BOSTON — The investigational bispecific HER2/HER3 antibody therapeutic MCLA-128 showed radiological and clinical responses in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) or metastatic non-small cell lung cancer (NSCLC) that harbor fusions in the gene neuregulin 1 (NRG1), according to a study presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
, held Oct. 26-30.
“NRG1 fusions have recently been described in several cancer types and are enriched in diseases in desperate need of better therapy, including pancreatic and lung cancer,” said Alison Schram, MD
, a medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center (MSK). “Identifying a new, effective treatment strategy for these patients could make a big impact in their lives.”
Less than 1 percent of solid tumors across different cancer types are known to have fusions in the gene NRG1, noted Schram. MCLA-128 has a dual mechanism against cancer, as it prevents NRG1 fusions from binding to the protein HER3 and it blocks the interaction of HER3 with HER2, which the cancer cells depend on to survive and multiply.
Schram and the MSK team performed next-generation sequencing of solid tumors from patients and identified 29 patients whose tumors (pancreatic, lung, breast, prostate, and gallbladder cancer, and sarcoma and lymphoma, among others) were positive for NRG1 fusions. Of these patients, three were treated with 750 mg MCLA-128 intravenously every other week, and all three had significant tumor shrinkage.
Preclinical experiments using NRG1-fusion-positive cancer cell lines and mouse xenograft models found that MCLA-128 effectively inhibited cell proliferation and caused tumors to shrink in the mice.
In one patient with NRG1-fusion-positive advanced pancreatic ductal carcinoma with liver metastases, treatment with MCLA-128 resulted in CA 19-9, a tumor biomarker for pancreatic cancer, dropping from 262 units/ml to 50 units/ml (the normal rage for this protein is less than 40 units/ml). At eight weeks, imaging revealed a 44 percent reduction in tumor diameter, which further decreased to a 54 percent reduction on his subsequent scan. The patient was considered to have a partial response by RECIST v1.1
and a complete response by PET response criteria
. Importantly, within weeks of his first treatment his fatigue improved, and he started to gain back the weight he had unintentionally lost in previous months, Schram noted.
In another patient with NRG1-fusion-positive advanced pancreatic ductal carcinoma with liver metastases, treatment with MCLA-128 resulted in the reduction of CA 19-9 from 418 units/ml to 11 units/ml. Imaging at six weeks showed 22 percent reduction in tumor diameter, which further decreased to a 25 percent reduction at the next scan; FDG-PET
imaging also revealed that the liver metastases were not metabolically active. The patient’s tumor-related abdominal pain also subsided following treatment.
A third patient’s NRG1-fusion positive NSCLC with brain metastases had previously progressed on six lines of therapy, including the tyrosine kinase inhibitor (TKI) afatinib (Gilotrif). Upon treatment with MCLA-128, the patient’s tumor shrank by 33 percent, with improvement in his brain metastases. “This emphasizes the potential superiority of this approach over TKIs,” Schram said.
All three patients being treated at MSK continue to remain on therapy at the time of this interview.
“Treating these three 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,” said Schram.
“It is important to note that the patients felt remarkably well on treatment and reported immediate improvement in quality of life,” Schram noted. Data from an ongoing clinical trial showed MCLA-128 has a tolerable safety profile, with fewer than 5 percent of patients reporting presumed drug-related grade 3-4 adverse events, no reports of clinically significant cardiotoxicity or rash, and minimal gastrointestinal toxicity, she added.
“Initial data from these three patients suggests that it is important to look for NRG1 fusions in tumors, particularly in KRAS-negative pancreatic cancer and invasive mucinous adenocarcinoma of the lung [a type of lung cancer], and when identified, patients should consider treatment in a clinical trial targeting this alteration,” Schram said. Based on these data, a phase II trial of MCLA-128 is actively accruing and treating patients with NRG1 fusion-positive tumors (NCT02912949
The three patients described here were treated through the U.S. Food and Drug Administration-approved single-patient investigational drug applications initiated by MSK as part of an expanded access program. This approach must continue to be tested in a larger patient population as part of a clinical trial for further validation, Schram noted.
The biotechnology company that developed MCLA-128, Merus N.V., provided the therapeutic for the clinical study; preclinical laboratory studies were performed by Merus. Schram has no conflicts of interest to declare.
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