Ado-trastuzumab emtansine (T-DM1): a novel antibody-drug conjugate for the treatment of HER2-positive metastatic breast cancer

Baron, Jessica; Boster, Bonnie L; Barnett, Chad M.

doi:10.1177/1078155214527144

Cited by 50 publications

(42 citation statements)

References 22 publications

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“…Currently, microtubule inhibitors are clinically validated ADC payloads. Both Kadcyla (trastuzumab emtansine; Genentech) and Adcetris (brentuximab vedotin; Seattle Genetics) are FDA-approved ADC therapeutics, and more than 40 other ADCs have advanced to the clinic (7,8). A microtubule inhibitor-based ADC targeting EGFR is an attractive therapeutic strategy that may improve on the activity of approved EGFR antagonists by circumventing resistance mediated by downstream signaling mutations.…”

Section: Introductionmentioning

confidence: 99%

ABT-414, an Antibody–Drug Conjugate Targeting a Tumor-Selective EGFR Epitope

Phillips

Boghaert

Vaidya

et al. 2016

Molecular Cancer Therapeutics

162

121

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Targeting tumor-overexpressed EGFR with an antibody-drug conjugate (ADC) is an attractive therapeutic strategy; however, normal tissue expression represents a significant toxicity risk. The anti-EGFR antibody ABT-806 targets a unique tumor-specific epitope and exhibits minimal reactivity to EGFR in normal tissue, suggesting its suitability for the development of an ADC. We describe the binding properties and preclinical activity of ABT-414, an ABT-806 monomethyl auristatin F conjugate. In vitro, ABT-414 selectively kills tumor cells overexpressing wild-type or mutant forms of EGFR. ABT-414 inhibits the growth of xenograft tumors with high EGFR expression and causes complete regressions and cures in the most sensitive models. Tumor growth inhibition is also observed in tumor models with EGFR mutations, including activating mutations and those with the exon 2-7 deletion [EGFR variant III (EGFRvIII)], commonly found in glioblastoma multiforme. ABT-414 exhibits potent cytotoxicity against glioblastoma multiforme patient-derived xenograft models expressing either wild-type EGFR or EGFRvIII, with sustained regressions and cures observed at clinically relevant doses. ABT-414 also combines with standard-of-care treatment of radiation and temozolomide, providing significant therapeutic benefit in a glioblastoma multiforme xenograft model. On the basis of these results, ABT-414 has advanced to phase I/II clinical trials, and objective responses have been observed in patients with both amplified wild-type and EGFRvIII-expressing tumors. Mol Cancer Ther; 15(4);

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Section: Introductionmentioning

confidence: 99%

ABT-414, an Antibody–Drug Conjugate Targeting a Tumor-Selective EGFR Epitope

Phillips

Boghaert

Vaidya

et al. 2016

Molecular Cancer Therapeutics

162

121

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“…The ToGA trial is a landmark in the treatment of gastric cancer, since following the successful completion of the study, trastuzumab, in combination with chemotherapy, approved for this indication. Results showed that median overall survival was 13·8 months (95% confidence interval [95% CI] 12–16) in those received trastuzumab plus chemotherapy compared to 11·1 months[10111213] in those received chemotherapy alone (hazard ratio 0·74; 95% CI 0·60–0·91; P = 0·0046). Prolonged overall survival in trastuzumab administrated group, led to the guidelines recommendation that HER2 testing should be routinely performed in patients with metastatic or recurrent gastric cancer.…”

Section: Ado-trastuzumab Emtansine In Human Epidermal Growth Factor Rmentioning

confidence: 99%

Whether HER2-positive non-breast cancers are candidates for treatment with Ado-trastuzumab emtansine?

Moghaddas

Borhani

2016

J Res Pharm Pract

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The National Comprehensive Cancer Network (NCCN) has recommended Ado-trastuzumab emtansine (T-DM1) as a preferred agent for patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer and prior trastuzumab therapy. Overexpression of HER2 was reported in other cancer types such as bladder, gastric and urogenital carcinosarcomas similar to what is discovered in breast cancer. Some preclinical studies demonstrated the potential anti-tumor effects of T-DM1 in HER2-positive non-breast cancers. There is a paucity of data over the clinical evaluation of T-DM1 in human studies of non-breast cancer patients. We review some preclinical and ongoing clinical studies that assessed the efficacy of T-DM1 administration in the treatment of non-breast HER2 positive malignancies. Performing large and well-designed trials in this area is matter of interest and highly recommended.

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“…Препарат обладает двойным противоопухолевым эффектом: анти-HER-2, опосредованным трастузумабом, и цитотоксическим за счет селективного транспорта мощного антимито-тического агента DM1 в цитоплазму опухолевой клет-ки. Данный механизм действия повышает эффектив-ность противоопухолевой терапии, уменьшая ее токсичность [44,45].…”

Section: опухоли женской репродуктивной системы Tumors Of Female Reprunclassified

Role of targeted therapy in the treatment of HER-2-positive breast cancer brain metastases

Дашян¹,

Семиглазов²,

Krivorotko³

et al. 2016

Tumors of female reproductive system

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46М а м м о л о г и я / M a m m o l o g y 1 ' 2 0 1 6 Том 12 / Vol. 12 ОПУХОЛИ ЖЕНСКОЙ РЕПРОДУКТИВНОЙ СИСТЕМЫ TUMORS OF FEMALE REPRODUCTIVE SYSTEM Лечение После рака легких 2-й наиболее частой причиной метастазов в головной мозг (ГМ) является рак мо-лочной железы (РМЖ), метастазирование при кото-ром наблюдается в 10-16 % случаев [1]. Еще у 10 % больных происходит бессимптомное метастазирова-ние, что подтверждается данными аутопсии [2]. В по-следние годы отмечается более частое выявление метастазов в ГМ, что, вероятно, связано с более дли-тельной выживаемостью больных, получающих со-временные эффективные методы лечения, а также с применением более чувствительных методов визу-ализации.Развитие метастазов в ГМ представляет собой сложный процесс, предполагающий инвазию клеток РМЖ в окружающие ткани и сосуды, циркуляцию

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Ado-trastuzumab emtansine (T-DM1): a novel antibody-drug conjugate for the treatment of HER2-positive metastatic breast cancer

Cited by 50 publications

References 22 publications

ABT-414, an Antibody–Drug Conjugate Targeting a Tumor-Selective EGFR Epitope

ABT-414, an Antibody–Drug Conjugate Targeting a Tumor-Selective EGFR Epitope

Whether HER2-positive non-breast cancers are candidates for treatment with Ado-trastuzumab emtansine?

Role of targeted therapy in the treatment of HER-2-positive breast cancer brain metastases

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