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

Rugo, Hope S.; Lerebours, Florence; Ciruelos, Eva; Drullinsky, Pamela; Ruíz‐Borrego, Manuel; Neven, Patrick; Park, Yeon Hee; Prat, Aleix; Bachelot, Thomas; Juric, Dejan; Turner, Nicholas C.; Sophos, Nickolas A.; Zarate, Juan Pablo; Arce, Christina; Shen, Yu-Ming; Turner, Stuart; Kanakamedala, Hemanth; Hsu, Wei‐Chun; Chia, Stephen

doi:10.1016/s1470-2045(21)00034-6

Cited by 254 publications

(229 citation statements)

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“…The phase II, open‐label, multicenter, noncomparative, 3‐cohort BYLieve trial (NCT03056755) is the first study designed to assess the safety and efficacy of alpelisib combined with ET in patients with PIK3CA ‐mutated, HR+, HER2– ABC and who progressed on/after prior CDK4/6i‐based therapy. BYLieve confirmed efficacy and safety of alpelisib combined with fulvestrant in patients with confirmed PIK3CA ‐mutated disease who received a CDK4/6i with AI as immediate prior therapy (cohort A) [ 16 , 17 ]. The primary endpoint of the trial was met, as 50.4% (95% CI, 41.2%–59.6%) of patients in cohort A were alive without disease progression at 6 months, with the lower bound of the CI being greater than the prespecified threshold of 30%.…”

Section: Introductionmentioning

confidence: 97%

“…The safety profile in this cohort was consistent with the known safety profile of alpelisib [ 1 , 18 ]; the most commonly experienced all‐grade adverse events (AEs) were diarrhea (59.8%), hyperglycemia (58.3%), nausea (45.7%), fatigue (29.1%), decreased appetite (28.3%), rash (28.3%), and stomatitis (26.8%), with no new safety signals observed. Overall AE‐related discontinuations in this cohort were 20.5% [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…As more patients are treated with CDK4/6i combined with ET in the first‐line setting, it is possible to use an external control group and compare data from BYLieve with data from the real world. With careful data abstraction, collection, and standardization, and with appropriate statistical analysis, real‐world data may be used to address the lack of comparative evidence in the clinical trial setting [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we assess the efficacy of treatment with alpelisib combined with fulvestrant in a cohort of patients with PIK3CA ‐mutated disease, whose most recent treatment was with a CDK4/6i combined with AI, compared with the effectiveness of real‐world standard treatments in the post‐CDK4/6i setting using data from the deidentified clinico‐genomics database (CGDB) [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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Background. The BYLieve trial (NCT03056755) confirmed efficacy and safety of alpelisib with fulvestrant for hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2À), 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 and Methods. 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 2 cohorts.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Patients in cohort C must have had progress on an AI and recently received chemotherapy or endocrine therapy as immediate prior treatment and were intended for a treatment with alpelisib and fulvestrant. Results of cohort A have already been published and showed 61 of 121 patients (50.4%; 95% confidence interval [CI] 41.2-59.6) being alive without progressive disease at 6 months [2]. This primary endpoint was also met in cohort B (n = 112) when 46.1% (95% CI 36.8-55.6%) of the patients were alive without disease progression at 6 months.…”

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confidence: 91%

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SummaryRecent findings support the role of alpelisib in advanced HR-positive breast cancer harboring a PIK3CA mutation. A retrospective biomarker analysis on the intrinsic subtypes of HR-positive breast cancer reveals a subgroup that will not benefit under the addition of a CDK 4/6 inhibitor treatment. The detection of circulating tumor cells before start and during tumor treatment is associated with worse outcome in metastatic breast cancer patients.

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Evaluation of Alisertib Alone or Combined With Fulvestrant in Patients With Endocrine-Resistant Advanced Breast Cancer

et al. 2023

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ImportanceAurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i–resistant MBC is unknown.ObjectiveTo assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC.Design, Setting, and ParticipantsThis phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)–negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (&lt;10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022.InterventionsAlisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2).Main Outcomes and MeasuresImprovement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%.ResultsAll 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]).Conclusions and RelevanceThis randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i–resistant MBC. The overall safety profile was tolerable.Trial RegistrationClinicalTrials.gov Identifier: NCT02860000

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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

Cited by 254 publications

References 18 publications

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

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

Post San Antonio update—my top three abstracts!

Evaluation of Alisertib Alone or Combined With Fulvestrant in Patients With Endocrine-Resistant Advanced Breast Cancer

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