What You Need to Know About the FDA's Approval of Nerlynx-Xeloda Combo for HER2-Positive Breast Cancer

The Food and Drug Administration (FDA) recently approved the supplemental new drug application for the combination of Nerlynx (neratinib) and Xeloda (capecitabine) for the treatment of adults with advanced or metastatic HER2-positive breast cancer who previously received two or more anti-HER2-based therapies in the metastatic setting.

The agency based its approval on data from the phase 3 multicenter NALA trial that looked at 621 patients with metastatic HER2-positive breast cancer. The goal was to compare the effectiveness of Nerlynx, a targeted therapy for patients with breast cancer, and Xeloda, chemotherapy, to the combination of Tykerb (lapatinib), another targeted therapy, and Xeloda.

Researchers found that the combination of Nerlynx and Xeloda showed a significant improvement in patient’s progression free survival (the time from treatment to disease progression or worsening) compared to Tykerb and Xeloda. The progression free survival rate at 12 months for patients receiving Nerlynx and Xeloda was 29% compared to 15% for those receiving Tykerb and Xeloda.

“The difference between neratinib (Nerlynx) and lapatinib (Tykerb) is that neratinib is an irreversible binder of the HER2 tyrosine kinase,” explained Dr. Adam M. Brufsky, of Magee-Womens Hospital and the Hillman Cancer Center at the University of Pittsburgh Medical Center and study investigator on the NALA trial, in an interview with CURE. “So, the whole idea is that, you may get away with giving less neratinib because it irreversibly binds the tyrosine kinase (of HER2), and that was the idea behind the NALA trial.”

Tyrosine kinase is an enzyme that is an important part of the signal process in cells that allows the cell to function and proliferate and even undergo programmed cell death properly, however, in cancer cells the Tyrosine kinase can be genetically altered and give an advantage to the cancer cells allowing them to spread. This is why researchers on the NALA trial have been excited by the potential of Nerlynx to bind this signal pathway.

This also allows the combination of Nerlynx and Xeloda to better combat CNS (central nervous system) metastases. At 54 moths, the overall incidence for CNS metastases intervention was 22.8% versus 29.2% in the Tykerb and Xeloda arm.

“The overall incidence of brain metastases went down about 10%, but the bottom line is that what I tell people is (Nerlynx) gets into the brain and because it's an irreversible binder it stays there,” said Dr. Brufsky. “It could either prevent new brain metastases or treat the ones you have and stabilize them because as long as you can stabilize them, people will be fine.”

The most common side effects, at any grade, included diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decrease, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment and muscle spasms. Moreover, 83% of patients who received Nerlynxexperienced all-grade diarrhea compared to 66% in the Tykerb arm.

At this time, there is a new trial being submitted called CONTROL looking at various methods to manage the grade 3 diarrhea in patients on this combination, explained Brufsky. One of these management methods would include a dose escalation of Nerlynx from 160 mg a day to 240 mg a day with medication for diarrhea that has shown the incidence of grade 3 diarrhea go down. Moreover, Brufsky cited these new ways of controlling diarrhea as part of what makes Nerlynx, in combination with Xeloda, an advanced for patients with metastatic HER2-positive breast cancer.

“Every new advance in the fight against breast cancer gives us great hope. It demonstrates that the monies invested in research are finding new treatment options and advancing therapies to help fight the most aggressive forms of breast cancer,” Kate Watt, Executive Director of Susan G. Komen Florida, added in a statement to CURE. “Through grassroots support at Komen Florida, we will continue to raise money to support research innovation and increase access to care so that everyone can benefit from advancements in breast cancer treatment. We will not stop until there is a cure for all.”

Read CURE®’s original coverage of the approval.