Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial

Tolaney, Sara M.; Wardley, Andrew M; Zambelli, Stefania; Hilton, John; Troso-Sandoval, Tiffany A.; Ricci, Francesco; Im, Seock Ah; Kim, Sung‐Bae; Johnston, Stephen; Chan, Arlene; Goel, Shom; Catron, Kristen; Chapman, Sonya C.; Price, Gregory L.; Yang, Zhengyu; Gainford, M. Corona; André, Fabrice

doi:10.1016/s1470-2045(20)30112-1

Cited by 170 publications

(130 citation statements)

References 26 publications

Supporting

Mentioning

126

Contrasting

Unclassified

Order By: Relevance

“…However, no patients received concomitant HER2-targeted tyrosine kinase inhibitors with known CNS penetration (10)(11)(12)(13)(14). Abemaciclib plus fulvestrant and trastuzumab has demonstrated clinical activity and PFS prolongation in heavily pretreated HR þ , HER2 þ MBC patients, compared with trastuzumab plus chemotherapy (35). Future studies exploring combinations of abemaciclib with ET and brain-penetrating HER2-directed tyrosine kinase inhibitors are indicated in patients with HR þ , HER2 þ brain metastases, including assessing tolerability of the combination, given potential overlapping toxicities, such as gastrointestinal AEs.…”

Section: Discussionmentioning

confidence: 99%

A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor–Positive Breast Cancer

Tolaney

Sahebjam

Rhun

et al. 2020

Clinical Cancer Research

Self Cite

124

103

View full text Add to dashboard Cite

The primary objective was to evaluate intracranial objective response rate (iORR) in patients receiving abemaciclib with brain or leptomeningeal metastases (LM) secondary to hormone receptor-positive (HR þ) metastatic breast cancer (MBC). Secondary objectives evaluated extracranial response, abemaciclib pharmacokinetics, brain metastases tissue exposure, and safety. Patients and Methods: This nonrandomized, phase II study (NCT02308020) enrolled patients in tumor subtype-specific cohorts AD: A (HR þ , HER2 À MBC), B (HR þ , HER2 þ MBC), C (HR þ MBC LM), and D (brain metastases surgical resection). Abemaciclib 200 mg was administered twice daily as monotherapy or with endocrine therapy, or 150 mg twice daily with trastuzumab. Cohorts A and B used a Simon two-stage design. Results: In cohort A (n ¼ 58), 3 patients were confirmed responders resulting in an iORR of 5.2% [95% confidence interval (CI), 0.0-10.9], and the intracranial clinical benefit rate (iCBR) was 24% (95% CI, 13.1-35.2). Median overall survival (OS) was 12.5 months (95% CI, 9.3-16.4). A volumetric decrease in target intracranial lesions was experienced by 38% of patients. In cohort B (n ¼ 27), there were no confirmed intracranial responses. An iCBR of 11% (95% CI, 0.0-23.0) was observed. Median OS was 10.1 months (95% CI, 4.2-14.3). A volumetric decrease in target intracranial lesions was experienced by 22% of patients. In cohort C (n ¼ 10), one confirmed complete parenchymal response was observed. In cohort D (n ¼ 9), unbound brain metastases concentrations of total active abemaciclib analytes were 96-[cyclindependent kinase 4 (CDK4)] and 19-fold (CDK6) above in vitro IC 50. Safety was consistent with prior studies. Conclusions: This study did not meet its primary endpoint. Abemaciclib was associated with an iCBR of 24% in patients with heavily pretreated HR þ , HER2 À MBC. Abemaciclib achieved therapeutic concentrations in brain metastases tissue, far exceeding those necessary for CDK4 and CDK6 inhibition. Further studies are warranted, including assessing novel abemaciclibbased combinations.

show abstract

Section: Discussionmentioning

confidence: 99%

A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor–Positive Breast Cancer

Tolaney

Sahebjam

Rhun

et al. 2020

Clinical Cancer Research

Self Cite

124

103

View full text Add to dashboard Cite

show abstract

“…Consistent with our data, ER (+) HER2 (+) tumor cells and clinical samples showed increased ER expression with acquired resistance to lapatinib. In the MONARCHER trial, investigators showed superior progression free survival with combination of fulvestrant, trastuzumab, and abemaciclib compared to trastuzumab plus standard-of-care chemotherapy in patients with treatment-resistant ER (+) HER2 (+) metastatic breast cancers [42]. This finding proved that co-targeting ER and HER2 is a better strategy than continued HER2 inhibition with chemotherapy in the ER (+) sub-population.…”

Section: Discussionmentioning

confidence: 98%

HSP90 Inhibitor, 17-DMAG, Alone and in Combination with Lapatinib Attenuates Acquired Lapatinib-Resistance in ER-positive, HER2-Overexpressing Breast Cancer Cell Line

Lee

Shin

Kang

et al. 2020

Cancers

View full text Add to dashboard Cite

Lapatinib, a Human Epidermal growth factor Receptor 2 (HER2)-targeting therapy in HER2-overexpressing breast cancer, has been widely used clinically, but the prognosis is still poor because most patients acquire resistance. Therefore, we investigated mechanisms related to lapatinib resistance to evaluate new therapeutic targets that may overcome resistance. Lapatinib-resistant cell lines were established using SKBR3 and BT474 cells. We evaluated cell viability and cell signal changes, gene expression and protein changes. In the xenograft mouse model, anti-tumor effects were evaluated using drugs. Analysis of the protein interaction network in two resistant cell lines with different lapatinib resistance mechanisms showed that HSP90 protein was commonly increased. When Heat Shock Protein 90 (HSP90) inhibitors were administered alone to both resistant cell lines, cell proliferation and protein expression were effectively inhibited. However, inhibition of cell proliferation and protein expression with a combination of lapatinib and HSP90 inhibitors showed a more synergistic effect in the LR-BT474 cell line than the LR-SKBR3 cell line, and the same result was exhibited with the xenograft model. These results suggest that HSP90 inhibitors in patients with lapatinib-resistant Estrogen Receptor (ER) (+) HER2 (+) breast cancer are promising therapeutics for future clinical trials.

show abstract

“…Recently, results from the phase II monarchHER trial, showed that the combination of abemaciclib, fulvestrant, and trastuzumab significantly improved PFS compared to standard chemotherapy plus trastuzumab (8.3 vs. 5.7 months, HR 0.67, p = 0.051) with a tolerable safety profile [116].…”

Section: Her2-positive Bcmentioning

confidence: 99%

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Piezzo

Cocco

Caputo

et al. 2020

IJMS

View full text Add to dashboard Cite

Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment.

show abstract

Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial

Cited by 170 publications

References 26 publications

A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor–Positive Breast Cancer

A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor–Positive Breast Cancer

HSP90 Inhibitor, 17-DMAG, Alone and in Combination with Lapatinib Attenuates Acquired Lapatinib-Resistance in ER-positive, HER2-Overexpressing Breast Cancer Cell Line

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Contact Info

Product

Resources

About