Palbociclib + rintodestrant

Palbociclib + rintodestrant is a combination therapy being investigated for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. This combination pairs two distinct mechanisms of action to potentially improve outcomes in patients with this type of breast cancer. ## Drug Components Rintodestrant (G1T48) is an oral selective estrogen receptor degrader (SERD) that competitively binds to the estrogen receptor and blocks ER signaling in tumors resistant to other endocrine therapies[1]. The optimal dose of rintodestrant was determined to be 800 mg once daily[1]. Palbociclib is an oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitor that has been previously approved for use in combination with other endocrine therapies for ER+/HER2- breast cancer[1][5]. ## Clinical Development The combination was evaluated in a Phase 1 clinical trial (NCT03455270) which included three parts: - Part 1: Dose escalation of monotherapy rintodestrant - Part 2: Dose expansion of monotherapy rintodestrant - Part 3: Rintodestrant in combination with palbociclib therapy[1] ## Safety Profile The combination demonstrated a favorable safety profile in clinical trials: - Rintodestrant combined with palbociclib was very well tolerated, with no rintodestrant-related serious adverse events (SAEs) or dose-reductions reported[3][5]. - The addition of rintodestrant to palbociclib did not result in additional or more severe toxicities, particularly nausea, vomiting, or diarrhea[3][5]. - The most common treatment-emergent adverse events (TEAEs) were neutropenia (88%) and leukopenia (45%), which are consistent with the known safety profile of palbociclib[6]. - No discontinuations or deaths due to TEAEs were reported[3][5]. - One case (3%) each of diarrhea and fatigue was reported, but neither was considered related to the rintodestrant/palbociclib combination[3][5]. - Importantly, no ocular toxicity or bradycardia was observed during the trial, which are common adverse events in trials of other oral SERDs[5]. ## Efficacy The combination showed promising antitumor activity: - The clinical benefit rate (CBR) doubled from 30% to 60% when palbociclib was added to rintodestrant, suggesting favorable antitumor activity in patients with ER+/HER2- advanced breast cancer, including those with tumors harboring ESR1 variants[3][5]. - The CBR among patients with early relapse was 73% (8/11)[3][5]. - In the full analysis set, 65% of patients experienced stable disease[3]. - Median progression-free survival was 7.4 months (95% CI: 3.7 not reached), although the data were not yet mature as of the April 7, 2021 cutoff date[3]. - In the early phase 1 data, 2 patients (5%) had a confirmed partial response, and 27 (68%) had stable disease[6]. This combination represents a potential new treatment approach for patients with ER+/HER2- advanced breast cancer, particularly for those who have developed resistance to other endocrine therapies.

Brand names

Ibrance (for palbociclib only; combination has no unique brand name)