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.

An investigational first-in-class therapy for tumors harboring NRG1 fusions shows early efficacy, albeit in a modest number of patients so far. The response rate with zenocutuzumab (MCLA-128; Merus) appears especially striking in pancreatic ductal adenocarcinoma (PDAC), said Alison Schram, MD, of Memorial Sloan Kettering Cancer Center in New York, NY. She presented data from the ongoing phase I/II eNRGy trial during the American Society of Clinical Oncology 2021 Annual Meeting, June 4–8.

“Chromosomal rearrangements involving NRG1 are rare oncogenic drivers,” Schram said, “and enriched in KRAS–wild-type pancreatic cancer, as well as in invasive mucinous adenocarcinoma of the lung,” a subtype of non–small cell lung cancer (NSCLC). Through RNA sequencing, numerous fusion partners with NRG1 have been identified, she added, including ATP1B1, CD74, and SDC4.

Zenocutuzumab, a bispecific antibody, targets HER2 and HER3, working via a “dock and block” mechanism, explained Merus's CEO Bill Lundberg, MD. First, “it docks onto HER2, which is abundant, so it's highly concentrated on the cell surface and can then bind HER3, blocking interactions with NRG1—HER3's ligand—or with NRG1 fusions.” By preventing HER2–HER3 dimerization, zenocutuzumab also halts downstream activation of cell-proliferative PI3K/mTOR signaling. As well, it induces enhanced antibody-dependent cellular cytotoxicity.

eNRGy has enrolled 61 patients to date, all with locally advanced, metastatic, or inoperable NRG1 fusion–positive (NRG1+) cancers. Schram reported results for 45 evaluable patients across three cohorts: 12 with PDAC; 24 with NSCLC; and nine with various other solid tumors, including cholangiocarcinoma. The objective response rates (ORR) were 42%, 29%, and 22%, respectively. In the PDAC group, another 50% experienced stable disease, and of 11 patients assessed for the tumor biomarker CA19-9—often used to monitor efficacy—“all had sustained declines of more than 50% while on treatment.”

“The median age in this cohort was 47.5 years, consistent with prior findings that NRG1+ PDAC tends to occur in younger patients,” Schram observed. “Since the approval of a PARP inhibitor [olaparib (Lynparza; AstraZeneca)] for PDAC, genomic sequencing has become more common, so in this context, if KRAS–wild-type turns up and your patient is young, I'd consider looking for NRG1 fusions as well.”

Zenocutuzumab was “extremely well tolerated,” Schram said, with low-grade fatigue, anemia, and diarrhea being the main side effects, and a “notable absence” of severe gastrointestinal, skin, or cardiac toxicities.

With eNRGy, “we now have the first prospective clinical validation of NRG1 fusions as actionable oncogenic drivers,” Schram concluded, and “the first demonstration of effective targeting of a genomically altered ligand” rather than receptors such as TRK or RET.

Thus far, “all approved fusion-targeting drugs are small molecules—for instance, larotrectinib [Vitrakvi; Bayer],” said study discussant Ignacio Garrida-Laguna, MD, PhD, of Huntsman Cancer Institute in Salt Lake City, UT. Zenocutuzumab is therefore “proof-of-concept that antibody-based therapies can also hit” fusion oncoproteins. “The drug's size is undisclosed, but it would be interesting to learn more about its potential to cross the blood–brain barrier and treat brain metastases” in NSCLC.

As well, “we need to learn if NRG1 fusions are prognostic in PDAC—analysis of real-world datasets with annotated genomic information will be critical,” Garrida-Laguna said. Because zenocutuzumab “looks incredibly effective” against this notoriously difficult-to-treat cancer, “it begs the question of what ORR and ‘n’ of patients would support an accelerated approval,” he added. “For context, vemurafenib [Zelboraf; Genentech] was approved for Erdheim Chester disease with efficacy data in only 26 patients.”


Currently, zenocutuzumab holds orphan drug designation for PDAC and fast-track status for metastatic NRG1+ cancers that have progressed on standard therapy. An update on its path to registration, which Merus indicated could be tumor-agnostic or tumor-specific, is expected by the first half of 2022. –Alissa Poh