Novel Preclinical Patient-Derived Lung Cancer Models Reveal Inhibition of HER3 and MTOR Signaling as Therapeutic Strategies for NRG1 Fusion-Positive Cancers

Odintsov, Igor; Mattar, Marissa S.; Lui, Allan J.W.; Offin, Michael; Kurzatkowski, Christopher; Delasos, Lukas; Khodos, Inna; Asher, Marina; Daly, Robert Michael; Rekhtman, Natasha; Stanchina, Elisa de; Ganji, Gopinath; Ladanyi, Marc; Somwar, Romel

doi:10.1016/j.jtho.2021.03.013

Cited by 20 publications

(15 citation statements)

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“…The LUAD-0061AS3 PDX model was generated from a sample obtained from a patient with SLC3A2-NRG1 fusion-driven lung cancer. The patient exhibited disease progression while on treatment with afatinib (40 mg/day) at the time of collection of the sample used to generate the model as described previously (29). The LUAD-0061AS3 cell line was generated from LUAD-0061AS3 PDX tumor tissue obtained after seven serial passages (29).…”

Section: Methodsmentioning

confidence: 99%

“…The patient exhibited disease progression while on treatment with afatinib (40 mg/day) at the time of collection of the sample used to generate the model as described previously (29). The LUAD-0061AS3 cell line was generated from LUAD-0061AS3 PDX tumor tissue obtained after seven serial passages (29). Cell lines were tested for mycoplasma every 3-6 months (MycoAltert kit, Lonza) with the most recent testing conducted three months prior to completion of the studies in this manuscript.…”

Section: Methodsmentioning

confidence: 99%

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Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements

et al. 2022

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NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. Targeting ERBBs, therefore, represents a therapeutic strategy for these cancers. We investigated zenocutuzumab (Zeno, MCLA-128), an ADCC-enhanced anti-HER2xHER3 bispecific antibody, in NRG1 fusion-positive isogenic and patient-derived cell lines and xenograft models. Zeno inhibited HER3 and AKT phosphorylation, induced expression of apoptosis markers, and inhibited growth. Three chemotherapy-resistant NRG1 fusion-positive metastatic cancer patients were treated with Zeno. Two patients with ATP1B1-NRG1-positive pancreatic cancer achieved rapid symptomatic, biomarker, and radiographic responses, and remained on treatment for over 12 months. A CD74-NRG1-positive NSCLC patient who had progressed on six prior lines of systemic therapy including afatinib responded rapidly to treatment with a partial response. Targeting HER2 and HER3 simultaneously with Zeno is a novel therapeutic paradigm for patients with NRG1 fusion-positive cancers. Statement of significanceNRG1 rearrangements encode chimeric ligands that activate the ERBB receptor tyrosine kinase family. Here we show that targeting HER2 and HER3 simultaneously with the bispecific antibody Zeno leads to durable clinical responses in patients with NRG1 fusion-positive cancers, and is thus an effective therapeutic strategy.Research.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements

et al. 2022

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“…Notably, the only partial response in the present study was also in a patient with NSCLC of the invasive mucinous adenocarcinoma (IMA) subtype, harboring a CD74‐NRG1 fusion, with a prolonged response lasting 19 months (described in detail in [24]). Even though clinical responses to GSK2849330 were limited to this one patient, it is noteworthy that we have observed profound antitumor activity by way of durable tumor regressions and substantial PD effects in multiple patient‐derived models, harboring other NRG1 fusions and constitutive activation/dependence on the pathway [37, 38]. Furthermore, this patient expressed HER3 levels comparable to or even lower than nonresponders and was the only patient in which GSK2849330 elicited a robust immune response in paired tumor biopsy data, particularly increased CD16 tumor infiltrating cells, suggesting ADCC activity.…”

Section: Discussionmentioning

confidence: 95%

A Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors

et al. 2021

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Background. GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/NRG1 signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors. Patients and Methods. Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the doseexpansion phase, patients received 30 mg/kg GSK2849330 IV weekly. Results. Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n=18, dose expansion: n=11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1rearranged non-small cell lung cancer. Conclusion. GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited anti-tumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers. The Oncologist 2021;9999:• • Implications for Practice: This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this ADCC-and CDC-enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich for potential responders to anti-HER3 agents in ongoing trials.

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“…3 Since NRG1 proteins are ligands of ErbB receptors, there is intense interest in the use of ErbB-targeted treatments, such as monoclonal antibodies and small molecular tyrosine kinase inhibitors (TKIs), in NRG1-rearranged cancers, with efficacy demonstrated in preclinical models. [11][12][13][14][15] Partial responses have been reported in patients with invasive mucinous adenocarcinomas of the lung and pancreatic ductal adenocarcinomas. [16][17][18][19] In contrast, a few case reports have shown progressive disease following afatinib or anti-ErbB3 antibody treatment.…”

Section: Nrg1 Fusion Transcriptmentioning

confidence: 99%

“…[4][5][6][7][8][9][10] The use of anti-ERBB2 and/or anti-ERBB3 inhibitors has been tested in preclinical models and clinical trials as a novel treatment paradigm in NRG1-rearranged cancers. [11][12][13][14][15][16][17][18][19] To date, NRG1 gene rearrangements have largely been reported only in carcinomas. We present the first case series of NRG1-rearranged sarcomas, describing the characteristic histopathologic features and clinical behavior of this novel mesenchymal tumor entity.…”

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confidence: 99%

Neuregulin 1 (NRG1) fusion‐positive high‐grade spindle cell sarcoma: A distinct group of soft tissue tumors with metastatic potential

Dermawan

Zou

Antonescu

2021

Genes Chromosomes & Cancer

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Neuregulin 1 (NRG1) is an epidermal growth factor (EGF)-like ligand that activates receptor tyrosine kinases of the ErbB family of receptors. NRG1 gene fusions, which are rare (<1%) but recurrent events in solid tumors, are an emerging oncogenic driver that is potentially actionable using ErbB-targeted tyrosine kinase inhibitors. Largely characterized only in carcinomas, we describe three cases of NRG1-rearranged sarcomas. The patients were all female, aged 32-47 years old. Two cases were deep-seated tumors in the lower extremities (right thigh and calf); one case presented as a uterine mass. The tumors measured 9-11.5 cm in the greatest dimensions. Histologically, all three tumors were highgrade spindle cell sarcomas composed of monomorphic spindle cells arranged in interlacing fascicles. The tumor cells were set in the loose collagenous stroma with branching, curvilinear thin-walled vasculature in the background. Cytologically, the neoplastic cells displayed ovoid to fusiform nuclei with finely stippled chromatin, inconspicuous nucleoli, scant to moderate clear to eosinophilic cytoplasm, occasional cytoplasmic vacuoles, and elongated cytoplasmic processes. Mitotic activity was elevated (> 20/10 high power fields) and tumor necrosis was present. None of the tumors expressed lineage-specific immunophenotypical markers. Targeted RNA-sequencing uncovered gene fusions involving NRG1 and the 5 0 untranslated regions of PPHLN1, HMBOX1, or MTUS1. In all cases, the Cterminal EGF-like domain of NRG1 was preserved in the predicted chimeric protein product. All three patients developed metastatic disease within 2 years from initial presentation and were alive with disease at last follow-up (mean follow-up period = 19 months). In conclusion, we present the first case series of NRG1-rearranged sarcomas characterized by high-grade fascicular spindle cell morphology, non-specific immunoprofile, and aggressive clinical behavior. Further studies are needed to determine whether this distinct subgroup of spindle cell sarcomas are amenable to targeted therapies.

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Novel Preclinical Patient-Derived Lung Cancer Models Reveal Inhibition of HER3 and MTOR Signaling as Therapeutic Strategies for NRG1 Fusion-Positive Cancers

Cited by 20 publications

References 36 publications

Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements

Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements

A Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors

Neuregulin 1 (NRG1) fusion‐positive high‐grade spindle cell sarcoma: A distinct group of soft tissue tumors with metastatic potential

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