seribantumab (MM-121)

A 78-year-old woman with Stage IV NSCLC (adenocarcinoma, no actionable mutations, PD-L1 negative) initially received carboplatin, pemetrexed, and pembrolizumab, complicated by neutropenic fever. She later enrolled in the SHERLOC trial (MM-121 + docetaxel), discontinued due to colitis and neutropenia...The patient received hydroxyurea, transfusion support, and tumor lysis prophylaxis...LC at the time of initial AML diagnosis is uncommon and portends poor prognosis. Clinicians should remain vigilant for new skin lesions and cytopenias in cancer survivors previously exposed to chemotherapy, as early recognition of extramedullary AML may expedite timely diagnosis and care planning.

Seribantumab, an ERBB3-targeting monoclonal antibody, inhibited ERBB3-HIF1A-ABCB1 cascade, and its combination with regorafenib exerted marked synergistic anti-tumor effects on ERBB3-high tumors resistant to sorafenib or lenvatinib both in vitro and in vivo. This study revealed that ERBB3 was a key resistance factor driving limited efficacy to sequential regorafenib, but also an effective therapeutic target whose inhibition enhanced regorafenib sensitivity after sorafenib or lenvatinib resistance.

These results support the antitumor activity and safety of seribantumab in patients with advanced solid tumors harboring NRG1 fusions.

P2, N=54, Terminated, Elevation Oncology | Trial completion date: Mar 2025 --> Feb 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2025 --> Feb 2024; Business decision

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.