Important Safety Information


PIQRAY® (alpelisib) tablets is contraindicated in patients with severe hypersensitivity to it or any of its components. Severe Hypersensitivity: Severe hypersensitivity reactions, including anaphy...

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Indication
PIQRAY is indicated in combination with fulvestrant for the treatment of 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.

Efficacy

SOLAR-1 Study

First phase 3 trial leading to an approval specifically for aBC patients with a PIK3CA mutation

Randomized, double-blind, prospective, placebo-controlled trial in HR+/HER2- aBC1

  • A total of 572 patients were enrolled in the trial, including 341 patients with a PIK3CA mutation*
  • Patients were stratified by:
    • Presence of liver and/or lung metastases
    • Prior CDK4/6 inhibitor treatment
ALT TEXT: SOLAR-1 study design for cohort with a PIK3CA mutation ALT TEXT: SOLAR-1 study design for cohort with a PIK3CA mutation

endpoints endpoints

AI, aromatase inhibitor; CDK, cyclin D–dependent kinase; ECOG, Eastern Cooperative Oncology Group; IM, intramuscularly; PO, orally.
*A total of 572 patients were enrolled in the SOLAR-1 trial but 571 patients were included in safety assessments. Two hundred thirty-one of these patients did not have a PIK3CA mutation and were included as a separate cohort as a proof of concept, but the proof of concept criteria were not met for this cohort. No PFS benefit was observed in patients whose tumors did not have a PIK3CA tissue mutation (HR=0.85; 95% CI, 0.58-1.25).
Fulvestrant given on day 1 and day 15 of the first 28-day cycle, then day 1 of subsequent 28-day cycles.

Important Safety Information

Severe Hypersensitivity: Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, were reported in patients treated with PIQRAY. Severe hypersensitivity reactions were manifested by symptoms including, but not limited to, dyspnea, flushing, rash, fever, or tachycardia. The incidence of grade 3 and 4 hypersensitivity reactions was 0.7%. Advise patients of the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue PIQRAY in the event of severe hypersensitivity.

Please see additional Important Safety Information below.

 

Patients with a broad range of characteristics were represented1

Characteristica
PIQRAY + fulvestrant (n=169)b
PLACEBO + fulvestrant (n=172)c
Median age, years (range)
Race
Caucasian
Asian
Other/unknown
ECOG Performance Status
0
1
Metastatic sites
Visceral disease
Lung metastasis
Liver metastasis
Bone-only disease
Line of advanced anticancer treatmentd
First line
Second line
Prior chemotherapy
Neoadjuvant
Adjuvant
Prior CDK4/6 inhibitor treatment
63 (25-87)
 
117 (69.2)
34 (20.1)
18 (10.7)
 
112 (66.3)
56 (33.1)
 
93 (55.0)
57 (33.7)
49 (29.0)
42 (24.9)
 
88 (52.1)
79 (46.7)
 
25 (14.8)
78 (46.2)
9 (5.3)
64 (38-92)
 
109 (63.4)
40 (23.3)
23 (13.4)
 
113 (65.7)
58 (33.7)
 
100 (58.1)
68 (39.5)
54 (31.4)
35 (20.3)
 
89 (51.7)
82 (47.7)
 
29 (16.9)
86 (50.0)
11 (6.4)

 

aCharacteristics are given as n (%) unless otherwise stated.
bOne man was enrolled in the PIQRAY + fulvestrant arm. All other study participants were postmenopausal women.
cOne patient randomized to placebo was not treated.
dIn the SOLAR-1 study, first line was defined as patients whose disease progressed ≤1 year after (neo)adjuvant endocrine therapy (ET) or whose disease progressed >1 year after (neo)adjuvant ET, and who did not receive prior treatment for aBC. Second line was defined as patients whose disease progressed >1 year after (neo)adjuvant ET and while on or after one line of ET for aBC or patients with newly diagnosed aBC whose disease progressed while on or after one line of ET.

Progression-Free Survival

 Nearly doubled mPFS in patients with a PIK3CA mutation1

mPFS was 11.0 months with PIQRAY + fulvestrant versus 5.7 months with placebo + fulvestrant (HR=0.65) (95% CI, 0.50-0.85; P=.0013) mPFS was 11.0 months with PIQRAY + fulvestrant versus 5.7 months with placebo + fulvestrant (HR=0.65) (95% CI, 0.50-0.85; P=.0013)

Rapid separation of PFS curve evident at 2 months. Results reported at 2 months were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error Rapid separation of PFS curve evident at 2 months. Results reported at 2 months were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error
  • Results reported at 2 months were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error

mPFS, median PFS. 

Important Safety Information (cont)

Severe Cutaneous Reactions: Severe cutaneous reactions, including Stevens-Johnson syndrome (SJS) and erythema multiforme (EM) were reported in patients treated with PIQRAY. SJS and EM were reported in 0.4% and 1.1% of patients, respectively. Do not initiate PIQRAY treatment in patients with a history of SJS, EM, or toxic epidermal necrolysis (TEN). If signs or symptoms of severe cutaneous reactions occur, interrupt PIQRAY until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended.
If SJS, TEN, or EM is confirmed, permanently discontinue PIQRAY. Do not reintroduce PIQRAY in patients who have experienced previous severe cutaneous reactions during PIQRAY treatment. If it is not confirmed, PIQRAY may require dose modifications, topical corticosteroids, or oral antihistamine treatment.

Advise patients of the signs and symptoms of severe cutaneous reactions (eg, a prodrome of fever, flu-like symptoms, mucosal lesions, or progressive skin rash).

Please see additional Important Safety Information below.

 

Consistent PFS results across subgroups1

PFS in select patient subgroups with a PIK3CA mutation PFS in select patient subgroups with a PIK3CA mutation
  • The data are from prespecified subgroup analyses of the primary endpoint (mPFS) in SOLAR-1 and are not powered to detect statistical significance

a In the SOLAR-1 study, first line was defined as patients whose disease progressed ≤1 year after (neo)adjuvant ET or whose disease progressed >1 year after (neo)adjuvant ET, and who did not receive prior treatment for aBC. Second line was defined as patients whose disease progressed >1 year after (neo)adjuvant ET and while on or after one line of ET for aBC or patients with newly diagnosed aBC whose disease progressed while on or after one line of ET.

b In the SOLAR-1 study, primary endocrine resistance was defined as relapse within 24 months on adjuvant ET or progression within 6 months on ET for advanced disease. Secondary endocrine resistance was defined as relapse after 24 months on adjuvant ET, relapse within 12 months of the end of adjuvant ET, or progression after 6 months on ET for advanced disease. Endocrine sensitive was defined as relapse ≥12 months after completion of ET in the adjuvant setting.

 

Important Safety Information (cont)

Hyperglycemia: Severe hyperglycemia, including ketoacidosis, has been reported in patients treated with PIQRAY. Hyperglycemia was reported in 65% of patients treated with PIQRAY. Grade 3 (FPG >250-500 mg/dL) and Grade 4 (FPG >500 mg/dL) hyperglycemia was reported in 33% and 3.9% of patients, respectively. Ketoacidosis was reported in 0.7% of patients (n=2) treated with PIQRAY.

Before initiating treatment with PIQRAY, test FPG, HbA1c, and optimize blood glucose. After initiating treatment with PIQRAY, monitor blood glucose and/or FPG at least once every week for the first 2 weeks, then at least once every 4 weeks, and as clinically indicated. Monitor HbA1c every 3 months and as clinically indicated. If a patient experiences hyperglycemia after initiating treatment with PIQRAY, monitor blood glucose and/or FPG as clinically indicated, and at least twice weekly until blood glucose or FPG decreases to normal levels. During treatment with antidiabetic medication, continue monitoring blood glucose or FPG at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Consider consultation with a health care practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.

The safety of PIQRAY in patients with type 1 and uncontrolled type 2 diabetes has not been established as these patients were excluded from the SOLAR-1 trial. Patients with a medical history of type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified diabetic treatment. Closely monitor patients with diabetes.

Based on the severity of the hyperglycemia, PIQRAY may require dose interruption, reduction, or discontinuation. Advise patients of the signs and symptoms of hyperglycemia (eg, excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss).

Please see additional Important Safety Information below.

Overall Response Rate

More than doubled the response rate1

ORR in patients with measurable disease ORR in patients with measurable disease

ORR was defined as the percentage of subjects with confirmed complete response or partial response. Measurable disease was defined as the presence of at least one measurable nodal or non-nodal lesion as per RECIST v1.1 criteria.

References: 1. Piqray [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 2. Data on file. Novartis Pharmaceuticals Corp; 2018. 3. Andre F, Ciruelos EM, Rubovszky G, et al. Alpelisib + fulvestrant for HR+, HER2– advanced breast cancer: results of the phase III SOLAR-1 trial. Presented at: 2018 European Society for Medical Oncology (ESMO) Congress; October 19-23, 2018; Munich, Germany.

Indication

PIQRAY® (alpelisib) tablets is indicated in combination with fulvestrant for the treatment of 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.

Important Safety Information

PIQRAY is contraindicated in patients with severe hypersensitivity to it or any of its components.

Severe Hypersensitivity: Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, were reported in patients treated with PIQRAY. Severe hypersensitivity reactions were manifested by symptoms including, but not limited to, dyspnea, flushing, rash, fever, or tachycardia. The incidence of grade 3 and 4 hypersensitivity reactions was 0.7%. Advise patients of the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue PIQRAY in the event of severe hypersensitivity.

Severe Cutaneous Reactions: Severe cutaneous reactions, including Stevens-Johnson syndrome (SJS) and erythema multiforme (EM) were reported in patients treated with PIQRAY. SJS and EM were reported in 0.4% and 1.1% of patients, respectively. Do not initiate PIQRAY treatment in patients with a history of SJS, EM, or toxic epidermal necrolysis (TEN). If signs or symptoms of severe cutaneous reactions occur, interrupt PIQRAY until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended.

If SJS, TEN, or EM is confirmed, permanently discontinue PIQRAY. Do not reintroduce PIQRAY in patients who have experienced previous severe cutaneous reactions during PIQRAY treatment. If it is not confirmed, PIQRAY may require dose modifications, topical corticosteroids, or oral antihistamine treatment.

Advise patients of the signs and symptoms of severe cutaneous reactions (eg, a prodrome of fever, flu-like symptoms, mucosal lesions, or progressive skin rash).

Hyperglycemia: Severe hyperglycemia, including ketoacidosis, has been reported in patients treated with PIQRAY. Hyperglycemia was reported in 65% of patients treated with PIQRAY. Grade 3 (FPG >250-500 mg/dL) and Grade 4 (FPG >500 mg/dL) hyperglycemia was reported in 33% and 3.9% of patients, respectively. Ketoacidosis was reported in 0.7% of patients (n=2) treated with PIQRAY.

Before initiating treatment with PIQRAY, test FPG, HbA1c, and optimize blood glucose. After initiating treatment with PIQRAY, monitor blood glucose and/or FPG at least once every week for the first 2 weeks, then at least once every 4 weeks, and as clinically indicated. Monitor HbA1c every 3 months and as clinically indicated. If a patient experiences hyperglycemia after initiating treatment with PIQRAY, monitor blood glucose and/or FPG as clinically indicated, and at least twice weekly until blood glucose or FPG decreases to normal levels. During treatment with antidiabetic medication, continue monitoring blood glucose or FPG at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Consider consultation with a health care practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.

The safety of PIQRAY in patients with type 1 and uncontrolled type 2 diabetes has not been established as these patients were excluded from the SOLAR-1 trial. Patients with a medical history of type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified diabetic treatment. Closely monitor patients with diabetes.

Based on the severity of the hyperglycemia, PIQRAY may require dose interruption, reduction, or discontinuation. Advise patients of the signs and symptoms of hyperglycemia (eg, excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss).

Pneumonitis: Severe pneumonitis, including acute interstitial pneumonitis and interstitial lung disease, has been reported in patients treated with PIQRAY. Pneumonitis was reported in 1.8% of patients treated with PIQRAY.

In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, interrupt PIQRAY immediately and evaluate the patient for pneumonitis. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations.

Permanently discontinue PIQRAY in all patients with confirmed pneumonitis. Advise patients to immediately report new or worsening respiratory symptoms.

Diarrhea: Severe diarrhea, including dehydration and acute kidney injury, occurred in patients treated with PIQRAY. Most patients (58%) experienced diarrhea during treatment with PIQRAY. Grade 3 diarrhea occurred in 7% (n=19) of patients. Based on the severity of the diarrhea, PIQRAY may require dose interruption, reduction, or discontinuation. Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their health care provider if diarrhea occurs while taking PIQRAY.

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, PIQRAY can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for 1 week after the last dose. Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.

The most common adverse reactions (all grades, incidence ≥20%) were diarrhea (58%), rash (52%), nausea (45%), fatigue (42%), decreased appetite (36%), stomatitis (30%), vomiting (27%), weight decreased (27%), and alopecia (20%). The most common grade 3/4 adverse reactions (incidence ≥2%) were rash (20%), diarrhea (7%), fatigue (5%), weight decreased (3.9%), nausea (2.5%), stomatitis (2.5%), and mucosal inflammation (2.1%).

The most common laboratory abnormalities (all grades, incidence ≥20%) were glucose increased (79%), creatinine increased (67%), lymphocyte count decreased (52%), gamma glutamyl transferase (GGT) increased (52%), alanine aminotransferase (ALT) increased (44%), hemoglobin decreased (42%), lipase increased (42%), calcium decreased (27%), glucose decreased (26%), and activated partial thromboplastin time (aPTT) prolonged (21%). The most common grade 3/4 laboratory abnormalities (incidence ≥5%) were glucose increased (39%), GGT increased (11%), lymphocyte count decreased (8%), and lipase increased (7%), and potassium decreased (6%).

Please see full Prescribing Information.