NALA Trial: Neratinib Plus Capecitabine Shows Benefit in Metastatic Breast Cancer

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In the global phase III NALA trial, treatment of metastatic HER2-positive breast cancer with neratinib plus capecitabine significantly improved progression-free survival, delayed the time to intervention for central nervous system disease, and showed a trend toward improved overall survival vs lapatinib plus capecitabine.1 The study was reported at the 2019 ASCO Annual Meeting.

“The landmark analysis showed the curves began to separate after 6 months, almost doubling the progression-free survival from 15% to 29% at 12 months. Even out to 18 months, the curves remained separated,” reported senior investigator Adam Brufsky, MD, PhD, of Magee-Womens Hospital of the University of Pittsburgh Medical Center. The study’s first author was Cristina Saura, MD, of Vall d’Hebron University Hospital, Barcelona.

The landmark analysis showed the curves began to separate after 6 months, almost doubling the progression-free survival from 15% to 29% at 12 months.
— Adam Brufsky, MD, PhD

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NALA is a multinational, randomized, open-label, phase III trial of neratinib plus capecitabine in patients with heavily pretreated stage IV HER2-positive metastatic breast cancer. The novel regimen was compared with lapatinib plus capecitabine in 662 women who had received at least two prior HER2-directed regimens for metastatic disease. Approximately 80% had visceral metastases, and about 30% had received at least three anti-HER2 therapies.

As Dr. Brufsky explained, neratinib is a pan-HER inhibitor, targeting and irreversibly binding to HER1, HER2, and HER4; lapatinib targets and binds reversibly to HER1 and HER2. Neratinib is approved by the U.S. Food and Drug Administration and the European Medicines Agency based on a reduced risk of recurrence of invasive disease in the ExteNET trial.2 In the I-SPY2 neoadjuvant trial, neratinib plus chemotherapy led to higher pathologic complete response rates than chemotherapy plus trastuzumab.3 In metastatic HER2-positive disease, activity has been shown for neratinib plus various agents, including capecitabine, trastuzumab emtansine (T-DM1), and paclitaxel.

NALA Details

In the NALA trial, patients were randomly assigned to neratinib (240 mg daily) plus capecitabine (750 mg/m2 twice daily) or lapatinib (1,250 mg daily) plus capecitabine (1,000 mg/m2 twice daily) until disease progression. The co-primary endpoints were centrally assessed progression-free survival and overall survival by central review. The study was to be considered positive if either co-primary endpoint was met, with P < .01 for progression-free survival and P < .04 for overall survival. The design called for performing a prespecified restricted means analysis if the assumption of constant proportional hazards was not shown.

Benefits of Neratinib/Capecitabine

Neratinib/capecitabine reduced the risk of disease progression or death by 24% (hazard ratio [HR] = 0.76; P = .0059). The rates of progression-free survival were 47% vs 38%, respectively, at 6 months; 29% vs 15% at 12 months; and 16% and 7% at 18 months.

“The separation of the curves occurred after roughly 6 months; therefore, statistical testing showed that the proportional hazards assumption of constant proportional hazard was not met,” Dr. Brufsky reported. “For that reason, we performed a prespecified restricted means analysis for progression-free survival, restricting follow-up to 24 months—since few events occurred after 24 months—and compared the area under the survival curve for the regimens,” he said.

In the restricted means analysis, the difference between the arms was 2.2 months, based on a mean progression-free survival of 8.8 months in the neratinib arm vs 6.6 months in the lapatinib arm (P = .0003).

Cristina Saura, MD

Cristina Saura, MD

According to subgroup analysis, statistically significant reductions in risk, favoring neratinib, were observed in patients with nonvisceral metastases (HR = 0.44) and hormone receptor–negative tumors (HR = 0.42). For most other subgroups, trends favored the neratinib arm as well.

In the restricted means analysis of overall survival, with time to disease progression or death set at 48 months, a difference of 1.7 months nonsignificantly favored neratinib. The mean overall survival was 24.0 months in the neratinib arm and 22.2 months in the lapatinib arm (HR = 0.88; P = .2086).

Response rates were also numerically higher with neratinib/capecitabine in patients with measurable disease (33% vs 27%; P = .1201), and statistically significant improvements were shown in the clinical benefit rate (45% vs 36%; P = .0328). In addition, the median duration of response (8.5 vs 5.6 months; HR = 0.50; P = .0004) favored the novel combination.

The time to intervention for symptomatic disease of the central nervous system was significantly delayed, with an overall cumulative incidence of 23% with neratinib/lapatinib vs 29% with lapatinib/capecitabine (P = .043). “Intervention was predominantly with radiation therapy, which was needed less in the neratinib arm (11% vs 15%),” said Dr. Brufsky. “It is important to note, there was a significant difference in the absolute percentage of patients who required intervention.”

Tolerability of Regimens

Dose reductions and dose holds were comparable between the treatment groups. There were slightly more dose reductions with capecitabine/lapatinib due to the higher dose of capecitabine used in that arm.

Treatment-emergent adverse events were similar between the arms. There was a higher rate of grade 3 diarrhea with neratinib (24% vs 13%), but treatment discontinuation due to diarrhea was similar, about 2.5% in each arm, and the median number of cumulative days with grade 3 diarrhea was four in each arm. Loperamide prophylaxis was mandated during the first month of neratinib treatment and could be continued at the physician’s discretion.

More patients discontinued lapatinib/capecitabine because of a treatment-emergent adverse event (15% vs 11%), “most likely because of more hand-foot syndrome due, again, to the higher dose of capecitabine,” Dr. Brufsky noted. Quality of life was similar between the arms and was maintained throughout the study, he added. 

DISCLOSURE: Dr. Brufsky has held consulting or advisory roles for Agendia, Bayer, Bioarray Therapeutics, bioTheranostics, Celgene, Eisai, Genentech/Roche, Genomic Health, Lilly, Merck, Myriad Pharmaceuticals, NanoString Technologies, Novartis, Pfizer, and Puma Biotechnology.


1. Saura C, Oliveira M, Feng YH, et al: Neratinib + capecitabine vs lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. 2019 ASCO Annual Meeting. Abstract 1002. Presented June 4, 2019.

2. Martin M, Holmes FA, Ejlertsen B, et al: Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18:1688-1700, 2017.

3. Park JW, Liu MC, Yee D, et al: Adaptive randomization of neratinib in early breast cancer. N Engl J Med 375:11-22, 2016.

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