Alpelisib: A New Hope for Patients with PIK3CA-Mutated Breast Cancer
Alpelisib: A New Hope for Patients with PIK3CA-Mutated Breast Cancer
Breast cancer is the most common cancer among women worldwide, and about 70% of cases are hormone receptor (HR)-positive, meaning that they depend on hormones such as estrogen and progesterone for growth. However, some of these cancers also have mutations in a gene called PIK3CA, which encodes a protein that regulates cell growth and survival. These mutations make the cancer cells more resistant to hormone therapy and more aggressive.
Fortunately, there is a new drug that targets PIK3CA mutations and enhances the effectiveness of hormone therapy. This drug is called alpelisib, and it belongs to a class of drugs called PI3K inhibitors. Alpelisib works by blocking the activity of the mutated PIK3CA protein, which restores the sensitivity of the cancer cells to hormone therapy and slows down their growth.
Alpelisib has been tested in clinical trials involving patients with HR-positive, HER2-negative advanced breast cancer who have PIK3CA mutations and who have received previous treatment with hormone therapy and/or CDK4/6 inhibitors. CDK4/6 inhibitors are another class of drugs that interfere with cell cycle progression and are often used in combination with hormone therapy.
The results of these trials have been promising. In the SOLAR-1 trial1, alpelisib plus fulvestrant (a type of hormone therapy) significantly improved progression-free survival (the time without disease worsening) compared to placebo plus fulvestrant in patients with PIK3CA-mutated breast cancer who had progressed on or after aromatase inhibitors (another type of hormone therapy). The median progression-free survival was 11.0 months in the alpelisib group versus 5.7 months in the placebo group, which translates to a 35% reduction in the risk of disease progression or death1. Alpelisib also increased the overall response rate (the percentage of patients who had a partial or complete shrinkage of their tumors) from 12.8% to 26.6%1.
In the BYLieve trial2, alpelisib plus fulvestrant showed efficacy in patients with PIK3CA-mutated breast cancer who had progressed on or after CDK4/6 inhibitors plus aromatase inhibitors. The proportion of patients who were alive without disease progression at 6 months was 50.4%, and the median progression-free survival was 7.3 months2. Alpelisib also improved the overall response rate from 6.5% to 20.7%2.
Based on these results, alpelisib was approved by the US Food and Drug Administration (FDA) in 2019 and by the European Medicines Agency (EMA) in 2020 for the treatment of HR-positive, HER2-negative advanced breast cancer with PIK3CA mutations in combination with fulvestrant after disease progression following endocrine therapy.
However, alpelisib is not without side effects. The most common adverse events of grade 3 or higher (severe or life-threatening) were hyperglycemia (high blood sugar), rash, diarrhea, nausea, and decreased appetite12. These side effects can be managed with dose adjustments, supportive care, and monitoring.
Alpelisib is a novel and effective option for patients with HR-positive, HER2-negative advanced breast cancer who have PIK3CA mutations and who have failed previous endocrine therapy. It offers a personalized approach that targets the specific genetic alteration that drives the disease. Alpelisib represents a new hope for this subgroup of patients who have limited treatment options and poor prognosis.
References: André F, Ciruelos EM, Rubovszky G, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor–Positive Advanced Breast Cancer. N Engl J Med. 2019;380(20):1929-1940. 2: Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22(5):646-656.