Ipatasertib Plus Fulvestrant and Palbociclib Shows Strong Preliminary Activity in HR-Positive, HER2-Negative Breast Cancer

Clinical Summary

• Design/Population: The phase 1b TAKTIC trial evaluated ipatasertib plus endocrine therapy with or without palbociclib in heavily pretreated patients with HR-positive, HER2-negative metastatic breast cancer. 
• Key Outcomes: The triplet combination demonstrated preliminary clinical activity with manageable but expected hematologic and gastrointestinal toxicities. 
• Clinical Relevance: Combined AKT and continued CDK4/6 inhibition may represent a potential strategy to overcome resistance in HR-positive /HER2-negative metastatic breast cancer.

Results from the phase 1b TAKTIC trial demonstrate that ipatasertib plus fulvestrant and palbociclib shows strong preliminary activity among heavily pretreated patients with HR-positive, HER2-negative metastatic breast cancer.

“PI3K/AKT pathway activation is implicated in CDK4/6 inhibitor resistance,” stated Seth Wander, MD, PhD, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, and coauthors. “The use of AKT inhibition with continued CDK4/6 blockade after CDK4/6 inhibitor resistance remains unexplored.”

In this open-label study, 77 patients received 400 mg of ipatasertib plus 500 mg of fulvestrant either alone (n = 19) or in combination with palbociclib (n = 42) or ipatasertib plus 1 mg of anastrozole, 25 mg of exemestane, or 2.5 mg of letrozole (n = 16) in 28-day cycles. Patients enrolled in the ipatasertib plus fulvestrant and palbociclib arm underwent dose escalation using a standard 3+3 design beginning with 125 mg of palbociclib and 200 mg of ipatasertib on days 1 through 21. Primary end points included safety, recommended phase 2 dose, and progression-free survival (PFS).

At a median follow-up of 12.5 months, the recommended phase 2 dose was established as 400 mg of ipatasertib plus 100 mg of palbociclib and 500 mg of fulvestrant. The median PFS was 5.5 months. 

Treatment-related serious adverse events were reported in 17% of patients in the ipatasertib plus palbociclib and fulvestrant arm and 5% of patients in the ipatasertib plus fulvestrant arm, including events related to neutropenia, leukopenia, thrombocytopenia, and hyperglycemia. The most common treatment-related adverse events occurring in >5% of patients included neutropenia (39%), leukopenia (19%), diarrhea (18%), rash (9%), lymphopenia (4%), and anemia (5%). 

There were 4 on study deaths, including 1 possibly treatment-related due to grade 5 hyperglycemia in the ipatasertib plus fulvestrant arm.

“The combination of fulvestrant, ipatasertib, and palbociclib showed preliminary signs of clinical activity and showed expected adverse events in heavily pretreated patients with [HR-positive, HER2-negative] metastatic breast cancer, warranting further evaluation in those with CDK4/6 inhibitor-refractory disease,” concluded Dr Wander et al. 

Source: 

Wander SA, Lloyd MR, Keenan JC, et al. Safety and antitumour activity of ipatasertib combined with endocrine therapy and a CDK4/6 inhibitor in HR+/HER2– metastatic breast cancer (TAKTIC): A single-centre, open-label, phase 1b trial. Lancet Oncol. Published online: May 1, 2026. doi:10.1016/S1470-2045(26)00059-8