Nerlynx (neratinib) is being developed by Puma Biotechnology as an adjuvant or add-on treatment of HER2-positive (HER2+) breast cancer. It is taken after an initial treatment to lower the risk of cancer recurrence.
Nerlynx was approved by the U.S. Food and Drug Administration (FDA) in 2017 as adjuvant therapy in adults with early-stage HER2+ breast cancer who have previously been treated with Herceptin (trastuzumab). The following year, Nerlynx received marketing authorization in Europe by the European Commission (EC).
Puma submitted an application to the FDA for the approval of Nerlynx as a combination treatment with Xeloda (capecitabine) for HER2+ breast cancer in patients whose cancer has spread to other parts of the body. The approval request is for use in patients who have not responded to two or more HER2 targeted treatments.
Other names of Nerlynx include PB272 and HKI-272.
How Nerlynx works
HER2+ breast cancer is a type of breast cancer in which a protein called the human epidermal growth factor receptor 2 (HER2) is abundant (overexpressed) in the cancer cells. This receptor is responsible for the rapid growth and spread of these cells.
Nerlynx is a tyrosine kinase inhibitor (TKI), a small molecule that irreversibly binds and blocks the HER2 protein. By blocking HER2, Nerlynx inhibits the function of this receptor, thus preventing cancer growth and multiplication.
Nerlynx in clinical trials
The efficacy and tolerability of Nerlynx have been evaluated in several clinical trials.
A Phase 3 placebo-controlled trial (NCT00878709) called ExteNET assessed Nerlynx in patients with early-stage HER2+ breast cancer — stage 2 or 3 cancers that were treated with chemotherapy and Herceptin-based adjuvant therapy before the study. A total of 2,840 women from 40 countries were enrolled. They were randomly grouped to receive either Nerlynx (1,420 women) or a placebo (1,420 women) for one year.
Five-year follow-up results showed that clinically relevant relapses of breast cancer were significantly lowered after one year of Nerlynx treatment. At the median follow-up of 5.2 years, significantly fewer cancer-recurrence-related events were noted in the Nerlynx-treated group than in the placebo-treated group. Also, the five-year invasive disease-free survival rate (percentage of people who live for at least five years without cancer progression) in patients in the Nerlynx group was 90.2% compared with 87.7% in the placebo group.
Diarrhea was the most common adverse event reported in 40% of Nerlynx-treated patients compared with 2% in the placebo group.
The results of this trial were instrumental in getting FDA and EC approvals for Nerlynx.
A multinational Phase 2 study (NCT02400476) is currently evaluating the incidence and severity of diarrhea in early-stage HER2+ breast cancer patients who are treated with Nerlynx and several anti-diarrheal agents including loperamide (brand name Imodium A-D).
Anti-diarrhea medications alleviated the severity and duration of Nerlynx-induced diarrhea and improved the tolerability of the treatment, according to results presented at the 2019 American Society of Clinical Oncology (ASCO) annual meeting. The study is still enrolling participants in the U.S., Australia, Canada, and Europe.
A Phase 2 open-label clinical trial (NCT00300781) assessed the safety and benefits of Nerlynx administered as a single agent to 136 patients with advanced HER2+ breast cancer. Some patients had received prior treatment with the FDA-approved cancer treatment Herceptin. Trial results showed that Nerlynx was reasonably well-tolerated by pre-treated patients and those not previously treated with Herceptin.
A Phase 2 study (NCT03289039) is underway to evaluate Nerlynx either alone or in combination with Faslodex (fulvestrant) in patients with inoperable locally advanced or metastatic HER2+ breast cancer who have previously received either Herceptin, Perjeta (pertuzumab) or Kadcyla (ado-trastuzumab emtansine).
The study aims to enroll 152 female patients, older than 17, at several sites in the U.S. In this five-year study, progression-free survival and overall survival will be assessed as the primary and secondary outcomes, respectively.
A randomized Phase 3 study (NCT01808573) is testing the effect of Nerlynx plus Xeloda (capecitabine) versus Tykerb (lapatinib) plus Xeloda as a third-line combo therapy in patients with HER2+ metastatic breast cancer. A total of 621 adult patients were enrolled in this global study and were randomly grouped to receive one of the two combinations tested.
Overall, the Nerlynx-Xeloda combination was markedly more effective compared with the Tykerb-Xeloda therapy, according to results presented at the 2019 ASCO annual meeting. At 24 months, mean progression-free survival in patients treated with Nerlynx plus Xeloda was 8.8 months compared with 6.6 months for those in the Tykerb plus Xeloda group. The mean overall survival at 48 months was also better in the Nerlynx plus Xeloda group (24 months) compared with those treated with Tykerb plus Xeloda (22.2 months). Incidences of tumor spread to the central nervous system were also lower in those treated with Nerlynx plus Xeloda group (22.8%) compared with those in the Tykerb plus Xeloda treatment group (29.2%).
These findings help to support Puma’s supplemental new drug application to the FDA for approval of Nerlynx plus Xeloda combination therapy for HER2 + metastatic breast cancer.
An ongoing Phase 2 trial (NCT01494662) is evaluating the potential of Nerlynx plus Xeloda combination therapy in HER2+ breast cancer patients whose tumors have spread to the brain. The trial is assessing the ability of this combination treatment to reach the central nervous system. According to preliminary results presented at the 2017 ASCO annual meeting, the combination therapy was able to shrink the tumors in the brains of nearly half of the patients. The treatment was also well-tolerated by the patients. The study is still underway, and enrollment is ongoing at sites across the U.S.
In a Phase 1/2 study (NCT03377387), researchers will be evaluating the safety, tolerability, and efficacy of Nerlynx combination therapy with different doses of Xeloda in patients with HER2+ metastatic breast cancer. This one-year study aims to enroll 48 women, 18 or older. Enrollment is ongoing at multiple centers in the U.S.
Another Phase 1/2 (NCT03101748) study is investigating the effect of Nerlynx in combination with Taxol (paclitaxel) as neoadjuvant therapy (or a first treatment given to shrink a tumor before surgery) for patients with HER2+ breast cancer. A total of 99 adult patients will be enrolled in the study and assigned to receive one of the three treatment combinations: Nerlynx-Taxol combination with Perjeta and Herceptin, or Nerlynx-Taxol combination with Perjeta and Herceptin followed by chemotherapy with doxorubicin hydrochloride, and cyclophosphamide, or Nerlynx-Taxol combination alone. The study is currently recruiting participants in Texas, U.S., and is expected to be completed in January 2026.
Through an expanded access program, Nerlynx is also available to HER2+ breast cancer patients who are not eligible to take part in clinical trials due to issues such as age and other coexisting conditions.
Last updated: 07/11/2019
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