6 June 2019 - - US-based biopharmaceutical company Puma biotechnology, Inc. (NASDAQ: PBYI) has presented results from the Phase III NALA trial of PB272 (neratinib) in patients with HER2-positive metastatic breast cancer who have failed two or more prior lines of HER2-directed treatments (third-line disease) in the setting of metastatic disease at the American Society of Clinical Oncology 2019 annual meeting in Chicago, the company said.
The Phase III NALA trial is a randomised controlled 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 to receive either neratinib plus capecitabine or lapatinib plus capecitabine.
This 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 and overall survival. 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 US Food and Drug Administration under a Special Protocol Assessment for the design of the Phase III clinical trial and the European Medicines Agency also provided follow-on scientific advice consistent with that of the FDA regarding the company's Phase III trial design and endpoints used in the trial.
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 of CNS metastases was 22.8% for the neratinib plus capecitabine arm and 29.2% for the lapatinib plus capecitabine arm (p=0.043, descriptive).
For the secondary enpoint 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.
Puma plans to submit its New Drug Application to the US Food and Drug Administration based on the Phase III NALA trial results in 2Q19 or 3Q19.
Puma biotechnology is a biopharmaceutical company with a focus on the development and commercialization of innovative products to enhance cancer care. Puma in-licenses the global development and commercialisation rights to three drug candidates -- PB272 (neratinib, oral), PB272 (neratinib, intravenous) and PB357.
Neratinib, oral was approved by the US 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 (neratinib) tablets.
Nerlynx was granted marketing authorisation by the European Commission in September 2018 for the extended adjuvant treatment of adult patients with early stage hormone receptor-positive HER2-overexpressed/amplified breast cancer and who are less than one year from completion of prior adjuvant trastuzumab-based therapy.
Nerlynx is a registered trademark of Puma biotechnology, Inc.