Zenocutuzumab has shown therapeutic value in patients with metastatic solid tumors of NRG1+

On January 7, 2021, Merus NV announced that the FDA has granted Zenocutuzumab (Zeno) Fast-Track Qualification for the treatment of patients with metastatic solid tumors carrying NRG1 gene fusion that progress after receiving standard therapy (NRG1+ cancer).

NRG1 (Neuroregulin1, neuroregulator protein 1) gene fusion is a rare set of genomic variants that appear as drivers of tumorigenesis and growth in many types of solid tumors, including lung, breast, pancreas, ovarian, and colorocoloral cancers
.

Zenocutuzumab（MCLA-128； PB-4188) is an ADCC-enhanced IgG antibody developed using Merus' Biclonics and MeMo technologies to target HER-2 and HER-3
.

Since neuroregulator signaling pathway activation requires HER2 and HER3 to bind to form heterodimers, zenocutuzumab can block signaling
of neuromodulins by preventing the formation of heterodimers.

Blocking ligand interactions between HER2 and HER3 in NRG1 fusion-positive patients has been shown to be a clinically viable approach, and the novel drug zenocutuzumab (MCLA-128) can improve prognosis
.

Thoracic malignancy represents only one histology
containing NRG1 fusion that requires a treatment option.

Inclusion criteria for studies required patients with locally advanced, unresectable or metastatic solid tumors and confirmed positive for
NRG1.

Patients receive 750 mg of zenocutuzumab intravenously every 2 weeks until disease progression, tumor evaluation every 8 weeks, and survival follow-up for up
to 2 years.

As of April 12, 2022, data as of April 2022 has 110 patients enrolled
in 64 research centers in 17 countries.

Data presented at the 2022 American Society of Clinical Oncology (ASCO) meeting showed that the primary analysed population included 83 patients who
had passed a clinical trial site (n = 72) or who had early access to a bispecific drug (n = 11).

At a median follow-up of 6.

In 46 patients with NSCLC, ORR was 35% (95% CI, 21% to 50%)
.

In addition to the durable response, pharmacokinetic data suggest that the drug has a half-life of approximately 4 days, with predicted receptor occupancy of HER3 and HER2 exceeding 95%
throughout the dosing interval.

Most toxicity of zenotuzumab is low-level, with less than 1% of patients discontinuing treatment
due to adverse events.

At the 2022 ASCO conference, invited panelists at the Vall d'Hebron Cancer Institute, Elena Garralda, MD, MSc, described zenocutuzumab as a "pioneering story.

"eNRGy is the first clinical trial
to prospectively assess the role of ERBB3 inhibition in NRG1-positive tumors.

"Zenocutuzumab is the first breakthrough therapy
approved by the FDA for NRG1-positive tumors.
This is the first time we've targeted ligands
.
This is the first time we have done this
with an antibody that targets it indirectly.
Bispecific drugs are expected to expand the possibility
of monoclonal antibody therapy.
”

As zenocutuzumab research continues, key considerations include the prognostic effects
of NRG1 fusion.
"There is evidence that in NRG1 fusion-positive NSCLC, patients appear to respond less
to other therapies.
We need to build these to fully understand the value of targeting NRG1.
.
.
We need to understand brain activity, which is particularly relevant for non-small cell lung cancer," she said
.

RNA-based NRG1 detection is key

In the detection of NRG1 fusion, the eNRGy1 registry reports that the most common method is RNA sequencing, which detects 74% of cases (n = 81).

In RNA-based analysis, 62% of fusions were identified using amplicon-based RNA sequencing using anchored multiplex PCR, 27% by reverse transcription PCR, and 11%
by expression analysis using nCounter.
For DNA-based sequencing for 26% of cases (n = 29), detection rates of second-generation sequencing (NGS) and fluorescence in situ hybridization were nearly equal, 52% and 48%,
respectively.
The researchers note that almost all NGS tests used mixed-capture-based testing (93%)
.

"RNA-based analysis appears to be the best molecular test method for identifying NRG1 fusions," Drilon et al.
wrote
in the findings of the eNRGy1 registry.
Areas
that are difficult to tile and capture by DNA-based analysis.
”

In addition, in the data presented at the 2022 ASCO Annual Meeting, Garralda agrees to add that in the eNRGy study, "of the 83 patients presented, 64 were identified based on RNA
.
" This is important
.
If we want to look for these fusions, we will need to use RNA-based sequencing methods
.
”

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