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The investigational agent zenocutuzumab induced fast and major radiologic tumor regression and biomarker responses in heavily pretreated patients with metastatic neuregulin 1 fusion (NRG1)-positive pancreatic cancer, a researcher reported.

There were five responders among 12 patients with pancreatic ductal adenocarcinoma, for an overall response rate (ORR) of 42% in this group, and seven remained on treatment after a median of 5.7 months, according to Alison Schram, MD, of Memorial Sloan Kettering Cancer Center in New York City.

Among 45 evaluable patients in the phase I/II study, which also included non-small cell lung cancer (NSCLC) and other solid tumor types, there were 13 partial responses for an ORR of 29%, with 19 patients remaining on treatment for a median treatment exposure of 5.5 months, Schram reported at the American Society of Clinical Oncology (ASCO) virtual meeting.

"We saw activity across multiple NRG1-positive cancer types and fusion partners," Schram stated.

ASCO-invited discussant Ignacio Garrido-Laguna, MD, PhD, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City, commented that "This was the first proof-of-concept study showing that an antibody can target a fusion oncoprotein in patients with solid tumors [with an] NRG1-fusion. The drug has an excellent safety profile, and, importantly, no evidence of cardiac toxicity."

"Moving forward, we need to find which NRG1 are actionable, and whether brain metastases, as seen with lung cancer, are treatable. And we need to determine the mechanisms of resistance to zenocutuzumab," as well as optimal treatment sequencing, Garrido-Laguna said.

Activity of zenocutuzumab, a bispecific antibody targeting NRG1 fusion-positive cancers, is being evaluated in the global multicenter phase II part of the and in a global early access program.

Earlier this year, the drug received for the treatment of patients with metastatic solid tumors harboring NRG1 gene fusions whose disease has progressed on standard of care therapy. "NRG1 gene fusions are a group of rare genomic alterations emerging as potential actionable drivers of tumorigenesis and growth across many types of solid tumors, including lung, breast, pancreatic, ovarian, and colorectal cancers," drugmaker Merus explained.

For the study, 61 enrolled patients had advanced NRG1-positive pancreatic cancer, NSCLC, or other solid tumors previously treated with standard therapy. Patients had to have an ECOG performance status ≤1, adequate organ function, and measurable disease via RECIST v1.1.

The study agent was given intravenously at a dose of 750 mg every 2 weeks until progression or unacceptable toxicity. The study's primary endpoint was investigator-assessed ORR, while secondary endpoints included ORR per central independent radiologist review, and safety. Tumor imaging was done every 8 weeks. For the primary analysis, 47 patients (median age 56; median of two lines of prior therapy; about 60% women) were deemed evaluable.

Overall, 76% of patients saw some form of tumor shrinkage. Four of the pancreatic cancer patients left the study because of disease progression, and one patient left due to investigator decision, said Schram.

In the 24 NSCLC group, the ORR was 25% (six patients). And among nine patients with other solid tumors, the ORR was 22% (two responders).

The agent had a favorable and tolerable safety profile, with the majority of adverse events being mild or moderate. The researchers also reported no cases of severe gastrointestinal and skin toxicities or clinical cardiotoxicity. The incidence of infusion reactions was low, at 7%.

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