Efficacy and safety outcomes in a subgroup of patients participating in the randomized phase III NALA study of neratinib (Nerlynx®; Puma Biotechnology) plus capecitabine (N+C) versus lapatinib (Tykerb®; Novartis) plus capecitabine (L+C) in patients with third-line HER2+ metastatic breast cancer (NCT01808573) 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.
Up to 20% of patients with breast cancer tumors over-express the HER2 protein (HER2-positive disease) and in the ExteNET study* (NCT00878709), 57% of patients were found to have tumors that were hormone-receptor-positive.
HER2+ breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab (Herceptin®; Genentech/Roche) can reduce the risk of early-stage HER2+ breast cancer recurring, up to 25% of patients treated with trastuzumab experience recurrence within 10 years, the majority of which are metastatic recurrences.
Approximately 50% of patients with HER2+ metstatic breast cancer will develop brain metastases. And while the overal survival of women diagnosed with HER2+ metastaic breast cancer has improved over the last decade, up to 50% of patients with HER2+ metastatic breast cancer develop CNS metastases during the course of their disease.
The development CNS metastases present a considerable challenge in metastatic breast cancer (MBC) and with limited evidence-based treatments, recurrent CNS events remain a major source of morbidity and mortality for these patients. 
In 2 phase II clinical studies (the NEfERT-T trial; NCT00915018 and the TBCRC 022 study; NCT01494662) neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated activity against CNS metastases in HER2+ metastatic breast cancer.
The results of these studies confirmed that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy.
Phase III NALA
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 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 study results, presented as Spotlight Poster Discussion Session during the 2020 Virtual San Antonio Breast Cancer Symposium (SABCS) by Cristina Saura Manich, M.D., Ph.D., Head of Breast Cancer Unit, Vall d’Hebrón University Hospital, Barcelona, Catalonia (Spain), an investigator of the trial, show the results of patients who had central nervous system (CNS) metastases at baseline, with a particular focus on CNS-specific endpoints.
In the poster (Abstract #PD13-09) Saura Manich and her team 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.
One unique feature of the NALA trial was the inclusion of patients with leptomeningeal disease, also known as called leptomeningeal carcinomatosis, a rare complication of cancer in which the disease spreads from the original tumor site to the meninges surrounding the brain and spinal cord.
Two patients with leptomeningeal disease 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 leptomeningeal disease 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%).
“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,” Saura Manich noted.
“CNS metastases from HER2-positive breast cancer present a clinical challenge due to the limited availability of effective treatments,” said Alan H. Auerbach, Chief Executive Officer and President of Puma.
Commenting on the trial’s outcome, Auerbach added: “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.”
* The ExteNET study, a multicenter, randomized, double-blind, placebo-controlled phase III trial was designed to investigate extended adjuvant therapy with 1 year of neratinib or placebo after standard locoregional treatment, and adjuvant ± neoadjuvant therapy with chemotherapy and trastuzumab (n = 2840). The study was initiated in April 2009 and conducted in 40 countries worldwide.
A Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ Metastatic Breast Cancer Who Have Received Two or More Prior HER2 Directed Regimens in the Metastatic Setting (NALA) – NCT01808573
Study Evaluating The Effects Of Neratinib After Adjuvant Trastuzumab In Women With Early Stage Breast Cancer (ExteNET) – NCT00878709
Study Evaluating Neratinib Plus Paclitaxel VS Trastuzumab Plus Paclitaxel In ErbB-2 Positive Advanced Breast Cancer (NEfERT-T trial ) – NCT00915018
HKI-272 for HER2-Positive Breast Cancer and Brain Metastases – NCT01494662
Highlights of prescribing information
Neratinib (Nerlynx®; Puma Biotechnology) [Prescription Information]
Lapatinib (Tykerb®; Novartis) [Prescribing Information]
Trastuzumab (Herceptin®; Genentech/Roche) [Prescribing Information]
 Saura C, Ryvo L, Hurvitz S, Gradishar W, Moy B, Delaloge S, Kim S-B, et al. Impact of neratinib on outcomes in HER2-positive metastatic breast cancer patients with central nervous system disease at baseline: Findings from the phase 3 NALA trial (Abstract #PD13-09)
 Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, Robert NJ, Silovski T, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):367-377. doi: 10.1016/S1470-2045(15)00551-3. Epub 2016 Feb 10. PMID: 26874901.
 Lin NU, Winer EP. Brain metastases: the HER2 paradigm. Clin Cancer Res. 2007 Mar 15;13(6):1648-55. doi: 10.1158/1078-0432.CCR-06-2478. PMID: 17363517.
 Freedman RA, Gelman RS, Anders CK, Melisko ME, Parsons HA, Cropp AM, Silvestri K, Cotter CM, Componeschi KP, et al. TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases. J Clin Oncol. 2019 May 1;37(13):1081-1089. doi: 10.1200/JCO.18.01511. Epub 2019 Mar 12. PMID: 30860945; PMCID: PMC6494354.
Featured image: Images of the 2018 San Antonio Breast Cancer Symposium (SABCS) being held at the Henry B. Gonzalez Convention Center in San Antonio, TX. Photo courtesy © AACR. Used with permission.