- Based on results from the CAPITello-291 phase III study, co-led by VHIO’s Mafalda Oliveira, Senior Medical Oncologist at Vall d’Hebron and Clinical Investigator at VHIO, the European Medicines Agency (EMA) recently approved the combination of novel AKT inhibitor capivasertib with fulvestrant for patients with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer harboring alterations in the AKT signaling pathway, with disease progression on or after previous endocrine therapy.
- Published today in The Lancet Oncology, analysis of quality of life as a patient-reported outcomes (PROs) show that patients who received this treatment combination maintained quality of life for longer compared with those treated with standard of care. These present findings further support the positive benefit-risk balance of this dual therapy in this setting.
- Data previously reported in The New England Journal of Medicine, showed that capivasertib plus fulvestrant reduced the risk of disease progression or death by 50% in patients with tumors harboring specific biomarker alterations, with a median progression-free survival of 7.3 months in patients treated with this new combination compared to 3.1 months with placebo-fulvestrant.
- HR-positive breast cancer is the most common subtype of breast cancer with approximately 70% of tumors considered HR-positive and HER2-negative. Alterations in the AKT singaling pathway occur in around 50% of patients with advanced disease. For these patients, endocrine therapy is the mainstay of first-line treatment, combined with fulvestrant in patients with tumor progression or resistance.
Published today in The Lancet Oncology (1), results of exploratory analysis of quality of life as a patient-reported outcomes (PROs) from the phase III CAPITello-291 clinical trial further support the combination of the novel AKT inhibitor capivasertib plus fulvestrant in patients with advanced HR+/HER2- breast cancer who experience tumor progression of resistance to endocrine-based treatment regimens.
Developed by AstraZeneca, capivasertib is a highly potent oral pan-AKT kinase inhibitor that has now been approved by the European Medicines Agency (EMA) as the first and only AKT inhibitor approved in the EU for the treatment of patients with HR+/HER2- locally advanced or metastatic disease with tumors harboring one or more alterations in the PIK3CA, AKT1 or PTEN genes. This approval follows the positive opinion of the Committee for Medicinal Products for Human Use (CHMP) and is based on the results from CAPItello-291, published last year in The New England Journal Of Medicine (2). This double-blind, randomized study was directed by Nicholas C. Turner at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, and co-led by Mafalda Oliveira, Senior Medical Oncologist at the Vall d’Hebron University Hospital and Clinical Investigator of VHIO’s Breast Cancer Group.
Data published today show that capivasertib-fulvestrant combination prolongs time to deterioration of health and quality of life in patients compared with those who received fulvestrant alone, with a median of 24.9 months versus 12 months, respectively.
“Results of this exploratory analysis, in addition to previously reported data that demonstrated clinical efficacy and a manageable safety profile, further support the positive benefit-risk balance of this treatment combination,” said Mafalda Oliveira, co-first author of this present article, along with Hope S. Rugo at the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center.
Alterations in the AKT singaling pathway occur in an estimated 50% of patients with advanced HR+/HER2- breast cancer
Female breast cancer is the second leading cause of global cancer incidence in 2022, with an estimated 2.3 million new cases, accounting for 11.6% of all cancer cases (3). Approximately 70% of breast cancer tumors are HR+/HER2-, and mutations in the AKT singaling pathway (alterations in the PIK3CA, AKT1 or PTEN genes) affect an estimated 50% of patients with advanced HR+ positive breast cancer.
For these patients, endocrine therapy combined with CDK4/6 inhibitors is the mainstay of first-line treatment. “Many patients with advanced disease experience tumor progression or cancer drug resistance with first-line therapy, representing an unmet clinical need. Current treatment strategies include fulvestrant, a selective estrogen receptor downregulator, either as monotherapy or in combination with targeted therapies,” explained Oliveira.
She added, “The approval of this novel AKT inhibitor represents an important development for the treatment of approximately half of patients with ER-positive breast cancer in Europe who have tumors with these specific biomarker alterations. It is important for clinicians to test and identify eligible patients who may derive benefit from this new combination.”
Approval based on CAPItello-291
Enrolling 708 patients, this multi-center international study was designed to evaluate the efficacy and safety of capivasertib plus fulvestrant versus placebo and fulvestrant in patients whose disease had relapsed or progressed during or after aromatase inhibitor therapy, with or without a CDK4/6 inhibitor.
“This study included a prespecified biomarker subgroup of patients whose tumors had alterations in the PIK3CA, AKT1 or PTEN genes, and patients with tumors lacking a qualifying alterations detected in any of these three genes or with an unknown test result. The heterogeneous nature of the CAPItello-291 population reflects the patients attended in routine clinical practice,” observed Mafalda Oliveira.
Results of global analysis showed a 40% decrease in the risk of disease progression or death in the group of patients treated with capivasertib-fulvestrant, versus those who received placebo plus fulvestrant in the overall population. The median progression-free survival was 7.2 months in the capivasertib-fulvestrant group and 3.6 months in placebo-fulvestrant group.
In the AKT pathway-altered population the reduction in risk of disease progression or death was 50%, with a median progression-free survival of 7.3 months in patients treated with the new combination compared to 3.1 months with placebo-fulvestrant. The most common adverse events observed with capivasertib and fulvestrant were rash, diarrhea and hyperglycemia, but the combination was generally well tolerated.
Published today, the results of exploratory analysis of quality of life as a patient-reported outcome further support the positive benefit-risk balance of this treatment combination in this patient population.
Regulatory applications are currently under review in China and several other countries. Similar indications for capivasertib in combination with fulvestrant are already approved in the US, Japan and several other countries based on the CAPItello-291 trial.
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References
- Mafalda Oliveira*, Hope S Rugo*, Sacha J Howell, Florence Dalenc, Javier Cortes, Henry L Gomez, Xichun Hu, Masakazu Toi, Komal Jhaveri, Petr Krivorotko, Sibylle Loibl, Serafin Morales Murillo, Meena Okera, Zbigniew Nowecki, Yeon Hee Park, Joo Hyuk Sohn, Eriko Tokunaga, Samih Yousef, Lyudmila Zhukova, Marta Fulford, Haylee Andrews, Ian Wadsworth, Celina D’Cruz, Nicholas C Turner. Capivasertib and fulvestrant for patients with hormone receptor-positive/HER2-negative advanced breast cancer: Patient-reported outcomes from the phase 3 randomised, double-blind, placebo-controlled CAPItello-291 trial. Capivasertib and fulvestrant for patients with hormone receptor-positive/HER2-negative advanced breast cancer: Patient-reported outcomes from the phase 3 randomised, double-blind, placebo-controlled CAPItello-291 trial. The Lancet Oncology, Volume 25, Issue 9, 1231 – 1244
- Turner NC, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez Moreno HL, Hu X, Jhaveri K, Krivorotko P, Loibl S, Morales Murillo S, Okera M, Park YH, Sohn J, Toi M, Tokunaga E, Yousef S, Zhukova L, de Bruin EC, Grinsted L, Schiavon G, Foxley A, Rugo HS; CAPItello-291 Study Group. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023 Jun 1;388(22):2058-2070. doi: 10.1056/NEJMoa2214131. PMID: 37256976.
- Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263.
