On February 25, 2020, neratinib (Nerlynx) was approved for use in combination with capecitabine for treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti–HER2-based regimens in the metastatic setting.^1,2

Supporting Efficacy Data

The current approval was based on findings in the open-label phase III NALA trial (ClinicalTrials.gov identifier NCT01808573).^2,3 In the trial, 621 patients with metastatic HER2-positive breast cancer who had received two or more prior anti–HER2-based regimens in the metastatic setting were randomly assigned to receive oral neratinib at 240 mg once daily on days 1 to 21 with oral capecitabine at 750 mg/m² twice daily on days 1 to 14 for each 21-day cycle (n = 307) or oral lapatinib at 1,250 mg once daily on days 1 to 21 with capecitabine at 1,000 mg/m² twice daily on days 1 to 14 for each 21-day cycle (n = 314). Patients were treated until disease progression or unacceptable toxicity. The primary efficacy outcome measures were progression-free survival assessed by blinded independent central review using Response Evaluation Criteria in Solid Tumors, v1.1, and overall survival.

Overall, 59% of patients had hormone receptor–positive disease, 69% had received two prior anti–HER2- based regimens, 81% had visceral disease, and 16% had asymptomatic or stable brain metastases.

Progression-free survival was 29% vs 15% at 12 months and 12% vs 3% at 24 months. Median overall survival was 21 months (95% CI = 17.7–23.8 months) vs 18.7 months (95% CI = 15.5–21.2 months; hazard ratio = 0.88, 95% CI = 0.72–1.07, P = .2086). Objective response rates were 32.8% vs 26.7%. Median response duration was 8.5 months vs 5.6 months.

How It Works

Neratinib is an intracellular kinase inhibitor that irreversibly binds to EGFR, HER2, and HER4. In studies in vitro, neratinib reduces 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 starting dose of neratinib in the current indication is 240 mg once daily with food on days 1 to 21 of a 21-day cycle plus capecitabine (750 mg/m² twice daily) on days 1 to 14 of a 21-day cycle until disease progression or unacceptable toxicity. The starting dose is 80 mg in patients with severe hepatic impairment. No modification of the starting dose is recommended for patients with mild to moderate hepatic impairment.

Antidiarrheal prophylaxis should be given to all patients and should be initiated with the first dose of neratinib. Neratinib prescribing information provides detailed instructions for dosing of prophylactic loperamide. If diarrhea occurs despite prophylaxis, patients should receive additional antidiarrheals, fluids, and electrolytes as clinically indicated. Neratinib dose interruptions and dose reductions may also be required to manage diarrhea.

Dose reductions of neratinib for adverse events when used in combination with capecitabine are sequentially to 160 mg and 120 mg daily. Neratinib prescribing information provides detailed instructions for dose modification for general grade 3 or 4 toxicities, diarrhea, and hepatotoxicity. Capecitabine prescribing information should be consulted for dose modifications for adverse events.

Concomitant use of neratinib with proton pump inhibitors should be avoided. An H2 receptor antagonist or antacid should be used if a gastric acid–reducing agent is required, with neratinib dosing separated by at least 2 hours before or 10 hours after H2 receptor antagonists. Concomitant use of neratinib with strong CYP3A4 inhibitors and moderate CYP3A4 and P-glycoprotein dual inhibitors (which may increase neratinib concentrations) and strong or moderate CYP3A4 inducers (which may reduce neratinib concentrations) should be avoided.

Safety Profile

In the NALA trial, the median duration of treatment was 5.7 months with neratinib and 4.4 months with lapatinib. The most common adverse events of any grade with neratinib plus capecitabine were diarrhea (83% vs 66% in lapatinib/capecitabine group), nausea (53% vs 42%), vomiting (46% vs 31%), fatigue/asthenia (45% vs 40%), decreased appetite (35% vs 22%), constipation (31% vs 13%), and decreased weight (20% vs 13%). The most common grade 3 or 4 adverse events were diarrhea, nausea, and vomiting.

The most common serious adverse events in the neratinib group were diarrhea, vomiting, nausea, and acute kidney injury. Adverse events required neratinib dose reduction in 10% of patients and permanent discontinuation in 14%; the most common adverse events leading to treatment discontinuation were vomiting, diarrhea, nausea, and palmar-plantar erythrodysesthesia syndrome. Neratinib has warnings/precautions for diarrhea, hepatotoxicity, and embryofetal toxicity.

Neratinib should be permanently discontinued in patients experiencing grade 4 diarrhea or grade ≥ 2 diarrhea that occurs after maximal dose reduction. Liver function tests should be monitored monthly for the first 3 months of treatment and then every 3 months while on treatment and as clinically indicated. Neratinib should be permanently discontinued in patients with grade 4 liver abnormalities. Patients should be advised not to breastfeed while receiving neratinib. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves neratinib for metastatic HER2-positive breast cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neratinib-metastatic-her2-positive-breast-cancer. Accessed March 4, 2020.

2. Nerlynx (neratinib) tablets, for oral use, Puma Biotechnology, February 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208051s005s006lbl.pdf. Accessed March 4, 2020.

3. Saura C, Oliveira M, Feng YH, et al: Neratinib + capecitabine vs 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. 2019 ASCO Annual Meeting. Abstract 1002. Presented June 4, 2019.