On July 17, 2017, neratinib (Nerlynx) a dual inhibitor of HER2 and epidermal growth factor receptor (EGFR), was approved for extended adjuvant treatment of adults with early-stage HER2-overexpressed/amplified breast cancer following adjuvant trastuzumab (Herceptin)-based therapy.^1,2

Supporting Efficacy Data

Approval was based on the finding of prolonged invasive disease–free survival in the double-blind phase III ExteNET trial, in which 2,840 women who had completed adjuvant trastuzumab within the prior 2 years were randomized to receive oral neratinib at 240 mg (n = 1,420) or placebo (n = 1,420) once daily for 1 year.^2,3 The primary endpoint was invasive disease–free survival.

The median age of the patients was 52 years (range = 23–83 years, 12% ≥ 65 years), 81% were white, 57% had hormone receptor–positive disease, 24% had node-negative disease, 47% had one to three positive nodes, and 30% had ≥ four positive nodes; and 10% had stage I, 41% had stage II, and 31% had stage III disease. Most patients (81%) were enrolled within 1 year of completing trastuzumab, with a median time from the last trastuzumab treatment of 4.4 months in the neratinib group and 4.6 months in the placebo group.

At 2 years, invasive disease–free survival was 94.2% in the neratinib group vs 91.9% in the placebo group (hazard ratio = 0.66, P = .008). Hazard ratios were 0.49 among hormone receptor–positive patients; 0.93 among hormone receptor–negative patients; and 0.72, 0.68, and 0.62 for 0, 1 to 3, and ≥ 4 involved nodes.

How It Works

Neratinib is a kinase inhibitor that irreversibly binds to epidermal growth factor receptor (EGFR), HER2, and HER4. In studies in vitro, neratinib reduced EGFR and HER2 autophosphorylation, downstream MAPK and AKT signaling pathways, and exhibits antitumor activity in EGFR- and/or HER2-expressing carcinoma cell lines. Neratinib human metabolites M3, M6, M7, and M11 inhibit the activity of EGFR, HER2, and HER4. Oral administration of neratinib inhibited tumor growth in mouse xenograft models with tumor cell lines expressing HER2 and EGFR.

How It Is Used

The recommended dose of neratinib is 240 mg once daily with food for 1 year. The starting dose is 80 mg in patients with severe hepatic impairment.

Antidiarrheal prophylaxis with loperamide is recommended during the first 2 cycles (56 days) of treatment and should be started with the first dose of neratinib. Loperamide should be given as follows, with titration to one to two bowel movements per day: 4 mg 3 times daily on days 1 to 14, 4 mg twice daily on days 15 to 56, and 4 mg as needed (not to exceed 16 mg/d) on days 57 to 365. Additional antidiarrheals may be required to manage loperamide-refractory diarrhea; neratinib dose interruptions and reductions may also be required.

Dose reductions of neratinib for adverse events are sequentially to 200 mg/d, 160 mg/d, and 120 mg/d. Neratinib should be discontinued in patients with grade 4 diarrhea, those with other grade 4 adverse events, those with diarrhea recurring to grade 2 at 120 mg/d, those who fail to recover to grade 0 or 1 from higher-grade treatment-related toxicity, those with toxicities that result in a treatment delay > 3 weeks, and those unable to tolerate 120 mg daily. 

Concomitant use of neratinib with such gastric acid-reducing agents as proton pump inhibitors or H2-receptor antagonists should be avoided. Neratinib should not be given until 3 hours after an antacid is taken. Concomitant use of strong (eg, clarithromycin, cobicistat) or moderate (eg, aprepitant, cimetidine) CYP3A4 inhibitors (which increase neratinib exposure) should be avoided. Concomitant use of strong (eg, carbamazepine, enzalutamide [Xtandi]) or moderate (eg, bosentan, efavirenz) CYP3A4 inducers (which decrease neratinib exposure) should be avoided. Patients should be monitored for adverse reactions of narrow therapeutic agents that are P-glycoprotein substrates (eg, digoxin, fexofenadine) when receiving neratinib.

Safety Profile

In the phase III trial, the most common adverse events of any grade in the neratinib group were diarrhea (95% vs 35% in placebo group), nausea (43% vs 22%), abdominal pain (36% vs 15%), fatigue (27% vs 20%), and vomiting (26% vs 8%). Serious adverse events in the neratinib group included diarrhea, vomiting, and dehydration. Adverse events led to dose reduction in 31.2% of the neratinib patients vs 2.6% of placebo patients and to discontinuation of treatment in 27.6% of neratinib patients, with the most common cause of treatment discontinuation being diarrhea (16.8%).

Neratinib carries warnings/precautions for diarrhea, hepatotoxicity, and embryofetal toxicity. Diarrhea occurring despite recommended prophylaxis should be aggressively managed with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Liver function tests should be monitored monthly for the first 3 months, every 3 months during treatment, and as clinically indicated. ■

REFERENCES

1. FDA: Available at www.fda.gov. Accessed November 7, 2017.

2. Nerlynx (neratinib) tablets prescribing information, Puma Biotechnology, July 2017. Available at www.accessdata.fda.gov. Accessed November 7, 2017.

3. Chan A, et al: Lancet Oncol 17:367-377, 2016.