By Mark L. Fuerst
BOSTON—An investigational bispecific HER2/HER3 antibody leads to clinical responses in patients who harbor fusions in the gene neuregulin 1 (NRG1), including those with metastatic pancreatic ductal adenocarcinoma (PDAC) or metastatic non-small cell lung cancer (NSCLC), according to a new study.
NRG1 is a ligand that binds HER3, promoting HER2/HER3 heterodimerization and activation of PI3K/AKT/mTOR signaling. NRG1 fusions are rare oncogenic drivers found across numerous solid tumor types, with less than 1 percent incidence. MCLA-128 is a bispecific antibody that binds HER2, optimally positioning an anti-HER3 arm to block the HER3/ligand interaction. 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 mice.
Alison Schram, MD, a medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center (MSKCC), presented clinical proof of concept of MCLA-128 to treat NRG1 fusion cancers at a press conference before the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.
"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 Schram. "Identifying a new, effective treatment strategy for these patients could make a big impact in their lives."
The MSKCC team performed next-generation sequencing of solid tumors from patients and identified 29 patients with tumors that were positive for NRG1 fusions, including those with pancreatic, lung, breast, prostate, and gallbladder cancers, as well as sarcoma and lymphoma, among others. Three of these patients were treated with 750 mg MCLA-128 intravenously every other week, and all three showed significant tumor shrinkage, said Schram.
One patient, a 52-year-old man with NRG1-fusion-positive advanced PDAC developed liver metastases, was put on additional chemotherapy, and developed side effects. His tumor was sequenced tumor, with no KRAS mutation found, and he was put on MCLA-128.
On MCLA-128 treatment, his levels of CA 19-9, a tumor biomarker for pancreatic cancer, dropped from 262 units/mL to 50 units/mL, which was close to the normal range of less than 40 units/mL. At 8 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 criteria 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, noted Schram.
Another patient, a 34-year-old man with NRG1-fusion-positive advanced PDAC, took prolonged chemotherapy, progressed, and developed liver metastases. Treatment with MCLA-128 resulted in the reduction of CA 19-9 from 418 units/mL to 11 units/mL. Imaging at 6 weeks showed 22 percent reduction in tumor diameter, which further decreased to a 25 percent reduction at the next scan; PET imaging also revealed that the liver metastases were not metabolically active. The patient's tumor-related abdominal pain also subsided following treatment, she said.
"Both patients remain on therapy for more than 7 months, and have tolerated therapy extremely well," said Schram.
A third patient, a 54-year-old man with NRG1-fusion positive NSCLC with brain metastases, had previously progressed on six lines of therapy, including the tyrosine kinase inhibitor (TKI) afatinib, as well as two lines of radiation therapy. Upon treatment with MCLA-128, the patient's tumor shrank by 33 percent at 8 weeks, with improvement in his brain metastases, and by 41 percent at 16 weeks, confirming a partial response. "This emphasizes the potential superiority of this approach over TKIs," Schram said. "This patient says he continues to feel well on therapy.
"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."
Importantly, she noted that the patients feel well on treatment and report immediate improvement in their quality of life. Data from an ongoing clinical trial of 117 patients show 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. Minor infusion reactions have been managed by decreasing the dose.
"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, 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 FDA-approved single-patient investigational drug applications initiated by MSKCC 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. "From our preliminary experience, we feel this is a novel paradigm to target these alterations."
Mark L. Fuerst is a contributing writer.