Zenocutuzumab case study shows activity in NRG1+ breast cancer

Targeted therapies have provided more therapies for ever-growing cancer subsets, with the goal of providing personalized therapy tailored to each individual molecular abnormality. In this effort, NRG1 gene fusions represent a promising new target in this pursuit, with several agents in development.

Results from 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 underscores the importance of molecular profiling to detect targetable genetic alterations and expand treatment options,” the study authors explain. JCO Precision Medicine paper wrote.

The patient in the case report was a 58-year-old female, who was initially diagnosed with stage IIIA, grade 2 bifocal invasive non-mucinous ductal carcinoma in April 2013. Throughout her illness, the patient received therapies endocrine disorders, CDK4/6, chemotherapy, and bevacizumab (Avastin), with short-lived responses to each treatment. In March 2018, she received the combination palbociclib (Ibrance) and fulvestrant (Faslodex), with better stable disease response. 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.

The Oncofocus test revealed a gene fusion between exon 6 of NRG1 and exon 5 of SLC3A2, which was confirmed during his 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 given intravenously at 750 mg once every 2 weeks. Premedication of antipyretics, antihistamines and corticosteroids was administered before each 2 hour infusion.

After the first 2 cycles of treatment, the patient had a complete metabolic response by PET in 4 of her liver lesions, which ranged in size from SUVmax 5.6 to 15.7 at baseline. Additionally, a partial metabolic response was observed in bone metastases. According to RECIST v1.1 criteria, a 35% reduction in size was observed in the target lesions, indicating a partial response. These responses remained ongoing at 21 months after treatment. In addition, zenocutuzumab was well tolerated, with the only adverse events being intermittent grade 1 nausea, well managed with metoclopramide, and intermittent grade 1 diarrhea, managed with loperamide.

“This case supports emerging evidence that NRG1 fusions are targetable motor mutations in metastatic breast cancer and that NRG1 fusions deserve to be added to the screening panel for actionable oncogenic alterations in this patient population,” noted the authors. authors. “This case highlights the value of targeted sequencing for precision cancer medicine and demonstrates that inhibiting HER2/HER3 signaling with zenocutuzumab is effective in treating ER-positive and HER2-negative metastatic breast cancer. harboring an NRG1 fusion, supporting the application of zenocutuzumab in a tissue-independent therapeutic context.

NRG1 gene fusions occur in 0.2% of cancer diagnoses and are part of the EGF receptor family, with malignant cell proliferation typically caused by binding to HER3 and subsequent activation of HER2. NRG1 is most common in non-small cell lung cancer (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, 83 of whom met 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 unknown primary cancer (5%).

The overall response rate (ORR) by RECIST criteria in the study was 34% by investigator assessment for all tumor types (95% CI, 24% to 46%). In those specifically with PDAC, the ORR was 42% (95% CI, 20% to 67%) and in patients with NSCLC, the ORR was 35% (95% CI, 21% to 50%). Tumor shrinkage of any grade was observed in 70% of study patients, and the median time to response was 1.8 months. The median duration of response was 9.1 months, with 24% of patients continuing treatment at the time of the cut.

“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 very well tolerated,” said Bill Lundberg, MD, chairman, CEO of Merus, the company developing the NRG1 agent, said in a statement in early August, “We continue to believe that zenocutuzumab has the potential to be both first and best in class for patients with NRG1 fusion cancer.”

A pivotal phase 2 trial is currently recruiting patients with solid tumors harboring a NRG1 (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 endpoint of the study is ORR.

References

  1. Schram AM, Goto K, Kim DW, et al. Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion (NRG1+) cancers. J Clin Oncol. 2022;40(supplement 16):105. doi:10.1200/JCO.2022.40.16_suppl.105
  2. 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 and Estrogen Receptor-Positive Breast Cancer after progression on a cyclin-dependent kinase 4/6 inhibitor. JCO Accurate Oncol. 2022;6:e2100446. doi: 10.1200/PO.21.00446.

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