We have reported the first clinical experience with a novel CDK7 inhibitor (CDK7i) samuraciclib, (ICEC0942; CT7001), a potent small molecule, adenosine triphosphate (ATP) competitive inhibitor of CDK7. Originally discovered at Imperial College UK, the molecule is now progressing in Phase 2 Clinical Development.   The development program, initiated in the United Kingdom and later expanded to the United States has been a successful academic/biotech partnership with Carrick Therapeutics.  As a direct result of this work samuraciclib is now being further investigated in combination with fulvestrant and with oral SERDs elacestrant (OSERDU^TM)) and giredestrant as well as the oral Estrogen Receptor (ER) PROTAC vepdegestrant (ARV-471).

CDK7 plays a key role in regulation of the cell cycle as well as transcriptional control and is implicated in resistance to endocrine therapies. CDK7 is over‑expressed in several cancers and its expression is associated with poor prognosis¹.

Our report presents the First-in-Human dose escalation experience with a paired biopsy cohort and expansions in advanced Triple Negative Breast Cancer (TNBC) (as monotherapy) and advanced Hormone Receptor positive (HR+)/HER2- Breast Cancer (in combination with fulvestrant). The results demonstrated an acceptable safety profile and evidence of clinical activity for samuraciclib.

In line with other CDK7i common drug-related adverse events were gastrointestinal (diarrhea, nausea, vomiting)² and were generally low grade, reversible and ameliorated by standard anti‑nausea and anti‑diarrhea therapies. An upcoming switch from the dosing formulation used in this study (multiple instant-release capsules) to a single tablet formulation has the potential to further enhance tolerability.  Neither neutropenia nor alopecia were observed even at the highest dose of samuraciclib.

The dose escalation and paired biopsy cohorts provided initial evidence of anti-tumor activity with a Disease Control Rate (DCR) of 52.8%, predominantly consisting of stable disease across a range of tumor types, and a reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue, demonstrating pharmacodynamic activity.

In TNBC evidence of anti-tumour activity was demonstrated with a Clinical Benefit Rate at 24 weeks (CBR) of 20.0%, including 1 Partial Response (PR). Although treatment of TNBC has recently improved with the introduction of PARP inhibitors and immunomodulators, these treatments are only temporarily effective.  It is possible that, since haematological adverse effects were rarely encountered, samuraciclib could be added to cytotoxic chemotherapy, PARP inhibitors or immunotherapy.

There is currently a paucity of effective targeted treatments and currently no consensus regarding standard of care for the treatment of women with advanced HR+/HER2- breast cancer whose disease progresses on CDK4/6 inhibition. While patients are frequently switched to cytotoxic agents such as paclitaxel and capecitabine, if combination endocrine treatment is continued options include the mTOR inhibitor everolimus and the PI3K inhibitor alpelisib.  Selective estrogen receptor degraders (SERDs) such as fulvestrant have limited activity after progression on CDK4/6 inhibitors when given as a single agent⁴.

In this study of samuraciclib in combination with the injectable SERD fulvestrant, 3 patients achieved PR with CBR 36.0% (9/25). In patients without a detectable TP53-mutation CBR was 47.4% (9/19). The results suggest the combination of fulvestrant with samuraciclib may provide clinically meaningful activity, particularly in those with wild-type TP53 status.

Given that approximately 70% of patients with metastatic breast cancer do not have TP53 mutations, the predictive potential of TP53 status for samuraciclib in combination with SERD therapy will now be studied in future samuraciclib clinical trials. No significant relationship between ESR1 mutations in ctDNA and response to samuraciclib was seen, therefore ESR1 mutation-positive patients could also potentially benefit from samuraciclib therapy. 

Overall samuraciclib has potential to address the significant medical need of patients with advanced HR+/HER2- breast cancer whose disease has progressed on CDK4/6 inhibitors, and this will be investigated further in future studies. A number of co‑administration studies with both fulvestrant and new oral SERDs are now being initiated. Additionally, further studies are warranted to evaluate which other cancer types and combination strategies are most promising for samuraciclib therapy.

References:

1. Patel, H. et al. ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment. Mol. Cancer Ther. 17, 1156-1166 (2018). doi:10.1158/1535‑7163.
2. Papadopoulos, K. P. et al. First-in-human phase I study of SY‑5609, an oral, potent, and selective noncovalent CDK7 inhibitor, in adult patients with select advanced solid tumors. J. Clin. Oncol. 38, 15_suppl, TPS3662-TPS3662 (2020).
3. Bardia, A. et al. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial. Cancer Res82 (4_Supplement): GS2-02 (2022).