Novartis Korea said Friday that the Ministry of Food and Drug Safety has approved Piqray (ingredient: alpelisib) for treating menopausal patients with advanced breast cancer through combined use with fulvestrant....The drug can be prescribed to menopausal women with breast cancer whose tumors have PIK3A mutation and are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 (HER2) negative...

CONTRADICTING EVIDENCE: Alpelisib (Piqray®) is not recommended for use within NHSScotland....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, locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine therapy as monotherapy.

Novartis Pharmaceuticals Canada Inc. (Novartis) is pleased to announce that PIQRAY® (alpelisib) is approved and now available in Canada. PIQRAY® in combination with fulvestrant is indicated 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 after disease progression following an endocrine-based regimen.

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, locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine therapy as monotherapy...

PIQRAY is a kinase inhibitor 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.

For patients with prior CDK4/6 inhibitor treatment and ESR1 wildtype tumors, appropriate subsequent ET options include fulvestrant, aromatase inhibitor monotherapy, other older ET options such as tamoxifen, or ET in combination with targeted agents such as alpelisib (for PIK3CA mutated tumors), or everolimus.

NICE has recommended Piqray (also called alpelisib and made by Novartis Pharmaceuticals UK), used with the hormonal therapy fulvestrant, for treating hormone receptor-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer that has grown after treatment with combined hormonal therapy and a cancer growth inhibitor.

NCCN recommendations for second-line: For postmenopausal women with HR-positive, HER2-positive recurrent/stage IV breast cancer, the preferred options available include…those with tumor PIK3CA mutations, fulvestrant with alpelisib…

In the PIK3CA-alt cohort, ALP + FUL clinical benefit was seen across TMB quartiles (Q1: 0 -<2.52, Q2: 2.52 -<3.78, Q3: 3.78 -<5.04, Q4: ≥ 5.04 mut/megabase).

Cohort A: HR+/HER2- pts receiving fulvestrant (FUL) alone (n = 124) or ALP/FUL (n = 111) in treatment line ≥2L were considered in survival analysis....median rwPFS was 4.1 mo on FUL [95%CI: 3-6.2] versus 6.5 mo on ALP/FUL [95%CI: 4.8-9.5] (p = 0.027)....This study validates the activity of ALP among a diverse real world population, showing pts with PIK3CA mutations have longer rwPFS on ALP/FUL than FUL alone.

Men and postmenopausal women with HR+, HER2- ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1:1 to receive alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on Day 15) or placebo plus fulvestrant….In the PIK3CA-mutated cohort (n=341), median OS (95% confidence interval [CI]) was 39.3 months (34.1-44.9) for alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant (hazard ratio [HR] = 0.86 [95% CI, 0.64-1.15; P=0.15])....there was a 7.9-month numeric improvement in median OS when alpelisib was added to fulvestrant treatment for patients with PIK3CA-mutated, HR+, HER2- ABC.

ALP plus FUL prolonged mPFS in pts with PIK3CA alterations detected in plasma ctDNA by NGS…

Primary and secondary endpoints were to evaluate and compare progression-free survival and proportion of pts remaining progression free at 6 mo after the index date (date of the start of the next line of therapy), respectively, with ALP + FUL in BYLieve vs. CGDB real-world cohorts....In unadjusted results and in 3 methods to weight/match pts, primary and secondary endpoints consistently favored treatment with ALP + FUL in BYLieve over standard treatments in either real-world cohort.

ALP+FUL met the primary endpoint by significantly extending PFS vs PBO+FUL and demonstrated a manageable tolerability profile. This is the first study to show statistically significant, clinically meaningful PFS treatment improvement with an α-specific PI3K inhibitor in PIK3CA-mut HR+, HER2– ABC.

We report here real-life datda of patients prospectively registered in the French alpelisib early access program (EAP) opened to PIK3CA-mutant HR+/HER2- ABC patients treated with alpelisib and fulvestrant....After a median follow-up of 7.1 months and 168 events, median PFS was 5.3 months (95% CI: 4.7-6.0). Among 186 evaluable patients, CBR at 6 months was 45.3% (95% CI: 37.8-52.8).

Alpelisib (ALP), an αselective PI3K inhibitor and degrader, demonstrated clinical benefit in combination with fulvestrant (FUL) in the SOLAR-1 study in pts with PIK3CA-mut HR+, HER2− ABC....we compare the gene alteration landscape in pts with altered (alt) and non-alt PIK3CA and the efficacy of ALP + FUL in pts whose tumors have alterations...Clinical benefit of ALP vs PBO was observed in pts with PIK3CA-alt disease who also had alterations in analyzed genes and/or genes associated with the MAPK pathway.

In patients with HR+/HER2- ABC and PIK3CAm receiving alpelisib/fulvestrant (ALP+FUL; n = 182) or fulvestrant alone (FUL; n = 119), median real-world progression free survival (rwPFS) was 5.9 months on ALP+FUL [95%CI: 5.1 - 7.4] versus 3.1 months on FUL [95%CI: 2.7 - 3.7] (p < 0.0001).

Within an early access program for Alpelisib in a single oncology center, patients diagnosed with metastatic HR-positive, Her2 -negative breast cancer were screened for PIK3CA mutations….Patients who progressed and carried PIK3CA mutations received Alpelisib and fulvestrant as subsequent line of therapy....Ten pts were evaluable for response to treatment with Alpelisib. One (10%) had CR, 5 (50%) SD and 4 (40%) PD as best response.

Alpelisib and endocrine therapy provides ongoing treatment benefits for patients with HR-positive, HER2-negative, PIK3CA-mutated advanced breast cancer, according to updated findings from all 3 cohorts of the phase II BYLieve trial.

In pts with HR+, HER2-, PIK3CA-mutated ABC, ALP was effective in the post-CDK4/6i setting regardless of ET partner and tumor genomic profile (including in presence of alterations in genes associated with CDK4/6i resistance).

127 pts were enrolled in Cohort C (1 pt discontinued prior to treatment start) with ≥6 mo follow-up by the cutoff date (14 Jun 2021); 115 had a centrally confirmed PIK3CA mutation....The primary endpoint was met, with 48.7% (95% CI, 39.3%-58.2%) of pts alive and without disease progression at 6 mo....Cohort C confirms clinically relevant activity of ALP + FUL in a heterogeneous population...Together, these data confirm that ALP targets the effects of the PIK3CA-driver oncogene in HR+, HER2- ABC.

This demonstrates that pts with PIK3CA-mut, HR+, HER2- ABC who achieved ≤6-mo duration of disease control with prior CDK4/6i had a numerically longer PFS in Cohort A, and almost the same clinical efficacy in Cohort B, to ALP + ET vs pts with >6-mo duration of disease control, with a comparable safety profile. Pts in Cohort A received ALP 300 mg PO QD + FUL 500 mg IM Q28D + C1D15; pts in Cohort B received ALP 300 mg PO QD + LET 2.5 mg PO QD. This confirms targeting PI3Kɑ with ALP provides clinical benefit in pts with CDK4/6i-resistant ABC, including early progressors, and supports consideration of ALP + ET as an immediate next-line option in this setting, possibly delaying chemotherapy.

...PIK3CA-mutant, HR-positive, HER2-negative advanced breast cancer (ABC) patients...alpelisib +fulvestrant had a clinically relevant efficacy in the French EAP population.

...median PFS for patients treated with alpelisib in BYLieve was 7.3 versus 3.7 months in the real‐world cohort, and 6‐month PFS was 54.6% versus 40.1%, respectively....clinical benefit of alpelisib with fulvestrant for treatment of HR+, HER2−, PIK3CA‐mutant ABC post‐CDK4/6i treatment.

...median progression-free survival was 6∙0 months (95% CI: 3∙7-8∙4), and 1-year overall survival was 59∙1% (95% CI: 45∙8-76∙2)....BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor.

Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2- breast cancer.