FDA Accepts sNDA for Neratinib Combo for HER2+ Breast Cancer

Alan H. Auerbach

The FDA has accepted a supplemental new drug application (sNDA) for neratinib (Nerlynx) for use in combination with capecitabine (Xeloda) for the treatment of patients with HER2-positive metastatic breast cancer who have failed at least 2 prior lines of HER2-directed treatments.

The sNDA is based on data 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. The hazard ratio (HR) for progression-free survival (PFS) favoring neratinib was 0.76 (95% CI, 0.63-0.93; log-rank P value = .0059). Landmark analysis showed that the PFS curves began to separate after 6 months with 6-month PFS rates of 47% versus 38%, 1-year rates of 29% versus 15%, and 18-month rates of 16% versus 7% for the neratinib arm versus the lapatinib arm, respectively.

A prespecified restricted means analysis for PFS was conducted that was limited to a follow-up of 24 months. The analysis showed a mean PFS of 8.8 months for the neratinib arm compared with 6.6 months for the lapatinib arm (P = .0003).

For overall survival (OS), there was a numerical but not a statistically significant benefit with neratinib. A prespecified restricted means analysis showed a mean OS of 24.0 months for the neratinib arm compared with 22.2 months for the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; log-rank P = .2086). The analysis was restricted to a follow-up of 48 months.

The FDA is scheduled to make a final decision on the application by the end of April 2020.

“The FDA’s acceptance of our sNDA marks another important regulatory milestone for my team,” Alan H. Auerbach, chief executive officer and president of Puma Biotechnology, the manufacturer of neratinib, said in in press release. “We look forward to working with the FDA during its review of this submission, which targets patients with HER2-positive metastatic breast cancer who have progressed on two or more prior treatments and who need additional treatment options.”

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.

Response data were available for 256 patients in the neratinib arm and 270 patients in the lapatinib arm. The objective response rate was 33% in the neratinib arm versus 27% in the lapatinib group. The clinical benefit rate was 45% versus 36%, respectively. The median duration of response was 8.5 months versus 5.6 months in the neratinib versus lapatinib arms, 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).

Neratinib is currently approved by the FDA for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy.

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).

The coprimary endpoints were PFS and 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 P <.04 for OS.