Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer

Baselga, José; Phillips, Gail D. Lewis; Verma, Sunil; Ro, Jungsil; Huober, Jens; Guardino, Alice E.; Samant, Meghna; Olsen, Steve; Haas, Sanne L. de; Pegram, Mark D.

doi:10.1158/1078-0432.ccr-15-2499

Cited by 177 publications

(172 citation statements)

References 35 publications

(66 reference statements)

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“…Although alterations in some genes (e.g., EGFR, HER3, and PTEN protein expression and PIK3CA mutations; ref. 34) have been found to not correlate with T-DM1 response, data in this report warrant the investigation of caveolae-mediated endocytosis of T-DM1 in patient tumors as a potential predictive biomarker for response to T-DM1 and other non-cleavablelinked ADCs.…”

Section: Discussionmentioning

confidence: 65%

Caveolae-Mediated Endocytosis as a Novel Mechanism of Resistance to Trastuzumab Emtansine (T-DM1)

Sung

Tan

et al. 2018

Molecular Cancer Therapeutics

139

111

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Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) that has demonstrated clinical benefit for patients with HER2þ metastatic breast cancer; however, its clinical activity is limited by inherent or acquired drug resistance. The molecular mechanisms that drive clinical resistance to T-DM1, especially in HER2 þ tumors, are not well understood. We used HER2 þ cell lines to develop models of T-DM1 resistance using a cyclical dosing schema in which cells received T-DM1 in an "onoff" routine until a T-DM1-resistant population was generated. T-DM1-resistant N87 cells (N87-TM) were cross-resistant to a panel of trastuzumab-ADCs (T-ADCs) with non-cleavablelinked auristatins. N87-TM cells do not have a decrease in HER2 protein levels or an increase in drug transporter protein (e.g., MDR1) expression compared with parental N87 cells.

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Section: Discussionmentioning

confidence: 65%

Caveolae-Mediated Endocytosis as a Novel Mechanism of Resistance to Trastuzumab Emtansine (T-DM1)

Sung

Tan

et al. 2018

Molecular Cancer Therapeutics

139

111

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“…More specifically, progression-free survival was 10.6 months for patients receiving therapy with tumors expressing higher Her2 levels versus 8.2 months for lower Her2 expression levels (8). Similarly, patients who received therapy harboring tumors with above median levels of Her2 had a median overall survival of 34.1 versus 26.5 months for patients with lower Her2 levels (8). These findings also have broad implications in formulating patient stratification strategies for a given ADC antigen target.…”

Section: Considerations For Target Selectionmentioning

confidence: 86%

“…As a case in point, the FDA approval of Kadcyla® for Her2-positive breast cancer was based on data from the phase III EMILIA trial; data from this trial suggested that patients with increased breast tumor expression levels of Her2 exhibited improved progression-free survival and overall survival. More specifically, progression-free survival was 10.6 months for patients receiving therapy with tumors expressing higher Her2 levels versus 8.2 months for lower Her2 expression levels (8). Similarly, patients who received therapy harboring tumors with above median levels of Her2 had a median overall survival of 34.1 versus 26.5 months for patients with lower Her2 levels (8).…”

Section: Considerations For Target Selectionmentioning

confidence: 97%

Antibody Drug Conjugates: Preclinical Considerations

Bornstein

2015

AAPS J

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ABSTRACT. The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg®, the first in class FDA-approved ADC, are highlighted.

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“…Based on the biomarker analyses from EMILIA and TH3RESA studies, T-DM1 was similarly effective in the presence of PI3K wild-type or mutated tumours, and the benefit with T-DM1 was seen irrespective of HER2 mRNA, HER3 mRNA, or PTEN protein level. 17,18 The current study is limited by its retrospective design, possible information bias during data retrieval/extraction/coding, as well as the small number of patients (especially for subgroup analysis) and inadequate follow-up period for OS. Although the results could not be compared directly with reported prospective trials, patients were representative, and treatment and outcomes reflect routine clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and tolerability of trastuzumab emtansine in advanced human epidermal growth factor receptor 2–positive breast cancer

et al. 2018

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Introduction:The management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer has changed dramatically with the introduction and widespread use of HER2-targeted therapies. There is, however, relatively limited real-world information about the effectiveness and safety of trastuzumab emtansine (T-DM1) in Hong Kong Chinese patients. We assessed the efficacy and toxicity profiles among local patients with HER2-positive advanced breast cancer who had received T-DM1 therapy in the second-line setting and beyond. Methods: This retrospective study involved five local centres that provide service for over 80% of the breast cancer population in Hong Kong. The study period was from December 2013 to December 2015. Patients were included if they had recurrent or metastatic histologically confirmed HER2+ breast cancer who had progressed after at least one line of anti-HER2 therapy including trastuzumab. Patients were excluded if they received T-DM1 as firstline treatment for recurrent or metastatic HER2+ breast cancer. Patient charts including biochemical and haematological profiles were reviewed for background information, T-DM1 response, and toxicity data. Adverse events were documented during chemotherapy and 28 days after the last dose of medication. Results: Among 37 patients being included in this study, 28 (75.7%) had two or more lines of anti-HER2 agents and 26 (70.3%) had received two or more lines of palliative chemotherapy. Response assessment revealed that three (8.1%) patients had a complete response, eight (21.6%) a partial response, 11 (29.7%) a stable disease, and 12 (32.4%) a progressive disease; three patients could not be assessed. The median duration of response was 17.3 (95% confidence interval, 8.4-24.8) months. The clinical benefit rate (complete response + partial response + stable disease, ≥12 weeks) was 37.8% (95% confidence interval, 22.2%-53.5%). The median progressionfree survival was 6.0 (95% confidence interval, 3.3-9.8) months and the median overall survival had Efficacy and tolerability of trastuzumab emtansine in advanced human epidermal growth factor receptor 2-positive breast cancer New knowledge added by this study • This study confirms that the efficacy and toxicity profiles of trastuzumab emtansine (T-DM1) among Chinese patients are similar to the published data that have been based mainly on western populations. Implications for clinical practice or policy • T-DM1 is effective in HER2-positive advanced breast cancer in the second-line setting and beyond. It has tolerable toxicity. Further research is warranted to enable identification of the appropriate patient population to enhance cost-effectiveness.

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Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer

Cited by 177 publications

References 35 publications

Caveolae-Mediated Endocytosis as a Novel Mechanism of Resistance to Trastuzumab Emtansine (T-DM1)

Caveolae-Mediated Endocytosis as a Novel Mechanism of Resistance to Trastuzumab Emtansine (T-DM1)

Antibody Drug Conjugates: Preclinical Considerations

Efficacy and tolerability of trastuzumab emtansine in advanced human epidermal growth factor receptor 2–positive breast cancer

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