ESMO 2024 – combos could be the way forward for CDK2

So far the data behind CDK2 inhibition haven’t backed up the amount of industry activity here. Two early datasets presented at ESMO on Saturday, involving Incyte’s INCB123667 and Pfizer’s PF-07104091, on the whole look better than what has been seen with this mechanism before, but with the ideal doses still being nailed down these projects have a long way to go.

And the best results came with a combination of Pfizer’s project and its selective CDK4 inhibitor atirmociclib. Toxicity with CDK inhibitor monotherapy has raised eyebrows, so this will be a key consideration as more combination data emerge.

Incyte monotherapy

The first dataset concerned monotherapy with Incyte’s CDK2 inhibitor INCB123667; until now this project had yet to yield anything beyond anecdotal case reports.

In the dose-escalation stage of a phase 1 study in heavily pretreated solid tumours there were eight partial responses among 76 patients, giving an unimpressive 11% ORR.

Zooming in on ovarian cancer produced a better result, with two complete and 12 partial responses among 68 subjects (ORR 21%) in both the dose-escalation and dose-expansion stages, at a cutoff date of 15 July.

Incyte provided a later data cut, showing a 24% ORR among 37 ovarian cancer patients receiving the go-forward doses of 50-125mg once daily. The discussant, Dr Alex Adjei of Cleveland Clinic, described the results as “promising”, but Evercore ISI analysts said they were “on the weaker side”.

Safety didn’t look too troublesome: 88% of patients had treatment-related adverse events, but only 27% were grade 3 or higher. The most common high-grade events were thrombocytopenia (13%), neutropenia (8%) and anaemia (7%). 2% of patients discontinued because of vomiting and aesthenia.

During an ESMO investor event on Saturday Incyte raised the possibility of accelerated approval in ovarian cancer, but it still needs to discuss this with the FDA. A pivotal trial here is due to start in 2025; the company also mooted breast and endometrial cancers as potential indications.

Pfizer combo

The ESMO presentation on Pfizer’s contender, PF-07104091, focused on breast cancer patients in a phase 1/2 trial, in which this CDK2 inhibitor was given alongside endocrine therapy and the company’s selective CDK4 inhibitor atirmociclib.

Atirmociclib is designed to limit CDK6 inhibition in an attempt to lower the neutropenia seen with CDK4/6 inhibitors like Kisqali. Pfizer also hopes that the combo could overcome resistance to CDK4/6 inhibitors.

The trial population was heavily pretreated; all had received prior CDK4/6 inhibitors, and 81% had previously received Faslodex.

Among 18 evaluable patients with HR-positive, HER2-negative breast cancer there were five partial responses. Adjei, the ESMO discussant, described the 28% ORR as “impressive”, and the data look better than those previously seen with PF-07104091 monotherapy.

Cross-trial comparison of CDK2 inhibitors

Source: ESMO & OncologyPipeline.

As for side effects, absolute numbers weren’t given, but the most common grade 3 or higher treatment-emergent adverse events were neutropenia (27%), leukopenia (24%) and anaemia (12%).

Five dose-limiting toxicities were seen at two of the highest doses tested; Pfizer is now focused on 100mg atirmociclib plus 225mg PF-07104091, and 300mg atirmociclib and 75mg PF-07104091, all twice daily.

Adjei noted no evidence of overlapping DLTs, but said there was overlapping gastrointestinal toxicity. With a combo looking like the way forward for Pfizer, at least, this will be worth keeping an eye on.