Efficacy of second-line treatment option for patients with ER-positive/HER2-negative metastatic breast cancer who progress on an aromatase inhibitor plus CDK4/6 inhibitor is poor. In a first-in-human phase 2 trial, samuraciclib, an oral, selective inhibitor of CDK7, in combination with fulvestrant shows promising activity.
At the moment, there is no current agreed standard-of-care treatment for women with ER-positive/HER2-negative metastatic breast cancer who progress on first-line treatment with CDK4/6 inhibitor plus aromatase inhibitor or selective estrogen receptor degrader (SERD). Available options for second-line treatment, like chemotherapy, mTOR inhibitor, PIK3CA inhibitor, or SERD, are unsatisfactory in terms of efficacy and/or toxicity [1–3]. Therefore, patients with ER-positive/HER2-negative metastatic breast cancer post-CDK4/6 inhibitor-treatment have a poor prognosis with a median progression-free survival (PFS) of about 8 weeks for fulvestrant post-CDK4/6 inhibitor. CDK7 inhibition is a promising therapeutic strategy in cancer because it acts as a regulator of the cell cycle, transcription, and endocrine receptor signaling. Pre-clinical breast cancer models indicate the potential for synergy when the CDK7 inhibitor samuraciclib is combined with fulvestrant . Prof. Charles Coombes (Imperial College London, UK) presented results of a first-in-human, phase 2 trial assessing the tolerability and efficacy of samuraciclib in combination with standard dose fulvestrant in 31 patients with metastatic ER-positive/HER2-negative breast cancer who had previously received an aromatase inhibitor and a CDK4/6 inhibitor for advanced disease . All patients received the combination of samuraciclib and standard dose fulvestrant. The combination treatment was generally well tolerated, with adverse drug reactions of note being grade 1–2 nausea, vomiting, and diarrhea; the majority of patients stayed on treatment until disease progression. No neutropenia was observed. Clinical benefit rate at 24 weeks was 36%. Of note: a TP53 mutation was a negative predictor of response to samuraciclib plus fulvestrant. Clinical benefit rate in patients TP53-wildtype patients was 53%. Median PFS for TP53-wildtype patients was 32 weeks versus 7.9 weeks for TP53-mutant patients. In addition, liver metastases were a negative predictive factor: median PFS for patients without liver metastases was over 48 weeks versus 11.9 weeks for patients with liver metastases. “These first results demonstrate that samuraciclib has an acceptable safety profile with evidence of anti-tumor activity in combination with fulvestrant for patients with metastatic ER-positive/HER2-negative breast cancer who have progressed on their prior CDK4/6 inhibitor,” concluded Prof Coombes.
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- Coombes C, et al. Study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in combination with fulvestrant in patients with advanced hormone receptor positive HER2 negative breast cancer (HR+BC). SABCS 2021 Virtual Meeting, abstract GS3-10.
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