MCLA-128 Fights NRG1 Fusion–Positive Cancers

Three patients harboring NRG1 fusions—two with pancreatic cancer and one with lung cancer—exhibited tumor shrinkage and improvement in symptoms when treated with Merus's bispecific antibody MCLA-128 (zenocutuzumab) in a clinical proof-of-concept study. Researchers reported the results at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston, MA, October 26–30.

NRG1 fusions occur in less than 1% of cancers overall, but they are “enriched in diseases in desperate need of better therapy,” such as KRAS–wild-type pancreatic ductal adenocarcinomas (PDAC) and invasive mucinous lung adenocarcinomas, said Alison Schram, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY, who presented the findings. Directed against HER2 and HER3, MCLA-128 docks on HER2 and blocks NRG1-fusion binding to HER3, preventing downstream PI3K–AKT–mTOR signaling and inhibiting tumor-cell proliferation. It also engages the immune system by enhancing antibody-dependent cellular cytotoxicity.

Preclinical testing of MCLA-128 demonstrated its effectiveness in ovarian and breast cancer models harboring various NRG1 fusions, including CLU–NRG1, TNFRSF10B–NRG1, and DOC4–NRG1 (Cancer Discov 2018;8:686–95).

Schram reported on three men who received MCLA-128 as part of an expanded access protocol. Two of them had KRAS–wild-type PDAC and had previously received chemotherapy, but the disease progressed. DNA sequencing revealed that they had ATP1B1–NRG1 fusions, so they opted for MCLA-128.

The first patient experienced a partial response: Imaging showed a 54% reduction in tumor diameter after 5 months, and levels of CA 19-9, a biomarker for pancreatic cancer, decreased from 262 units/mL to 50 units/mL. (A normal level is less than 40 units/mL.) In addition, Schram noted that he regained weight and had improved quality of life. The second patient experienced stable disease, with a 25% reduction in tumor diameter; his CA 19-9 level dropped from 418 units/mL to 11 units/mL.

“Both patients remain on treatment 7-plus months into therapy and are tolerating it extremely well, with improvement in both disease-related symptoms and resolution of chemotherapy-associated toxicity,” reported Schram.

The third patient had been diagnosed with non–small cell lung cancer (NSCLC). He received several chemotherapies and the HER2 inhibitor afatinib (Gilotrif; Boehringer Ingelheim), but the disease progressed. After DNA sequencing uncovered a CD74–NRG1 fusion, he tried MCLA-128. He experienced a partial response, with a 41% decrease in tumor diameter after 4 months and improvement in brain metastases. He remains on treatment.

Research presented at earlier medical meetings found that less than 5% of 117 patients experienced grade 3 or 4 toxicity. Most side effects were mild, with diarrhea, weakness, fatigue, and nausea being the most common. None of the three patients with NRG1 fusions treated at MSKCC experienced adverse events greater than grade 2.

The biggest limitation of the MSKCC research is the small number of patients. Although the researchers had identified 29 patients whose tumors carried NRG1 fusions, several died before therapy could begin, and several more had localized disease and weren't eligible to receive the drug. However, based on their experience treating the three patients, researchers have launched a phase II basket trial of MCLA-128 in patients with NRG1 fusion–positive PDAC, NSCLC, and other solid tumors. “We feel that this is a novel paradigm for targeting these rare genomic alterations,” said Schram. –Suzanne Rose

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