zenocutuzumab (MCLA-128)

P2, N=105, Completed, Merus N.V. | Active, not recruiting --> Completed | Trial completion date: Feb 2024 --> Jul 2023

Zenocutuzumab is a novel, bispecific IgG1 antibody that targets both HER2 and HER3 proteins and inhibits NRG1 binding through a 'Dock & Block®' mechanism of action. Here, we describe the rationale and design of the phase II component of the eNRGy trial, part of the overall, open-label phase I/II, multicenter trial exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of zenocutuzumab in patients with NRG1+ NSCLC, PDAC or other solid tumors.

P2, N=250, Recruiting, Merus N.V. | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2022 --> Dec 2026

P2, N=90, Recruiting, Merus N.V.

Lysates were collected and prepared for western blot analysis to assess for activation of downstream signaling cascades, both with and without zenocutuzumab and enzalutamide treatment. Here, we show that NRG1 promotes prostate cancer cell survival and resistance to AR inhibition in PTEN wild-type prostate cancer cells. Activation of downstream PI3K-AKT signaling in a prostate cancer epithelial cell line was seen after both recombinant NRG1 stimulation and culturing with cancer associated fibroblast conditioned media. This supports a paracrine mediated action of NRG1 whereby it is secreted by stromal cells in the tumor microenvironment to promote resistance through PI3K signaling.

No pt discontinued Zeno for a treatment related AE. Conclusions In this updated analysis, Zeno provides robust and durable efficacy in advanced NRG1+ NSCLC, with a well-tolerated safety profile.

MP was performed by using Next Generation sequencing by using Foundation one CDX/liquidCDX & it was based on 3 protocols: STING (NCT04932525), MCLA-128 (NCT03321981) & STARTRK (NCT02568267) which allowed liquid & tissue biopsies studies...Molecularly matched tx was administered to 15 pts: anti-MEK (n = 11) & imatinib (n = 2)...Conclusions Potentially actionable mutations can be found in more than 50% of pts with resistant melanoma. Tumor agnostic trials based on molecular alterations should be more broadly available to evaluate the potential benefit of innovative precision medicine in this population.

Pts had a median of 2 prior systemic therapies (range 0-5), 93% with FOLFIRINOX and/or gemcitabine-based therapy...No pt discontinued Zeno for a treatment related AE. Conclusions In this updated analysis, Zeno continues to demonstrate unprecedented efficacy in pts with previously treated advanced/metastatic NRG1+ PDAC with robust and durable responses and a well-tolerated safety profile.

No pt discontinued Zeno for a treatment related AE. Conclusions In this updated analysis, Zeno provides robust and durable efficacy in advanced NRG1+ NSCLC, with a well-tolerated safety profile.

Agents targeting the HER2/HER3 pathway have shown early clinical promise in NRG1 fusion-positive cancers: currently zenocutuzumab has FDA Fast Track Designation for tumors harboring NRG1-fusions... NRG1 fusions are rare but actionable genomic events with significant heterogeneity of tumor type and fusion partner.

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=90, Recruiting, Merus N.V. | Not yet recruiting --> Recruiting

P2, N=90, Not yet recruiting, Merus N.V.

We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68% of patients with GC harbor potential targetable gene fusions, which were enriched in patients with ERBB2 amplification. Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.

Although an early clinical study failed to demonstrate benefit of adjuvant trastuzumab for ERBB2-low disease, several novel anti-ERBB2 therapies have shown efficacy in ERBB2-low breast cancer, including the antibody-drug conjugate trastuzumab deruxtecan in a phase 3 trial, and trastuzumab duocarmazine and the bispecific antibody zenocutuzumab in early-phase studies. This review suggests that ERBB2-low may be a distinct, clinically relevant breast cancer entity warranting reassessment of traditional diagnostic and therapeutic paradigms. Ongoing clinical trials and further investigations may provide optimized strategies for diagnosing and treating ERBB2-low breast cancer, including reproducible, consistent definitions to identify patients in this diagnostic category and demonstration of benefits of emerging therapies.

No abstract available

P2, N=250, Recruiting, Merus N.V. | Phase classification: P1/2 --> P2 | Trial completion date: Sep 2022 --> Dec 2024 | Trial primary completion date: Sep 2021 --> Dec 2022

A patient with CD74-NRG1-positive non-small cell lung cancer who had progressed on six prior lines of systemic therapy, including afatinib, responded rapidly to treatment with a partial response. 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.

Zeno demonstrated robust and durable efficacy in pts with advanced NRG1+ cancer regardless of tumor histology. A well tolerated safety profile of Zeno was observed.

Data from several phase II and III trials evaluating HER2-directed therapy following second-line T-DM1 have recently become available...In phase III trials, margetuximab and neratinib combinations demonstrated significant 1.3-month (hazard ratio, HR = 0.71, p < 0.001) and 0.1-month (HR = 0.76, p = 0.006) net improvements in median progression-free survival (PFS), respectively, with no significant improvements in overall survival (OS)...Finally, trastuzumab-deruxtecan, zenocutuzumab, and poziotinib demonstrated benefit in phase II trials with the most robust overall response rate (62.0%) and median duration of response (18.2 months) observed for trastuzumab-deruxtecan among heavily pretreated patients. Tucatinib plus trastuzumab and capecitabine significantly prolongs OS, and promising preliminary response outcomes for trastuzumab-deruxtecan suggest that sequencing of these regimens following second-line therapy is reasonable.

Methods This open-label study planned to enroll up to 40 evaluable pts with HER2+ MBC progressing after up to 5 anti-HER2 lines of therapy including trastuzumab, pertuzumab, and an anti-HER2 ADC...Conclusion Updated analyses confirm that the efficacy of zenocutuzumab combinations with trastuzumab/vinorelbine in heavily pretreated, HER2+ MBC, with progression after TDM-1, met prespecified protocol criteria for success. The regimen is safe and well tolerated with AEs mostly related to chemotherapy.

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.

Zenocutuzumab, an investigational bispecific antibody, has shown early efficacy in an ongoing phase I/II study of patients with tumors harboring NRG1 fusions. The data so far appear particularly promising in NRG1 fusion-positive pancreatic ductal adenocarcinoma, which tends to occur in younger patients.

In the overall NRG1+ population, tumor regression was observed in 25 of 33 pts and confirmed INV-assessed responses were seen in 9 of 33 pts (ORR 27%; 90% CI, 15;43), including in pts who previously received afatinib . Zeno induces rapid and major radiologic tumor regression and biomarker responses in heavily-pretreated metastatic KRAS wild-type NRG1+ pancreas cancer, with minimal toxicity . Zeno is a promising novel targeted therapeutic option for pts with NRG1+ cancers.

A narrative review is also performed regarding the rationale behind the consolidated and ongoing clinical trials studying anti-HER2 agents in combination with unrelated agents, such as immunotherapy, endocrine therapy, and CDK4/6 inhibitors. Hopefully, all this ongoing research effort will be able to extend the survival benefits seen with anti-HER2 agents in HER2-positive disease, at least to some degree, to the greater proportion of patients with HER2-low BC.

Finally, we assessed the ability of Zeno to induce antibody-dependent cellular cytotoxicity using a chromium release assay and peripheral blood mononuclear cells. Zeno induced significant cytotoxicity in MDA-MB-175-VII cells while a non-ADCC enhanced, non-specific IgG had no effect.Here we show that Zeno effectively blocks the growth of NRG1 fusion-positive cell line and xenograft models of tumors arising from lung, pancreas and other organs, and these results support the continued development of Zeno to treat patients with this molecularly defined subset of cancers.

The current treatment options for metastatic PDAC are modified (m)FOLFIRINOX /FOLFIRINOX or nab-paclitaxel and gemcitabine in patients with good performance status (PS) (ECOG 0-1/KPS 70-100%) and gemcitabine with or without a second agent for those with ECOG PS 2-3...Olaparib was recently approved by the US Food and Drug Administration for maintenance therapy in germline BRCA1/2 mutated PDAC following demonstration of survival benefit in a phase 3 trial. Pembrolizumab is approved for patients with defects in mismatch repair/microsatellite instability...Small-molecule inhibitors including ERBB inhibitors (e.g., afatinib, MCLA-128), TRK inhibitors (e.g., larotrectinib, entrectinib), ALK/ROS inhibitor (e.g., crizotinib), and BRAF/MEK inhibitors are in development. In a small subset of patients with the KRASG12C mutation, a KRASG12C inhibitor, AMG510, and other agents are being investigated. Major efforts are underway to effectively target the tumor microenvironment and to integrate immunotherapy into the treatment of PDAC, and although thus far the impact has been modest to ineffective, nonetheless, there is optimism that some of the challenges will be overcome.

Eligible patients receive a dosing regimen of 750 mg of Zeno (2-hour infusion), every 2 weeks, in 4-week cycles. The study is actively accruing patients in more than 30 sites across North America, Europe, and Asia.

We recently reported promising responses in patients with cancers harboring NRG1 fusions treated with the bispecific antibody MCLA-128 (Schram 2019)...We recently reported promising responses in patients with cancers harboring NRG1 fusions treated with the bispecific antibody MCLA-128 (Schram 2019)... NRG1 fusions are present across a wide range of different solid tumor types, most frequently in NSCLC and PDAC. NRG1 fusion-driven cancers represent a potential tumor-agnostic therapeutic target. The advent of new treatment options and increased genomic testing will allow a more precise estimation of the frequency of NRG1 fusions in cancer.

The addition of MCLA-128 to the last line of ET showed clinical activity after ET+CDK4/6i failure and a favorable safety profile. Research Funding: Merus NV

Previously presented at ESMO 2019, 685TiP, Schram et al.-Reused with permission. Research Funding: Merus NV

This analysis demonstrated that the pharmacokinetics of MCLA-128 exhibits similar disposition characteristics to other therapeutic monoclonal antibodies and that a flat dose of MCLA-128 in patients with various solid tumors is appropriate.