H S Rugo1, F André2, T Yamashita3, H Cerda4, I Toledano5, S M Stemmer6, J C Jurado7, D Juric8, I Mayer9, E M Ciruelos10, H Iwata11, P Conte12, M Campone13, C Wilke14, D Mills14, A Lteif15, M Miller15, F Gaudenzi14, S Loibl16. 1. Department of Medicine, Division of Hematology and Oncology, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, USA. Electronic address: Hope.Rugo@ucsf.edu. 2. Department of Medical Oncology, INSERM U981, Gustave Roussy, Université Paris-Sud, Villejuif, France. 3. Department of Breast and Endocrine Surgery, Kanagawa Cancer Center Hospital, Yokohama, Japan. 4. Clinica RedSalud Vitacura, Santiago, Chile. 5. Institut Curie, Paris, France. 6. Institute of Oncology, Davidoff Center, Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel. 7. Hospital Universitario Canarias, S/C Tenerife, Islas Canarias, Spain. 8. Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, USA. 9. Department of Medicine, Hematology and Oncology, Vanderbilt University, Nashville, USA. 10. Medical Oncology Department, Breast Cancer Unit, Hospital Universitario 12 de Octubre, Madrid, Spain. 11. Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan. 12. Department of Surgery, Oncology and Gastroenterology, University of Padua and Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padua, Italy. 13. Department of Medical Oncology, Institut de Cancérologie de l'Ouest, St Herblain, France. 14. Novartis Pharma AG, Basel, Switzerland. 15. Novartis Pharmaceuticals Corporation, East Hanover, USA. 16. Department of Medicine and Research, German Breast Group, Neu-Isenburg; Centre for Haematology and Oncology Bethanien, Frankfurt, Germany.
Abstract
BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICALTRIALS. GOV ID: NCT02437318.
BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICALTRIALS. GOV ID: NCT02437318.
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