CHMP Recommends Capivasertib/Fulvestrant for Pretreated ER+/HER2– Advanced Breast Cancer With PIK3CA, AKT1, or PTEN Alterations

Mafalda Oliveira, MD, PhD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of capivasertib (Truqap) in combination with fulvestrant (Faslodex) 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.¹

The recommendation was supported by data from the phase 3 CAPItello-291 trial (NCT04305496), which demonstrated that treatment with capivasertib plus fulvestrant reduced the risk of disease progression or death by 50% compared with fulvestrant alone in patients with tumors harboring PI3K, AKT or PTEN alterations (HR, 0.50; 95% CI, 0.38-0.65; P <.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).²

“There is an urgent need to extend the effectiveness of widely used endocrine therapies in patients with advanced ER-positive breast cancer to delay disease progression or resistance,” Mafalda Oliveira, MD, PhD, a senior consultant in the Department of Medical Oncology at Vall d’Hebron University Hospital and a senior clinical investigator of the Vall d’Hebron Institute of Oncology’s Breast Cancer Group in Barcelona, Spain, stated in a news release.¹ “With this combination demonstrating a 50% reduction in disease progression or death in patients with tumors harboring PIK3CA, AKT1, or PTEN alterations in the CAPItello-291 trial, this positive recommendation marks an important step in providing a much-needed new treatment option for approximately half of patients in this setting with these specific tumor biomarkers.”

In November 2023, the FDA approved capivasertib plus fulvestrant for the treatment of adult patients with hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer harboring 1 or more PIK3CA, AKT1, or PTEN alterations, as detected by an FDA-approved test, following progression on at least 1 endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. That regulatory decision was supported by data from CAPItello-291.³

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.²

Investigators randomly assigned patients 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.

PFS 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, and safety.

In the overall population, patients treated in the capivasertib arm (n = 355) achieved a median PFS 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 <.001).

An exploratory analysis showed that in patients who did not harbor ATK pathway alterations—excluding patients with unknown next-generation sequencing results—capivasertib plus fulvestrant (n = 142) elicited a median PFS 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 showed that in the population of patients harboring AKT pathway alterations, the estimated 18-month OS rate was 73.2% (95% CI, 64.8%-80.0%) for capivasertib/fulvestrant compared with 62.9% (95% CI, 53.1%-71.2%) for placebo/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 (AEs) reported in the capivasertib/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 AEs were rash (12.1%; 0.3%), diarrhea (9.3%; 0.3%), and hyperglycemia (2.3%; 0.3%).

Serious AEs were reported in 16.1% of patients in the capivasertib/fulvestrant arm vs 8.0% of patients in the placebo/fulvestrant arm. AEs led to death in 4 patients (1.1%) in the experimental arm (acute myocardial infarction, cerebral hemorrhage, aspiration pneumonia, and sepsis, n = 1 each) vs 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, AEs led to dose interruption, dose reduction, and treatment discontinuation in 34.9%, 19.7%, and 13.0% of patients, respectively. Those respective rates were 10.3%, 1.7%, and 2.3% in the placebo arm.

References

1. Truqap plus Faslodex recommended for approval in the EU by CHMP for patients with advanced ER-positive breast cancer. News release. AstraZeneca. April 29, 2024. Accessed April 29, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/truqap-recommended-for-eu-breast-cancer-approval.html#!
2. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131
3. FDA approves capivasertib with fulvestrant for breast cancer. FDA. November 16, 2023. Accessed April 29, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer