On July 1, 2019 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported that it has submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for neratinib in combination with capecitabine for the treatment of patients with HER2-positive metastatic breast cancer who have failed two or more prior lines of HER2-directed treatments (third-line disease) (Press release, Puma Biotechnology, JUL 1, 2019, View Source [SID1234537344]).
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Neratinib was originally approved by the U.S. Food and Drug Administration in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX tablets. In September 2018 NERLYNX was granted marketing authorization by the European Commission for the extended adjuvant treatment of adult patients with early stage hormone receptor-positive HER2-overexpressed/amplified breast cancer and are less than one year from completion of prior adjuvant trastuzumab-based therapy.
The sNDA is supported by the results of the Phase III NALA trial, a randomized controlled trial of neratinib plus capecitabine versus Tykerb (lapatinib) plus capecitabine in patients with third-line HER2-positive metastatic breast cancer.
For the primary analysis of centrally confirmed PFS, treatment with neratinib plus capecitabine resulted in a statistically significant improvement in centrally confirmed PFS (hazard ratio=0.76, p=0.0059) compared to treatment with lapatinib plus capecitabine. Because the proportional hazard assumption did not hold, the statistical analysis plan for the NALA trial prespecified that a restricted means survival analysis at 24 months would be performed. In this prespecified analysis the mean PFS for the patients treated with neratinib plus capecitabine was 8.8 months and the mean PFS for the patients treated with lapatinib plus capecitabine was 6.6 months.
For the primary analyses of OS, neratinib plus capecitabine resulted in an improvement in OS that trended positively in favor of the neratinib plus capecitabine arm of the study (hazard ratio = 0.88, p=0.21). The median OS for the patients treated with neratinib plus capecitabine was 21.0 months and the median OS for the patients treated with lapatinib plus capecitabine was 18.7 months. In the prespecified restricted means analysis the mean OS at 48 months for the patients treated with neratinib plus capecitabine was 24.0 months and the mean OS for the patients treated with lapatinib plus capecitabine was 22.2 months.
For the secondary endpoint of time to intervention for symptomatic central nervous system disease (also referred to as brain metastases), the results of the trial showed that treatment with neratinib plus capecitabine led to an improvement over the combination of lapatinib plus capecitabine. The overall cumulative incidence for intervention for CNS metastases at 54 months was 22.8% of patients for the neratinib plus capecitabine arm and 29.2% of patients for the lapatinib plus capecitabine arm (p=0.043, descriptive). For the secondary endpoint of duration of response, neratinib plus capecitabine treatment resulted in a longer duration of response compared to lapatinib and capecitabine treatment, with a median response of 8.54 months compared to a median response of 5.55 months (HR = 0.495, p = 0.0004, descriptive).
Treatment-emergent adverse events (TEAEs) were similar between arms: TEAEs leading to neratinib/lapatinib discontinuation were lower with neratinib (10.9%) than with lapatinib (14.5%). There was a higher rate of grade 3 diarrhea with neratinib plus capecitabine compared to lapatinib plus capecitabine (24.4% vs 12.5%); however, the discontinuations due to diarrhea (neratinib plus capecitabine: 2.6%, lapatinib plus capecitabine: 2.3%) were similar in both arms.
"We are very pleased to announce this important regulatory milestone," said Alan H. Auerbach, Chief Executive Officer and President of Puma. "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."
About NALA
The NALA trial is a randomized controlled Phase III trial of neratinib plus capecitabine versus Tykerb (lapatinib) plus capecitabine in patients with third-line HER2-positive metastatic breast cancer. The trial enrolled 621 patients who were randomized (1:1) to receive either neratinib plus capecitabine or lapatinib plus capecitabine. The trial was conducted globally at sites in North America, Europe, Asia-Pacific and South America. The co-primary endpoints of the trial are centrally confirmed progression free survival (PFS) and overall survival (OS). An alpha level of 1% was allocated to the PFS and 4% allocated to OS. The study was to be considered positive if either of the co-primary endpoints was positive. Puma reached agreement with the FDA under a Special Protocol Assessment (SPA) for the design of the Phase III clinical trial and the European Medicines Agency (EMA) also provided follow-on scientific advice (SA) consistent with that of the FDA regarding the Company’s Phase III trial design and endpoints used in the trial.