Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer

•Hyperglycemia, rash, and diarrhea were the most common grade 3/4 adverse events in patients receiving alpelisib.•These adverse events were predictable, manageable with concomitant medications, and generally reversible.•Implementation of more detailed AE management guidelines improved various markers of safety during the study. BackgroundAlpelisib (α-selective phosphatidylinositol 3-kinase inhibitor) plus fulvestrant is approved in multiple countries for men and postmenopausal women with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer following progression on or after endocrine therapy. A detailed understanding of alpelisib's safety profile should inform adverse event (AE) management and enhance patient care.Patients and methodsAEs in the phase III SOLAR-1 trial were assessed in patients with and without PIK3CA mutations. The impact of protocol-specified AE-management recommendations was evaluated, including an amendment to optimize hyperglycemia and rash management.ResultsPatients were randomly assigned to receive fulvestrant plus alpelisib (n = 284) or placebo (n = 287). The most common grade 3/4 AEs with alpelisib were hyperglycemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), and diarrhea (grade 3, 6.7%). Median time to onset of grade ≥3 toxicity was 15 days (hyperglycemia, based on fasting plasma glucose), 13 days (rash), and 139 days (diarrhea). Metformin alone or in combination with other antidiabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% versus 64.1%) and severity of rash (grade 3, 11.6% versus 22.7%) versus no preventative medication. Discontinuations due to grade ≥3 AEs were lower following more-detailed AE management guidelines (7.9% versus 18.1% previously). Patients with PIK3CA mutations had a median alpelisib dose intensity of 248 mg/day. Median progression-free survival with alpelisib was 12.5 and 9.6 months for alpelisib dose intensities of ≥248 mg/day and <248 mg/day, respectively, compared with 5.8 months with placebo.ConclusionsHyperglycemia and rash occurred early during alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progression-free survival at higher alpelisib dose intensities support the need for optimal AE management.ClinicalTrials.gov IdNCT02437318. Alpelisib (α-selective phosphatidylinositol 3-kinase inhibitor) plus fulvestrant is approved in multiple countries for men and postmenopausal women with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer following progression on or after endocrine therapy. A detailed understanding of alpelisib's safety profile should inform adverse event (AE) management and enhance patient care. AEs in the phase III SOLAR-1 trial were assessed in patients with and without PIK3CA mutations. The impact of protocol-specified AE-management recommendations was evaluated, including an amendment to optimize hyperglycemia and rash management. Patients were randomly assigned to receive fulvestrant plus alpelisib (n = 284) or placebo (n = 287). The most common grade 3/4 AEs with alpelisib were hyperglycemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), and diarrhea (grade 3, 6.7%). Median time to onset of grade ≥3 toxicity was 15 days (hyperglycemia, based on fasting plasma glucose), 13 days (rash), and 139 days (diarrhea). Metformin alone or in combination with other antidiabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% versus 64.1%) and severity of rash (grade 3, 11.6% versus 22.7%) versus no preventative medication. Discontinuations due to grade ≥3 AEs were lower following more-detailed AE management guidelines (7.9% versus 18.1% previously). Patients with PIK3CA mutations had a median alpelisib dose intensity of 248 mg/day. Median progression-free survival with alpelisib was 12.5 and 9.6 months for alpelisib dose intensities of ≥248 mg/day and <248 mg/day, respectively, compared with 5.8 months with placebo. Hyperglycemia and rash occurred early during alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progression-free survival at higher alpelisib dose intensities support the need for optimal AE management.