Targeted therapies have provided more therapies for ever-growing subsets of cancer, with the goal of delivering a personalized therapy that is tailored to each individual molecular abnormality. In this effort, NRG1 gene fusions represent a promising new target in this chase, with several agents in the development pipeline.
Findings for one such agent, zenocutuzumab (MCLA-128), were recently presented at the 2022 ASCO Annual Meeting1 and in a case study published August 18, 2022, in the journal JCO Precision Medicine.2 “The case of our patient with metastatic breast cancer emphasizes the importance of molecular profiling for detecting targetable genetic alterations and broadening treatment options,” the authors of the JCO Precision Medicine paper wrote.
The patient in the case report was a 58-year-old woman, who received an initial diagnosis of stage IIIA, grade 2 bifocal infiltrating nonmucinous ductal carcinoma in April 2013. Throughout the course of her disease, the patient received endocrine therapies, a CDK4/6 inhibitor, chemotherapy, and bevacizumab (Avastin), with short-lived responses to each course of therapy. In March 2018, she received the combination palbociclib (Ibrance) and fulvestrant (Faslodex), with a best response of stable disease. In March 2019, progression was noted in the liver and capecitabine was initiated, with a partial metabolic response noted; however, liver and bone metastases were reported in January 2020.
Oncofocus test revealed a gene fusion between exon 6 of NRG1 and exon 5 of SLC3A2, which was confirmed at her progression on capecitabine. Genetic testing did not detect any other actionable mutations, and the patient was subsequently enrolled in an early access program to receive zenocutuzumab, which was administered intravenously at 750 mg once ever 2 weeks. Premedication of antipyretics, antihistamines, and corticosteroids were given before each 2-hour infusion.
After the first 2 treatment cycles, the patient experienced a complete metabolic response by PET scan in 4 of her liver lesions, which ranged in size from SUVmax of 5.6 to 15.7 at baseline. Additionally, a partial metabolic response was seen in bone metastases. By RECIST v1.1 criteria, there was a 35% size reduction seen in target lesions, indicating a partial response. These responses remained ongoing at 21 months post treatment. Additionally, zenocutuzumab was well tolerated, with the only adverse events being grade 1 nausea, which was intermittent and well managed with metoclopramide, and intermittent grade 1 diarrhea, which was managed with loperamide.
“This case supports emerging evidence that NRG1 fusions are targetable driver mutations in metastatic breast cancer and that NRG1 fusions merit being added to the screening panel of actionable oncogenic alterations in this patient population,” the authors noted. “This case highlights the value of targeted sequencing for cancer precision medicine and demonstrates that inhibition of HER2/HER3 signaling with zenocutuzumab is effective for treating ER-positive, HER2-negative metastatic breast cancer harboring an NRG1 fusion, supporting the application of zenocutuzumab in a tissue-agnostic therapeutic context.”
NRG1 gene fusions occur in 0.2% of cancer diagnoses and is a member of the EGF receptor family, with malignant cell proliferation commonly caused by binding to HER3 and subsequent activation of HER2. NRG1 is most common in non–small-cell lung cancers (NSCLC) and KRAS wild type pancreatic adenocarcinoma (PDAC) but also occurs in 0.04% to 0.7% of breast cancer diagnoses.
There were 110 patients enrolled in the phase 1/2 study presented at the ASCO annual meeting, with 83 meeting the criteria for the primary analysis. The most common tumor types were NSCLC (57%) and PDAC (23%). Additional histologies treated included breast cancer (8%), cholangiocarcinoma (4%), colorectal cancer (4%), endometrial soft tissue sarcoma, pancreatic neuroendocrine carcinoma, renal cell carcinoma, and cancer of unknown primary (5%).
The overall response rate (ORR) per RECIST criteria in the study was 34% by investigator assessment across all tumor types (95% CI, 24%-46%). In those specifically with PDAC, the ORR was 42% (95% CI, 20%-67%) and in patients with NSCLC the ORR was 35% (95% CI, 21%-50%). Tumor shrinkage of any level was observed in 70% of patients in the study, and the median time to response was 1.8 months. Median duration of response was 9.1 months, with 24% of patients continuing therapy at the time of the cutoff.
“At the 2022 ASCO Annual Meeting, we provided an update on our lead bispecific antibody, zenocutuzumab, which demonstrated strong efficacy across multiple tumor types, clinically meaningful duration of response, and a very well tolerated safety profile,” Bill Lundberg, MD, president, chief executive officer of Merus, the company that develops the NRG1 agent said in a statement in early August. “We continue to believe zenocutuzumab has the potential to be both first in class and best in class for patients with NRG1 fusion cancer.”
A pivotal phase 2 trial is currently enrolling patients with solid tumors harboring an NRG1 fusion (NCT02912949). According to Merus, the trial, which is labeled eNRGy, is designed to support a biologics license application for zenocutuzumab, based on feedback received from the FDA in 2021. The study plans to enroll 250 patients and the estimated primary completion date is December 31, 2022. The primary end point of the study is ORR.
- Schram AM, Goto K, Kim DW, et al. Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers. J Clin Oncol. 2022;40(suppl 16):105. doi:10.1200/JCO.2022.40.16_suppl.105
- Fontana E, Torga G, Fostea R, et al. Sustained Tumor Regression With Zenocutuzumab, a Bispecific Antibody Targeting Human Epidermal Growth Factor Receptor 2/Human Epidermal Growth Factor Receptor 3 Signaling, in NRG1 Fusion-Positive, Estrogen Receptor-Positive Breast Cancer After Progression on a Cyclin-Dependent Kinase 4/6 Inhibitor. JCO Precis Oncol. 2022;6:e2100446. doi: 10.1200/PO.21.00446.