Safety, Tolerability of Capivasertib Plus Palbociclib and Fulvestrant Among Patients With HR-Positive, HER2-Negative Advanced Breast Cancer

Updated Phase 1b Results From the CAPItello-292 Study 

Patrick Neven, MD, PhD, University Hospitals Leuven, Belgium, discusses phase 1b analysis results from the CAPITELLO-292 study which demonstrated that capivasertib plus palbociclib and fulvestrant was safe and tolerable among heavily pre-treated patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. 

These results were first reported at the 2023 San Antonio Breast Cancer Symposium. 

Transcript: 

My name is Patrick Nevin, I’m a gynecological oncologist from UAD Leuven in Belgium. It's my pleasure to summarize the CAPItello-292 study that we presented during San Antonio Breast Cancer Symposium 2023. 

Just a background is that patients with advanced breast cancer most likely are expressing ER without expressing HER2. These patients in general are treated with endocrine treatment first combined with the CDK4/6 inhibitor, which has clearly shown to improve the median progression-free survival [PFS] and also the overall survival as compared to endocrine treatment alone. Unfortunately, all of these patients one day will progress and then we have to think about the follow up treatment—in my country, in Belgium, this follow up treatment most likely is another endocrine treatment like exemestane or fulvestrant, a selective estrogen receptor degrader [SERD]. 

We know that when we combine this treatment with another treatment, which is a targeted treatment, that it can prolong the median PFS as compared to the endocrine treatment alone and we have knowledge about this treatment called the SOLAR-1 study in patients who have a PIK3CA mutation, which is the case in 40% of the patients, that combining fulvestrant with the PIK3CA inhibitor alpelisib doubles the median progression-free survival as compared to fulvestrant alone. Now, within this pathway of PIK3CA we also have AKT, PTEN being part of this activating pathway that is present in half of the patients who have progressed on endocrine treatment with a CDK4/6 inhibitor. But there is a drug that we know is very efficacious when it's combined with fulvestrant, it’s called capivasertib, and it’s a AKT inhibitor. It has proven in 2 randomized controlled trials, that when combined to fulvestrant, it clearly doubles the median PFS, and one of these studies is called the CAPItello-291 study and that was published in the New England Journal of Medicine and has led to the approval of capivasertib in this setting. 

Now, the CAPItello-292 study that we have updated during the 2023 San Antonio Breast Cancer Symposium was an updated analysis on the safety and the efficacy of triple treatment where we simultaneously inhibit PIK3, AKT, and PTEN pathway with a CDK4/6 inhibitor together with fulvestrant. And we know that this can lead to re-sensitizing these tumors to endocrine treatment, even when they have been pretreated with the CDK4/6 inhibitor, and even when they have been pretreated with fulvestrant. In this phase 1b/3 study, we looked for the recommended phase 3 dose, we looked to the safety and to the efficacy in 40 patients looking for the dose. The dose that was selected based on these findings is capivasertib, the AKT inhibitor, 400 milligram twice daily, 125 palbociclib dose for the CDK4/6 inhibitor, and the standard dose of fulvestrant. 

Now, the findings of this study, with the 3 different doses, were that we did see patients with measurable disease where there was a clearly response to the treatment, even if the patients were pretreated with fulvestrant or with the CDK4/6 inhibitor. So, combining capivasertib with the CDK4/6 inhibitor and with the fulvestrant led to really clinical meaningful results without new toxicity events. We know that one toxicity that does appear in these patients is sometimes hyperglycemia, which is controllable, and that's why this drug is given 4 days out of the 7; the capivasertib is not continuously given, it's only given 4 days out of the 7, together with the standard treatment of palbociclib, the CDK4/6 inhibitor, and with the standard dose of fulvestrant. Now, what we also did see was that patients who were included in this phase 1b study, the circulating tumor DNA at that dose of capivasertib showed a 50% or more decrease in the circulating tumor DNA burden, really suggesting also a molecular response even very early in the treatment, and that this can control the disease for quite a long time. 

We can conclude that this treatment is highly efficacious and is now ready for the phase 3 study, in the CAPItello-292 study. Thank you for your attention.

Source:

Hamilton E, Neven P, Pistilli B, et al. Capivasertib plus cyclin-dependent kinase 4/6 inhibitor and fulvestrant in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Updated Phase 1b analysis from CAPItello-292. Presented at the 2023 San Antonio Breast Cancer Symposium; December 5-9; San Antonio, Texas. Abstract PS12-09