A phase 2 modular study has revealed significant clinical activity for the combination of samuraciclib (CT7001) and fulvestrant (Faslodex) in patients with hormone receptor (HR)-positive breast cancer who had previously received CDK4/6 inhibitor therapy. The findings, presented at the 2021 San Antonio Breast Cancer Conference, highlight a potential new treatment option for patients with limited therapeutic alternatives.
The study demonstrated tumor shrinkage in 72% (18 of 25) of evaluable patients. More notably, the research identified key biomarkers that may predict treatment response, potentially allowing for more personalized treatment approaches.
TP53 Status Predicts Treatment Response
The study revealed a striking difference in outcomes based on TP53 mutational status. Patients with TP53 wild-type tumors (76% of participants) achieved a median progression-free survival (PFS) of 32 weeks, compared to just 7.9 weeks in those with TP53 mutations (HR, 0.17; 95% CI, 0.05-0.53; P = .0008).
"P53 reacts to the stress induced by CDK7 inhibition…When [P53] is wild type, [it] responds to CDK7 inhibition to induce apoptosis and senescence. This is important because, at this stage of the disease and ER+ breast cancer, nearly 70% of patients still have wild type P53," explained Charles Coombes, MD, director of Cancer Research at the UK Imperial Centre.
Liver Metastasis Status Impacts Outcomes
Another significant finding was the impact of liver metastasis on treatment outcomes. Patients without liver metastases at baseline (17 participants) had not reached median PFS at the time of analysis (≥48 weeks), while those with liver metastases (14 patients) had a median PFS of 11.9 weeks (HR, 0.16; 95% CI, 0.05-0.59; P = .0021).
Liver metastasis is a known risk factor for poor prognosis in HR+ breast cancer. Future studies will evaluate whether liver metastasis status is specifically predictive for samuraciclib-based therapy or simply prognostic.
Addressing an Unmet Clinical Need
The combination therapy addresses a significant unmet need in metastatic HR+ and HER2-negative breast cancer treatment. Current options following progression on standard therapies typically show unsatisfactory efficacy and toxicity.
"On average, we get about a 2-month progression-free survival with fulvestrant in patients who've become resistant to CDK4/6 inhibitors," noted Dr. Coombes during his presentation. Although patients generally tolerate hormonal therapy well, its efficacy is limited after CDK4/6 inhibitor therapy.
Mechanism of Action and Study Design
Samuraciclib is a once-daily, oral, small molecule selective inhibitor of CDK7 that has shown synergistic activity with hormonal therapy in HR-positive breast cancer models. The drug's mechanism of action has three primary effects on ER-positive breast cancer cells: inhibition of serine phosphorylation, inhibition of CDK1, and inhibition of cell transcription.
The study enrolled 31 patients who received either 240 mg of samuraciclib orally once daily plus 500 mg of fulvestrant every 4 weeks (n = 6) or 360 mg of samuraciclib orally once daily plus 500 mg of fulvestrant every 4 weeks (n = 25).
Eligible patients were at least 18 years old with confirmed metastatic or locally advanced ER-positive and/or PGR-positive, HER2-negative breast cancer. All participants had prior CDK4/6 inhibitor therapy, with a maximum of one line of chemotherapy or two lines of endocrine therapy, and no prior fulvestrant treatment. The median age of participants was 60 years (range, 41-81).
Clinical Benefit and Safety Profile
Investigators observed a clinical benefit rate (CBR) in 36% of patients at 24 weeks. This rate improved to 55% in patients without liver metastases. When excluding patients with TP53 mutations, the overall CBR rose from 36% to 53%, further supporting the predictive value of TP53 status.
The most common adverse events were reversible, low-grade gastrointestinal (GI) events, including diarrhea (90%), nausea (81%), vomiting (74%), and fatigue (36%). Few grade 3 or higher adverse events occurred, with diarrhea (19%) and nausea (10%) being the most common. Six patients discontinued treatment due to GI-related adverse events. Of 11 patients who required dose reductions, 9 continued treatment. Notably, no neutropenia or significant myelosuppression was observed.
Future Directions
Samuraciclib has been granted fast-track status by the FDA, highlighting the potential significance of this treatment approach. Future clinical studies will evaluate samuraciclib in combination with oral selective estrogen receptor degraders to extend the limited PFS of single-agent endocrine therapy.
The promising results from this study suggest that samuraciclib plus fulvestrant could become an important treatment option for patients with HR-positive breast cancer who have progressed on CDK4/6 inhibitor therapy, particularly those with TP53 wild-type tumors and without liver metastases.
