receiving a 50mg twice-daily dose, and 36% among 14 patients getting 100mg daily. These numbers look in line with the 32% ORR that got AbbVie’s Elahere FDA accelerated approval in late-line platinum-resistant ovarian cancer, albeit in a different population, those with high folate receptor alpha (FRα) expression.

However, Incyte's ORR with a higher 125mg once-daily dose of INCB123667 was a less impressive 13%. The new clinicaltrials.gov listing doesn’t specify what dose(s) Maestra-2 will evaluate, but presumably it will include one or both of the 100mg daily doses.

Incyte’s regulatory strategy is also unclear. The company said in September 2024 that one scenario could see it filing for accelerated approval of INCB123667 based on an ongoing single-arm phase 2 trial in ovarian cancer, pending regulatory feedback.

In this scenario, the upcoming phase 3 would be a confirmatory trial. However, the group’s second-quarter earnings presentation made no mention of this possibility.

Either way, Incyte is ahead of the pack in CDK2 inhibition. Pfizer and Incyclix have both presented early data with their candidates, tegtociclib and INX-315 respectively – as had Blueprint with its contender, BLU-222, although that asset was deprioritised in January, and doesn’t look likely to be a big focus for Blueprint’s new owner, Sanofi.

Meanwhile, Roche signalled its intent here with its $850m purchase of CDK inhibitors from Regor last year. The lead project, now known as GDC-4198, also hits CDK4, but Roche reckons it could overcome resistance to CDK4/6 inhibition, and Pfizer seems to be pursuing a similar path with a combo of tegtociclib and its CDK4 inhibitor atirmociclib.

Other projects, such as Novartis’s ECI830, only went into human trials fairly recently.

Mid-to-late-stage CDK2 inhibitors

Notes: *also inhibits CDK4; PROC=platinum-resistant ovarian cancer. Source: OncologyPipeline.