Reply to R. Nishihara et al

Bidard, François‐Clément; Kaklamani, Virginia; Bardia, Aditya

doi:10.1200/jco.22.01768

Cited by 3 publications

(8 citation statements)

References 10 publications

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“…While alisertib did not restore sensitivity to fulvestrant as preclinical studies 5,6 conducted before the CDK 4/6i era had suggested, it is feasible the hypothesis was not fairly tested given that accumulating clinical data demonstrate minimal antitumor activity of endocrine monotherapy following CDK 4/6i progression 17,24 and the fact that the entire cohort received prior CDK 4/6i therapy. Furthermore, the role of continued ER block- ade in combination with targeted therapies after CDK 4/6i progression is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…24 In the phase 3 EM-ERALD trial, the oral selective ER degrader elacestrant was associated with a significantly improved mPFS compared with standard ET (fulvestrant or AI); however, mPFS was only 2.8 months. 17 In the BYLieve trial, a single-arm study of alpelisib with fulvestrant in patients with CDK 4/6i-resistant, PIK3CAvariant, ER + MBC, those with measurable disease (n = 100) had an ORR (calculated as best overall response) of 21% (95% CI, 14%-30%) and a 24-week CBR of 42% (95% CI, 35%-52%). 25 In the overall cohort (n = 121), including those with the more clinically favorable nonmeasurable disease, mPFS was 7.3 months; (95% CI, 5.6-8.3) and mOS was 17.3 months (95% CI, 17.2-20.7).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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“…The eligible population in this study utilized the sample characteristics of the EMERALD clinical trial: Participants were advanced/metastatic ER+/HER2-breast cancer; Their disease has progressed or relapsed on or after 1 or 2 lines of endocrine therapy, 1 of which was given in combination with a CDK4/6 inhibitor, for advanced or metastatic breast cancer; The ECOG PS 0 or 1 (11).…”

Section: Cohort Patientsmentioning

confidence: 99%

“…The subgroup was included to compare the effectiveness of treatment between different groups of patients with detectable ESR1 mutations (16). EMERALD was an international, randomized, open-label, activecontrolled, Phase III clinical study (11) (NCT03778931) accessing the efficacy and safety of an investigational oral hormone therapy, ELA (RAD1901), to the SOC hormone therapy options of FUL or an AI in patients with A/MBC that expresses the ER-positive and does not express HER2. In the EMERALD trial, patients treated with ELA had better progression-free survival (PFS) than patients treated with FUL.…”

Section: Introductionmentioning

confidence: 99%

“…ESR1 mutations result in estrogen-independent endoplasmic reticulum activation and therefore resistance to AIs, but not to endoplasmic reticulum inhibitors (e.g., selective endoplasmic SERDs and selective endoplasmic reticulum modulators). And in patients who have previously received CDK4/6 or mammalian target of rapamycin inhibition, ELA can fulfill this need for limited clinical activity of endocrine monotherapy (16). Although ELA has markedly contributed to A/MBC therapy, the high cost ($22511.06 for 30 tablets, 345mg per tablet) may be a heavy burden for patients and families.…”

Section: Introductionmentioning

confidence: 99%

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Cost-effectiveness analysis of elacestrant versus standard endocrine therapy for second-/third-line treatment of patients with HR+/HER2- advanced or metastatic breast cancer: a US payer perspective

Zeng,

Cao,

Lin

et al. 2023

Front. Oncol.

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BackgroundThis study evaluated the cost-effectiveness of elacestrant (ELA) and standard-of-care (SOC) as second-/third-line treatment for pretreated estrogen receptor (ER)– positive/human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer (A/MBC) in the US.MethodsThe 3 health states partitioned survival model (PSM) was conducted from the perspective of the US third-party payers. The time horizon for the model lasted 10 years. Effectiveness and safety data were derived from the EMERALD trial (NCT03778931). Costs were derived from the pricing files of Medicare and Medicaid Services, and utility values were derived from published studies. One-way sensitivity analysis as well as probabilistic sensitivity analysis were performed to observe model stability.ResultELA led to an incremental cost-effectiveness ratio (ICER) of $8,672,360/quality-adjusted life year (QALY) gained compared with SOC in the overall population and $2,900,560/QALY gained compared with fulvestrant (FUL) in the ESR1(estrogen receptor 1) mutation subgroup. The two ICERs of ELA were significantly higher than the willingness-to-pay (WTP) threshold values of $150,000/QALY.ConclusionsELA was not cost-effective for the second-/third-line treatment of patients with ER+/HER2–A/MBC compared with SOC in the US.

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Treatment options for patients with hormone receptor-positive, HER2-negative advanced-stage breast cancer: maintaining cyclin-dependent kinase 4/6 inhibitors beyond progression

Horani,

Abdel-Razeq

2023

Front. Oncol.

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Breast cancer is the most commonly diagnosed cancer in women worldwide. Over the past decade, the treatment paradigm for patients with metastatic breast cancer (MBC) has taken an important shift towards better survival and improved quality of life (QOL), especially for those with hormone receptor (HR)-positive diseases which represent the majority of breast cancer subtypes. The introduction of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in the upfront therapy of such patients has resulted in dramatic improvement in progression-free survival (PFS) and overall survival (OS), too. However, almost all patients would, sooner or later, develop disease progression and necessitate transition to different lines of treatment that may include chemotherapy. The idea of maintaining CDK4/6 inhibitors beyond disease progression seems attractive, as this approach has the potential to improve outcome in this setting despite the fact that the true benefit, in terms of survival, might not carry the same weight as it initially does. Researchers have been investigating potential mechanisms of resistance and identify possible biological markers for response after disease progression. Much of the available data is retrospective; however, few randomized clinical trials were recently published and few more are ongoing, addressing this point. In this paper, we intend to review the available published studies investigating the potential role for keeping CDK4/6 inhibitors in play beyond disease progression.

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Reply to R. Nishihara et al

Cited by 3 publications

References 10 publications

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

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

Cost-effectiveness analysis of elacestrant versus standard endocrine therapy for second-/third-line treatment of patients with HR+/HER2- advanced or metastatic breast cancer: a US payer perspective

Treatment options for patients with hormone receptor-positive, HER2-negative advanced-stage breast cancer: maintaining cyclin-dependent kinase 4/6 inhibitors beyond progression

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