Phase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for HER2-positive metastatic breast cancer

Spring, Laura; Clark, Shealagh L; Li, Tianyu; Goel, Shom; Tayob, Nabihah; Viscosi, Elene; Abraham, Elizabeth J.; Juric, Dejan; Isakoff, Steven J.; Mayer, Erica L.; Moy, Beverly; Supko, Jeffrey G.; Tolaney, Sara M.; Bardia, Aditya

doi:10.1038/s41523-021-00311-y

Cited by 19 publications

(14 citation statements)

References 39 publications

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“…Most recently, the data of a phase 1b trial in a very small cohort ( N = 12) show promising clinical activity of ribociclib in combination with T-DM1 in HER2+ MBC patients regardless of their HR status (66.7% of patients had HR+/HER2+) [ 110 ]. While CDKi can impair the efficacy of T-DM1 by preventing cells from entering into the S or M phase [ 111 ], it can potentially be avoided with a non-overlapping dosing strategy [ 110 ]. This scheme can also mitigate toxicities common with both agents, e.g., thrombocytopenia.…”

Section: Towards a Common Goal Of A Chemotherapy-sparing Treatment Planmentioning

confidence: 99%

“…T-DM1 was administered intravenously on day 1 of each 21-day cycle, followed by ribociclib on days 8–21 of a 21-day cycle. After a median follow-up of 12.4 months, the median PFS was 10.4 months, and the combination was generally well-tolerated, with the majority of toxicities reported in grades 1 and 2 [ 110 ].…”

Section: Towards a Common Goal Of A Chemotherapy-sparing Treatment Planmentioning

confidence: 99%

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Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity

Koirala

Dey

Aske

et al. 2022

IJMS

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The development of HER2-targeted therapies has dramatically improved patient survival and patient management and increased the quality of life in the HER2+ breast cancer patient population. Due to the activation of compensatory pathways, patients eventually suffer from resistance to HER2-directed therapies and develop a more aggressive disease phenotype. One of these mechanisms is the crosstalk between ER and HER2 signaling, especially the CDK4/6-Cyclin D-Rb signaling axis that is commonly active and has received attention for its potential role in regulating tumor progression. CDK 4/6 inhibitors interfere with the binding of cell-cycle-dependent kinases (CDKs) with their cognate partner cyclins, and forestall the progression of the cell cycle by preventing Rb phosphorylation and E2F release that consequentially leads to cancer cell senescence. CDK 4/6 inhibitors, namely, palbociclib, ribociclib, and abemaciclib, in combination with anti-estrogen therapies, have shown impressive outcomes in hormonal receptor-positive (HR+) disease and have received approval for this disease context. As an extension of this concept, preclinical/clinical studies incorporating CDK 4/6 inhibitors with HER2-targeted drugs have been evaluated and have shown potency in limiting tumor progression, restoring therapeutic sensitivity, and may improving the management of the disease. Currently, several clinical trials are examining the synergistic effects of CDK 4/6 inhibitors with optimized HER2-directed therapies for the (ER+/-) HER2+ population in the metastatic setting. In this review, we aim to interrogate the burden of HER2+ disease in light of recent treatment progress in the field and examine the clinical benefit of CDK 4/6 inhibitors as a replacement for traditional chemotherapy to improve outcomes in HER2+ breast cancer.

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Section: Towards a Common Goal Of A Chemotherapy-sparing Treatment Planmentioning

confidence: 99%

Section: Towards a Common Goal Of A Chemotherapy-sparing Treatment Planmentioning

confidence: 99%

Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity

Koirala

Dey

Aske

et al. 2022

IJMS

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“…No dose-limiting toxicities were observed, and the majority of adverse events were graded as 1 or 2, with only grade 3 neutropenia, leukopenia, and anemia, usually reported with CDK4/6 monotherapy. 19 …”

Section: Emerging Combinations In Metastatic Settingmentioning

confidence: 99%

Ribociclib in the Treatment of Hormone-Receptor Positive/HER2-Negative Advanced and Early Breast Cancer: Overview of Clinical Data and Patients Selection

Parati¹,

Pedersini²,

Perego³

et al. 2022

BCTT

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Among pre- and postmenopausal women with hormone receptor-positive (HR+) breast cancer (BC), combinations of an aromatase inhibitor (AI) or fulvestrant with a CDK 4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) have demonstrated improved progression-free survival (PFS) and overall survival (OS) compared to standard single-agent hormone therapy alone as first-line therapy for de novo metastatic disease or relapse during or after adjuvant therapy and no previous therapies in an advanced setting. We here reviewed clinical data about ribociclib in advanced and early BC. Also, we shed light on patient selection and special settings in which medical oncologists urgently await an advance in treatment. Ribociclib was FDA-approved in combination with letrozole based on a Phase III study in which 668 postmenopausal women with HR+, HER2-negative recurrent or metastatic BC were treated with first-line letrozole with or without ribociclib. For patients with metastatic disease at presentation or after a course of AIs, the results of the MONALEESA-3 trial suggest ribociclib’s efficacy in combination with fulvestrant, and this combination is FDA-approved for initial- and subsequent-line endocrine therapy for postmenopausal women with metastatic hormone receptor-positive, HER2-negative BC. In adjuvant and neoadjuvant settings, the use of CDK 4/6 inhibitors may be useful to boost outcomes in high-risk patients with HR+ BC, but data contrast with those of a phase III study, which produced positive results. New combinations are being explored in upfront disease (neoadjuvant) or in association with other targeted agents in metastatic disease. Compared to other CDK 4/6 available, ribociclib has a higher incidence of liver function test abnormalities than the other agents and can cause QTc prolongation, and therefore may be prudently avoided in patients with cardiac morbidities or other risk factors for QTc prolongation (drugs, interactions). In these cases, different agents (palbociclib or abemaciclib) may be used. In conclusion, ribociclib with letrozole or with fulvestrant is effective for the entire spectrum of patients with HR+ BC in the advanced setting. Ribociclib has all the characteristics of an innovative drug able to change the clinical practice and most BC patients’ prognoses.

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“…42 A phase 1b study combined ribociclib and T-DM1 in patients with HER2+ MBC previously treated with trastuzumab and a taxane. 43 Based on the pharmacokinetic analysis, AEs, and dose reductions, 400 mg was determined to be the recommended phase II dose (RP2D) for ribociclib given with T-DM1.…”

Section: Combination Of T-dm1 and Cdk4/6 Inhibitorsmentioning

confidence: 99%

“…Cardiotoxicity was an unusual finding among patients treated with T-DM1 after anthracycline-based chemotherapy. 43,44 Verma et al 8 reported that 97% of patients receiving T-DM1 maintained an LVEF of ≥ 45%. This is consistent with the results of other landmark studies reporting that very few patients discontinue treatment due to cardiotoxicity.…”

Section: Cardiovascular Toxicitiesmentioning

confidence: 99%

Antibody drug conjugates (ADCs): an expanding rational treatment paradigm in breast cancer (CME article)

Yan

Sun

et al. 2022

International Journal of Cancer Care and Delivery

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Recent advances in bioengineering and manufacturing have catapulted Antibody–drug conjugates (ADCs) to broader clinical applications. ADCs take advantage of the exquisite specificity of monoclonal antibodies (mAb) to deliver a highly potent cytotoxic agent to a specifically targeted cell expressing a selected antigen. HER2-positive breast cancer has served as a testing ground for ADC development in solid tumors that over-express HER2/neu by linking trastuzumab to a payload agent. With the current advances, ADCs leverage the selective targeting of monoclonal antibodies to deliver highly potent agents which otherwise have a narrow therapeutic index. Ado-trastuzumab emtansine (T-DM1) was the first ADC approved for patients with HER2-postive metastatic breast cancer (MBC) and fam-trastuzumab deruxtecan-nxki (T-DXd) was recently approved as well. Sacituzumab govitecan-hziy (SG) was approved in 2020 for patients with triple negative breast cancer (TNBC). Studies focusing on utilizing ADCs in earlier stages of breast cancer in the neoadjuvant or adjuvant setting, and central nervous system (CNS) disease are in progress. New ADCs and bispecific antibodies (bAbs) are also in development.

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Phase 1b clinical trial of ado-trastuzumab emtansine and ribociclib for HER2-positive metastatic breast cancer

Cited by 19 publications

References 39 publications

Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity

Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity

Ribociclib in the Treatment of Hormone-Receptor Positive/HER2-Negative Advanced and Early Breast Cancer: Overview of Clinical Data and Patients Selection

Antibody drug conjugates (ADCs): an expanding rational treatment paradigm in breast cancer (CME article)

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