FDA Accepts sNDA for Neratinib Combo for Third-Line HER2+ Metastatic Breast Cancer

The FDA has accepted a supplemental New Drug Application (sNDA) for the use of neratinib (Nerylnx) in combination with capecitabine for the treatment of patients with HER2-positive metastatic breast cancer following failure of ≥2 prior lines of HER2-directed therapy.¹

The sNDA, which is based on findings from the phase III NALA trial, was submitted to the FDA in July. The agency has set a target action date for a decision on the sNDA of late April 2020.

“The FDA’s acceptance of our sNDA marks another important regulatory milestone for my team,” Alan H. Auerbach, CEO and president of Puma, the company developing neratinib, said in a statement. “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 2 or more prior treatments and who need additional treatment options.”

NALA is a randomized, international, open-label trial that investigated neratinib plus capecitabine in a 1:1 comparison with lapatinib (Tykerb) and capecitabine in the third-line or beyond setting in 621 patients with HER2-positive metastatic breast cancer. Patients in the neratinib arm were also given antidiarrheal prophylaxis with loperamide.

Sixty-nine percent of patients had received 2 prior HER2-targeted therapies in the metastatic setting, and 31% had received 3 or more. The prior HER2-targeted therapies included single-agent trastuzumab (Herceptin; 38%), trastuzumab plus pertuzumab (Perjeta; 7.5%), trastuzumab plus T-DM1 (ado-trastuzumab emtansine; Kadcyla; 20%), and trastuzumab plus pertuzumab and T-DM1 (35%).

The results of the NALA trial were presented at the 2019 ASCO Annual Meeting.²A statistically significant improvement in progression-free survival (PFS), one of the primary endpoints, was observed with a hazard ratio of 0.76 (95% CI, 0.63-0.93; log-rankPvalue = .0059). At 1 year, the PFS rates were 29% with neratinib and capecitabine versus 15% with lapatinib and capecitabine.

A prespecified restricted means analysis for PFS was conducted with 24 months’ follow-up. 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).

OS, the other primary endpoint, was also improved with neratinib but did not result in a statistically significant improvement, with a hazard ratio of 0.88 (95% CI, 0.72-1.07; log-rankP= .2086). The prespecified restricted means analysis for OS was conducted at 48 months and showed a mean OS of 24.0 months for patients treated with neratinib combination compared with 22.2 months in patients treated with the lapatinib regimen.

The ORR was 33% in the neratinib arm compared with 27% in the lapatinib arm, and the CBR was 45% versus 36%, respectively. The median DoR with the neratinib combination was 8.5 months versus 5.6 months with the lapatinib combination (HR, 0.495;P= .0004).

At 54 months, 22.8% of patients in the neratinib arm required intervention for symptomatic CNS disease compared with 29.2% in the lapatinib arm (P= .043).

The incidence of diarrhea (any grade) was 83% in the neratinib arm compared with 66% in the lapatinib arm, with grade 3 diarrhea occurring in 24% versus 13% of patients, respectively. No cases of grade 4 diarrhea were reported in either group.

The median time to first onset of grade 2/3 diarrhea was 9 days in the neratinib arm versus 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 compared with 9 days in the lapatinib arm. The median cumulative duration of grade 3 diarrhea was 4 days in 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 any treatment-emergent adverse event (TEAE) occurred in 10.9% of patients in the neratinib arm compared with 14.5% of those in the lapatinib arm. Beyond diarrhea, the other most common all-grade TEAEs for the neratinib arm were nausea (53% vs 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 3/4 TEAEs beyond diarrhea in the neratinib arm were hand-foot syndrome (10% vs11% 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 was initially approved by the FDA in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy. Additionally, the agent received an orphan drug designation from the FDA in September 2019 for the treatment of patients with breast cancer—related brain metastases.

References

1. Puma Biotechnology Announces U.S. FDA Acceptance of Supplemental New Drug Application for Neratinib to Treat HER2-Positive Metastatic Breast Cancer [press release]. Los Angeles, CA: Puma Biotechnology; September 11, 2019. https://bwnews.pr/2lJqwSY. Accessed September 11, 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).