Novel ADCs and Strategies to Overcome Resistance to Anti-HER2 ADCs

During recent years, a number of new compounds against HER2 have reached clinics, improving the prognosis and quality of life of HER2-positive breast cancer patients. Nonetheless, resistance to standard-of-care drugs has motivated the development of novel agents, such as new antibody-drug conjugates (ADCs). The latter are a group of drugs that benefit from the potency of cytotoxic agents whose action is specifically guided to the tumor by the target-specific antibody. Two anti-HER2 ADCs have reached the clinic: trastuzumab-emtansine and, more recently, trastuzumab-deruxtecan. In addition, several other HER2-targeted ADCs are in preclinical or clinical development, some of them with promising signs of activity. In the present review, the structure, mechanism of action, and potential resistance to all these ADCs will be described. Specific attention will be given to discussing novel strategies to circumvent resistance to ADCs.

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RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer

Nature Communications ◽

10.1038/s41467-021-26018-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Olav Engebraaten ◽

Christina Yau ◽

Kristian Berg ◽

Elin Borgen ◽

Øystein Garred ◽

...

Keyword(s):

Breast Cancer ◽

Drug Transport ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

Cytotoxic Agents ◽

Trastuzumab Emtansine ◽

Targeted Therapeutics ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Drug Conjugates

AbstractHER2 is a predictive biomarker for HER2-targeted therapeutics. For antibody–drug conjugates (ADCs; e.g., trastuzumab emtansine (T-DM1)), HER2 is utilized as a transport gate for cytotoxic agents into the cell. ADC biomarkers may therefore be more complex, also reflecting the intracellular drug transport. Here we report on a positive correlation between the early endosome marker RAB5A and T-DM1 sensitivity in five HER2-positive cell lines. Correlation between RAB5A expression and T-DM1 sensitivity is confirmed in breast cancer patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial (NCT01042379), but not in the trastuzumab/paclitaxel control arm. The clinical correlation is further verified in patients from the KAMILLA trial (NCT01702571). In conclusion, our results suggest RAB5A as a predictive biomarker for T-DM1 response and outline proteins involved in endocytic trafficking as predictive biomarkers for ADCs.

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Systemic Treatment Options for HER2-Positive Breast Cancer Patients with Brain Metastases beyond Trastuzumab: A Literature Review

Breast Care ◽

10.1159/000467387 ◽

2017 ◽

Vol 12 (3) ◽

pp. 168-171 ◽

Cited By ~ 12

Author(s):

Elena Laakmann ◽

Volkmar Müller ◽

Marcus Schmidt ◽

Isabell Witzel

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Cancer Patients ◽

Systemic Treatment ◽

Treatment Options ◽

Cytotoxic Agents ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

Background: The incidence of brain metastases (BM) in breast cancer patients has increased. Many retrospective analyses have shown that first-line treatment with trastuzumab prolongs survival in patients with HER2-positive BM. In contrast, the evidence for other therapies targeting HER2 for patients with BM is rare. Methods: The aim of this review is to update the reader about current systemic treatment options in patients with HER2-positive metastatic breast cancer with BM who had already received trastuzumab. A literature search was performed in the PubMed database in June 2016. 30 relevant reports concerning the efficacy of trastuzumab emtansine (T-DM1), lapatinib and its combination with other cytotoxic agents, pertuzumab and novel HER2-targeting substances were identified. Results: There is limited but promising evidence for the use of T-DM1 and pertuzumab in the treatment of BM. Up to now, most reported studies used lapatinib as treatment of HER2-positive breast cancer with BM, a treatment with only a modest effect and a high toxicity profile. The combination of lapatinib with cytotoxic agents seems to result in better response rates. Conclusion: Further prospective investigations are needed to investigate the efficacy of the established and novel HER2-targeting agents on BM in HER2-positive breast cancer patients.

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Pharmacokinetics of trastuzumab emtansine (T-DM1) as a single agent or in combination with pertuzumab in HER2-positive breast cancer patients with recurrent or locally advanced metastatic breast cancer

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-019-03852-z ◽

2019 ◽

Vol 84 (1) ◽

pp. 175-185 ◽

Cited By ~ 2

Author(s):

Dan Lu ◽

Chunze Li ◽

Matthew Riggs ◽

Daniel Polhamus ◽

Jonathan French ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Patients ◽

Single Agent ◽

Locally Advanced ◽

Metastatic Breast ◽

Trastuzumab Emtansine ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Positive Breast Cancer

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Breast Cancer Treatment and Antibody Drug Conjugates: Beyond T-DM1

Medical Research Archives ◽

10.18103/mra.v9i8.2435 ◽

2021 ◽

Vol 9 (8) ◽

Author(s):

Mony Ung ◽

Jean Lacaze ◽

Eleonora Maio ◽

Florence Dalenc

Keyword(s):

Breast Cancer ◽

Anticancer Agents ◽

Bystander Effect ◽

Cytotoxic Agents ◽

Clinical Activity ◽

Trastuzumab Emtansine ◽

Her2 Positive ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Antibody Drug

Antibody–drug conjugates (ADCs) are a new class of anticancer agents that combine cytotoxic agents attached by a linker to a monoclonal antibody. These engineered drugs can selectively deliver a cytotoxic payload to targeted cancer cells and the local microenvironment (bystander effect), thereby increasing activity and reducing off-target toxicity. The association of ADCs with other anti-cancer therapies is therefore promising. Trastuzumab-emtansine was the first approved ADC in breast cancer (BC), specifically for the management of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. New ADCs are in development in BC. Some have shown meaningful clinical benefit and have been recently approved, such as trastuzumab deruxtecan in HER2-positive trastuzumab emtansine (T-DM1) pretreated BC and Trop-2 guided sacituzumab govitecan in triple-negative BC. Trastuzumab deruxtecan also has potential clinical activity in HER2-low BC thanks to a bystander effect. In this article, we review the ADCs under development in advanced BC.

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Health-related quality of life in the Swedish PREDIX HER2 trial, evaluating docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.583 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 583-583 ◽

Cited By ~ 2

Author(s):

Yvonne Brandberg ◽

Anne Andersson ◽

Judith Bjohle ◽

Ana Bosch ◽

Lena Carlsson ◽

...

Keyword(s):

Breast Cancer ◽

Quality Of Life ◽

Trastuzumab Emtansine ◽

Her2 Positive ◽

Related Quality ◽

Eortc Qlq C30 ◽

Health Related ◽

Eortc Qlq ◽

Positive Breast Cancer

583 Background: Neoadjuvant therapy combining docetaxel, trastuzumab and pertuzumab (DTP) was compared to trastuzumab emtansine (T-DM1) in the randomized phase 2 PREDIX HER2 trial. Patients, ≥18 years with HER2 positive breast cancer, ≥20mm or with verified lymph node metastases, were randomized to six courses of DTP (Standard arm) or T-DM1 (Experimental arm). Primary endpoint was pathological objective response to primary medical therapy at post-treatment surgery. Health related quality of life (HRQoL) was a secondary outcome, and is of specific interest as there was no difference between the randomization groups regarding the main endpoint (results presented in a separate abstract sent to ASCO 2019, Bergh et al.). Methods: Of 202 randomized patients, 190 are available for evaluation at this point. HRQoL was measured, using EORTC QLQ-C30 + EORTC QLQ-BR23, at baseline before randomization and after six courses. Results: No differences between the randomization arms were found at baseline. Results after six courses, based on 163 patients (86%) and adjusted to baseline values, revealed statistical significant differences (p≤0.01), favoring the experimental T-DM1 arm on 7 out of 15 of the EORTC QLQ-C30 variables (Physical functioning, Role functioning, Social functioning, Global quality of Life, Fatigue, Dyspnea, and Diarrhea). For the breast cancer specific questionnaire (EORTC-BR23), the experimental arm scored statistically significantly better on 5 out of 7 subscales (Body image, Sexual functioning, Sexual enjoyment, Systemic therapy side effects and Upset by hair loss). All of the statistical significant differences were of moderate or large clinical significance (≥10 scale scores). No differences between the randomization arms were found for the remaining HRQoL variables. Conclusions: The experimental arm reported better HRQoL than the control arm after six courses. Trastuzumab emtansine may be a useful treatment alternative due to better HRQoL and lower toxicity. Clinical trial information: NCT02568839.

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Adverse Events of Trastuzumab Emtansine (T-DM1) in the Treatment of HER2-Positive Breast Cancer Patients

Breast Care ◽

10.1159/000480492 ◽

2017 ◽

Vol 12 (6) ◽

pp. 401-408 ◽

Cited By ~ 11

Author(s):

Lidia Kowalczyk ◽

Rupert Bartsch ◽

Christian F. Singer ◽

Alex Farr

Keyword(s):

Breast Cancer ◽

Adverse Events ◽

Targeted Therapies ◽

Kinase Inhibitor ◽

Trastuzumab Emtansine ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Anti Tumor Activity ◽

Positive Breast Cancer

The human epidermal growth factor receptor 2 (HER2) is commonly associated with poor prognosis and is overexpressed in approximately 15-20% of all breast cancers. The introduction of HER2-targeted therapies led to significant improvement in the prognosis of patients with HER2-positive breast cancer, for both early and advanced disease. These targeted therapies include the antibodies trastzumab and pertuzumab, the tyrosine kinase inhibitor lapatinib, and the antibody-drug conjugate trastuzumab emtansine (T-DM1). T-DM1 combines the anti-tumor activity of trastuzumab with that of DM1, a highly potent derivative of the anti-microtubule agent maytansine, resulting in increased anti-tumor activity. Notably, this agent has been demonstrated to be safe and is associated with low toxicity rates. However, maytansinoid, the cytotoxic component of T-DM1, does have the potential to induce various adverse events, particularly radiation necrosis, when used in combination with stereotactic radiosurgery. In this review, we aimed to summarize the current literature regarding T-DM1 safety and toxicity, with special emphasis on the existing landmark studies.

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