Efficacy of Palbociclib Combinations in Hormone Receptor–Positive Metastatic Breast Cancer Patients After Prior Everolimus Treatment

Dhakal, Ajay; Matthews, Christina; Levine, Ellis G.; Salerno, Kilian E.; Zhang, Fan; Takabe, Kazuaki; Early, Amy P.; Edge, Stephen B.; O’Connor, Tracy; Khoury, Thaer; Young, Joseph C.; Opyrchal, Mateusz

doi:10.1016/j.clbc.2018.04.015

Cited by 28 publications

(26 citation statements)

References 14 publications

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“…These data are consistent with previous reports of in vitro studies that show CDK4/6 inhibitors can reverse acquired resistance to inhibitors of PI3K [36]. Data from two clinical studies with small numbers of patients indicate that palbociclib-based therapies have limited efficacy after progression on the mTORC1 inhibitor everolimus (RAD001) [37,38]. However, the efficacy of CDK4/6 inhibition post-progression on PI3K inhibitor-based therapies is yet to be investigated.…”

Section: Discussionsupporting

confidence: 90%

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

et al. 2020

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Background: Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/ HER2− breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance. Methods: In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance. Results: We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2− breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2− breast cancer models. Conclusions: These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2− breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.

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Section: Discussionsupporting

confidence: 90%

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

et al. 2020

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“…In the whole population, we found that patients who had been treated with everolimus had signi cantly worse DCR (50.0%) and PFS (3.4 months) than everolimus-naïve patients. This nding appears to be consistent with that of a retrospective study of 23 patients in the United States (18). In that study, Dhakal et al found that palbociclib-based therapy had a DCR of 17.4% and a median PFS of 2.9 months in patients with metastatic breast cancer pretreated with everolimus (18).…”

Section: Discussionsupporting

confidence: 86%

Treatment patterns and clinical outcomes in patients with metastatic breast cancer treated with palbociclib-based therapies: Real-world data in the Han population

et al. 2020

Preprint

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Background: Palbociclib combined with endocrine therapy has become the standard treatment for estrogen receptor-positive (ER+) metastatic breast cancer. However, little is known about the effectiveness of diverse palbociclib-based regimens other than letrozole and fulvestrant in the real-world clinical setting. This study aimed to reveal the treatment patterns and clinical outcomes in Han patients in routine clinical practice.Methods: The clinical data of patients with ER+ metastatic breast cancer treated with palbociclib were collected from the China National Cancer Center database. The efficacy profile of palbociclib in this Han population was evaluated, especially in patients younger than 40 years, in those with bone-only metastasis, for various regimen combinations, and as different treatment lines. Propensity score matching was employed to match patients with or without previous everolimus treatment. Results: A total of 186 patients from 89 cities in 18 provinces in China were enrolled. The median progression-free survival (PFS) was similar among different palbociclib-combined groups (P=0.566): 10.0 months (95% confidence interval [CI] 3.8–16.1) in the exemestane plus palbociclib group, 9.7 months (95% CI 6.3–13.1) in the letrozole plus palbociclib group, 7.8 months (95% CI 5.5–10.2) in the fulvestrant plus palbociclib group, 7.2 months (95% CI 3.2–11.3) in the toremifene plus palbociclib group, and 6.1 months (95% CI 1.2–11.0) in the anastrozole plus palbociclib group. Kaplan-Meier analysis revealed that patients with bone-only metastasis (median PFS: 8.8 vs. 7.8 months; P=0.023) and those who received palbociclib as first-line treatment (median PFS: 14.0 months, 95% CI 11.4–16.6; P<0.001) had prolonged PFS compared with other patients. Patients pretreated with everolimus had significantly worse PFS (3.4 months, 95% CI 0.7–6.1) than those in the everolimus-naïve group (8.8 months, 95% CI 6.6–11.0, P=0.001) in the whole population. After propensity score matching, patients pretreated with everolimus had inferior PFS (4.4 months, 95% CI 0.5–8.2) compared with everolimus-naïve patients (6.1 months, 95% CI 4.7–7.5, P=0.439). Conclusions: Various palbociclib-based regimens have promising efficacy in real-world settings, even in patients with bone-only metastasis. Palbociclib resistance is more common in patients pretreated with everolimus, and in the settings of subsequent treatment compared with first-line treatment.

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“…Finally, combined targeting of CDK4/6 and PI3K pathways resulted in greater tumour regression compared with PI3K or CDK4/6 inhibition alone; and triplet therapy with CDK4/6 and PI3K inhibitors was more effective than dual therapy with respect to tumour regression (O'Brien et al 2014, Herrera-Abreu et al 2016. In two recent studies, cohorts of heavily pre-treated patients who had received everolimus obtained limited benefit from the addition of palbociclib, suggesting that CDK4/6 inhibitors should be used prior to or concurrently with drugs targeting the PI3K pathway (Dhakal et al 2018, du Rusquec et al 2018. The multiple types of PI3K inhibitors in clinical development, combined with the three lead CDK4/6 inhibitors, multiple classes of ER-directed therapies, and next generation selective ER degraders, in different lines of therapy, have resulted in a large number of combinations and permutations, creating a challenge when determining the optimal therapeutic strategy for a given patient.…”

Section: Strategies To Avert and Overcome Cdk4/6 Inhibitor Resistancementioning

confidence: 99%

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

Portman

Alexandrou

Carson

et al. 2019

Endocrine-Related Cancer

116

121

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Three inhibitors of CDK4/6 kinases were recently FDA approved for use in combination with endocrine therapy, and they significantly increase the progression-free survival of patients with advanced estrogen receptor-positive (ER+) breast cancer in the first-line treatment setting. As the new standard of care in some countries, there is the clinical emergence of patients with breast cancer that is both CDK4/6 inhibitor and endocrine therapy resistant. The strategies to combat these cancers with resistance to multiple treatments are not yet defined and represent the next major clinical challenge in ER+ breast cancer. In this review, we discuss how the molecular landscape of endocrine therapy resistance may affect the response to CDK4/6 inhibitors, and how this intersects with biomarkers of intrinsic insensitivity. We identify the handful of pre-clinical models of acquired resistance to CDK4/6 inhibitors and discuss whether the molecular changes in these models are likely to be relevant or modified in the context of endocrine therapy resistance. Finally, we consider the crucial question of how some of these changes are potentially amenable to therapy.

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Efficacy of Palbociclib Combinations in Hormone Receptor–Positive Metastatic Breast Cancer Patients After Prior Everolimus Treatment

Abstract: There is a limited clinical activity of palbociclib combinations after progression with everolimus combination therapy. Further studies are necessary to confirm these findings.

Cited by 28 publications

References 14 publications

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

Treatment patterns and clinical outcomes in patients with metastatic breast cancer treated with palbociclib-based therapies: Real-world data in the Han population

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

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