Time Course and Management of Key Adverse Events During the Randomized Phase 3 SOLAR-1 Study of PI3K Inhibitor Alpelisib Plus Fulvestrant in Patients With HR-Positive Advanced Breast Cancer
Mené sur 284 et 287 patientes atteintes d’un cancer du sein HR+ de stade avancé, cet essai de phase III évalue le délai avant la survenue d'événements indésirables liés à un traitement combinant alpélisib et fulvestrant et analyse les modalités de prise en charge de ces toxicités
Background : Alpelisib (?-selective PI3K inhibitor) plus fulvestrant is approved in multiple countries for men and post-menopausal women with PIK3CA-mutated, hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–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 methods : AEs in the phase 3 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. Results : Patients were randomized to 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 anti-diabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% vs 64.1%) and severity of rash (grade 3, 11.6% vs 22.7%) vs no preventative medication. Discontinuations due to grade ?3 AEs were lower following more-detailed AE management guidelines (7.9% vs 18.1% previously). Patients with PIK3CA mutations had a median alpelisib dose intensity of 248 mg/day. Median progression-free survival (PFS) with alpelisib was 12.5 and 9.6 months for alpelisib dose intensities ?248 mg/day and <248 mg/day, respectively, compared with 5.8 months with placebo. Conclusions : Hyperglycemia and rash occurred early during alpelisib treatment, while diarrhea occurred at a later timepoint. Early identification, prevention, and intervention, including concomitant medications and alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved PFS at higher alpelisib dose intensities support the need for optimal AE management.