Alpelisib and fulvestrant in PIK3CA-mutated hormone receptor-positive HER2-negative advanced breast cancer included in the French early access program

Abstract

BackgroundSOLAR-1 and BYLIEVE trials documented the e cacy of the PI3K-inhibitor alpelisib in pre-treated PIK3CAmutant, hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC) patients.We report here real-life data of patients prospectively registered in the French alpelisib early access program (EAP). Patients and methods:The French EAP was opened to PIK3CA-mutant HR+/HER2-ABC patients treated with alpelisib and fulvestrant, managed per standard of care. Primary endpoint was PFS by local investigators using RECIST1.1. ResultsEleven centers provided individual data on 233 consecutive patients. Patients had received a median number of 4 (range: 1-16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. 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). In multivariable analysis, characteristics signi cantly associated with a shorter PFS were age < 60 years (HR = 1.5, 95%CI = 1.1-2.1), > 5 lines of prior treatments (HR = 1.4, 95%CI = 1.0-2.0) and the C420R PI3KCA mutation (HR = 4.1, 95%CI = 1.3-13.6). Most frequent grade 3/4 adverse events (AEs) were hyperglycemia, rash, fatigue and diarrhea occurring in 11.6, 9.9, 4.3 and 3% of patients, respectively. N = 91 (39.1%) patients discontinued alpelisib due to AEs. DiscussionTo our knowledge, this is the largest real-life assessment of alpelisib e cacy. Despite heavy pretreatments, patients derived a clinically relevant bene t from alpelisib and fulvestrant. PFS was not overtly impaired by a prior use of either everolimus or fulvestrant. No new safety signal was found.

Fulvestrant and everolimus efficacy after CDK4/6 inhibitor: a prospective study with circulating tumor DNA analysis

“…This median PFS is apparently shorter than that reported in the PrE0102 and MANTA trials, which included patients not pre-treated with CDK4/6i [ 9 , 10 ]. A similar shortening of second line PFS in CDK4/6i pretreated patients was previously observed with the fulvestrant-alpelisib combination, with median PFS of 11.0 months when given to CDK4/6i-naïve (SOLAR-1 trial [ 17 ]) versus 7.3 (BYLieve trial [ 18 ]) and 5.3 (French early access program [ 19 ]) months in CDK4/6i-pretreated mBC patients. In the post CDK4/6i setting, few retrospective studies have reported short-lived efficacy of everolimus-based combination (with exemestane or fulvestrant) : median PFS was 4.9 months in N = 12 patients [ 20 ], 4.2 months in N = 41 patients [ 21 ] and 3.8 months in N = 79 patients [ 22 ].…”

Study of Liquid-Based Cytology Using Next-Generation Sequencing as a Liquid Biopsy Application in Patients with Advanced Oncological Disease

“…Recently, PIK3CA mutations have reached level 1 evidence to predict the benefit of alpelisib, an alpha-specific inhibitor of PI3K, in combination with fulvestrant in patients with advanced hormone receptor-positive/HER2-negative breast cancer previously treated with endocrine therapy, highlighting the usefulness of determining these affectations in oncological practice [ 16 , 17 , 18 , 19 ]. Additionally, in the context of hormone receptor-positive metastatic breast cancer, interactions in the estrogen receptor 1 ( ESR1 ) gene are a frequent cause of acquired resistance to estrogen deprivation due to aromatase inhibition [ 20 ]. The prevalence of ESR1 in primary mammary tumors is approximately 3%, however, in the metastatic setting, it is 13.6% [ 20 ].…”

“…Additionally, in the context of hormone receptor-positive metastatic breast cancer, interactions in the estrogen receptor 1 ( ESR1 ) gene are a frequent cause of acquired resistance to estrogen deprivation due to aromatase inhibition [ 20 ]. The prevalence of ESR1 in primary mammary tumors is approximately 3%, however, in the metastatic setting, it is 13.6% [ 20 ]. This ESR1 difference between primary and metastatic tumors suggests that ESR1 mutation emerges during metastasis [ 20 ].…”

“…The prevalence of ESR1 in primary mammary tumors is approximately 3%, however, in the metastatic setting, it is 13.6% [ 20 ]. This ESR1 difference between primary and metastatic tumors suggests that ESR1 mutation emerges during metastasis [ 20 ]. The presence of mutated ESR1 found in a patient with pleural effusion is consistent with what has been described in metastatic breast cancers.…”

Circular RNA PRKCI (hsa_circ_0067934): a potential target in the pathogenesis of human malignancies

“…PI3K/AKT signaling is an important target for breast cancer treatment, and mutations in these pathways have been related to aggressive tumor behavior and treatment resistance ( 44 ). Prospective research has proven that the use of the PI3K inhibitor alpelisib can bring clinical benefits to patients with breast cancer, and has been approved for the targeted treatment of breast cancer ( 45 ). Therefore, circPRKCI is expected to become a potential therapeutic target for breast cancer.…”