“Zenocutuzumab is extremely well tolerated, and patients often feel better within weeks,” said Dr. Alison Schram of Memorial Sloan Kettering Cancer Center, lead investigator on the trial behind the drug’s approval.
The Food and Drug Administration gave zenocutuzumab, sold as Bizengri, an accelerated approval for people with pancreatic or non-small cell lung cancer (NSCLC) whose tumors carry an NRG1 fusion, a very rare genetic alteration, and whose disease has worsened despite standard treatment. It is the first drug aimed at that alteration.
How the drug works
An NRG1 fusion forms when part of the NRG1 gene joins part of another gene. The resulting protein switches on two proteins on the cell surface, HER2 and HER3, and the pair sends signals telling cells to keep growing and dividing. Zenocutuzumab blocks the fusion protein before it can drive that complex.
The trial numbers
The phase 2 study enrolled adults with advanced or metastatic solid tumors that had an NRG1 fusion. They received the drug intravenously every 2 weeks until their disease got worse. Approval rested on data from 158 patients: 93 with advanced NSCLC, 36 with advanced pancreatic cancer, and the rest with breast, colorectal, bile duct and other cancers.
One-third of treated patients had tumor shrinkage of at least 30% that held for a median of 11 months. Lung and pancreatic patients were the most likely to respond. Nearly 30% of those with NSCLC saw shrinkage, lasting a median of 12.7 months. In pancreatic cancer the figure was 42%, with responses lasting a median of 7.4 months. One patient’s tumors disappeared entirely.
Side effects were mostly mild, and included diarrhea, fatigue, nausea and anemia. Just one patient stopped treatment because of a drug-related side effect.
A modest response rate, with caveats
Dr. Stephen V. Liu of Georgetown University’s Lombardi Comprehensive Cancer Center, a co-investigator, called the study “an important advance” but noted that a response rate of 30% is still fairly low. “These are tumors that don’t do well with standard treatment,” he said. “Having zenocutuzumab now gives us a targeted drug that has a better chance of working.”
Because the approval is accelerated, Partner Therapeutics, which licensed the drug from Merus, has to run more studies confirming it helps patients clinically, which can include helping them live longer than they would on other treatments.
The team is working to learn why some patients respond and others do not, and what causes resistance. Researchers hope the approval can grow to other cancer types as more people receive the drug. Other drugs, including afatinib (Gilotrif), which blocks HER2 activity, are under study in tumors with NRG1 fusions.
Testing is the other bottleneck. NRG1 fusions are mostly found through RNA testing, since DNA testing is less sensitive for this kind of change. Schram urges clinicians to add RNA testing to the diagnostic workup “to make sure we’re not missing patients who could benefit from this therapy.” Liu agreed: to see the full effect, “we need to do a better job of testing for alterations like this.”
