Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications

Vernieri, Claudio; Corti, Francesca; Nichetti, Federico; Ligorio, Francesca; Manglaviti, Sara; Zattarin, Emma; Rea, Carmen G.; Capri, Giuseppe; Bianchi, Giulia; Braud, Filippo de

doi:10.1186/s13058-020-01271-0

Cited by 30 publications

(19 citation statements)

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“…In addition, in May 2019, alpelisib in combination with fulvestrant was approved for PIK3CA mutated hormone-positive metastatic breast cancer based on the SOLAR-1 trial which reported PFS of 11 months [ 22 ]. Everolimus inhibits mTORC1 downstream of PI3K and may remain a valuable treatment option for patients who do not qualify for or who progress on alpelisib [ 23 ]. As new treatment combinations become available, more clinical trials will be needed to assess the optimal sequence of therapies.…”

Section: Discussionmentioning

confidence: 99%

Patterns of treatment with everolimus exemestane in hormone receptor-positive HER2-negative metastatic breast cancer in the era of targeted therapy

et al. 2021

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Background There is currently no clinical trial data regarding the efficacy of everolimus exemestane (EE) following prior treatment with CDK4/6 inhibitors (CDK4/6i). This study assesses the use and efficacy of everolimus exemestane in patients with metastatic HR+ HER2− breast cancer previously treated with endocrine therapy (ET) or endocrine therapy + CDK4/6i. Methods Retrospective analysis of electronic health record-derived data for HR+ HER2− metastatic breast cancer from 2012 to 2018. The proportion of patients receiving EE first-line, second-line, or third-line, and the median duration of EE prior to next line of treatment (TTNT) by line of therapy was calculated. OS for patients receiving EE first-line, second-line, or third-line, indexed to the date of first-line therapy initiation and stratified by prior treatment received, was calculated with Kaplan-Meier method with multivariable Cox proportional hazards regression analysis. Results Six hundred twenty-two patients received EE first-line (n = 104, 16.7%), second-line (n = 273, 43.9%) or third-line (n = 245, 39.4%). Median TTNT was 8.3 months, 5.5 months, and 4.8 months respectively. Median TTNT of EE second-line was longer following prior ET alone compared to prior ET + CDK4/6i (6.2 months (95% CI 5.2, 7.3) vs 4.3 months (95% CI 3.2, 5.7) respectively, p = 0.03). Similarly, EE third-line following ET alone vs ET + CDK4/6i in first- or second-line resulted in median TTNT 5.6 months (95% CI 4.4, 6.9) vs 4.1 months (95% CI 3.6, 6.1) respectively, although this was not statistically significant (p = 0.08). Median OS was longer for patients who received EE following prior ET + CDK4/6i. EE second-line following ET + CDK 4/6i vs ET alone resulted in median OS 37.7 months vs. 32.7 months (p = 0.449). EE third-line following ET + CDK4/6i vs prior ET alone resulted in median OS 59.2 months vs. 40.8 months (p < 0.010). This difference in OS was not statistically significant when indexed to the start of EE therapy. Conclusion This study suggests that EE remains an effective treatment option after prior ET or ET + CDK4/6i use. Median TTNT of EE was longer for patients who received prior ET, whereas median OS was longer for patients who received prior ET + CDK4/6i. However, this improvement in OS was not statistically significant when indexed to the start of EE therapy suggesting that OS benefit is primarily driven by prior CDK4/6i use. EE remains an effective treatment option regardless of prior treatment option.

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Section: Discussionmentioning

confidence: 99%

Patterns of treatment with everolimus exemestane in hormone receptor-positive HER2-negative metastatic breast cancer in the era of targeted therapy

et al. 2021

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“…Although the widespread use of alpelisib in the daily treatment of HR+/HER2-aBC patients bearing PIK3CA-mutated tumors might be limited by several factors, including the lack of an extensive tumor genomic profiling in several cancer centers, the suboptimal safety profile of alpelisib and recent labels limiting alpelisib use in Europe and Italy to patients previously treated with single-agent endocrine therapy (which has now been replaced by endocrine therapy plus CDK 4/6 inhibitor-based combinations as a standard-of-care first-line therapy), the alpelisib-fulvestrant combination remains a potentially useful therapy that could be used in up to 40% of all HR+/HER2-aBC patients. Therefore, since the incidence of severe (grade 3 or 4) hyperglycemia is common with alpelisib (actually more common than with EVE) despite the precocious use of metformin in the SOLAR-1 study (24), exploring strategies to prevent or promptly manage alpelisib-induced hyperglycemia/diabetes is a clinically relevant issue, especially for patients with normal baseline blood glucose levels.…”

Section: Discussionmentioning

confidence: 99%

Impact of Baseline and On-Treatment Glycemia on Everolimus-Exemestane Efficacy in Patients with Hormone Receptor–Positive Advanced Breast Cancer (EVERMET)

Vernieri

Nichetti

Lalli

et al. 2021

Clinical Cancer Research

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We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and on-treatment (i.e., during first three months of therapy) blood glucose levels on progression-free survival (PFS) in HR+/HER2-aBC patients treated with EVE-EXE. Results:We evaluated 809 HR+/HER2-aBC patients treated with EVE-EXE as any-line of therapy for advanced disease. When evaluated as dichotomous variables, baseline and on-treatment glycemia were not significantly associated with PFS. However, when blood glucose concentration was evaluated as a continuous variable, a multivariable model accounting for clinically relevant patient-and tumor-related variables revealed that both baseline and on-treatment glycemia are associated with PFS, and this association is largely attributable to their interaction. In particular, patients who are normoglycemic at baseline and experience on-treatment diabetes have lower PFS compared to patients who are already hyperglycemic at baseline and experience diabetes during EVE-EXE therapy (mPFS 6.34 vs. 10.32 months; HR 1.76; 95% CI 1.15-2.69; p=0.008). Conclusions:The impact of on-treatment glycemia on the efficacy of EVE-EXE therapy in HR+/HER2 aBC patients depends on baseline glycemia. This study lays the foundations for investigating novel therapeutic approaches to target the glucose/insulin axis in combination with PI3K/AKT/mTORC1 inhibitors in HR+/HER2 aBC patients.

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“…Currently, the crucial role of the PI3K/AKT/mTOR pathway in stimulating tumor cell proliferation, changing metabolism, and inhibiting apoptosis is widely accepted in breast cancer [ 50 ]. Some potential interactions between estrogen receptors and the PI3K/AKT/mTOR pathway have been documented [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Comparison of Endocrine Therapies in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced or Metastatic Breast Cancer: A Network Meta-Analysis

Liu

Sun

et al. 2020

J Breast Cancer

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We aimed to explore what kind of endocrine treatments are optimal for hormone receptor-positive and human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer in some specific clinical situations. We searched randomized controlled trials in Embase, Medline, the Cochrane library, and PubMed from inception to April 1, 2020 and performed a network meta-analysis based on a Bayesian fixed-effects model. Progression-free survival (PFS) with hazard ratios and corresponding 95% confidence interval was defined as the primary endpoint, while overall survival (OS), objective response rate (ORR), clinical benefit rate and serious adverse events were used as secondary endpoints. A total of 35 studies involving 12,285 patients and 24 treatment options were included. In general, most co-treatment options prolonged PFS compared to single-agent therapy, of which aromatase inhibitor (AI) plus everolimus and fulvestrant plus palbociclib were probably the most effective agents, and the latter had the best safety record. However, despite the superior efficacy of fulvestrant plus capecitabine for PFS and OS, palpable toxic effects have been demonstrated for this treatment, so its application must be scrupulously considered. The results of subgroup analysis indicated that fulvestrant combined with palbociclib improved prognosis for phosphatidylinositol 3-kinase (PI3K)-mutated patients, PI3K-unmutated patients, patients with endocrine therapy resistance, and visceral metastatic patients, while no obvious improvement was detected in OS. Moreover, the efficacy of fulvestrant plus cyclin-dependent kinase 4/6 (CDK4/6) inhibitors was slightly better than that of AI plus CDK4/6 inhibitors, while AI plus everolimus was more efficacious than fulvestrant combined with everolimus in terms of PFS, OS, and ORR. In conclusion, our results provide moderate evidence that fulvestrant plus palbociclib and AI plus everolimus were the most effective treatments, while the efficacy and safety of fulvestrant plus palbociclib was obviously superior in some specific clinical situations.

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Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications

Cited by 30 publications

References 58 publications

Patterns of treatment with everolimus exemestane in hormone receptor-positive HER2-negative metastatic breast cancer in the era of targeted therapy

Patterns of treatment with everolimus exemestane in hormone receptor-positive HER2-negative metastatic breast cancer in the era of targeted therapy

Impact of Baseline and On-Treatment Glycemia on Everolimus-Exemestane Efficacy in Patients with Hormone Receptor–Positive Advanced Breast Cancer (EVERMET)

Comparison of Endocrine Therapies in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced or Metastatic Breast Cancer: A Network Meta-Analysis

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