Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in breast cancer patients: Phase 1 dose escalation study.

Kogawa, Takahiro; Yonemori, Kan; Masuda, Norikazu; Takahashi, Shunji; Takahashi, Masato; Iwase, Hirotaka; Nakayama, Takahiro; Sendo, Toshiaki; Toyama, Tatsuya; Takano, Toshimi; Onuma, Hiroshi; Ogawa, Hayao; Tanaka, Yoshimi; Igari, Yoshiko; Sugihara, Masahiro; Vigliotti, Michele; Yu, Channing; Olivo, Martin; Ueno, Suguru; Iwata, Hiroji

doi:10.1200/jco.2018.36.15_suppl.2512

Cited by 21 publications

(22 citation statements)

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“…Many therapeutic agents targeting HER3 have demonstrated promising results in preclinical studies, whereas the clinical use of those agents has not resulted in meaningful benefits . In contrast, the U3‐1402 anti‐HER3 antibody (patritumab) conjugated with topoisomerase demonstrated impressive efficacy with a 48% response rate in patients with HER3‐positive pretreated breast cancer . However, some patients were still refractory to U3‐1402 in this early‐phase clinical trial .…”

Section: Discussionmentioning

confidence: 94%

“…In contrast, the U3‐1402 anti‐HER3 antibody (patritumab) conjugated with topoisomerase demonstrated impressive efficacy with a 48% response rate in patients with HER3‐positive pretreated breast cancer . However, some patients were still refractory to U3‐1402 in this early‐phase clinical trial . Hereafter, combination strategies might improve the efficacy of U3‐1402 against these HER3‐positive tumors.…”

Section: Discussionmentioning

confidence: 97%

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Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer

et al. 2019

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HER2‐targeted therapy, especially the anti‐HER2 antibody trastuzumab, is standard for HER2‐positive breast cancer; however, its efficacy is limited in a subpopulation of patients. HER3 ligand (heregulin)‐dependent HER2‐HER3 interactions play a critical role in the evasion of apoptosis and are therefore a target for oncotherapy to treat HER2‐positive breast cancer. The anti‐HER2 antibody pertuzumab and anti‐HER3 antibody patritumab both target this heregulin–HER3‐HER2 complex in different ways. This study examined the anticancer efficacy of dual HER2 and HER3 blockade in trastuzumab‐resistant HER2‐positive breast cancer. HER2‐positive SKBR3 or BT474 cells overexpressing heregulin (SKBR3‐HRG, BT474‐HRG) were used to evaluate the efficacy of trastuzumab, pertuzumab, and patritumab in vitro by performing cell viability, immunoblotting, and clonogenic assays. The effects of these agents were then evaluated in vivo using BT474‐HRG and an intrinsic heregulin‐expressing and HER2‐positive JIMT‐1 xenograft models. SKBR3‐HRG and BT474‐HRG cells lost sensitivity to trastuzumab, which was accompanied by Akt activation. Unexpectedly, trastuzumab in combination with pertuzumab or patritumab also showed limited efficacy toward these cells. In contrast, trastuzumab/pertuzumab/patritumab triple treatment demonstrated potent anticancer efficacy, concomitant with strong repression of Akt. Finally, in heregulin‐expressing BT474‐HRG and JIMT‐1 xenograft models, the addition of pertuzumab and patritumab to trastuzumab also enhanced antitumor efficacy leading to tumor regression. The current study found that triple blockade of HER2 and HER3 using trastuzumab, pertuzumab, and patritumab could overcome resistance to trastuzumab therapy in heregulin‐expressing and HER2‐positive breast cancer, which could be exploited clinically.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 97%

Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer

et al. 2019

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“…Additionally, flow cytometry analyses using patritumab as a primary antibody to recognize HER3 confirmed cell-membrane expression of HER3 on CM-3 tumor cells, which was equivalent or somewhat superior to that on the known HER3-expressing human lung cancer cells HCC827 (29), indicating the adequacy of CM-3 to evaluate the antitumor effects of U3-1402 ( Figure 1B). Indeed, in in vitro growth inhibition assays, wherein the drug concentration corresponded to that achievable in ongoing human clinical trials (U3-1402: <100 μg/ ml) (25), CM-3 cells were sensitive to U3-1402, while HER3-negative CT26 cells were not ( Figure 1C). The in vitro growth inhibition assay also showed that patritumab did not affect the growth of CM-3 cells, and this verified that the observed cytotoxic activity of U3-1402 was caused by its payload DXd and not by HER3 signal blockade by patritumab ( Figure 1C).…”

Section: Introductionmentioning

confidence: 99%

“…U3-1402, a potential first-in-class anti-HER3 ADC (with patritumab as the carrier and DXd as the payload), is currently under development to act on these targets (24). Indeed, an early report of a clinical trial suggested that U3-1402 could be safely administered and demonstrated promising antitumor efficacy in heavily treated HER3-expressing (immunohistochemical HER3 score of tumor cells was 2+/3+) metastatic breast cancer (the ORR was 47%, and the disease control rate was 94%, both of which were far superior to that of the historical control) (25). This satisfactory result has led to the investigation here of U3-1402 in combination with cancer immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

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U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation

Haratani¹,

Yonesaka²,

Takamura³

et al. 2019

Journal of Clinical Investigation

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New era for emerging therapeutic targeting human epidermal growth factor receptor 3 (HER 3) in advanced nonsmall cell lung cancer and metastatic breast cancer

et al. 2022

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Human epidermal growth factor receptor 3 (HER3) is a member of the transmembrane receptor tyrosine kinase family. Upregulation of HER3 pathway has been implicated as a mechanism of resistance in solid tumors, particularly in estrogen receptor positive, HER2 positive breast cancer and epidermal growth factor (EGFR) mutant nonsmall cell lung cancer. Several studies suggest that HER3 overexpression represents a negative prognostic biomarker associated with poor survival. Preclinical and clinical studies of anti‐HER3 investigational therapies suggest that expression of the HER3 ligand, neuregulin, may predict response to treatment. Despite its emergence as a key cancer therapeutic target, HER3 cannot be targeted with traditional tyrosine kinase inhibitors therapy due to its weak kinase activity. Monoclonal and bispecific antibodies targeting HER3 have been developed and tested in early phase trials. Objective responses were limited when first‐generation HER3‐specific monoclonal antibodies were investigated as monotherapies in phase 1 and 2 clinical trials for nonsmall cell lung cancer (NSCLC) and metastatic breast cancer (MBC). MBC and NSCLC HER3 specific antibody‐drug conjugates have shown encouraging results in resistance in cancer cells, particularly in those that overexpress HER3. These agents have shown some promise in early phase trials in both NSCLC and MBC setting in heavily pretreated patients with varying degrees of response. It is unclear which subgroup of patients will truly benefit from targeting HER3 as these therapies are under investigation.

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Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in breast cancer patients: Phase 1 dose escalation study.

Cited by 21 publications

References 0 publications

Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer

Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer

U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation

New era for emerging therapeutic targeting human epidermal growth factor receptor 3 (HER 3) in advanced nonsmall cell lung cancer and metastatic breast cancer

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