A subgroup of patients participating in the randomized phase III NALA study of neratinib plus capecitabine (N+C) versus lapatinib plus capecitabine (L+C) in patients with third-line HER2+ metastatic breast cancer demonstrated improved central nervous system (CNS) outcomes with neratinib-based regimens in the treatment and prevention of CNS metastases from human epidermal growth factor receptor 2 (HER2+) breast cancer.
The phase III NALA trial enrolled 621 patients who were randomized (1:1) to receive either neratinib plus capecitabine or lapatinib plus capecitabine. The co-primary endpoints of the trial were independently adjudicated progression-free survival (PFS) and overall survival (OS). The NALA study met its primary endpoint, with the neratinib arm having significantly improved PFS versus the lapatinib arm (hazard ratio [HR], 0.76; mean PFS, 8.8 months vs. 6.6 months). The data showed no statistical difference in OS between treatment arms (HR 0.88). Time to intervention for symptomatic central nervous system disease was a predefined secondary endpoint of the trial. In the intent to treat population, significantly fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% vs. 29.2%).
Full Press Release:
Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, presented efficacy and safety outcomes in a subgroup of patients from the NALA trial who had central nervous system (CNS) metastases at baseline, with a particular focus on CNS-specific endpoints, at the 2020 Virtual San Antonio Breast Cancer Symposium (SABCS) that is currently taking place. The presentation, entitled “Impact of neratinib plus capecitabine on outcomes in HER2-positive metastatic breast cancer patients with central nervous system disease at baseline: Findings from the phase 3 NALA trial,” is being presented at a Spotlight Poster Discussion Session by Cristina Saura, M.D., Ph.D., Head of Breast Cancer Unit, Vall d’Hebrón University Hospital, an investigator of the trial. A copy of this poster presentation is available on the Puma website.
The Phase III NALA trial was a randomized controlled trial of neratinib plus capecitabine (N+C) versus Tykerb® (lapatinib) plus capecitabine (L+C) in patients with third-line HER2-positive metastatic breast cancer (NCT01808573). The trial enrolled 621 patients who were randomized (1:1) to receive either N+C or L+C. The co-primary endpoints of the trial were independently adjudicated progression free survival (PFS) and overall survival (OS). The NALA study met its primary endpoint, with the neratinib arm having significantly improved PFS vs. the lapatinib arm (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63-0.93; stratified log-rank P = .0059; mean PFS 8.8 mo vs. 6.6 mo). The data showed no statistical difference in OS between treatment arms (HR 0.88; 95% CI, 0.72-1.07; P = .2098). Time to intervention for symptomatic central nervous system disease (also referred to as brain metastases) was a predefined secondary endpoint of the trial. In the ITT population, significantly fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% vs. 29.2%; P = .043).
The poster presented at the 2020 SABCS meeting describes results for the subset of patients who entered the trial with CNS metastases. Of the 621 patients randomized to study treatment, 101 (16.3%) had asymptomatic CNS metastases at baseline (N+C, n=51; L+C, n=50). Within the CNS at baseline subgroup, the data suggested an association between N+C and improved PFS compared with L+C (HR 0.66; 95% CI, 0.41-1.05). The mean PFS was 7.8 months in the neratinb arm vs. 5.5 months in the laptinib arm. Consistent with results in the overall population, there was no apparent difference in OS between arms in the CNS at baseline group. With respect to the CNS-specific outcomes, N+C was associated with fewer interventions for CNS disease compared with L+C; the 12 month incidence of interventions for CNS metastases was 25.5% in the N+C arm and 36.0% in the L+C arm. The data also suggested an association between neratinib and improved CNS progression free survival (CNS-PFS), an ad hoc composite endpoint assessing disease progression in the brain or death from any cause (HR 0.62; 95% CI, 0.32-1.18). The median CNS-PFS was 12.4 months in the patients treated with N+C and 8.3 months in the patients treated with L+C.
As described in the poster, a unique feature of the NALA trial was the inclusion of patients with leptomeningeal disease (LMD), two of whom were treated with N+C with good outcomes (progression after 5.6 and 9.8 months, and OS times of 17.4 and 19.8 months, respectively). One patient with LMD received L+C and had disease progression after 4.3 months and an OS of 6.5 months.
The safety profile in patients with CNS metastases at baseline was consistent with that observed in the overall NALA safety population. Diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia syndrome were the most common adverse events. Common CNS adverse events (grade 1-4) included headache (N+C, 18% vs L+C, 29%), dizziness (18% vs. 16%), hemiparesis (4% vs. 4%), seizure (4% vs. 4%), and gait disturbance (0% vs. 8%).
Cristina Saura, M.D., Ph.D., Head of Breast Cancer Unit, Vall d’Hebrón University Hospital, said, “The data suggest an association between neratinib and improved PFS and CNS outcomes in patients with CNS metastases from HER2-positive metastatic breast cancer. These findings are consistent with three other prospective studies.”
Alan H. Auerbach, Chief Executive Officer and President of Puma, added, “CNS metastases from HER2-positive breast cancer present a clinical challenge due to the limited availability of effective treatments. These findings from the NALA trial add to the growing body of data on the efficacy of neratinib in patients with HER2 positive metastatic breast cancer that has metastasized to the brain and may suggest a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies.”