Triple meeting – targeted focus validates Merus’s change of tack

Merus’s anti-Her2/Her3 bispecific could have a future in a new targeted setting.

Bispecific antibody approaches are enjoying a resurgence in popularity, and this weekend’s Triple meeting saw a pitch from another player – a little-known Dutch biotech called Merus, which floated on Nasdaq three years ago.

What makes Merus unusual is that its lead bispecific, zenocutuzumab, is being used in a targeted setting, specifically in tumours with a rare mutation called NRG1 fusion. The Triple meeting data explain the company’s recent decision to overhaul a phase I/II solid tumour study so that it now focuses solely on cancers with NRG1 fusions.

Zeno is a bispecific targeting Her2 and Her3. The results presented on Sunday at the Triple (EORTC-NCI-AACR) meeting came not from a formal clinical trial but from an expanded access programme run by Memorial Sloan-Kettering Cancer Center, under which an IND is sought from the FDA for each patient treated.

This involved a targeted approach from the outset, with molecular profiling prospectively identifying 29 subjects with NRG1-positive tumours. Only three have been given zeno so far, as many of the rest had died before access to zeno became available or had localised disease and were deemed not to be in need of ongoing therapy, MSKCC’s Dr Alison Schram told a Triple meeting press briefing.

Tumour shrinkage

Remarkably, all three zeno subjects have shown impressive signs of tumour shrinkage, the Triple meeting heard, including partial remissions in a patient with pancreatic ductal adenocarcinoma and another with Gilotrif-refractory NSCLC metastatic to the brain. The latter’s scans showed tumour shrinkage in the brain, too.

The third subject, also with pancreatic ductal adenocarcinoma as well as long-standing abdominal pain, achieved pain resolution and tumour reduction that fell short of partial response. Merus’s amended study now focuses on three NRG1-positive cohorts: NSCLC, pancreatic cancer, and a basket cohort of any other solid tumours.

Dr Schram said NRG1 fusion patients represented the most likely effective group for zeno, though “perhaps there are other biomarkers”.

A separate Merus-sponsored trial testing zeno in breast cancer has completed enrolment, but this did not preselect for NRG1 fusions, and an unplanned interim analysis revealed overall remissions of just 0-4%. Accordingly Merus says it will not proceed into phase III. 

Clinical studies of zenocutuzumab
Trial Detail
NCT04100694 MSKCC-initiated single-patient IND programme, identifying subjects with NRG1 fusions 
NCT02912949 Formerly a breast/colorectal cancer trial, now focusing on NRG1 fusion pancreatic and NSCLC
NCT03321981 Combo trial in Her2-positive and low-Her2 expressing breast cancer, not being pursued into phase III
Source: clinicaltrials.gov & Merus.

Targeted approaches are typically the domain of small-molecule tyrosine kinase inhibitors, so Merus’s antibody approach with zeno (also known as MCLA-128) is mechanistically intriguing.

NRG1 fusions result in the formation of the oncogenic protein neuregulin 1, a ligand for Her3, and this assists Her3’s dimerisation with Her2, prompting downstream signalling and tumour growth. 

Zeno’s dual action is thought to make the MAb dock with Her2, and block neuregulin binding to Her3. In contrast to tyrosine kinase inhibitors zeno was preclinically shown to inhibit ligand-induced tumour growth, and NRG1 as a targetable alteration has only recently been recognised, Dr Schram said.

Only 1% of all solid tumours are thought to carry NRG1 fusions, but Dr Schram said it was important to look for such mutations especially in Kras-negative pancreatic cancer and invasive mucinous adenocarcinoma. As such Merus’s approach could herald a way in to some very intractable cancers.

The company floated in 2016, raising $61m, since when it stock has risen 60%. Its pipeline also includes early-stage bispecifics targeting Clec12A/CD3, Lgr2/EGFR, and PD-L1/4-1BB.

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