Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study

Banerji, Udai; Herpen, Carla M.L. van; Saura, Cristina; Thistlethwaite, Fiona; Lord, Simon; Moreno, Víctor; Macpherson, Iain; Boni, Valentina; Rolfo, Christian; Vries, Elisabeth G.E. de; Rottey, Sylvie; Geenen, Jill J.J.; Eskens, Ferry A.L.M.; Gil-Martín, Marta; Mommers, Ellen C.M.; Koper, N.P.; Aftimos, Philippe

doi:10.1016/s1470-2045(19)30328-6

Cited by 368 publications

(250 citation statements)

References 22 publications

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“…T-DXd is currently being evaluated in phase I/II clinical trials as a single agent (NCT03505710) or in combination with immune checkpoint inhibitor pembrolizumab (NCT04042701). Trastuzumab duocarmazine is another anti-HER2 ADC which has demonstrated activity in patients with T-DM1-resistant or low HER2-expressing breast cancers (40). Other anti-HER2 ADCs in early-phase development include ZW-49 (NCT03821233), DHES0815A (NCT03451162), RC48-ADC (NCT03500380), and A166 (NCT03602079).…”

Section: Discussionmentioning

confidence: 99%

HER2-Mediated Internalization of Cytotoxic Agents inERBB2Amplified or Mutant Lung Cancers

et al. 2020

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Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or-mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.

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Section: Discussionmentioning

confidence: 99%

HER2-Mediated Internalization of Cytotoxic Agents inERBB2Amplified or Mutant Lung Cancers

et al. 2020

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“…4). Trastuzumab-based Adcs with distinct linkers and payloads (trastuzumab deruxtecan and trastuzumab duocarmazine) (187,188); other Adcs targeting epidermal growth factor receptor (EGFR) (189), folate receptor-α (190), NEcTIN4 (191) and tumor-associated calcium signal transducer 2 (192); and cAR-Ts targeting…”

Section: Perspectives On Notch-targeted Precision Oncologymentioning

confidence: 99%

Precision medicine for human cancers with Notch signaling dysregulation (Review)

Katoh¹,

Katoh

2019

Int J Mol Med

107

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NOTcH1, NOTcH2, NOTcH3 and NOTcH4 are transmembrane receptors that transduce juxtacrine signals of the delta-like canonical Notch ligand (dLL)1, dLL3, dLL4, jagged canonical Notch ligand (JAG)1 and JAG2. canonical Notch signaling activates the transcription of BMI1 proto-oncogene polycomb ring finger, cyclin D1, CD44, cyclin dependent kinase inhibitor 1A, hes family bHLH transcription factor 1, hes related family bHLH transcription factor with YRPW motif 1, MYC, NOTCH3, RE1 silencing transcription factor and transcription factor 7 in a cellular context-dependent manner, while non-canonical Notch signaling activates NF-κB and Rac family small GTPase 1. Notch signaling is aberrantly activated in breast cancer, non-small-cell lung cancer and hematological malignancies, such as T-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, Notch signaling is inactivated in small-cell lung cancer and squamous cell carcinomas. Loss-of-function NOTCH1 mutations are early events during esophageal tumorigenesis, whereas gain-of-function NOTCH1 mutations are late events during T-cell leukemogenesis and B-cell lymphomagenesis. Notch signaling cascades crosstalk with fibroblast growth factor and WNT signaling cascades in the tumor microenvironment to maintain cancer stem cells and remodel the tumor microenvironment. The Notch signaling network exerts oncogenic and tumor-suppressive effects in a cancer stage-or (sub)type-dependent manner. Small-molecule γ-secretase inhibitors (AL101, MRK-560, nirogacestat and others) and antibody-based biologics targeting Notch ligands or receptors [ABT-165, AMG 119, rovalpituzumab tesirine (Rova-T) and others] have been developed as investigational drugs. The dLL3-targeting antibody-drug conjugate (Adc) Rova-T, and dLL3-targeting chimeric antigen receptor-modified T cells (CAR-Ts), AMG 119, are promising anti-cancer therapeutics, as are other Adcs or cARTs targeting tumor necrosis factor receptor superfamily member 17, cd19, cd22, cd30, cd79B, cd205, claudin 18.2, fibroblast growth factor receptor (FGFR)2, FGFR3, receptor-type tyrosine-protein kinase FLT3, HER2, hepatocyte growth factor receptor, NEcTIN4, inactive tyrosine-protein kinase 7, inactive tyrosine-protein kinase transmembrane receptor ROR1 and tumor-associated calcium signal transducer 2. Adcs and cARTs could alter the therapeutic framework for refractory cancers, especially diffuse-type gastric cancer, ovarian cancer and pancreatic cancer with peritoneal dissemination. Phase III clinical trials of Rova-T for patients with small-cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch-related knowledge-base and optimize Notch-targeted therapy for patients with cancer.

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“…[ 33 ] Therapies that target HER2 have proven especially effective for treatment of chemoresistant breast and ovarian cancers. [ 34 ] These data seem to support the physiological relevance and use of the polysaccharide hydrogels for such studies. This is in line with effects observed in the clinics where HER2‐overexpressing patients show maximum response to trastuzumab.…”

Section: Discussionmentioning

confidence: 56%

An Automatable Hydrogel Culture Platform for Evaluating Efficacy of Antibody‐Based Therapeutics in Overcoming Chemoresistance

Kletzmayr

Frey

Zimmermann

et al. 2020

Biotechnology Journal

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The microenvironment plays a major role in conferring chemoresistance to cancer cells. In order to better inform clinical response to chemoresistance, preclinical models that recapitulate its hallmark features are needed to enable screening for resistance-specific therapeutic targets. A novel platform for seeding cancer cells in 3D hydrogels is presented utilizing derivatives of chitosan and alginate that, critically, is amenable to high throughput screening: cell seeding in hydrogels, media changes, dosing of anticancer compounds, and cell viability assays are all automated using a standard and commercially available liquid handling robot. Culture in these hydrogels elicits resistance in ovarian, lung, and prostate cancer cells to treatment by doxorubicin and paclitaxel. In correlation, proteomics analysis of SKOV3 cells cultured in 3D reveals enrichment of proteins associated with extreme drug resistance including HMOX1 and ALDH2. Subsequently, therapeutic antibodies targeted to tumor-associated antigens upregulated in 3D cultures are shown to have higher efficacy compared to 2D cultures. Collectively, this automated 3D cell culture platform provides a powerful tool with utility in identification of drugs that may overcome chemoresistance. declare no conflict of interest. C.M. is a cofounder of the spinoff company CellSpring AG, a company in which he owns shares.

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Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study

Abstract: Banerji, U. et al. (2019) Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study.

Cited by 368 publications

References 22 publications

HER2-Mediated Internalization of Cytotoxic Agents inERBB2Amplified or Mutant Lung Cancers

HER2-Mediated Internalization of Cytotoxic Agents inERBB2Amplified or Mutant Lung Cancers

Precision medicine for human cancers with Notch signaling dysregulation (Review)

An Automatable Hydrogel Culture Platform for Evaluating Efficacy of Antibody‐Based Therapeutics in Overcoming Chemoresistance

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