seribantumab (MM-121)

Monoclonal antibodies such as lumretuzumab, seribantumab, and patritumab have shown potential in targeting HER3 to overcome resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Additionally, antibody-drug conjugates (ADCs) like HER3-DXd (patritumab deruxtecan) are new drug candidates that have demonstrated selective delivery of cytotoxic chemicals to NSCLC cells by exploiting HER3's widespread expression, minimizing cytotoxicity. This review aims to evaluate the efficacy of current HER3 therapeutics in development and their therapeutic potential in NSCLC, incorporating evidence from clinical trials.

P2, N=75, Active, not recruiting, Elevation Oncology | Trial completion date: Jun 2023 --> Mar 2025 | Trial primary completion date: Jun 2023 --> Jan 2025

Seribantumab also prevented tumor growth in both the chemosensitive BL0440 and chemoresistant BL0269 models. Our data demonstrate that cisplatin-associated increases in Akt and ERK phosphorylation is mediated by an elevation in HRG1, suggesting that inhibition of ErbB3 phosphorylation may be a useful therapeutic strategy in BlCa with high phospho-ErbB3 and HRG1 levels.

Seribantumab has an acceptable safety and tolerability profile as a single agent in pts with solid tumors harboring NRG1 fusions. Updated efficacy data indicate seribantumab has robust and durable clinical activity, including CRs, across different tumor types harboring an NRG1 fusion and is a promising treatment option.

An experimental therapy study using Ec1-LoPE and MM-121 in mice bearing EpCAM- and HER3-expressing BxPC3 xenografts demonstrated the feasibility of the therapy. Further development of the co-targeting approach using HER3 and EpCAM could therefore be justified.

Agents targeting the HER2/HER3 pathway have shown early clinical promise in NRG1 fusion-positive cancers: both zenocutuzumab and seribantumab have FDA Fast Track Designation for tumors with NRG1-fusions. CONCLUSION NRG1 fusions are rare but actionable genomic events in NSCLC but there is striking heterogeneity within this family of alterations. The clinical impact of this heterogeneity on response to targeted agents warrants close attention.

P2, N=75, Active, not recruiting, Elevation Oncology | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2022 --> Jun 2023

We found that EC-secreted neuregulins activated the HER3-AKT signaling axis, and that depleting neuregulins from EC CM or blocking HER3 with an antibody, seribantumab, attenuated EC-induced functions in HER3 +ve PDAC cells, but not in cells without HER3 expression...These findings elucidated a paracrine role of liver ECs in promoting PDAC cell growth, and identified the HER3-AKT axis as a key mediator in EC-induced functions in HER3 +ve PDAC cells. As over 70% mPDAC express HER3, this study highlights the potential of using HER3-targeted therapies for treating patients with HER3 +ve mPDAC.

CME Provider and Supporter(s): This event is organized and accredited by Research to Practice and supported through educational grants provided by AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Eisai Inc, Exelixis Inc, Genentech, a member of the Roche Group, Incyte Corporation, and Merck. Spectrum and frequency of molecular alterations in cholangiocarcinoma and other BTCs; optimal timing and type of genomic analysis to identify actionable abnormalities Principal findings with pemigatinib, infigratinib and futibatinib for patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or other rearrangements Published outcomes from the Phase III ClarIDHy study of ivosidenib for cholangiocarcinoma with an IDH1 mutation; FDA approval and optimal incorporation into clinical practice Ongoing research evaluating targeted therapies (eg, FGFR inhibitors, ivosidenib) for patients with newly diagnosed cholangiocarcinoma Efficacy and safety of trastuzumab deruxtecan among patients with HER2-positive and HER2-low BTCs in the Phase II HERB study Mechanism of action of seribantumab; design, eligibility criteria, key endpoints and early findings from the ongoing Phase II CRESTONE trial assessing seribantumab for advanced solid tumors with NRG1 fusions, including BTCs Other promising biomarker-based strategies for patients with advanced BTCs

No abstract available

Initial efficacy and safety data will be presented and was previously presented at ASCO 2022.Conclusions : Initial data indicate seribantumab induced durable responses in advanced solid tumors harboring NRG1 fusions with a favorable safety profile. These data support the evaluation of seribantumab in NRG1 fusion-positive solid tumors in the ongoing CRESTONE study.

P2, N=75, Recruiting, Elevation Oncology | Trial primary completion date: Aug 2022 --> Dec 2022

Moreover, we determined that blocking HER3, either by siRNA knockdown or the humanized antibody seribantumab, blocked EC-induced colorectal cancer survival in vitro in both KRAS wild-type and mutant colorectal cancer cells, and the HER3 antibody seribantumab significantly decreased colorectal cancer tumor growth and sensitized tumors to chemotherapy in an orthotopic xenograft model with colorectal cancer tumors developed in the liver. In summary, our findings demonstrated that blocking HER3 had significant effects on attenuating liver EC-induced CRC cell survival independent of the KRAS mutation status. Implications: This body of work highlighted a potential strategy of using HER3 antibodies in combination with standard chemotherapy agents for treating patients with either KRAS wild-type or KRAS mutant mCRC.

Initial data indicate seribantumab induced durable responses in advanced solid tumors harboring NRG1 fusions and has a favorable safety profile. These data support the continued evaluation of seribantumab in NRG1 fusion-positive solid tumors in the ongoing CRESTONE study.

An interim analysis is planned following enrollment of 20 patients in the overall global CRESTONE trial and treated at the 3g weekly IV schedule. CRESTONE (NCT04383210 is accruing patients in the US with MoST CRESTONE in Australia and Canadian sites to open Q4 2021.

Supporting data are limited to case reports and small series for now, but prospective trials are underway. While our understanding of these fusions is still evolving, it is clear that NRG1 will be a clinically relevant finding in the years to come.

As a result, ERBB3 inhibition by specific antibodies is lethal for GBM stem-like cells and xenotransplants. These findings highlight a subset of patients eligible for ERBB3-targeted therapy.

Safety and PK data from this study support further seribantumab investigations in genomically defined populations.Clinical trial registration NCT00734305. August 12, 2008.

Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of NRG1 fusion-dependent tumorigenesis in vitro and in vivo in breast, lung and ovarian patient-derived cancer models.

There was no shrinkage of afatinib-treated pancreatic PDX tumors.Our results here suggest that seribantumab is effective at reducing tumor growth in preclinical models of gastrointestinal cancers with NRG1 fusions. These data support the use of seribantumab to treat GI and other cancers with NRG1 fusions in the ongoing phase 2 CRESTONE study (NCT#04383210).

No abstract available

Inhibition of HER3 and its dimerization partners represents a rational and novel therapeutic approach for tumors harboring an NRG1 fusion supported by case studies of clinical responses to anti-HER3 antibodies or pan-ERBB (tyrosine kinase inhibitors) TKIs like afatinib. An interim analysis is planned following enrollment of 20 patients in Cohort 1. CRESTONE is open and accruing patients in the United States.

Using a real-world breast cancer registry allowed identification of potentially eligible patients for SHERBOC focusing on patients with HER3 overexpressing, HR-positive, HER2-negative metastatic breast cancer. This approach may provide insights into differences between patients eligible or non-eligible for clinical trials.

P2 | "Inhibition of HER3 and its dimerization partners represents a rational and novel therapeutic approach for tumors harboring an NRG1 fusion supported by case studies of clinical responses to anti-HER3 antibodies or pan-ERBB (tyrosine kinase inhibitors) TKIs like afatinib. CRESTONE is open and accruing patients in the United States. Clinical trial information: NCT04383210."

PET/CT imaging showed full receptor occupancy for all tested drug candidates. Treatment with 3A and 3A3 affibody constructs was more efficient than with 33A and similar to the anti-HER3 antibody seribantumab, showing that the molecular design of affibody-based therapeutics targeting HER3 in terms of the relative position of functional domains and valency has an impact on therapeutic effect.

Tumor responses have been observed with tyrosine kinase inhibitors afatinib and tarloxotinib, but durable responses are rare and emergence of toxicity and resistance to these drugs could not be avoided...In vivo activity of 9F7-F11 was evaluated in comparison to MM121 using xenograft models with MDA-MB-175 breast cancer cell line or CTG-0943 patient-derived pancreatic tumor bearing respectively DOC4-NRG1 and APP-NRG1 fusion... 9F7-F11 antibody displays a unique potential for targeted treatment of NRG1-positive cancers. 9F7-F11 binding to HER3 is promoted by the ligand NRG1. This binding property was translated in vivo by an outstanding activity against xenograft models bearing NRG1 fusion, characterized by 100% of eradicated tumors.

P2, N=75, Not yet recruiting, Elevation Oncology