HER2/HER3 Antibody Therapeutic Shows Potential in NRG1-Fusion-Positive Solid Tumors

A bispecific HER2/HER3 antibody therapeutic showed radiological and clinical responses in patients with certain types of cancer who harbored neuregulin 1 (NRG1) gene fusions, according to data presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

The investigational bispecific HER2/HER3 antibody therapeutic MCLA-128 has a dual mechanism against cancer: It prevents the NRG1 fusion from binding to the HER3 protein and blocks the interaction of HER3 with HER2. With less than 1% of solid tumors across different cancer types are known to have NRG1 gene fusions, more treatment options are needed.

“Identifying a new, effective treatment strategy for these patients could make a big impact in their lives,” Alison Schram, MD, medical oncologist, Early Drug Development Service, Memorial Sloan Kettering Cancer Center, said in a press release issued by the AACR.

The researchers performed next-generation sequencing of solid tumors from 29 patients with either pancreatic, lung, breast, prostate, or gallbladder cancer, as well as sarcoma and lymphoma, who were positive for NRG1 fusions.

Among these patients, 3 with chemotherapy-resistant metastatic cancer were treated with 750 mg MCLA-128 intravenously 2 weeks on FDA-approved single-patient protocols.

“Treating these 3 patients with MCLA-128 was a rational decision based on our understanding of biology, and our data provide important proof-of-concept demonstrating the promise of targeting NRG1 fusions with this novel approach,” Schram said. 

All 3 patients experienced significant tumor shrinkage. One patient with NRG1-fusion-positive advanced pancreatic ductal carcinoma with liver metastases had a 44% reduction in tumor diameter at 8 weeks,which further decreased to a 54% reduction on his subsequent scan.

Another patient with NRG1-fusion-positive advanced pancreatic ductal carcinoma with liver metastases had a 22% reduction in tumor diameter at 6 weeks, which further decreased to a 25% reduction at the next scan. Moreiver, FDG-PET imaging also revealed that the liver metastases were not metabolically active. 

Lastly, the third patient with NRG1-fusion positive non-small cell lung cancer with brain metastases experienced a 33% reduction in tumor shrinkage, with improvement in his brain metastases.

All patients remain on therapy with no substantial toxicity.

“It is important to note that the patients felt remarkably well on treatment and reported immediate improvement in quality of life,” Schram said. “Initial data from these 3 patients suggests that it is important to look for NRG1fusions in tumors, particularly in KRAS-negative pancreatic cancer and invasive mucinous adenocarcinoma of the lung, and when identified, patients should consider treatment in a clinical trial targeting this alteration.”

Based on these data, a global, multicenter phase II basket trial trial of MCLA-128 is actively accruing and treating patients with NRG1 fusion-positive tumors.

Reference:

Schram A. Clinical proof of concept for MCLA-128, a bispecific HER2/3 antibody therapy, in NRG1fusion-positive cancers. Presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2019; Boston.