Zenocutuzumab Displays Promising Activity in NRG1-Positive Malignancies

Kyle Doherty

The novel agent, zenocutuzumab demonstrated promise as treatment of patients with NRG1 fusion–positive cancers, in the phase 1/2 eNRGy study.

The novel agent, zenocutuzumab (MCLA-128) demonstrated promise as treatment of patients with NRG1 fusionpositive cancers, in the phase 1/2 eNRGy study (NCT02912949), according to results presented during the 2021 ASCO Annual Meeting.1

In 45 evaluable patients treated with zenocutuzumab the confirmed overall response rate (ORR) was 29%. Specifically, the ORRs for 12 patients with pancreatic adenocarcinoma (PDAC), 24 patients with non–small cell lung cancer (NSCLC), and 9 patients with other NRG1 fusion–positive cancers were 42%, 25%, and 22%, respectively. Additionally, tumor reduction was reported for 34 patients (76%).

“Zenocutuzumab is highly effective in pretreated NRG1 fusion-positive pancreatic cancer, with rapid and durable responses,” said Alison M. Schram, MD, lead study author and medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York. “There is activity across multiple NRG1 fusion-positive cancer types and an extremely well tolerated safety profile.”

NRG1, a ligand that binds to HER3, has been shown to be a clinically active target and tumors harboring NRG1 fusions are sensitive to HER2-, HER3-directed therapies. Zenocutuzumab is a bispecific, humanized, full-length IgG1 antibody with enhanced antibody-dependent cell-mediated cytotoxic activity that inhibits the HER3 signaling pathway. The agent has previously shown single-agent antitumor activity in several tumor types, specifically in heavily pretreated patients with metastatic breast cancer whose disease progressed on HER2 therapies in a phase 1/2 trial (NCT02912949).2

eNRGy enrolled a total of 61 adult patients with locally advanced, unresectable, or metastatic sold tumors that harbor NRG1 gene fusions. Patients were previously treated with, or unable to receive, standard therapy and had an ECOG performance status of 2 or less. The data cutoff date was April 13, 2021, at which point 47 patients were included in the primary analysis population.

The primary end point was investigator-assessed ORR. Secondary end points included ORR per central independent radiologist review, duration of response, and safety. Zenocutuzumab was administered at a dose of 750 mg intravenously every 2 weeks until disease progression. Tumor assessments occurred every 8 weeks. Patients included in the primary analysis population were those who had the opportunity for at least 1 post baseline tumor assessment at the time of cutoff.

The median age in the PDAC cohort was 47.5 years (range, 22-72) and was 58 years (range, 32-84) and 63 years (range, 31-81) in the NSCLC and basket/other groups, respectively. The basket cohort encompassed patients with breast (n = 3), unknown primary (n = 2), and other (n = 5) cancers. The median duration of exposure to zenocutuzumab was 5.7 months (range, 1-19), 4.6 months (range, 1-12), and 5.0 months (range, 2-10) in the PDAC, NSCLC, and basket cohorts respectively.

Patients had a median of 2 prior lines of therapy (range, 0-6). Nearly all patients in the primary analysis population had metastatic disease (n = 46) and 8 patients (17%) were previously treated with afatinib (Gilotrif). At the time of data cutoff 19 patients remained on treatment, including 7 with PDAC, 6 with NSCLC, and 6 with other cancers. The most common reason for treatment discontinuation was disease progression (53%).

In a more detailed analysis of the PDAC cohort, the confirmed partial response rate was 42% (90% CI, 18%-69%), stable disease was reported in 50% of patients and 9 patients experienced tumor shrinkage. These patients were heavily pretreated and had a median of 2.5 (range, 1-4) prior lines of therapy. Further, 100% of patients with CA 19-9 measurements (n = 11) had a decline of greater than 50% in follow-up analysis from baseline.

In addition to patients with PDAC, Schram presented a case study of a male patient aged 48 years with -NGR1-positive cholangiocarcinoma with metastases in the liver, lung, and lymph nodes. The patient received zenocutuzumab as third-line therapy following 2 lines of chemotherapy. “The patient had rapid tumor shrinkage and CA 19-9 normalization with an ongoing PR [partial response] of over 5 months into treatment,” Schram said.

Specifically, there was a 32% tumor reduction and an 84% reduction in CA 19-9 was observed (120 U/mL to 20 U/mL). At the time of data cutoff, the patient had received 7 cycles of zenocutuzumab and treatment was ongoing.

In terms of safety, the most common all-grade adverse effects (AEs) included asthenia/fatigue (35%), diarrhea (30%), and anemia (20%). Most AEs were grade 1 or 2 and no patients required dose reduction because of toxicity. There was a notable absence of severe gastrointestinal toxicity, skin toxicities, and clinical cardiotoxicity, Schram noted.

In January 2021, the FDA granted fast track designation to zenocutuzumab for the treatment of patients with metastatic solid tumors that harbor NRG1 gene fusions and have progressed on standard-of-care treatment.

“This is the first prospective clinical validation of NRG1 fusions as actionable oncogenic drivers,” Schram said. “[It’s also] the first demonstration of effective targeting of a genomically-altered ligand and the first proof-of-concept that antibody-based therapy can target a fusion oncoprotein. Zenocutuzumab is the first genome-directed therapy for NRG1 fusion–positive cancer offering a potential new standard of care.”


1. Schram AM, O’Reilly EM, O’Kane GM, et al. Efficacy and safety of zenocutuzumab in advanced pancreas cancer and other solid tumors harboring NRG1 fusions. J Clin Oncol. 2021;39(suppl 15):3003. doi:10.1200/JCO.2021.39.15_suppl.3003

2. Schram A, Macarulla T, O’Reilly E, et al. Phase 2 study of zenocutuzumab (MCLA-128), a bispecific HER2/HER3 antibody in NRG1 fusion-positive advanced solid tumors. J Thorac Oncol. 2021;16(suppl 3):S675. doi:10.1016/j.jtho.2021.01.1237