FDA Approves Neratinib Combo for HER2+ Breast Cancer

In Clinical Studies News by Barbara Jacoby

By: Gina Columbus

From: onclive.com

The FDA has approved a supplemental new drug application (sNDA) for neratinib (Nerlynx) in combination with capecitabine (Xeloda) for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received ≥2 prior anti–HER2-based regimens in the metastatic setting.1

The approval is based on findings from the phase III NALA trial, which showed that the combination of neratinib and capecitabine reduced the risk of disease progression or death by 24% compared with lapatinib (Tykerb) plus capecitabine (HR, 0.76; 95% CI, 0.63-0.93; log-rank P value = .0059).2

“Together with the NALA investigators around the world, I am pleased to see the FDA approval of Nerlynx for the treatment of advanced HER2-positive metastatic breast cancer,” Adam M. Brufsky, MD, PhD, of Magee-Womens Hospital and the Hillman Cancer Center at the University of Pittsburgh Medical Center, stated in a press release. “This approval is based on data from the NALA trial, which we presented at ASCO last year, demonstrating that neratinib in combination with capecitabine offers a significant improvement over currently available therapies in this heavily pretreated patient population and can be added to Nerlynx’s established role in the treatment of early breast cancer.”

The international, open-label, phase III NALA trial (NCT01808573) enrolled 621 patients with metastatic breast cancer and centrally confirmed HER2-positive disease. Patient characteristics were well balanced at baseline. Nearly 80% of patients in each arm were aged <65 years and about 80% of patients in each arm had visceral disease.

Sixty-nine percent of patients had 2 prior HER2-targeted treatments for metastatic breast cancer, with the remaining 31% having received 3 or more. Prior HER2-targeted regimens included single-agent trastuzumab (Herceptin; 38%), trastuzumab plus pertuzumab (Perjeta; 7.5%), trastuzumab plus T-DM1 (Kadcyla; 20%), and trastuzumab plus pertuzumab plus T-DM1 (35%).

Patients were randomized in a 1:1 ratio to 21-day cycles of either neratinib (n = 307; 240 mg daily) plus capecitabine (1500 mg/m2on days 1-14) or lapatinib (n = 314; 1250 mg daily) plus capecitabine (2000 mg/m2 on days 1-14). Patients on the neratinib arm also received antidiarrheal prophylaxis with loperamide.

The coprimary endpoints were progression-free survival (PFS) and overall survival (OS). The study was conducted under an FDA Special Protocol Assessment stipulating that the study would be considered positive if either of these coprimary endpoint measures were met: P <.01 for PFS or <.04 for OS.

Additional results showed that the 12-month PFS rates were 29% and 15%, for the neratinib and lapatinib arms, respectively; the 24-month PFS rates were 12% and 3%, respectively.

​​​Moreover, the median OS was 21 months (95% CI, 17.7-23.8) for those who received neratinib plus capecitabine compared with 18.7 months (95% CI, 15.5-21.2) for patients who received lapatinib plus capecitabine (HR,0.88; 95% CI, 0.72-1.07; P = .2086).

The objective responsive rate was 32.8% (95% CI, 27.1-38.9) for the neratinib arm and 26.7% (95% CI, 21.5-32.4) for the lapatinib arm, respectively. The median duration of response was 8.5 months (95% CI, 5.6-11.2) versus 5.6 months (95% CI, 4.2-6.4), respectively.

Fewer patients required intervention for CNS metastases with neratinib versus lapatinib. At 54 months, the cumulative incidence for intervention for CNS metastases was 22.8% versus 29.2% for the neratinib and capecitabine arms, respectively (P = .043).The median duration of treatment was 5.7 months for neratinib compared with 4.4 months for lapatinib. Dose reductions and holds occurred in 24% versus 20% and 48% versus 43% with neratinib versus lapatinib, respectively. The median duration of treatment, dose reductions, and dose holds, were similar for capecitabine between the 2 arms.

All-grade diarrhea occurred in 83% of the neratinib group compared to 66% of the lapatinib arm. Grade 3 diarrhea occurred in 24% versus 13% of the 2 arms, respectively. There were no cases of grade 4 diarrhea reported in either arm. The median time to first onset of grade 2/3 diarrhea was 9 days in the neratinib arm compared with 18 days in the lapatinib arm. The median time to first onset of grade 3 diarrhea was 11 days versus 38 days, respectively.

The median cumulative duration of diarrhea was 7 days for grade 2/3 diarrhea in the neratinib arm versus 9 days in the lapatinib arm. The median cumulative duration of grade 3 diarrhea was 4 days for both arms. Discontinuation due to diarrhea occurred in 2.6% of the neratinib arm compared with 2.3% of the lapatinib arm.

Discontinuations due to treatment-emergent adverse events (TEAEs) occurred in 10.9% of the neratinib arm compared with 14.5% of the lapatinib arm. Beyond diarrhea, the other most common all-grade TEAEs for the neratinib arm were nausea (53% versus 42% in the lapatinib arm), vomiting (46% vs 31%, respectively), hand-foot syndrome (46% vs 56%), decreased appetite (35% vs 22%), and fatigue (34% vs 31%).

The most common grade 3 TEAEs beyond diarrhea in the neratinib arm were hand-foot syndrome (10% versus 11% in the lapatinib arm), hypokalemia (5% vs 6%, respectively), nausea (4% vs 3%), vomiting (4% vs 2%), fatigue (3% each), neutropenia (3% vs 2%), asthenia (3% vs 2%), decreased appetite (3% vs 2%) and dehydration (2% each).

“Although there have been many new treatment options for patients with HER2-positive breast cancer, patients still need additional treatment options once they progress,” Alan H. Auerbach, MD, chief executive officer and president of Puma, the developer of neratinib. “Based on the results of our NALA data, we believe Nerlynx could be a promising therapeutic opportunity for these patients.”

Neratinib was initially indicated for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy.


  1. Puma Biotechnology Receives U.S. FDA Approval of Supplemental New Drug Application for Neratinib to Treat HER2-Positive Metastatic Breast Cancer [news release]: Los Angeles, CA. Puma Biotechnology. Published February 27, 2019. https://bwnews.pr/2I02Xx8. Accessed February 27, 2019.
  2. Saura C, Oliveira M, Feng Y-H, et al. Neratinib + capecitabine versus 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. J Clin Oncol. 2019;37 (suppl; abstr 1002).