Drugs Xagena
The European Medicines Agency ( EMA ) has recommended the approval of Truqap ( Capivasertib ) in combination with Fulvestrant for the treatment of patients with estrogen receptor (ER)–positive, HER2‑negative, locally advanced or metastatic breast cancer harboring at least 1 PIK3CA, AKT1, or PTEN alteration following recurrence or progression on or after an endocrine-based regimen.
The recommendation was supported by data from the phase 3 CAPItello-291 trial, which has demonstrated that treatment with Capivasertib plus Fulvestrant has reduced the risk of disease progression or death by 50% compared with Fulvestrant alone in patients with tumors harboring PI3K, AKT or PTEN alterations ( hazard ratio, HR, 0.50; 95% CI, 0.38-0.65; P less than 0.001 ).
Patients with AKT pathway–altered tumors (n = 155) experienced a median progression-free survival (PFS) of 7.3 months (95% CI, 5.5-9.0) vs 3.1 months (95% CI, 2.0-3.7) for patients given Fulvestrant plus placebo (n = 134).
The randomized, double-blind, placebo-controlled, multicenter trial enrolled 708 patients with locally advanced or metastatic hormone receptor–positive, HER2-negative breast cancer, including 289 patients whose tumors harbored PIK3CA/AKT1/PTEN alterations.
Patients at least 18 years of age were required to have histologically confirmed disease following recurrence or progression during or after an aromatase inhibitor, with or without a CDK4/6 inhibitor, and up to 1 line of chemotherapy for advanced disease.
HER2 negativity was defined as immunohistochemistry (IHC) 0 or 1+, or IHC 2+/negative in situ hybridization.
Patients were randomly assigned in a 1:1 fashion to receive 400 mg of oral Capivasertib or placebo twice per day for 4 days, followed by 3 days off, in 28-day treatment cycles. In both arms, patients also received 500 mg of intramuscular Fulvestrant on days 1 and 15 of cycle 1, then once every 28 days thereafter. Treatment continued until disease progression or unacceptable toxicity.
Progression-free survival in the overall patient population and in the population of patients whose tumors had PIK3CA, AKT1, or PTEN alterations in the AKT pathway served as the trial’s dual primary end points. Secondary end points consisted of overall survival (OS), objective response rate (ORR), and safety.
In the overall population, patients treated in the Capivasertib arm (n = 355) achieved a median progression free survival of 7.2 months (95% CI, 5.5-7.4) compared with 3.6 months (95% CI, 2.8-3.7) for patients treated in the placebo arm (n = 353; HR, 0.60; 95% CI, 0.51-0.71; P less than 0.001).
An exploratory analysis has shown that in patients who did not harbor ATK pathway alterations, Capivasertib plus Fulvestrant (n = 142) elicited a median progression-free survival of 5.3 months (95% CI, 3.6-7.3) compared with 3.7 months (95% CI, 3.5-5.1) for Fulvestrant plus placebo (n = 171; HR, 0.79; 95% CI, 0.61-1.02).
Additional data from the trial have shown that in the population of patients harboring AKT pathway alterations, the estimated 18-month overall survival rate was 73.2% (95% CI, 64.8%-80.0%) for Capivasertib plus Fulvestrant compared with 62.9% (95% CI, 53.1%-71.2%) for placebo plus Fulvestrant (HR, 0.69; 95% CI, 0.45-1.05).
In the overall population, these rates were 73.9% (95% CI, 68.3%-78.7%) and 65.0% (95% CI, 58.7%-70.6%), respectively (HR, 0.74; 95% CI, 0.56-0.98).
Regarding safety, the profile of Capivasertib plus Fulvestrant was similar between the AKT pathway–altered population and the overall population.
The most common any-grade adverse effects reported in the Capivasertib plus Fulvestrant group were diarrhea (experimental arm, 72.4%; placebo arm, 20.0%), rash (38.0%; 7.1%), and nausea (34.6%; 15.4%).
The most common grade 3 or higher adverse events were rash (12.1%; 0.3%), diarrhea (9.3%; 0.3%), and hyperglycemia (2.3%; 0.3%).
Serious adverse events were reported in 16.1% of patients in the Capivasertib plus Fulvestrant arm vs 8.0% of patients in the placebo plus fulvestrant arm.
Adverse events led to death in 4 patients (1.1%) in the experimental arm (acute myocardial infarction, cerebral hemorrhage, aspiration pneumonia, and sepsis, n = 1 each) versus 1 patient in the control arm (COVID-19); however, no deaths were considered related to Capivasertib or Fulvestrant, per local assessment.
In the Capivasertib arm, adverse events led to dose interruption, dose reduction, and treatment discontinuation in 34.9%, 19.7%, and 13.0% of patients, respectively; 10.3%, 1.7%, and 2.3% in the placebo arm. ( Xagena )
Source: AstraZeneca, 2024
XagenaMedicine_2024
