On May 24, 2019, alpelisib was approved for use in combination with fulvestrant for postmenopausal women, and men, with hormone receptor–positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer, as detected by a U.S. Food and Drug Administration (FDA)-approved test following disease progression on or after an endocrine-based regimen.^1,2

The FDA concurrently 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.

Supporting Efficacy Data

Approval was based on findings in the cohort of patients with PIK3CA-mutated disease in the double-blind phase III SOLAR-1 trial (ClinicalTrials.gov identifier NCT02437318).^2,3 In the trial, 572 patients with disease progressing on or after aromatase inhibitor treatment were randomly assigned to receive oral alpelisib at 300 mg daily plus fulvestrant at 500 mg intramuscularly on cycle 1, days 1 and 15, and then on day 1 of every 28-day cycle (n = 284) or placebo plus fulvestrant (n = 287), with treatment continuing until disease progression or unacceptable toxicity. Among these patients, 169 in the alpelisib group and 172 in the placebo group had PIK3CA-mutated tumors. The primary endpoint was investigator-assessed progression-free survival among patients with PIK3CA-mutated tumors.

The median age of patients was 63 years, 99.8% were women, 66% were white and 22% were Asian, and all had an Eastern Cooperative Oncology Group performance status of 0 (68%) or 1 (32%).

Among patients with PIK3CA-mutant disease, the median progression-free survival was 11.0 months in the alpelisib group vs 5.7 months in the placebo group (hazard ratio [HR] = 0.65, P = .001). The overall response rate was 35.7% vs 16.2%. Overall survival data were not mature at the time of analysis. No progression-free survival benefit was observed among patients treated with alpelisib vs those who received placebo whose tumors did not have a PIK3CA mutation (HR = 0.85, 95% confidence interval = 0.58–1.25).

How It Works

Alpelisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor with inhibitory activity predominantly against PI3Kα. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) led to activation of PI3Kα/Akt signaling, cellular transformation, and the generation of tumors in in vitro and in vivo models. In breast cancer cell lines, alpelisib inhibited the phosphorylation of PI3K downstream targets, including Akt, and showed activity in cell lines harboring a PIK3CA mutation.

In vivo, alpelisib inhibited the PI3K/Akt signaling pathway and reduced tumor growth in xenograft models, including models of breast cancer. PI3K inhibition by alpelisib treatment has been shown to induce an increase in estrogen receptor transcription in breast cancer cells. The combination of alpelisib and fulvestrant demonstrated increased antitumor activity compared with either treatment alone in xenograft models derived from estrogen receptor–positive, PIK3CA-mutated breast cancer cell lines.

How It Is Used

Patients should be selected for alpelisib treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer based on the presence of one or more PIK3CA mutations in tumor tissue or plasma specimens; if no mutation is detected in a plasma specimen, tumor tissue should be tested. The recommended dose of alpelisib is 300 mg once daily, with treatment continued until disease progression or unacceptable toxicity. When given with alpelisib, the recommended dose of fulvestrant is 500 mg administered on days 1, 15, and 29, and once monthly thereafter (full prescribing information for fulvestrant should be consulted).

Dose reductions for adverse events are stepwise to 250 and 200 mg once daily. Only one dose reduction should be made in patients with pancreatitis. Treatment should be discontinued if dose reduction to less than 200 mg is required.

Full prescribing information provides detailed instructions on dose modifications for hyperglycemia, rash, diarrhea, and other toxicities of any grade.

Full prescribing information provides information on drug interactions. In brief, coadministration of alpelisib with strong CYP3A4 inducers should be avoided. Concomitant use of breast cancer resistance protein inhibitors should be avoided; if alternative drugs cannot be used, patients should be closely monitored for increased adverse reactions. Coadministration with CYP2C9 substrates may reduce plasma concentration and activity of these agents, requiring close monitoring.

Safety Profile

In the SOLAR-1 trial, the most common adverse events of any grade including laboratory abnormalities among all patients in the alpelisib/fulvestrant group were increase in glucose (79% vs 34% in the placebo/fulvestrant group), increase in creatinine (67% vs 25%), diarrhea (58% vs 16%), rash (52% vs 7%), decrease in lymphocyte count (52% vs 40%), increase in gamma glutamyl transferase (GGT; 52% vs 44%), nausea (45% vs 22%), increase in alanine transaminase level (44% vs 34%), fatigue (42% vs 29%), decrease in hemoglobin level (42% vs 29%), increase in lipase (42% vs 25%), decreased appetite (36% vs 10%), and stomatitis (30% vs 6%). The most common grade 3 or 4 adverse events in the alpelisib group included rash (20%), diarrhea (7%), and fatigue (5%). The most common grade 3 or 4 laboratory abnormalities were an increase in glucose (39%) and an increase in GGT (11%).

Serious adverse events occurred in 35% of the alpelisib group, with the most common being hyperglycemia (10%), rash (3.5%), diarrhea (2.8%), acute kidney injury (2.5%), abdominal pain (2.1%), and anemia (2.1%). Osteonecrosis of the jaw was reported in 4.2% of patients in the alpelisib group vs 1.4% of the placebo group; all patients with osteonecrosis of the jaw had received prior or concomitant bisphosphonates or RANK ligand inhibitors.

Adverse events led to dose reductions in 55% of patients in the alpelisib group, with the most frequent causes being hyperglycemia (29%), rash (9%), and diarrhea (6%). Adverse events led to permanent discontinuation of both alpelisib and fulvestrant in 4.6% of patients and alpelisib alone in 21%, with the most common causes being hyperglycemia (6%), rash (4.2%), diarrhea (2.8%), and fatigue (2.5%).

Alpelisib has warnings and precautions for severe hypersensitivity; severe cutaneous reactions including Stevens-Johnson syndrome and erythema multiforme; hyperglycemia, including ketoacidosis; pneumonitis, including severe cases of pneumonitis and interstitial lung disease; diarrhea, including severe cases of diarrhea, dehydration, and acute kidney injury; and embryofetal toxicity. Treatment should be discontinued for severe hypersensitivity.

Treatment should not be started in patients with a history of Stevens-Johnson syndrome, erythema multiforme, or toxic epidermal necrolysis; treatment should be interrupted if signs or symptoms of severe cutaneous reactions are present and permanently discontinued if Stevens-Johnson syndrome, erythema multiforme, or toxic epidermal necrolysis is confirmed. The safety of alpelisib has not been established in patients with type 1 or uncontrolled type 2 diabetes. Prior to treatment, fasting plasma glucose and HbA1c should be monitored and blood glucose optimized; patients should be monitored periodically during treatment. Patients should be advised not to breastfeed while receiving alpelisib. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves alpelisib for metastatic breast cancer. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alpelisib-metastatic-breast-cancer. Accessed August 21, 2019.

2. Piqray (alpelisib) tablets prescribing information, Novartis Pharmaceuticals Corporation, May 2019. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212526s000lbl.pdf. Accessed August 21, 2019.

3. André F, Ciruelos E, Rubovszky G, et al: Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 380:1929-1940, 2019.