1. Treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer patients who have a mutated phosphatidylinositol 3-kinase (PIK3) with the PIK3 inhibitor alpelisib, in addition to fulvestrant, increased progression free survival compared to treatment with fulvestrant alone.
2. The most common severe adverse effects in alpelisib-fulvestrant treated patients were hyperglycemia and rash.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Over 70% of breast cancers are HR-positive, HER2-negative, and almost half of those patients have mutations in the PIK3 gene. Endocrine therapy is standard treatment for these patients, but many develop resistance to treatment. Endocrine therapy paired with the PIK3 inhibitor alpelisib has shown promise in prior phase 1 and 2 trials, and in the current study is compared to standard endocrine therapy in a phase 3 trial. Patients with HR-positive, HER2-negative, PIK3-mutated cancer profiles treated with combination therapy had significantly longer progression-free survival times compared to those treated with endocrine therapy alone. In patients without a mutated PIK3 gene, progression free survival was similar between treatments. Common adverse events experiences by alpelisib treated patients included hyperglycemia and rash.
This phase 3 trial provides strong evidence for an altered standard of treatment among patients with a specific breast cancer genetic profile who have failed prior endocrine therapy. Study strengths include treatment of patients with and without PIK3 mutations and its extensive subgroup analysis. The study is limited by its relatively short follow-up time not presently allowing for strong overall survival analysis.
In-Depth [randomized controlled trial]: This phase 3, double-blind, randomized, international, placebo-controlled trial enrolled patients between 2015 and 2017. Men and post-menopausal women with locally confirmed HR-positive, HER2-negative breast cancer and were eligible to receive further endocrine therapy after having progression or relapse following initial endocrine therapy treatment. Those who had previously received chemotherapy, fulvestrant therapy, or been treated with PI3K, AKT, or mTOR inhibitors were excluded from participating. Patients with and without PI3K mutations were recruited for the study. For each cohort of patients with (n=341) or without (n=231) a PI3K mutation, patients were randomly assigned to alpelisib-fulvestrant or placebo-fulvestrant groups. After a median of 20 months follow-up, the primary outcome of progression-free survival in patients with a PIK3-mutation was 11.0 and 5.7 months in the combination and placebo-fulvestrant groups, respectively (hazard ratio for progression or death [HR], 0.65; 95% confidence interval [CI], 0.50 to 0.85; P<0.001). Overall therapy response for those with a PIK3-mutation was greater in the combination therapy group (26.6% vs. 12.8%). For patients without a PIK3-mutation median survival time was 7.4 and 5.6 months in the combination and placebo-fulvestrant groups, respectfully (HR, 0.85; 95% CI, 0.58 to 1.25). Serious adverse events occurring in the combination therapy group, as compared to the placebo-fulvestrant group, included hyperglycemia (36.6% vs 0.7%) and rash (9.9% and 0.3%).
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