Arvinas and Pfizer have announced encouraging preliminary results from the Phase 1b portion of the TACTIVE-U sub-study, evaluating vepdegestrant in combination with abemaciclib for patients with locally advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer. The data, presented at the 2024 San Antonio Breast Cancer Symposium (SABCS), highlight the potential of this combination in patients who have progressed after prior CDK4/6 inhibitor therapy.
The Phase 1b sub-study involved 16 patients and demonstrated a tolerable safety profile for the combination of abemaciclib 150 mg twice daily (BID) with vepdegestrant (200mg once daily; QD), which is the recommended Phase 3 monotherapy dose. An encouraging clinical benefit rate (CBR) of 62.5% was observed among patients with both mutant ESR1 and wild-type ESR1 disease, all of whom had been previously treated with a CDK4/6 inhibitor.
Key Findings from the TACTIVE-U Sub-Study
The preliminary data revealed several important findings:
- Tolerability: The combination of vepdegestrant and abemaciclib was generally well-tolerated, with a safety profile consistent with the known properties of abemaciclib and previous vepdegestrant clinical trials. Common adverse events included diarrhea, nausea, and fatigue.
- Drug-Drug Interaction: Pharmacokinetic data showed no significant drug-drug interaction between vepdegestrant and abemaciclib, with no clinically meaningful effect on abemaciclib exposure.
- Antitumor Activity: The clinical benefit rate (CBR) was 62.5% in all CBR-eligible patients (10/16), 62.5% in patients with mutant ESR1 (5/8), and 62.5% in patients with wild-type ESR1 (5/8). The objective response rate (ORR) in evaluable patients was 26.7% overall (4/15), 37.5% in patients with mutant ESR1 (3/8), and 14% in patients with wild-type ESR1 (1/7).
Implications for Breast Cancer Treatment
These results suggest that vepdegestrant, a PROTAC (PROteolysis TArgeting Chimera) estrogen receptor (ER) degrader, may offer a valuable treatment option for patients with ER+/HER2- advanced breast cancer, particularly those who have progressed on CDK4/6 inhibitors. The ongoing Phase 2 portion of the TACTIVE-U study is evaluating the full dose of abemaciclib (150mg BID) in combination with vepdegestrant (200 mg QD) in this patient population.
"The preliminary results from this Phase 1b sub-study in patients whose cancer had previously progressed after receiving a CDK4/6 inhibitor are encouraging," said Noah Berkowitz, M.D., Ph.D., Chief Medical Officer at Arvinas. "These data further reinforce our belief that vepdegestrant can be used in multiple combination regimens across the metastatic breast cancer setting and has the potential to become a best-in-class backbone ER therapy."
Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer, added, "With vepdegestrant, we aim to develop a novel agent that has the potential to become a new backbone endocrine therapy in ER+ metastatic breast cancer. We are pleased to see these initial results, which complement previously reported data demonstrating the potential of combination therapy with vepdegestrant to address unmet needs for patients."
Arvinas and Pfizer are continuing to evaluate data from the ongoing TACTIVE-U clinical trial, which includes combinations of vepdegestrant plus abemaciclib, ribociclib, or samuraciclib.
