A supplemental New Drug Application has been submitted to the FDA for the potential approval of neratinib in combination with capecitabine for the treatment of patients with HER2-positive metastatic breast cancer who have progressed on 2 or more prior HER2-targeted treatments.
A supplemental New Drug Application (sNDA) has been submitted to the FDA for the potential approval of neratinib (Nerlynx) in combination with capecitabine for the treatment of patients with HER2-positive metastatic breast cancer who have progressed on ≥2 prior HER2-targeted treatments.1
“We are very pleased to announce this important regulatory milestone,” Alan H. Auerbach, CEO and president of Puma Biotechnology, the company developing neratinib, said in a statement. “Although the use of HER2 directed agents in the metastatic setting has positively impacted the treatment of the disease in the first- and second-line settings, patients with HER2-positive metastatic breast cancer who have progressed on 2 or more prior treatments continue to need additional treatment options. We look forward to working with the FDA during its review of this submission.”
The sNDA is being supported by the results of the phase III NALA trial, which were presented at the 2019 ASCO Annual Meeting.2The randomized, international, open-label trial 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.
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%).
Patients in the neratinib arm were given antidiarrheal prophylaxis with loperamide.
The coprimary endpoints for the study 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 orP<.04 for OS. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR), time to intervention for symptomatic central nervous system (CNS) disease, and safety.
There was a statistically significant improvement in PFS 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 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 (Herceptin)based therapy.