SABCS 2025 – Carrick sees a way forward in CDK7

Carrick Therapeutics reckons it’s found an option for post-CDK4/6 inhibitor breast cancer that won’t require patients to have certain mutations. The group presented promising mid-stage data with its CDK7 inhibitor samuraciclib in a poster at SABCS this week – and a look across the industry shows only a handful of others shooting at this target.

The results, from the phase 2 Sumit-BC trial, found improvements in response rates and progression-free survival with samuraciclib plus the injectable SERD Faslodex, versus Faslodex alone, in ER-positive, HER2-negative breast cancer patients who had previously been treated with an aromatase inhibitor plus a CDK4/6 inhibitor like Ibrance, Kisqali or Verzenio.

Among 18 evaluable patients receiving samuraciclib at 360mg plus Faslodex the ORR was 33%, and median PFS was 7.8 months, versus 14% and 5.6 months respectively among 14 patients receiving Faslodex alone.

TP53 wild type

Results looked better among 11 patients without TP53 mutations, where the combo produced an ORR of 55% and mPFS of 14.5 months, versus 29% and 6.8 months with Faslodex alone.

Privately held Carrick estimated that around 70% of patients in the second line setting are TP53 wild-type, and that testing should be “straightforward” to implement given the routine use of baseline ctDNA analysis.

Sumit-BC also evaluated a 240mg dose of samuraciclib plus Faslodex, but results here were less impressive.

As for adverse events, diarrhoea and nausea were fairly common with the 360mg dose, with 10% and 15% of patients respectively experiencing grade 3 events. There were also two cases of grade 3 liver enzyme elevations with the higher dose. One of 39 samuraciclib-treated patients discontinued owing to an adverse event.

The company said it would start a phase 3 trial of the project next year, but didn’t give further details. Focusing on the 360mg dose seems likely, and Carrick might choose to enrich the trial for TP53 wild types. Samuraciclib has also shown promise in patients without liver metastases, which could be another population to focus on.

The choice of SERD could be another question, as samuraciclib has shown promise combined with Roche’s oral candidate giredestrant, as well as Faslodex. Additionally, samuraciclib is being tested alongside Menarini’s Orserdu in the Sumit-Ela trial, and with Arvinas’s vepdegestrant in the Tactive-U study.

Post-CDK4/6

Endocrine therapy plus a CDK4/6 inhibitor is standard first-line therapy for ER-positive, HER2-negative metastatic breast cancer, but patients often develop resistance.

Oral SERDs have been tested in this setting, but so far have been limited to patients with ESR1 mutations. Other targeted options include PI3Kα inhibitors for patients with PIK3CA mutations, while projects in development across genetic mutations include KAT6 inhibitors.

In phase 1, Pfizer’s KAT6 project prifetrastat (PF-07248144) at 5mg plus Faslodex produced an ORR of 37% and mPFS of 10.7 months, so it looks slightly better than samuraciclib on a cross-trial basis. That project recently went into phase 3.

There are only a handful of other CDK7 inhibitors in development, with the most advanced being Recursion Pharmaceuticals’ REC-617 and Qurient’s mocaciclib; however, both have produced only one partial response apiece in their respective phase 1/2 trials.

CDK7 inhibitors in clinical development

Note: *also inhibits CK1α & CDK9. Source: OncologyPipeline.