Latest news on neratinib/neratinib in 2024

Neratinib/Neratinib is an irreversible pan-HER tyrosine kinase inhibitor (TKI) registered in Europe as an extended adjuvant treatment for HER2+/HR+ early breast cancer (eBC) in adult patients who have completed trastuzumab-based adjuvant therapy within 1 year. Administering neratinib for 12 months after completion of (neo)adjuvant trastuzumab-based therapy further reduces risk by switching the mode of action from extracellular HER2 blockade to intracellular pan-HER inhibition.

The ExteNET study demonstrated clinically meaningful benefits of neratinib compared with placebo. Neratinib improved 5-year invasive disease-free survival (iDFS) by 5.1% overall (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.41–0.82) and in patients who completed neratinib 7.4% (i.e. ≥11 months of treatment; hazard ratio 0.44, 95% confidence interval 0.28-0.68). Additionally, 8-year overall survival improved numerically for patients with HR+ ≤1 year after trastuzumab treatment (HR 0.79, 95% CI, 0.55–1.13) and for patients with HR+/center-confirmed HER2+ disease (HR 0.65, 95% CI, 0.41–1.03).

A particularly high benefit was observed in the descriptive HR+ subgroup of nonpCR patients; 5-year iDFS rate improved by 7.4% (HR 0.60, 95% CI, 0.33-1.07), the 8-year overall survival rate increased by 9.1% (HR0.47, 95%CI, 0.23-0.92); if neratinib treatment was completed, the 5-year iDFS rate increased by 11.9% (HR 0.42, 95%CI, 0.19-0.83). Of note, patients included in the ExteNET study had not previously received dual HER2 blockade and/or neoadjuvant T-DM1.

The tolerability of neratinib was consistent with otherTKIs, with diarrhea being the most common adverse event (AE); however, in the ExteNET study, without specific recommended precautions, 39% of neratinib patients reported grade ≥3 diarrhea, which was higher than patients with other TKIs. Controlled studies have investigated various prophylaxis and dose escalation approaches for neratinib and have shown that the frequency and severity of diarrhea can be improved based on the ExteNET study results. The incidence of grade ≥3 diarrhea was reduced by all study strategies, including a weekly dose escalation strategy (120 → 160 → 240 mg over 2 weeks), diarrhea-related discontinuations, and extended treatment duration.