Puma Applies to FDA to Extend Nerlynx’s Use to HER2-Positive Metastatic Breast Cancer

Puma Biotechnology is seeking to extend the use of its breast cancer medicine Nerlynx (neratinib), in combination with capecitabine, to treat women with HER2-positive breast cancer whose disease has spread to other parts of the body, and is metastatic.

In a supplemental New Drug Application (sNDA) filed with the U.S. Food and Drug Administration (FDA), Puma seeks the use of the Nerlynx-capecitabine combo for women who have failed two or more prior lines of targeted therapy.

The application is based on results from the NALA Phase 3 trial, which found that Nerlynx prolonged patients’ lives without disease worsening as compared with Novartis‘ Tykerb (lapatinib), another therapy for HER2-positive breast cancer.

“We are very pleased to announce this important regulatory milestone,” Alan H. Auerbach, CEO and president of Puma, said in a press release.

“Although the use of HER2 directed agents in the metastatic setting has positively impacted the treatment of the disease in the first and second line settings, patients with HER2 positive metastatic breast cancer who have progressed on two or more prior treatments continue to need additional treatment options. We look forward to working with the FDA during its review of this submission,” Auerbach said.

The NALA trial (NCT01808573) was a randomized, controlled study to evaluate the safety and efficacy of Nerlynx plus capecitabine (brand name Xeloda, generics also available) versus Tykerb plus capecitabine as third-line therapy for women with HER2-positive metastatic breast cancer.

The trial was conducted worldwide, enrolling 621 patients at sites in North America, Europe, Asia-Pacific, and South America.

Participants were randomly selected to receive either Nerlynx tablets (240 mg) plus capecitabine (1500 mg/m²), or Tykerb tablets (1250 mg) plus capecitabine (2000 mg/m²). Both Nerlynx and Tykerb were taken once daily continuously, while capecitabine was given on days 1 to 14, of each 21-day cycle.

Treatment with Nerlynx prolonged the time patients lived without cancer progression compared with treatment with Tykerb. At the two-year mark, mean time without disease worsening was 8.8 months for those on Nerlynx, compared with 6.6 months for the Tykerb group.

Nerlynx also tended to extend overall survival, although this improvement was not statistically significant — 24.0 vs. 22.2 months, at four years of study.

Trial results regarding time to interventions due to brain metastases also indicated that Nerlynx showed some advantages over Tykerb. Women taking Nerlynx had a total frequency of 22.8% of brain metastases interventions at 4.5 years, compared to 29.2% for those receiving Tykerb.

In addition, Nerlynx-treated patients had more durable responses — a median of 8.54 months versus 5.55 months.

Regarding safety, treatment-related adverse events were similar between the two groups. However, fewer participants quit therapy due to one or more such events with Nerlynx (10.9%) than in the Tykerb group (14.5%).

Severe diarrhea — a common side effect of Nerlynx — was more frequent among Nerlyx-treated patients (24.4% vs. 12.5%). However, discontinuations due to diarrhea were similar in both groups (2.6% vs. 2.3%).

Nerlynx was approved by the FDA in July 2017 for use as an extended, adjuvant treatment for adult patients with early-stage HER2-positive breast cancer. The treatment was designed to follow adjuvant therapy with trastuzumab (brand names Herceptin, and others). In September 2018, the medicine also was granted marketing authorization by the European Commission.

Nerlynx’s active substance neratinib, also known as PB272, is a small molecule that works as an irreversible tyrosine kinase inhibitor (TKI), blocking the passage of signals through the epidermal growth factor receptor HER2, as well as other receptors. It is designed to inhibit HER2 — overexpressed by some breast tumors and associated with a more aggressive disease — to prevent cancer cell proliferation and induce its death.