Samuraciclib regimen shows benefit in metastatic breast cancer subset
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Samuraciclib plus fulvestrant demonstrated durable efficacy among a small cohort of women with hormone receptor-positive, HER2-negative metastatic breast cancer, according to study results presented at San Antonio Breast Cancer Symposium.
Researchers observed this benefit for women with breast cancer previously treated with cyclin-dependent kinase 4/6 inhibitors, and specifically among those with no liver metastases and with TP53 wild-type disease.
“There is an urgent need in metastatic breast cancer for treating patients who become resistant to CDK 4/6 inhibitors. On average, patients who become resistant to CDK 4/6 inhibitors experience an approximate 2-month PFS with fulvestrant,” R. Charles Coombes, MD, PhD, FMedSci, professor of medical oncology at Imperial College London, said during a presentation.
Samuraciclib (Carrick Therapeutics) is an irreversible antagonist, ATP-competitive, selective inhibitor of CDK 7 that synergizes with endocrine therapy among patients with hormone receptor-positive breast cancer.
“[The agent] is active with tamoxifen and fulvestrant via direct inhibition of estrogen receptor phosphorylation,” Coombes said. “This is important because work that we published many years ago showed that if a patient has CDK 7 upregulated and is treated with tamoxifen and a low level of estrogen receptor, there is an amplification of estrogen receptor activity that is suppressed by CDK 7 inhibition.”
The phase 2 trial included 31 women (median age, 60 years) with histologically confirmed metastatic or locally advanced ER-positive and/or PR-positive, HER2-negative breast cancer. All patients had measurable disease and had received prior CDK 4/6 inhibitor therapy, up to one line of prior chemotherapy or up to two lines of endocrine therapy for advanced-stage disease. No study participants had received prior fulvestrant.
Six patients received 240 mg samuraciclib once daily plus 500 mg fulvestrant every 4 weeks. The other 25 patients received 360 mg samuraciclib once daily plus 500 mg fulvestrant every 4 weeks.
“Eighty-one-percent of women had visceral disease, but we excluded those with bone-only disease because patients had to have had measurable disease,” Coombes said.
Results showed an overall clinical benefit rate of 35% at 24 weeks. The majority (72%) of evaluable patients experienced tumor shrinkage.
Researchers reported a 55% clinical benefit rate among the 17 patients with no liver metastases. Patients without liver metastases achieved longer median PFS than those with liver metastases (48 weeks vs. 11.9 weeks; HR = 0.16; 95% CI, 0.05-0.59).
“The strength of the effect observed suggests that liver metastases have predictive potential for clinical benefit from samuraciclib-based therapy,” Coombes said. “This factor needs to be taken into consideration when designing future studies.”
Results showed a 53% clinical benefit rate for the 19 patients with TP53 wild-type disease. Patients with TP53 wild-type disease achieved longer median PFS than those with TP53 mutation-positive disease (32 weeks vs. 7.9 weeks; HR = 0.17; 95% CI, 0.05-0.53).
“A very important point of this study is the clinical benefit rate. The overall rate at 24 weeks was 35% but when we excluded patients with TP53 mutant disease, the rate increased to 53%,” Coombes said. “TP53 is so important because it reacts to the stress-induced by CDK 7 inhibition. Essentially, TP53 as wild-type responds to CDK 7 inhibition to induce apoptosis, and this is important because — at this stage of disease in estrogen receptor-positive breast cancer — nearly 70% of patients have wild-type TP53. The potential is quite great for this combination treatment.”
The most common grade 3 or higher adverse events included gastrointestinal events (19%), nausea (10%), vomiting (3%) and fatigue (3%). Six patients discontinued treatment due to gastrointestinal events.
Ondansetron prophylaxis is now routine for patients receiving treatment with samuraciclib, Coombes said.
“We have an effective combination here. This is a small study of only 31 patients; therefore, the data are preliminary, but the combination appears effective, particularly for patients with wild-type TP53 status,” Coombes said. “Although we conducted this study with fulvestrant, there is absolutely no reason to suppose that some of the other oral agents couldn’t be given in combination with samuraciclib to improve PFS in patients who have this devastating form of metastatic breast cancer after CDK 4/6 inhibitor therapy. It is for this reason that the FDA granted samuraciclib fast-track status.”
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Coombes RC, et al. Abstract GS3-10. Presented at: San Antonio Breast Cancer Symposium (virtual meeting); Dec. 7-10, 2021.
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