Discussion
gastrointestinal events, agentIf TP53, CRPC, diarrhea, breast cancer, stomatitis, cancer, developmentThrombocytopenia, vomiting, advanced/metastatic TNBC, PD, TNBC, nausea,
STOMATITIS, BREAST CANCER, CANCER, DISEASE, MALIGNANCIES
Samuraciclib is an orally bioavailable, potent, selective inhibitor of CDK7. Previous studies have shown that samuraciclib has 17-fold selectivity over the next most sensitive kinaseThe results from both modules demonstrated an acceptable safety profile and evidence of clinical activity for samuraciclib in a variety of advanced solid malignancies, in particular patients with advanced/metastatic TNBC and HR+/HER2− breast cancer. Common drug-related AEs were gastrointestinal events (diarrhea, nausea, vomiting), a profile similar to reports in conference abstract form for another CDK7 inhibitor in clinical developmentThrombocytopenia was reported as Grade ≥4 in 3 patients (1 with predisposing factors), but this was rapidly reversed after discontinuation of samuraciclib. A mild drop in platelets was seen across the cohorts and is likely to be an on-target consequence of CDK7 inhibition given that increased activity of CDK7 in megakaryocytes has been associated with their maturationPK analysis showed that samuraciclib is orally available, with exposure being dose-proportional and time independent. The relatively long half-life supports OD dosing. No clinical PK interactions have been found to date.In Module 1A, initial evidence of anti-tumor activity was demonstrated by a DCR of 52.8%, predominantly consisting of SD across a range of cancer types, with a notable benefit seen in CRPC. CRPC was predicted to be sensitive to samuraciclib due, potentially, to activation of androgen receptors by CDK7, which has been shown to occur in preclinical studies, in an analogous fashion to the reduction of estrogen receptor (ER) activity by CDK7 inhibitors in breast cancerIn the Module 1B-1 TNBC expansion, evidence of anti-tumor activity was demonstrated by a CBR of 20.0%, including 1 PR. Previous preclinical studies have suggested that enriching the TNBC patient population for SOX9, which interacts with FOXC1 to activate MYC may result in an improved DCRSelective estrogen receptor degraders (SERDs) such as fulvestrant have limited activity after progression on CDK4/6 inhibitors when given as a single agentIf TP53 status is borne out to be a predictive biomarker in future trials, the potential to achieve this magnitude of benefit is important due to the paucity of effective targeted treatments after resistance to endocrine therapy plus CDK4/6 inhibition. Unfortunately, there is 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. A non-randomized retrospective study of everolimus reported a median duration of treatment of 3.6 months, plus tolerability issues such as stomatitis and pneumonitisThe PK and PD of the 2 doses of 240 mg and 360 mg were reviewed by the Safety Review Committee (SRC) and a starting dose of 360 mg OD appeared to be the most promising dose level to start treatment based on PK and PD data. However, this is based on the understanding that a dose reduction to 240 mg could be considered if the 360 mg dose is not tolerated. In line with current best practice (Project OPTIMUS, FDA) further data to evaluate both the 240 mg and 360 mg doses are being collected in new Phase 2 trials.Overall, the data show an acceptable safety profile and initial evidence of activity for samuraciclib as a selective inhibitor of CDK7. Limitations of this dataset are that the studies were uncontrolled, non-randomized, single arm evaluations in a relatively small number of patients (TNBC cohort). Thus, in summary, samuraciclib has the potential to address the significant medical need of patients 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.