Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study.

Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755. Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported. 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. Novartis Pharmaceuticals.

Rugo HS ，Lerebours F ，Ciruelos E ，Drullinsky P ，Ruiz-Borrego M ，Neven P ，Park YH ，Prat A ，Bachelot T ，Juric D ，Turner N ，Sophos N ，Zarate JP ，Arce C ，Shen YM ，Turner S ，Kanakamedala H ，Hsu WC ，Chia S ... -  《-》

Effectiveness of Alpelisib + Fulvestrant Compared with Real-World Standard Treatment Among Patients with HR+, HER2-, PIK3CA-Mutated Breast Cancer.

The BYLieve trial (NCT03056755) confirmed efficacy and safety of alpelisib with fulvestrant for hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC), after cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with an aromatase inhibitor (AI) as immediate prior therapy. Further analyses were performed to compare efficacy from BYLieve with effectiveness of standard treatment in the real-world setting. Patients who progressed on a CDK4/6i plus AI and were treated with alpelisib with fulvestrant in BYLieve were matched with a real-world patient cohort who received standard-of-care from a deidentified clinico-genomics database (CGDB). Primary and secondary endpoints were to compare progression-free survival (PFS), estimated by the Kaplan-Meier method, and the proportion of patients remaining progression-free at 6 months, respectively, between the two cohorts. A total of 855 patients with PIK3CA-mutant disease who had prior CDK4/6i plus hormone therapy were selected from the CGDB; further matching to 120 patients from BYLieve selected 95 patients without exposure to HER2-targeting agents, clinical study drug, or alpelisib. In unadjusted and postmatching results, primary and secondary endpoints favored treatment with alpelisib with fulvestrant in BYLieve more than standard treatments in the real-world cohort. Postadjustment, 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. Matched/weighted analysis comparing BYLieve with the real-world setting further supports the clinical benefit of alpelisib with fulvestrant for treatment of HR+, HER2-, PIK3CA-mutant ABC after CDK4/6i treatment. Approximately 40% of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) have PIK3CA-mutated tumors, which have been associated with endocrine therapy resistance. Alpelisib, an α-selective phosphatidylinositol-3-kinase inhibitor, demonstrated significantly improved progression-free survival in SOLAR-1 and demonstrated clinical efficacy in BYLieve when combined with fulvestrant. Data are limited in comparing the efficacy of alpelisib combined with fulvestrant with effectiveness of standard therapy after CDK4/6i treatment. Using real-world data, this is the first analysis comparing alpelisib combined with fulvestrant with standard treatments for HR+, HER2-, PIK3CA-mutant ABC in the post-CDK4/6i setting.

Turner S ，Chia S ，Kanakamedala H ，Hsu WC ，Park J ，Chandiwana D ，Ridolfi A ，Yu CL ，Zarate JP ，Rugo HS ... -  《-》

Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial.

Juric D ，Janku F ，Rodón J ，Burris HA ，Mayer IA ，Schuler M ，Seggewiss-Bernhardt R ，Gil-Martin M ，Middleton MR ，Baselga J ，Bootle D ，Demanse D ，Blumenstein L ，Schumacher K ，Huang A ，Quadt C ，Rugo HS ... -  《-》

Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer.

PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies. In a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety. A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA-mutated cancer was greater with alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively. Treatment with alpelisib-fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.).

André F ，Ciruelos E ，Rubovszky G ，Campone M ，Loibl S ，Rugo HS ，Iwata H ，Conte P ，Mayer IA ，Kaufman B ，Yamashita T ，Lu YS ，Inoue K ，Takahashi M ，Pápai Z ，Longin AS ，Mills D ，Wilke C ，Hirawat S ，Juric D ，SOLAR-1 Study Group ... -  《-》

Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial.

Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants. Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8-7·8) in the buparlisib group versus 5·0 months (4·0-5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67-0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0-7·0) in the buparlisib group vs 4·5 months (3·3-5·0) in the placebo group (HR 0·80 [95% CI 0·68-0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9-7·1) in the buparlisib group versus 4·0 months (3·1-5·2) in the placebo group (HR 0·76 [0·60-0·97], one-sided p=0·014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred. The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. Novartis Pharmaceuticals Corporation.

Baselga J ，Im SA ，Iwata H ，Cortés J ，De Laurentiis M ，Jiang Z ，Arteaga CL ，Jonat W ，Clemons M ，Ito Y ，Awada A ，Chia S ，Jagiełło-Gruszfeld A ，Pistilli B ，Tseng LM ，Hurvitz S ，Masuda N ，Takahashi M ，Vuylsteke P ，Hachemi S ，Dharan B ，Di Tomaso E ，Urban P ，Massacesi C ，Campone M ... -  《-》