On May 24, 2019, the U.S. Food and Drug Administration (FDA) approved alpelisib (Piqray®) in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.
The FDA also approved the companion diagnostic test, therascreen® PIK3CA RGQ PCR Kit, to select patients who have PIK3CA mutations in tumor tissue specimens and/or in circulating tumor DNA (ctDNA) isolated from plasma specimens. If the test is negative for PIK3CA mutations in plasma, patients should undergo testing for PIK3CA mutations in tumor tissue.
Approval was based on SOLAR-1 (NCT02437318), a phase 3, randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant in 572 patients including postmenopausal women, and men, with HR-positive, HER2-negative, advanced or metastatic breast cancer whose disease had progressed or on or after receiving an aromatase inhibitor.
The primary endpoint was investigator-assessed progression-free survival (PFS) in the cohort with a PIK3CA mutation. The estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11.0 months (95% CI: 7.5, 14.5) compared with 5.7 months (95% CI: 3.7, 7.4) in the placebo plus fulvestrant arm (HR 0.65; 95% CI: 0.50, 0.85; p = 0.001). Overall survival data were not mature at the time of analysis. No PFS benefit was observed in patients whose tumors did not have a PIK3CA mutation (HR = 0.85; 95% CI: 0.58, 1.25).
The most common adverse reactions including laboratory abnormalities on the alpelisib plus fulvestrant arm were increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time (aPTT), and alopecia.
The recommended alpelisib dose is 300 mg (two 150 mg film-coated tablets) taken orally, once daily, with food. When given with alpelisib, the recommended dose of fulvestrant is 500 mg administered intramuscularly on days one, 15, and 29, and once monthly thereafter.
This is the first new drug application for a new molecular entity approved under the Real-Time Oncology Review pilot program. This application also used the Assessment Aid. With these two pilot programs, today’s approval of alpelisib comes approximately three months ahead of the PDUFA VI deadline of August 18, 2019.
FDA granted this application priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
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